Coma

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32 Coma

Joerg-Patrick Stübgen, Fred Plum, Patrick Kochanek

Altered states of consciousness are a common reason for visits to the emergency room and admission to intensive care units (ICUs). Few problems are more difficult to manage than the unconscious patient, because there are many potential causes of an altered mental status, and the time for diagnosis and effective intervention is short. Consciousness is defined as the state of awareness of the self and the environment. The phenomenon of consciousness requires two intact and interdependent physiologic and anatomic components: (1) arousal (or wakefulness) and its underlying neural substrate, the ascending reticular activating system (ARAS) and diencephalon, and (2) awareness, which requires the functioning cerebral cortex of both hemispheres. Most disorders that acutely disturb consciousness are in fact impairments of arousal that create circumstances under which the brain’s capacity for consciousness cannot be accurately assessed; in other words, failure of arousal renders it impossible to test awareness.

Alterations of arousal may be transient, lasting only several seconds or minutes (following seizures, syncope, and cardiac dysrhythmia) or sustained, lasting hours or longer. Four terms describe disturbed arousal of a patient: Alert refers to a normal state of arousal. Stupor describes a state of unarousability in which strong external stimuli can transiently restore wakefulness. Stupor implies at least a limited degree of cognitive activity accompanies the arousal, even if transient. Coma is characterized by an uninterrupted loss of the capacity for arousal. The eyes are closed, sleep/wake cycles disappear, and even vigorous stimulation elicits at best only reflex responses. Lethargy describes a range of behavior between arousal and stupor. Only the terms alert and coma have enough precision to be used without further qualification; possibly, coma has gradations in depth, but this cannot be accurately assessed once the patient no longer responds to external stimuli. Stupor and coma imply an acute or subacute brain insult. Cerebral reserve capacity is large, so altered consciousness reflects either diffuse and bilateral cerebral dysfunction, failure of the brainstem-thalamic ARAS, or both. All alterations in arousal should be regarded as acute and potentially life-threatening emergencies.

Evaluation of a comatose patient demands a systematic approach with appropriate directed diagnostic and therapeutic endeavors; time should not be wasted on irrelevant considerations. Urgent steps are required to prevent or minimize permanent brain damage from reversible causes. Patient evaluation and treatment must necessarily occur simultaneously. Such a systematic approach demands an understanding of the pathophysiology of consciousness and mechanisms by which it may be deranged.

Anatomy, Pathology, Pathophysiology

Consciousness depends upon an intact ARAS in the brainstem and adjacent thalamus, which acts as the alerting or awakening element of consciousness, together with a functioning cerebral cortex of both hemispheres, which determines the content of that consciousness.^1,² The ARAS lies within a more or less isodendritic core that extends from the medulla through the tegmentum of the pons to the midbrain and paramedian thalamus. The system is continuous caudally with the reticular intermediate gray matter of the spinal cord and rostrally with the subthalamus, hypothalamus, anterior thalamus, and basal forebrain.³ The ARAS itself arises within the rostral pontine tegmentum and extends across the mesencephalic tegmentum and its adjacent intrathalamic nuclei. ARAS functions and interconnections are considerable and likely contribute more than only a cortical arousal system. The specific role of the various links from the reticular formation to the thalamus has yet to be fully identified.⁴ Furthermore, the cortex feeds back on the thalamic nuclei to contribute an important loop that amplifies arousal mechanisms.^5,⁶

The ascending arousal system contains cholinergic, monoaminergic, and γ-amino butyric acid (GABA) systems, none of which has been identified as the arousal neurotransmitter.^2,^7,⁸ Acute structural damage to, or metabolic/chemical disturbance of, either the ascending brainstem-thalamic activating system or the thalamocorticothalamic loop can alter the aroused attentive state. Consciousness depends on continuous interaction between the mechanisms that provide arousal and awareness. The brainstem and thalamus provide the activating mechanism, and the cerebrum provides full cognition and self-excitation. Content of consciousness is best regarded as the amalgam and integration of all cognitive function that resides in the thalamocortical circuits of both hemispheres. Altered awareness is due to disruption of this cortical activity by diffuse pathology. Focal lesions of the cerebrum can produce profound deficits such as aphasia, alexia, amnesia, and hemianopsia, but only diffuse bilateral damage sparing the ARAS and diencephalon can lead to wakeful unawareness. Thus there are two kinds of altered consciousness: (1) altered arousal due to dysfunction of the ARAS-diencephalon and (2) altered awareness due to bilateral diffuse cerebral hemisphere dysfunction.

Four major pathologic processes can cause such severe global, acute reductions of consciousness.^1,⁹ (1) In the presence of diffuse or extensive multifocal bilateral dysfunction of the cerebral cortex, the cortical gray matter is diffusely and acutely depressed or destroyed. Concurrently, cortical-subcortical physiologic feedback excitatory loops are impaired, with the result that brainstem autonomic mechanisms become temporarily profoundly inhibited, producing the equivalent of acute “reticular shock” below the level of the lesion. (2) Direct damage to a paramedian upper brainstem and posterior-inferior diencephalic ascending arousal system blocks normal cortical activation. (3) Widespread disconnection between the cortex and subcortical activating mechanisms acts to produce effects similar to both conditions 1 and 2. (4) Diffuse disorders, usually metabolic in origin, concurrently affect both the cortical and subcortical arousal mechanisms, although to a different degree according to the cause.

Structural Lesions Causing Coma

Intracranial mass lesions that cause coma may be located in the supratentorial or infratentorial compartments. From either location, impaired arousal or coma is caused by compression of the brainstem-hypothalamic activating mechanisms secondary to swelling and displacement of deep-lying intracranial contents; the ultimate event occurs either by halting axoplasmic flow or by sustained neuronal depolarization due to ischemia or hemorrhage. Factors important to the degree of loss of arousal are rate of development, location, and ultimate size of the lesion. Cerebral mass lesions distort the intracranial anatomy and thereby alter the cerebrospinal fluid (CSF) circulation and brain blood supply. These changes result in increased bulk of the injured tissue and a reduction in intracranial compliance. Intercompartmental pressure gradients result in herniation syndromes that are not necessarily associated with large increases in intracranial pressure (ICP). Recently sustained or evolving mass lesions can disturb cerebral vascular autoregulation, which results in abrupt, briefly lasting vasodilatation. This in turn causes recurrent increases in ICP (pressure waves), with additional compromise of cerebral blood supply to injured regions.

Two herniation syndromes demonstrate the mechanism by which supratentorial lesions produce coma. The rate of evolution of a mass dictates whether the anatomic distortion precedes (in slowly evolving lesions) or parallels the patient’s deterioration of wakefulness. Transtentorial herniation can be central or predominantly unilateral. Central herniation results from caudal displacement by deep midline supratentorial masses, large space-occupying hemisphere lesions, or large uni- or bilateral compressive extraaxial lesions with compression of the ARAS. The progressive rostral-caudal pathologic and clinical stages of this herniation syndrome were outlined.¹ Pathologically, bilateral symmetric displacement of the supratentorial contents occurs through the tentorial notch into the posterior fossa. Alertness is impaired early, pupils become small (to 3 mm) and reactive, and bilateral upper motor neuron signs develop. Cheyne-Stokes breathing, grasp reflexes, roving eye movements, or depressed escape of oculocephalic reflexes are the clinical manifestations. In the absence of effective therapy at this diencephalic stage, herniation progresses caudally to compress the midbrain, leading to a deep coma and fixed midposition (3-5 mm) pupils, signifying both sympathetic and parasympathetic interruption. Spontaneous eye movements cease, and oculovestibular and oculocephalic reflexes become difficult to elicit. Spontaneous extensor posturing may occur. Once this stage is reached, full recovery becomes unlikely. As the caudal compression-ischemia process advances, pontine and medullary function becomes destroyed, with variable breathing patterns and absent reflex eye movements. Finally, autonomic cardiovascular and respiratory functions cease as medullary centers fail.

Uncus herniation results from laterally placed hemisphere lesions, particularly of the temporal lobes, that cause side-to-side cerebral displacement as well as transtentorial herniation. Focal hemisphere dysfunction (hemiparesis, aphasia, seizures) precedes unilateral (usually ipsilateral) compression paralysis of the third cranial nerve. An early sign of uncus herniation is an ipsilateral (rarely contralateral) enlarged pupil that responds sluggishly to light, followed by a fixed, dilated pupil and an oculomotor palsy (eye turned downward and outward).¹ The ipsilateral posterior cerebral artery can become compressed as it crosses the tentorium and causes ipsilateral occipital lobe ischemia. Progressively, the temporal lobe compresses the midbrain, with loss of arousal and bilateral or contralateral extensor posturing. Ipsilateral to the intracranial lesion, a hemiparesis may develop if the opposite cerebral peduncle becomes compressed against the contralateral tentorial edge (Kernohan notch). Abnormal brainstem signs become symmetric, and herniation proceeds in the same pattern seen with central herniation as rostrocaudal brainstem displacement progresses.

Infratentorial lesions cause coma by displacement, compression, or direct destruction of the pontomesencephalic tegmental activating system. Displacement of the medulla downward sufficient to push the brainstem and cerebellar tonsils into the foramen magnum causes cardiorespiratory collapse. Acute intrinsic lesions of the brainstem, usually hemorrhagic or ischemic, cause abrupt onset of coma and are associated with abnormal neuro-ophthalmologic findings. Pupils are pinpoint due to disruption of pontine sympathetic pathways, or are dilated due to destruction of the third cranial nerve nuclei or intraaxial exiting fibers. Disconjugate eye movements and nystagmus occur, while vertical eye movements are relatively spared. Ocular bobbing signifies pontine damage. Upper motor neuron signs develop, and patients can become quadriplegic; flaccidity in the upper extremities and flexor withdrawal responses in the lower extremities often accompany midbrain-pontine damage.

Pathologically, basilar artery occlusion leads to asymmetric ischemia of the brainstem, with involvement of the ARAS, the neighboring densely packed neuropil, as well as the descending and ascending motor and sensory tracts. Thrombosis of the rostral basilar artery leads to infarction of the midline thalamic nuclei and brief coma without other obvious brainstem signs. Hemorrhage into the ventral pons sometimes spares consciousness but produces neuro-ophthalmologic signs and motor dysfunction. Extension of hemorrhage into the rostral pontine tegmentum results in stupor, coma, or death. Basilar artery migraine can produce altered consciousness, possibly by interfering with arterial blood flow in the basilar artery system. Rapidly developing extensive central pontine myelinolysis may cause coma by extension into the pontine tegmentum. Other intrinsic brainstem lesions (e.g., tumor, abscess, granuloma, demyelination) tend to progress slowly and usually spare arousal mechanisms; however, they may reduce attention and other cognitive functions, leading to severe psychomotor retardation.

Extraaxial posterior fossa lesions cause coma by direct compression of the ARAS in the brainstem, and in the diencephalon by upward transtentorial herniation. Compression of the pons may be difficult to distinguish from intrinsic lesions but is often accompanied by headache, vomiting, and hypertension due to a Cushing reflex. Upward herniation at the midbrain level is initially characterized by coma, reactive miotic pupils, asymmetrical or absent caloric eye responses, and decerebrate posturing; caudal-rostral brainstem dysfunction then occurs, with midbrain failure and midposition fixed pupils.¹⁰ Causes of brainstem compression include cerebellar hemorrhage, infarction and abscess, rapidly expanding cerebellar or fourth-ventricle tumors, or less commonly, infratentorial epidural or subdural hematomas. Drainage of the lateral ventricles to relieve obstructive hydrocephalus due to posterior fossa masses can potentially precipitate acute upward transtentorial herniation.^11,¹²

Downward herniation of the cerebellar tonsils through the foramen magnum causes acute medullary dysfunction and abrupt respiratory and circulatory collapse. Less severe impaction of the tonsils in the foramen magnum can lead to obstructive hydrocephalus and consequent bihemispheric dysfunction with altered arousal. Clinical manifestations include headache, nausea, vomiting, lower cranial nerve signs, vertical nystagmus, ataxia, and irregular breathing. Lumbar puncture in this setting carries a risk of catastrophic consequences.¹¹

Nonstructural Causes of Coma

Nonstructural disorders such as metabolic or toxic disturbances produce coma by diffusely depressing the function of the brainstem and cerebral arousal mechanisms. The anatomic locus of metabolic brain diseases has not been clearly defined. Onset of coma can be abrupt, as with toxic drug ingestion, general anesthesia, or cardiac arrest, or it may evolve slowly after a period of confusion and inattention. The chief manifestations of metabolic encephalopathy are disturbances in arousal and cognitive function. Other findings include abnormalities of the sleep/wake cycle, autonomic disturbances, and abnormal breathing variations.

A helpful distinguishing clinical feature of diffuse encephalopathy is preservation of the pupillary light response; the only exceptions are overdose of anticholinergic agents, near-fatal anoxia, or self-initiated malingering. Usually, lack of pupillary reactivity requires a search for an underlying structural lesion. Neurologic examination shows a decreased level of arousal and widespread cognitive decline. Deeply comatose patients without brainstem or hemisphere function and no known cause for coma must be assumed to have suffered accidental or intentional poisoning. Metabolic disturbances of arousal and cognition particularly affect elderly patients who suffer serious systemic illnesses or have undergone complicated surgery.

Metabolic encephalopathy is clinically characterized by multilevel CNS dysfunction. At onset, abnormalities in cognition are at least as severe as the disturbance of arousal. Misperception, disorientation, hallucinations, concentration and memory deficits, and occasionally hypervigilance may progress to profound stupor and coma. The patient’s level of arousal and consciousness often fluctuates between examinations. Motor abnormalities, if present, usually are symmetric and bilateral. Patients often suffer tremor, asterixis, and multifocal myoclonus. Spontaneous motor activity may range from hypoactivity (in cases of sedating drug or endogenous metabolic disturbances) to hyperactivity (after drug withdrawal or overdose of stimulants such as cocaine and phencyclidine). Seizures occasionally occur, particularly after alcohol or drug withdrawal, and in patients with established cortical pathology. Focal seizures may occur even without structural disease during hypoglycemia, hepatic encephalopathy, uremia, abnormal calcium levels, or toxin ingestion. Autonomic dysfunction can manifest as hypothermia with hypoglycemia, myxedema, or sedative drug overdose. Hyperthermia can occur in withdrawal states, particularly delirium tremens, anticholinergic drug overdose, infection, neuroleptic malignant syndrome, or malignant hyperthermia.

The metabolic need of the brain largely depends on oxidation of glucose to carbon dioxide and water. Certain fatty acids and ketone bodies can supply part of the metabolic needs in emergency circumstances, but these alternate fuels never provide an entirely sufficient substrate to meet all energy requirements. Normal cerebral blood flow (CBF) is around 55 mL/100 g tissue/min. At CBF less than 20 mL/100 g/min, oxygen delivery becomes insufficient for normal levels of oxidative metabolism, and cerebral glycolytic rate increases. Patients lose consciousness, and the electroencephalogram (EEG) is suppressed secondary to synaptic failure at CBF levels between 16 and 20 mL/100 g/min. The cortical evoked response is abolished below about 15 mL/100 g/min. At CBF around 8 mL/100 g/min, the energy-dependent membrane pump fails, and the membrane potential collapses. Unless CBF is restored promptly, irreversible neuronal injury will ensue. However, the threshold for ischemic neuronal injury is time dependent. Complete cessation of CBF leads to loss of consciousness in 8 seconds, and EEG suppression occurs at 10 to 12 seconds. ATP exhaustion and ionic pump failure occurs in 120 seconds. Selective neuronal damage starts after periods as brief as 5 minutes, and severe neuronal damage occurs after 20 to 30 minutes. Brain necrosis or infarction starts in 1 to 2 hours.

Under physiologic conditions, glucose is the brain’s only substrate and crosses the blood-brain barrier by facilitated transport. The normal brain uses about 55 mg glucose/100 g/min. Hypoglycemia—in adults, a blood glucose concentration below 40 mg/dL—produces signs and symptoms of encephalopathy resulting from dysfunction of the cerebral cortex, before the brainstem. Neurologic presentation of hypoglycemia can vary from focal motor or sensory deficits to coma. Acute symptoms of hypoglycemia are better correlated with the rate at which blood glucose levels decrease than with the degree of hypoglycemia. The blood glucose level at which cerebral metabolism fails and symptoms develop varies among individuals, but in general, confusion occurs at levels below 30 mg/dL and coma below 10 mg/dL. The brain stores about 2 g of glucose and glycogen, so a patient in hypoglycemic coma may survive 90 minutes without suffering irreversible brain damage. The pathophysiology of coma from hypoglycemia is not well understood. The disorder cannot solely be attributed to glucose starvation of neurons. Rather than such an internal catabolic death, evidence suggests that neurons are killed from without. Around the time the EEG becomes isoelectric, endogenous neurotoxins are produced and released by the brain into tissue and CSF. The distribution of necrotic neurons is unlike that of ischemia and is related to white matter and CSF pathways. The toxins act by first disrupting dendritic trees, sparing the intermediate axons, an indication of excitotoxic neuronal injury. The exact mechanism of excitotoxic neuronal necrosis is now becoming clear and involves hyperexcitation and culminates in cell membrane rupture. Also during hypoglycemia, synthesis of amino acids such as GABA, glutamate, glutamine, and alanine, as well as acetylcholine, is suppressed. Whether reduction of these molecules or alteration in nerve synaptic transmission significantly contributes to the onset of coma associated with severe hypoglycemia is not established.

The pathophysiology of other metabolic encephalopathies is less well established and is extensively discussed elsewhere.¹ Hepatic encephalopathy is caused not merely by ammonia intoxication but likely also involves accumulation of neurotoxins such as short-chain and medium-chain fatty acids, mercaptans, and phenols. Altered neurotransmission may play a role with accumulation of benzodiazepine-like substances, imbalance of serotonergic and glutaminergic neurotransmission, and accumulation of false neurotransmitters. The identity of the neurotoxin in uremic encephalopathy is uncertain and includes urea itself, guanidine and related compounds, phenols, aromatic hydroxyacids, amines, various peptide “middle molecules,” myoinositol, parathormone, and amino acid imbalance. The cause of the dysequilibrium syndrome may entail more than osmotic water shifts from plasma into brain cells, and reduction is reported in cortical potassium, with intracellular acidosis due to increased production of organic acids in the brain. The pathogenesis of pancreatic encephalopathy may involve patchy demyelination of brain white matter due to liberated enzymes from a damaged pancreas, disseminated intravascular coagulation, or fat embolism.

The mechanism of action of exogenous toxins or drugs depends partly on the structure and partly on the dose. As well as can be determined, none of the sedatives taken acutely produces permanent damage to the nervous system, making prompt diagnosis and effective treatment particularly important.

Differential Diagnosis

Several different behavioral states appear similar to, and can be confused with, coma. Differentiation of such states from true coma has important diagnostic, therapeutic, and prognostic implications. Moreover, coma is not a permanent state; patients who survive initial coma may evolve through and into these altered behavioral states. All patients who survive beyond the stage of acute systemic complications reawaken and either proceed to recovery (with none or varying degrees of disability) or remain in a vegetative state.

The vegetative state can be defined as wakefulness without awareness and is the consequence of various diffuse brain insults.^1,¹³ It may be a transient phase through which patients in coma pass as the cerebral cortex recovers more slowly than the brainstem. Clinically, vegetative patients appear to be awake and to have cyclical sleep patterns; however, such individuals do not show evidence of cognitive function or learned behavioral responses to external stimuli. Vegetative patients may exhibit spontaneous eye opening, eye movements, and stereotypic facial and limb movements, but they are unable to demonstrate speech or comprehension, and they lack purposeful activity. Vegetative patients generate normal body temperature and usually have normally functioning cardiovascular, respiratory, and digestive systems, but they are doubly incontinent. The vegetative state should be termed persistent at 1 month after injury and permanent at 3 months after nontraumatic injury or 12 months after traumatic injury.^14,¹⁵ Extended observation of the patient is required to assess behavioral responses to external stimulation and demonstrate cognitive unawareness. The EEG is never isoelectric but shows various patterns of rhythm and amplitude, inconsistent from one patient to the next. Normal EEG sleep/wake patterns are absent.

In the locked-in syndrome, patients retain or regain arousability and self-awareness, but because of extensive bilateral paralysis (i.e., de-efferentation) can no longer communicate except in severely limited ways. Such patients suffer bilateral ventral pontine lesions with quadriplegia, horizontal gaze palsies, and lower cranial nerve palsies. Voluntarily they are capable only of vertical eye movements and/or blinking.¹ Sleep may be abnormal, with marked reduction in non-REM and REM sleep phases. The most common etiology is pontine infarction due to basilar artery thrombosis, but others are pontine hemorrhage, central pontine myelinolysis, and brainstem mass lesions. Neuromuscular causes of locked-in syndrome include severe acute inflammatory demyelinating polyradiculoneuropathies, myasthenia gravis, botulism, and neuromuscular blocking agents. In these peripheral disorders, upward gaze is not selectively spared.

Akinetic mutism describes a rare subacute or chronic state of altered behavior in which an alert-appearing patient is both silent and immobile but not paralyzed.¹⁶ External evidence of mental activity is unobtainable. The patient usually lies with eyes opened and retains cycles of self-sustained arousal, giving the appearance of vigilance. Skeletal muscle tone can be normal or hypertonic but usually not spastic. Movements are rudimentary even in response to unpleasant stimuli. Affected patients are usually doubly incontinent. Lesions that cause akinetic mutism may vary widely. One pattern consists of bilateral damage to the frontal lobe or limbic-cortical integration with relative sparing of motor pathways. Vulnerable areas involve both basal medial frontal areas. Somewhat similar behavior also can follow incomplete lesions of the deep gray matter (paramedian reticular formation of the posterior diencephalon and adjacent midbrain), but such patients usually suffer double hemiplegia and act slowly yet are not completely akinetic or noncommunicative.

Catatonia is a symptom complex associated most often with psychiatric disease. This behavioral disturbance is characterized by stupor or excitement and variable mutism, posturing, rigidity, grimacing, and catalepsy. Catatonia can be caused by a variety of illnesses, both psychiatric (affective more than psychotic) disorders and structural or metabolic diseases (e.g., toxic and drug-induced psychosis, encephalitis, alcoholic degeneration). Psychiatric catatonia may be difficult to distinguish from organic disease, because patients often appear lethargic or stuporous rather than totally unresponsive. Such patients also may have a variety of endocrine or autonomic abnormalities. Patients in catatonic stupor do not move spontaneously and appear unresponsive to the environment despite what appears to be a normal level of arousal and consciousness. This impression is supported by a normal neurologic examination and subsequent recall of most events that took place during the unresponsive period. Patients usually lie with eyes opened, may not blink to visual threat, but one can usually elicit optokinetic responses. The pupils are semidilated and reactive to light, oculocephalic reflexes are absent, and vestibulo-ocular testing evokes normal nystagmus. Patients may hypersalivate and be doubly incontinent. Passive movement of the limbs meets with waxy flexibility, and catalepsy is seen in 30% of patients. Choreiform jerks of the extremities and facial grimaces are common. The EEG, both of catatonic excitement and stupor, most often shows a reactive, low voltage, fast-normal record rather than the slow record of a comatose patient.

Approach to Coma

The initial approach to stupor and coma is based on the principle that all alterations in arousal are acute, life-threatening emergencies. Urgent steps are required to prevent or minimize permanent brain damage from reversible causes, often before the cause of coma is definitely established. Patient evaluation and treatment must necessarily occur simultaneously. Serial examinations are needed, with accurate documentation, to determine a change in state of the patient. Accordingly, management decisions (therapeutic and diagnostic) must be made. The clinical approach to an unconscious patient logically entails the following steps: (1) emergency treatment, (2) history (from relatives, friends, and emergency medical personnel), (3) general physical examination, (4) neurologic profile, the key to categorizing the nature of coma, and (5) specific management.

Emergency Management

Initial assessment must focus on the vital signs to determine the appropriate resuscitation measures; the diagnostic process begins later. Urgent, and sometimes empirical, therapy must be given to avoid additional brain insult.

Oxygenation must be ensured by establishing an airway and ventilating the lungs. The threshold for intubation should be low in the comatose patient, even if respiratory function is sufficient for proper ventilation and oxygenation: the level of consciousness may deteriorate, and breathing may decompensate suddenly and unexpectedly. An open airway must be maintained and protected from aspiration of vomitus and blood. While preparing for intubation, maximal oxygenation can be ensured by suctioning the upper airway, gently extending the neck, elevating the jaw, and manually ventilating with oxygen using a mask and bag. Bag-valve mask ventilation with 100% oxygen and 1 mg of intravenous (IV) atropine helps prevent cardiac dysrhythmias. If a severe neck injury is a possibility or has not been excluded, intubation should be performed by the most skilled practitioner available, with cervical spine precautions. A brief neurologic examination is mandatory prior to sedation required for intubation.

The key points of the rapid neurologic exam are: hand drop from over the head (to assess for malingering or hysterical loss of consciousness); pupillary size and response to light; abnormal eye movements (active disconjugate, unilaterally paralytic, passively induced, or absent); grimacing/withdrawal from noxious stimulation; and abnormal plantar response (unilateral or bilateral Babinski sign).¹⁷ Assisted ventilation should continue during the examination if necessary. Neuromuscular blockade required for patient management and care should be deferred if possible until the neurologic examination is completed (3-5 minutes). Signs of arousal or inadequate sedation include dilated reactive pupils, copious tears, diaphoresis, tachycardia, systemic hypertension, and increased pulmonary artery pressure. Thereafter, monitoring patients neurologically may require head computed tomography (CT) more frequently.

Evaluate respiratory excursions: Arterial blood gas measurement is the only certain method to determine adequate ventilation and oxygenation. Pulse oximetry is useful, however, because it provides immediate, continuous information regarding arterial oxygen saturation. The comatose patient ideally should maintain a PaO₂ greater than 100 mm Hg and a PaCO₂ between 34 and 37 mm Hg. Hyperventilation (PaCO₂ < 35 mm Hg) should be avoided unless herniation is suspected. PEEP should be avoided if increased ICP is suspected, unless hypoxemia is not responsive to supplemental oxygen. Place a nasogastric tube to facilitate gastric lavage and prevent regurgitation.

Maintain circulation to assure adequate cerebral perfusion. Appropriate resuscitation fluid is lactated Ringer’s solution; normal saline is also used when intracranial hypertension is suspected. A mean arterial pressure around 100 mm Hg is adequate and safe for most patients. While obtaining venous access, collect blood samples for anticipated tests (Box 32-1). Treat hypotension by replacing any blood volume loss, and use vasoactive agents. Judiciously manage systemic hypertension with hypotensive agents that do not substantially raise ICP by their vasodilating effect (labetalol, hydralazine, or a titrated nitroprusside infusion are the favored agents for managing uncontrollable hypertension). For most situations, systolic blood pressure should not be treated unless it is above 160 mm Hg. Maintain urine output at least 0.5 mL/kg/h; accurate measurement requires bladder catheterization.

Glucose and thiamine: Hypoglycemia is a frequent cause of altered consciousness; administer glucose (25 g as a 50% solution, IV) immediately after drawing blood for baseline values. Empirical glucose treatment will prevent hypoglycemic brain damage and outweighs the theoretical risks of additional harm to the brain in hyperglycemic, hyperosmolar, or anoxic coma. Thiamine (100 mg) must be given with the glucose infusion to prevent precipitation of Wernicke encephalopathy in malnourished, thiamine-depleted patients. Rarely, an established thiamine deficiency can cause coma.

Repeated generalized seizures damage the brain and must be stopped. Initial treatment should include IV benzodiazepines, lorazepam (2-4 mg), or diazepam (5-10 mg). Seizure control can be maintained with phenytoin (18 mg/kg IV at a rate of 25 mg/min). Seizure breakthrough requires additional benzodiazepines.

Careful and mild sedation should be given to the agitated, hyperactive patient to prevent self-injury. Sedation facilitates ventilator support and diagnostic procedures. Small doses of IV benzodiazepines, intramuscular haloperidol (1 mg as often as hourly until desired effect), or morphine (2-4 mg IV) are appropriate.

Consider specific antidotes: Drug overdose is the largest single cause (30%) of coma in the emergency room. Most drug overdose can be treated by supportive measures alone. However, certain antagonists specifically reverse the effects of coma-producing drugs. Naloxone (0.4-2 mg, IV) is the antidote for opiate coma. The reversal of narcotic effect, however, may precipitate acute withdrawal in an opiate addict. In suspected opiate coma, the minimum amount of naloxone should be administered to establish the diagnosis by pupillary dilatation and to reverse respiratory depression and coma. Do not attempt to reverse completely all drug effects with the first dose. IV flumazenil reverses all benzodiazepine-induced coma. Coma unresponsive to 5 mg flumazenil in divided doses given over 5 minutes is not due to benzodiazepine overdose. Recurrent sedation can be prevented with flumazenil (1 mg IV) every 20 minutes.¹⁸ The sedative effects of drugs with anticholinergic properties, particularly tricyclic antidepressants, can be reversed with physostigmine (1-2 mg IV). Pretreatment with 0.5 mg atropine will prevent bradycardia. Only full awakening is characteristic of an anticholinergic drug overdose, as physostigmine has nonspecific arousal properties. Physostigmine has a short duration of action (45-60 minutes), and doses may have to be repeated.

Adjust body temperature: hyperthermia is dangerous because it increases brain metabolic demand and, at extreme levels, denatures brain proteins.¹⁹ Hyperthermia greater than 40°C requires nonspecific cooling measures even before the underlying etiology is determined and treated. Hyperthermia most often indicates infection but may be due to intracranial hemorrhage, anticholinergic drug intoxication, or heat exposure. A body temperature of less than 34°C should be slowly increased to above 35°C to prevent cardiac dysrhythmia. Hypothermia accompanies profound sepsis, sedative-hypnotic drug overdose, drowning, hypoglycemia, or Wernicke encephalopathy.

History

Once vital functions have been protected and the patient’s condition is stable, clues to the cause of coma must be sought by interviewing relatives, friends, bystanders, or medical personnel who may have observed the patient before or during the decline in consciousness. The history should include:

• Witnessed events: Head injury, seizure, details of a motor vehicle accident, circumstances under which the patient was found.

• Evolution of coma: Abrupt or gradual, headache, progressive or recurrent weakness, vertigo, nausea and vomiting.

• Recent medical history: Surgical procedures, infections, current medication.

• Past medical history: Epilepsy, head injury, drug or alcohol abuse, stroke, hypertension, diabetes, heart disease, cancer, uremia.

• Previous psychiatric history: Depression, suicide attempts, social stresses.

• Access to drugs: Sedatives, psychotropic drugs, narcotics, illicit drugs, drug paraphernalia, empty medicine bottles.

General Physical Examination

A systematic, detailed examination is helpful and necessary in the approach to the comatose patient, who is in no condition to describe prior or current medical problems. This examination is an extension of the initial rapid evaluation and should look for:

• Efficacy of resuscitation measures, determined by repeated assessment of vital signs.

• External evidence of trauma.

• Evidence of acute or chronic medical illnesses.

• Evidence of ingestion or self-administration of drugs (needle marks, alcohol on breath).

• Evidence of nuchal rigidity. Caution is required if severe neck injury is possible or has not been excluded. Nuchal rigidity may disappear in deeply comatose patients with meningeal infection/inflammation.

Neurologic Profile

Establishing the nature of coma is critical for appropriate management and requires:

• Correct interpretation of neurologic signs that reflect either the integrity or impairment of various functional levels of the brain.

• Determining whether the pattern and evolution of these signs are best explained by a supratentorial or infratentorial structural lesion, a metabolic-toxic encephalopathy, or a psychiatric cause (Box 32-2 and Table 32-1).

TABLE32-1 Correlation Between Levels of Brain Function and Clinical Signs

Structure	Function	Clinical Sign
Cerebral cortex	Conscious behavior	Speech (including any sounds) Purposeful movement: Spontaneous To command To pain
Brainstem activating and sensory pathways (reticular activating system)	Sleep/wake cycle	Eye opening: Spontaneous To command To pain
Brainstem motor pathways	Reflex limb movements	Flexor posturing (decorticate) Extensor posturing (decerebrate)
Midbrain CN III	Innervation of ciliary muscle and certain extraocular muscles	Pupillary reactivity
Pontomesencephalic MLF	Connects pontine gaze center with CN III nucleus	Internuclear ophthalmoplegia
Upper pons:
CN V	Facial and corneal	Corneal reflex-sensory
CN VII	Facial muscle innervation	Corneal reflex-motor response: Blink Grimace
Lower pons:
CN VIII (vestibular portion) connects by brainstem pathways with CN III, IV, VI	Reflex eye movements	Doll’s eyes Caloric responses
Ponto-medullary junction	Spontaneous breathing Maintained BP	Breathing and BP do not require mechanical or chemical support
Spinal cord	Primitive protective responses	Deep tendon reflexes Babinski response

BP, Blood pressure; CN, cranial nerve.

The clinical neurologic functions that provide the most useful information in making a categorical diagnosis are outlined in (Box 32-3). These indices are easily and quickly obtained. Furthermore, they have a high degree of interexaminer consistency, and when applied serially, they accurately reflect the patient’s clinical course. Once the cause of coma can be assigned to one of these categories, specific radiographic, electrophysiologic, or chemical laboratory studies can be used to make a disease-specific diagnosis and detect existing or potential complications.

Box 32-3

Characteristics of Categories of Coma

Supratentorial Mass Lesion Affecting Diencephalon/Brainstem

Initial focal cerebral dysfunction

Dysfunction progresses rostral to caudal

Signs reflect dysfunction at one level

Signs often asymmetrical

Subtentorial Structural Lesion

Symptoms of brainstem dysfunction or sudden-onset coma

Brainstem signs precede/accompany coma

Cranial nerve and oculovestibular dysfunction

Early onset of abnormal respiratory patterns

Metabolic-Toxic Coma

Confusion/stupor precede motor signs

Motor signs usually symmetrical

Pupil responses generally preserved

Myoclonus, asterixis, tremulousness, and generalized seizures common

Acid-base imbalance common, with compensatory ventilatory changes

Psychogenic Coma

Eyelids squeezed shut

Pupils reactive or dilated, unreactive (cycloplegics)

Oculocephalic reflex unpredictable, nystagmus on caloric tests

Motor tone normal or inconsistent

No pathologic reflexes

(Awake-pattern EEG)

Specific Management

Acute Bacterial Meningitis

A lumbar puncture must be considered in any unconscious patient with fever and/or signs of meningeal irritation. If possible, an emergency head CT should be performed before lumbar puncture on a comatose patient to rule out unexpected mass lesions. Increased ICP is present in all cases of bacterial meningitis, but a lumbar puncture is not contraindicated when this diagnosis is suspected. Cerebral herniation seldom, if ever, occurs except in small children.²⁰ Clinical correlates of impending herniation demanding a more cautious approach to lumbar puncture include coma or rapidly deteriorating level of arousal, focal neurologic signs, and tonic or prolonged seizures. Papilledema is rare in acute bacterial meningitis. Should unexpected herniation occur after lumbar puncture, treatment with hyperventilation and IV mannitol is indicated. Appropriate antibiotic treatment can usually await the results of spinal fluid Gram stain. If the Gram stain is negative, yet a bacterial etiology is suspected, empirical broad-spectrum antibiotic treatment with a third-generation cephalosporin and vancomycin is appropriate.

Drug Overdose

Certain general principles apply to all patients suspected of having ingested sedative drugs.^21,²² Most drug overdose is treated by emergent and supportive measures (Table 32-2). Once vital signs are stable, attempts should be made to remove, neutralize, or reverse the effects of the drug. Patients in coma from recent drug ingestion require gastric lavage after otracheal intubation. A large (preferably double-lumen) gastric tube must be placed orally. Lavage is performed in the head-down position on the left side, using a 200- to 300-mL bolus of tap water or 0.45% saline and continued until the return is clear. After lavage, 1 or 2 tablespoons of activated charcoal are passed down the lavage tube. With meticulous supportive measures, patients with uncomplicated drug-induced coma should recover without neurologic deficit. The recovery from coma due to massive doses of barbiturates or glutethimide can be hastened by hemodialysis.

TABLE32-2 Neurologic Manifestations of Common Drug Poisoning

Constant vigilance and attention to the patient’s condition, with timely and appropriate diagnostic and therapeutic evaluation, assures the best possible outcome of metabolic coma. Effective care demands meticulous attention to maintenance of tissue perfusion and oxygenation, documentation and anticipation of acute neurologic events (particularly diminished cerebral perfusion, herniation, or seizures), aggressive, rapid treatment of initial or subsequent infections, and prevention of agitation. Deep venous thrombosis can be prevented with either subcutaneous heparin (5000 units every 12 hours) or full-length leg pneumatic compression boots. Enteral or parenteral feeding within 36 to 48 hours is required to satisfy nutritional needs. Corneal injury can be prevented by protecting the eyes with lubricants and taping the lids shut.

The Role of Special Investigations

Neurodiagnostic Imaging

Once the patient with altered mental status is appropriately resuscitated and stabilized, further investigation may be necessary to document the location and type of the lesion and provide guidance for therapeutic intervention. CT and MRI provide an anatomic and/or functional assessment of the CNS and helpful information for defining the localization of lesions that produce coma. Details on the use of these modalities in neurointensive care are provided in Chapter 31.

Cranial CT scan is currently the most expedient imaging technique for evaluating the comatose patient and gives the most rapid information about possible structural lesions with the least risk. The value of CT in demonstrating mass lesions, hemorrhage, and hydrocephalus is well established. The CT scan shows tissue shifts due to intracranial intercompartmental pressure gradients but compared to MRI may underestimate the anatomy of herniation.¹¹ Certain lesions such as early infarction (less than 12 hours duration), encephalitis, and isodense subdural hemorrhage may be difficult to visualize. Posterior fossa pathology may be somewhat obscured by bone artifact inherent in the CT technique. Raised ICP is suggested by effacement of cortical sulci, a narrow third ventricle, and obliteration of the suprasellar or quadrigeminal cisterns but cannot be otherwise quantified.

MRI can be performed depending on the clinical setting and stability of the patient’s condition. The use of MRI is limited in the urgent setting of coma evaluation because of the length of time required to perform the imaging, image degradation by even a slight movement of the patient, and the relative inaccessibility of the patient for emergencies that may occur during the imaging process. Nevertheless, MRI provides superb visualization of posterior fossa structures, which is useful when intrinsic brainstem lesions are suspected as the cause of coma.¹¹ MRI images anatomic lesions such as those resulting from acute stroke, encephalitis, central pontine myelinolysis, and traumatic shear injury, with greater resolution and at an earlier time than CT scanning. Injection of the paramagnetic substance, gadolinium, helps delineate areas of blood-brain barrier breakdown and may augment the sensitivity of this scanning technique. Diffusion imaging can demonstrate ischemic brain virtually immediately. Sagittal MRI views are particularly useful in documenting the degree of supratentorial or infratentorial herniations and may enable intervention before clinical deterioration (Figure 32-1).¹¹ Newer MRI techniques allow functional imaging of the CNS by measurement of CBF to a particular region. Future application of this technique may allow rapid determination of diminished CBF, such as occurs in stroke or vasospasm, and will probably be useful in assessing the effect of therapeutic interventions.

Figure 32-1 Midsagittal magnetic resonance imaging (MRI) views of a normal adult brain and a brain with reversible downward transtentorial herniation.

A, MRI view of normal adult male brain. B, Schematic representation. Opening of tentorium of cerebellum or anterior cerebellar notch lies along a line (incisural line) defined anteriorly by anterior tubercle of sella turcica and posteriorly by junction of Galen’s vein, inferior sagittal sinus, and confluence of straight sinus. Proximal opening of aqueduct of Sylvius, the iter ad infundibulum (top arrow), lies within 2 mm of incisural line. Foramen magnum line is defined between inferior tip of clivus anteriorly and bony base of posterior lip of foramen magnum. C, A 47-year-old man who experienced 1 week of headache, nausea, vomiting, and gait ataxia presented with abrupt-onset coma, palsy of cranial nerve III, hyperreflexia, and bilateral extensor plantar responses. MRI revealed third-ventricular mass, obstructive hydrocephalus, and displacement of iter ad infundibulum inferiorly by 6.5 mm. Cerebellar tonsils were not displaced. D, Subsequent MRI view in same patient 2 weeks after surgical removal of a colloid cyst. Iter ad infundibulum is 1.2 mm below incisural line. Patient had full neurologic recovery.

(A, C, and D From Reich JB, Sierra J, Camp W, et al. Magnetic resonance imaging measurements and clinical changes accompanying transtentorial and foramen magnum brain herniation. Ann Neurol 1993;33:159-70.)

Electroencephalogram

The EEG can sometimes give useful additional information in the evaluation of the unresponsive patient. With metabolic and toxic disorders, EEG changes generally reflect the degree and severity of altered arousal or delirium, characterized by decreased frequency of the background rhythm and appearance of diffuse slow activity in the theta (4-7 Hz) and/or delta (1-3 Hz) range. Bilaterally synchronous and symmetric medium- to high-voltage broad triphasic waves are seen in various metabolic encephalopathies, most often in hepatic coma. Rapid beta activity (>13 Hz) in a comatose patient suggests ingestion of sedative hypnotics such as barbiturates and benzodiazepines. Acute focally destructive lesions show focal slow activity. When periodic lateralized epileptiform discharges appear acutely in one or both temporal lobes, herpes simplex encephalitis must be strongly considered. A nonreactive diffuse alpha pattern in a comatose patient usually implies a poor prognosis and is most often seen after anoxic insults to the brain or after acute destructive pontine tegmentum damage.^23,²⁴ A normally reactive EEG in an unresponsive patient suggests psychiatric disease, but a relatively normal EEG can accompany the locked-in syndrome, some examples of akinetic mutism, and catatonia—all of which can be caused by structural brain lesions. Attempts to correlate the pattern and frequency spectra of post-resuscitative EEG with neurologic outcome have been unsatisfactory, since its predictive value is at best 88% accurate.²⁵ At present, the most useful information regarding patient prognosis is still obtained by the correct interpretation of physical signs.

Nonconvulsive generalized status epilepticus and repeated complex partial seizures may produce altered levels of awareness or arousal; the EEG is an indispensable tool in diagnosis and management of both these disorders. Continuous EEG monitoring optimizes management of status epilepticus, as clinical assessment is insufficiently sensitive to detect continued electrographic seizures. Furthermore, continuous EEG monitoring in the ICU has shown an unsuspected high incidence of electrographic seizure activity in critically ill neurologic patients.^26,²⁷

Jugular Venous Oximetry

Changes in jugular venous oxygen saturation measure the relationship between cerebral metabolic rate and CBF, and this monitoring tool is discussed in Chapter 31.²⁸ This form of monitoring offers the potential to minimize secondary insults after traumatic brain injury (TBI) by providing warning of cerebral ischemia. It should be considered in comatose patients in conjunction with ICP monitoring (discussed later) to provide a logical approach to the treatment of brain injury.

Transcranial Doppler Ultrasonography

Transcranial Doppler ultrasonography (discussed in Chapter 31) allows noninvasive measurement of blood flow velocity in basal cerebral arteries.²⁹ The high dynamic resolution provided and confirmed correlation with other hemodynamic modalities encourages increasing numbers of neurointensivists to adopt the technique. Its importance in coma is in early detection of vasospasm in subarachnoid hemorrhage and at the time of brain death,³⁰ where an oscillating reverbatory movement has been noted in flow-velocity waveforms. The diagnosis is suspected based on the finding of the reflux phenomenon during late systole following anterograde injection of blood into the vascular tree.

Evoked Potentials

Evoked potentials (EPs) are used to follow the level of CNS function in comatose patients.³¹ Clinical use of brainstem auditory evoked potential (BAEP) and short latency somatosensory evoked potential (SEP) responses stem from the correlation between EP waveform and presumed generators within certain CNS structures. The SEP shows special promise in the ICU field, because EP components generated supratentorially in the thalamus and primary sensory cortex can be identified and followed over time. Shifts of intracranial structures that lead to herniation syndromes are reflected in abnormalities in SEPs, whereas BAEPs are generated entirely at or below the lower midbrain and are less often affected. EPs are less affected than EEG readings by sedative medications and septic or metabolic encephalopathies, factors that frequently confound interpretations in comatose patients. Anatomic specificity and physiologic and metabolic immutability are the basis of clinical utility of EPs. Abnormal test results, however, are etiologically nonspecific and must be carefully integrated into the clinical situation by a physician familiar with their clinical use. Caution is needed in the interpretation of SEPs to insure that absent responses are not due to technical problems. Repeat SEPs are useful in following patients’ progress. A progressive decline in response amplitude appears to be associated with worsening prognosis. Studies have shown that all patients with anoxic coma and bilaterally absent SEPs had died or remained in persistent vegetative state.³² In traumatic coma, absent SEPs may be a less definitive prognostic indicator, as recovery of consciousness has been reported in some patients.³³ Furthermore, comatose patients, especially those with motor response of flexor posture or better, with an initial poor prognostic EEG pattern but normal SEPs, may have the potential for recovery and should be supported until their condition has changed to a more prognostically definitive category.³⁴ BAEPs and median SEPs obtained within 24 hours of coma onset had a 3-month predictive outcome (compared to Glasgow Outcome Scale [GOS]) in patients with head injury, brain hemorrhage, or neoplasm.³⁵ Diagnostic sensitivity for an unfavorable outcome was low for both parameters, though specificity and positive predictive value was equally high for abnormal wave VI of BAEPs and median SEPs.

Intracranial Pressure Monitoring

ICP monitoring in neurointensive care is discussed in detail in Chapters 30 and 31. A review of published randomized controlled studies of real-time ICP monitoring by invasive or semi-invasive means in acute coma (traumatic or nontraumatic etiology) versus no ICP monitoring (i.e., clinical assessment of ICP) looked at outcome measures of all-cause mortality and severe disability at the end of a given follow-up period.³⁶ The conclusion drawn is that there are insufficient data to clarify the role of routine ICP monitoring in all severe cases of acute coma. However, it is of value in TBI and should be considered on a case-by-case basis in other cases of coma.

Positron Emission Tomography

Recent studies comparing patients in a minimally conscious state and controls, using oxygen-15 positron emission tomography (PET), revealed activation patterns in key brain regions linked to pain processing that were distinguishable from patterns in patients in a persistent vegetative state. These observations suggest the need for analgesic treatment in the minimally conscious state but not for patients in the persistent vegetative state.³⁷ Additional use of brain PET as a research tool to study patients in comatose states will provide important further insight into this condition.

Prognosis

A complete evaluation of the comatose patient must include an estimate of prognosis. The outcome in a given comatose patient cannot be predicted with absolute certainty. Available serial data are not sufficiently specific or selective to help in establishing the prognosis in an individual patient. Guidelines on the outcome of coma have been compiled based on serial examinations. Although the status of the comatose patient on admission is valuable in providing early informed discussion with relatives of patients and medical colleagues, that moment in most instances does not provide sufficient information to withhold immediate therapy. However, early establishment of a highly probable poor outcome ideally should be made within 24 hours after hospital admission to ration intensive care services and protect families from false hope in futile cases. A logical and sensible approach to prognostication includes an etiological subcategorization into medical, drug-induced, and traumatic coma.

Numerous descriptive scoring systems, both pre- and in-hospital, are used to attempt to assess severity of illness and predict patient outcome. A 2-year prospective study compared severity-of-illness scoring systems (Acute Physiology and Chronic Health Evaluation [APACHE] II and Mainz Emergency Evaluation System [MEES]) to mental status measurement (Glasgow Coma Scale [GCS]) in predicting outcome of 286 consecutive adult patients hospitalized for nontraumatic coma.³⁸ There were no statistically significant differences among the scoring systems to correctly predict outcome. APACHE II and MEES should not replace GCS. For prediction of mortality, GCS score also provides the best indicator in nontraumatic comatose patients (simple, less time consuming, and accurate in an emergency situation). Useful factors in determining the outcome of medical coma include cause, depth, and duration of coma. Clinical signs reflecting brainstem, motor, and verbal function are the most helpful and best validated predictors (confidence interval 0.95).³⁹^–⁴² Overall, only 15% of patients in established medical coma for 6 hours will make a good or moderate recovery; others will die (61%), remain vegetative (12%), or become permanently dependent on others for daily living (11%). Prognosis depends on etiology of medical coma. Patients in coma due to a stroke, subarachnoid hemorrhage, or cardiorespiratory arrest have only about a 10% chance of achieving independent function. Some 35% of patients will achieve moderate to good recovery if coma is due to other metabolic reasons including infection, organ failure, and biochemical disturbances. As noted earlier, almost all patients who reach the hospital after sedative overdose or other exogenous agents will recover moderately or completely. Depth of coma affects individual prognosis. Patients who open their eyes in response to noxious stimuli after 6 hours of coma have a 20% chance of making a good recovery, versus 10% if eyes remain closed. The longer coma persists, the less likely the chances for recovery; 15% of patients in coma for 6 hours make a good or moderate recovery compared with only 3% who remain unconscious at 1 week.^39,⁴⁰ Coma following head trauma has a somewhat better prognosis (see later discussion).

The severity of signs of brainstem dysfunction on admission inversely correlates with the chance of good recovery in medical coma. Absent pupillary responses at any time after onset and, except in barbiturate or phenytoin poisoning, absent caloric-vestibular reflexes 1 day after onset indicate a poor prognosis (<2% recovery). Except for sedative drug poisoning, no patient with absent pupillary light reflexes, corneal reflexes, oculocephalic or caloric responses, or lack of a motor response to noxious stimulation at 3 days after onset is likely to ever regain independent function. In a prospective study of 500 patients in medical coma, a uniform group of 210 patients suffered anoxic injury: 52 of these had no pupillary reflex at 24 hours, all of whom died. By the third day, 70 were left with a motor response worse than withdrawal and all died. By the seventh day, the absence of roving eye movements was seen in 16 patients, all of whom died.^39,⁴⁰

Patients likely to recover to functional independence will within 1 to 3 days speak words, open their eyes to noise, show nystagmus on caloric testing, or have spontaneous eye movements. More than 25% of patients with anoxic injury who show roving conjugate eye movements within 6 hours of the onset of coma, or who show withdrawal responses to pain or eye opening to pain, will recover independence and make a moderate or good recovery. The use of combinations of clinical signs helps improve the accuracy of prognosis: at 24 hours, the absence of a corneal response, pupillary light reaction, or caloric or doll’s-eye response is not compatible with recovery to independence.

Postanoxic convulsive status epilepticus and/or myoclonic status epilepticus reflect a poor prognosis. Occasional patients recover consciousness but remain handicapped. Most die or become vegetative.^43,⁴⁴ Associated clinical findings such as loss of brainstem reflexes or eye opening at the onset of myoclonic jerks, and sinister EEG patterns such as suppression or burst-suppression, confirm a grim neurologic outcome in this group. Autopsy studies show that cerebral and cerebellar damage can be ascribed to the initial ischemic hypoxic event; there is no evidence that status epilepticus further contributes to this damage. We initially treat patients with an IV loading dose of a major anticonvulsant (phenytoin, 13-18 mg/kg at 25 mg/min; and/or phenobarbital, 20 mg/kg at 50 mg/min). Myoclonic status epilepticus is generally resistant to therapy; we give intermittent doses of benzodiazepines (lorazepam, 2-4 mg; or clonazepam, 0.5 mg IV) as needed to suppress particularly severe myoclonus that interferes with ventilatory support. Anesthetic agents are rarely indicated and are unlikely to alter outcome.

A meta-analysis of prognostic studies in anoxic-ischemic coma examined the value of biochemical markers of brain damage in CSF or serum.⁴⁵ Only concentrations of CSF markers (creatine kinase brain isoenzyme, neuron-specific enolase, lactate dehydrogenase, and glutamate oxaloacetate) reached 0% false-positive rate. Because of small numbers of patients involved in studies (wide confidence levels) and methodological limitations of studies, the results available are not sufficiently accurate to provide a solid basis for management decisions of patients in coma.

The most accurate prediction of outcome in a patient in medical coma is obtained from the use of a combination of clinical signs, and there is little to be added by more sophisticated testing, other than identifying the cause of the coma.^39,⁴⁰ Within the first week, it is hard to justify the withdrawal of therapy from patients in medical coma unless they are already brain dead or lack all signs of brainstem function. After that, the probability of being able to predict the quality of life increases steadily. A multi-society task force of neurologists and neurosurgeons obtained a large number of data concerning the persistent vegetative state that provides guidelines to outcomes in patients remaining vegetative 1 month following severe head trauma or coma-producing medical illness (mostly anoxic).¹⁵

The recent and widespread application of mild therapeutic hypothermia after cardiac arrest has raised concern about reduced or altered ability to prognosticate outcome. Clinical variables such as brainstem reflex recovery, myoclonus, and absent motor response to pain showed higher false-positive mortality predictions in comatose survivors of cardiac arrest compared to predictions by the American Academy of Neurology guidelines at 72 hours.⁴⁶ Greater use of higher doses of sedatives related to hypothermia therapy or direct effects of hypothermia may play a role.^47,⁴⁸ Therefore, caution in prognostication is advised until a better understanding of the effects of this important new therapy emerges.

Among adults with head trauma who were in a vegetative state at 1 month (n = 434), 33% died, 15% remained vegetative, and 28% suffered severe disability at 1 year. Among children vegetative for 1 month post trauma (n = 106), 9% died, 29% remained in a persistent vegetative state, and 35% were severely disabled at 1 year; only 27% attained moderate/good recovery.

Nontraumatic (medical) coma results were even worse. Among 169 adults with nontraumatic brain injury and vegetative at 1 month, 53% died within one year, 32% remained vegetative, and only 14% made a moderate/good recovery. Outcome of 45 children in similar circumstances showed 22% dead, 65% still vegetative, and only 6% made a moderate/good recovery at 1 year.

It is possible in a fraction of patients to predict within the first week those who will recover, those who will die in coma or enter a vegetative state, and those who will survive with severe disability. It is well established that patients in anoxic coma who are in a vegetative state at 1 month will never recover their full preanoxic physical or cognitive function.

Patients in coma due to exogenous agents (except carbon monoxide poisoning) carry an overall good prognosis, provided that circulation and respiration are protected by avoiding or correcting cardiac dysrhythmia, aspiration pneumonia, and respiratory arrest. Despite absent brainstem reflexes (electrocerebral silence on EEG), patients with deep sedative drug intoxication have the potential for complete recovery. Therefore, in the emergent situation, patients in coma of uncertain etiology should be supported vigorously until the precise cause of coma has been fully established.

The outcome of traumatic coma is generally better than medical coma, and prognostic criteria are somewhat different.^15,^33,⁴⁹ Many patients with head injury are young; prolonged posttraumatic unconsciousness of up to several months does not always preclude a satisfactory outcome; and compared to the initial degree of neurologic abnormality, patients in traumatic coma improve more than patients in medical coma. Patients in coma for longer than 6 hours after TBI have a 40% chance to recover to moderate disability or better at 6 months. The most reliable predictors of outcome at 6 months are:

1 Patient age (worse outcome especially after 60 years).

2 Depth and duration of coma (an inverse correlation with GCS).

3 Pupil reaction and eye movements (absence at 24 hours predicts death or a vegetative state in 90%).

4 Motor response in the first week of injury (Table 32-3).

TABLE32-3 Trauma Scale

Glasgow Coma Scale Total
14-15	5
11-13	4
8-10	3
5-7	2
3-4	1
Respiratory Rate
10-24/min	4
25-35/min	3
>35/min	2
1-9/min	1
None	0
Respiratory Expansion
Normal	1
None	0
Systolic Blood Pressure
>89 mm Hg	4
70-89 mm Hg	3
50-69 mm Hg	2
0-49 mm Hg	1
No pulse	0
Peripheral Perfusion (Capillary Refill)
Normal	2
Delayed	1
None	0
Total Trauma Score (Sum of Individual Scores)*:

* Scores < 10 represent < 60% chance of survival.

An independent poor prognostic indicator is sustained, uncontrollably increased ICP (>20 mm Hg). Additional factors play a role in the eventual outcome from traumatic coma. Specific lesions such as subdural hematoma that result in coma can have less than 10% recovery rate.⁵⁰ In studies with blunt trauma, comatose patients with increased plasma glucose, hypokalemia, or elevated blood leukocyte counts were associated with lower GCS scores and increased probability of death.⁵¹ There are some reports of patients who have suffered coma as a result of TBI in whom an improvement from the vegetative state has been recognized after months, but these anecdotal cases of recovery are difficult to validate. It seems possible that such patients were not truly vegetative but rather in a state of profound disability with minimal cognition at the beginning of observation.⁵² In a recent case report, however, patient recovery from a 19-year-duration TBI-induced minimally conscious state was associated with improvements in white matter tracts, demonstrated with MRI diffusion tensor technique.⁵³ Novel MRI technology may thus aid in explaining these unusual recoveries; additional studies are warranted.

A systematic review of trials reporting on multisensory stimulation programs in TBI patients in coma or the vegetative state found no reliable evidence of the effectiveness of such techniques when compared to standard rehabilitation.⁵⁴ Outcome measures included duration of unconsciousness (time between injury and response to verbal commands), level of consciousness (GCS), level of cognitive functioning, functional outcomes (GOS), or by disability rating scale. The overall methodological quality was poor, and studies differed widely in design and conduct. Owing to the diversity in reporting of outcome measures, a meta-analysis was not possible. Recently, continuous subcutaneous apomorphine infusion (to stimulate dopaminergic neurotransmission) has been suggested to facilitate awakening, specifically in traumatic coma.⁵⁵ Similarly, recent work has suggested possible arousal effects from either prolonged coma or minimally conscious state with zolpidem administration.⁵⁶ However, larger series are required to confirm or refute these findings.⁵⁷

Prognostic guidelines for medical and traumatic coma should be applied with care. One must be sure evaluation and interpretation of clinical signs are correct. The prognostic signs, however, predict general outcomes in large patient groups and cannot be applied with absolute precision to every individual comatose patient. In addition, one must selectively exclude the effects of anticholinergic agents (used during resuscitation) on pupillary reactivity and paralytic agents on motor response.

The ability to predict prognosis following coma can benefit the patient, family, and physician. Families can be spared both the emotional and financial burdens of caring for individuals with an insignificant chance of independent function and quality of life. Physicians can then properly allocate limited resources to patients with the potential to benefit from advanced medical care.

There are recognized difficulties in interpreting outcome studies of coma prognosis: lack of prospective studies, failure to state confidence intervals, and the fact that patients in coma may die of a non-neurological disease. The self-fulfilling nature of poor prognoses is difficult to eliminate: the care of a patient will reflect the treating physicians’ impressions and opinions on patient outcome. Ideally, prognostic studies should only be performed on patients who will receive maximal life support for as long as possible, but this is inconsistent with humane and sensitive management of patients and their relatives.

Analysis of the SUPPORT (Study to Understand the Prognoses and Preferences for Outcomes and Risks of Treatments) trial was used to estimate the cost-effectiveness of aggressive care for patients in nontraumatic coma.^58,⁵⁹ Patients with reversible metabolic causes of coma were excluded. The incremental cost-effectiveness was calculated for aggressive care versus withholding cardiopulmonary resuscitation and ventilatory support after day 3 of coma. The incremental cost-effectiveness of the more aggressive strategy was $140,000 (1998 dollars) per quality-adjusted life year for high-risk patients and $87,000 per quality-adjusted life year for low-risk patients (five risk factors were age older than 70 years, absent verbal response, absent withdrawal to pain, abnormal brainstem response, and serum creatinine >1.5 mg/dL). From a purely economic standpoint, making earlier decisions to withhold life-sustaining treatments for patients with very poor prognoses may yield considerable cost savings. On moral and ethical grounds, however, many physicians object to having to consider the cost factor when it comes to making treatment decisions for more or less sick patients. But growing financial constraints now imposed on the medical community from the top down by politicians and the business culture may no longer afford such luxury, even in a country like the United States.