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.

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