Outside the neurosurgical setting (e.g., head trauma, subarachnoid hemorrhage (SAH), brain tumor), metabolic encephalopathy is the most common cause of coma. A comparison of the usual clinical features of structural and metabolic coma is presented in Table 34-1. Because metabolic encephalopathy affects the cortex and brainstem diffusely, abrupt focal deficits and progressive rostrocaudal losses seen with supratentorial mass lesions do not usually occur. Rather, patients exhibit slowly evolving symmetric deficits, often preceded by somnolence or confusion. A variety of common disorders, including drug overdose, hypoxia, hypotension,
hypoglycemia, dehydration, sepsis, hepatic encephalopathy, and uremia can all contribute to impaired consciousness. The common reversible causes of coma are summarized in Table 34-2.

It is difficult to provide absolute guidelines as to the magnitude of a single abnormality necessary to cause coma, because multiple derangements often coexist, and the age of the patient, presence of underlying diseases, and the rapidity of development also determine impact. Yet, as a general rule, it is uncommon for glucose greater than 50 or less than 500 mg/dL, Na⁺ greater than 120 or less than 155 mEq/L, Ca²⁺ less than 12 mg/dL, or Mg²⁺ greater than 0.8 or less than 10 mg/dL to produce coma. Only very rarely do disorders of other electrolytes alter consciousness. The precise cause of unconsciousness in patients with renal failure is unknown; however, uremia alone rarely causes coma until the blood urea nitrogen (BUN) exceeds 100 mg/dL. (Renal insufficiency probably alters consciousness through multiple mechanisms, including metabolic acidosis, electrolyte abnormalities, metabolic toxin or drug accumulation, and increased permeability of the blood-brain barrier.) Similarly, the exact cause of coma in patients with liver failure is unknown, but accumulation of endogenous (e.g., glutamine) and exogenous toxins (e.g., drug metabolites) and cerebral edema all play some role in the process (see Chapter 31). Cerebral edema is a much bigger problem in the setting of acute hepatic failure. There is such a poor correlation between serum ammonia levels and mental status that no rule can be offered as to the level of ammonia associated with coma.

More firm guidelines can be offered with respect to the impact of hypoxemia and hypercapnia on consciousness. Tolerance of hypoxemia depends not only on the extent of desaturation but also on compensatory mechanisms available. The major mechanisms of acute compensation are increased cardiac output, O₂ extraction, and anaerobic metabolism, and improved unloading of O₂ resulting from tissue acidosis. Most individuals without cardiac disease or anemia remain asymptomatic until PaO₂ falls below 50 mm Hg. At that level, malaise, lightheadedness, nausea, vertigo, impaired judgment, and incoordination are noted. Confusion develops as PaO₂ falls into the 35 to 50 mm Hg range. As PaO₂ declines below 35 mm Hg, urine output slows, bradycardia and conduction system blockade develop, lactic acidosis appears, and the patient becomes lethargic or obtunded. At levels near 25 mm Hg, the normal unadapted individual loses consciousness, and minute ventilation falls because of respiratory center depression. As for all other metabolic toxins, the effects of carbon dioxide (CO₂) depend not only on the absolute level of CO₂ but also on its rate of accumulation. A PaCO₂ less than 60 mm Hg is often asymptomatic, but as levels rise above this threshold, headache and lethargy are commonly observed. Asterixis and myoclonus occur as levels mount even higher, but surprisingly massive elevations in CO₂ (often double or triple normal values) are usually necessary to render a patient unconscious.

Generally, a cerebral perfusion pressure (CPP) (mean arterial pressure [MAP]—intracranial pressure [ICP]) must exceed 50 mm Hg to perfuse the brain adequately; however, otherwise young healthy patients may maintain consciousness despite severe reductions in MAP. By contrast, patients with chronic hypertension, cerebrovascular disease, or elevated ICP may be underperfused at much higher pressures.

Severe sepsis frequently alters consciousness; however, mental status changes usually fall short of true coma. The mechanisms are multifactorial. Obviously, direct infection of the CNS can render a patient unconscious. In addition, severe sepsis is usually associated with some degree of hypoxemia and almost 75% of septic patients will develop hypotension—both factors which contribute to mental status changes. Possibly most interesting,
is the finding that inflammatory cytokines (e.g., interleukin-1) may directly impair consciousness. Sepsis-induced coma is particularly common in the febrile elderly patient, where altered mental status presents a difficult management decision. Frequently deliberated diagnoses are severe sepsis alone, or sepsis complicated by dehydration, electrolyte abnormalities, meningitis, and intracranial structural lesions such as a brain abscess or hemorrhage. Timely antibiotic therapy is desirable in all infectious situations, but confirming the diagnosis and nailing down a specific organism so as to best choose antimicrobial therapy usually requires a lumbar puncture (LP). Unfortunately, LP incurs some risk in the presence of coagulopathy, anticoagulation, or intracranial mass lesion. Therefore, deciding the order in which to perform a head computed tomography (CT) scan, do an LP, and administer antibiotic therapy is often debated. In febrile nonimmunocompromised patients without evidence of a focal neurologic defect, papilledema, or history of trauma, an LP is almost certainly safe and can be performed before or without a head CT scan. (Not that long ago, the decision to perform an LP was always made only based upon history and examination.) If head trauma, papilledema, new onset seizures, or focal neurologic deficit complicates the evaluation of a potentially infected patient, probably the best course is to obtain blood cultures, administer empiric antibiotics, and proceed to the CT scanner before LP. In any case, if logistical limitations preclude prompt CT scanning and intracranial infection is a real possibility, it is best to begin antibiotic treatment, even if doing so precludes a definitive microbiological diagnosis. Although it is rational to administer antibiotics as quickly as practical in patients with suspected meningitis, there is little if any data to support the often-quoted need to dose antibiotics within 1 h of suspecting the diagnosis.

Medication ingestion or toxin exposure is the most frequent cause of nontraumatic coma. Opiates, benzodiazepines, ethanol, and antidepressants are the most common drug classes implicated. Chemical-induced mental status changes are typically multifactorial; commonly several consciousness-depressing drugs are simultaneously ingested, and the drugs or toxins often lead to changes in oxygenation or perfusion that can cause coma in and of themselves. For example, narcotic overdose is often combined with benzodiazepine and alcohol ingestion. Although direct effects of these drugs alone can cause coma, they can also impair consciousness by producing hypoventilation or hypotension (see Chapter 33).

Generalized seizures may induce unconsciousness during the ictal phase or as a postictal phenomenon. Distinguishing a seizure from other causes of coma is easy if convulsive activity is observed or consciousness returns rapidly after a suspected seizure in an otherwise healthy patient. However, in the ICU many seizures do not cause visible convulsions. In addition, patients with previous stroke, metabolic encephalopathy, or prolonged seizures (status epilepticus) may suffer a long postictal period. In turn, status epilepticus often has an underlying structural or metabolic cause. Thus, delayed return of consciousness following a seizure should prompt consideration of a structural lesion (e.g., tumor, stroke, SAH, subdural hematoma) or underlying metabolic disorder (e.g., hypoglycemia, toxin ingestion, or electrolyte disturbance). As with metabolic encephalopathy, seizures that cause loss of consciousness generally tend to produce symmetric neurological defects unless there is an underlying structural abnormality. In contrast to metabolic encephalopathy, the loss of consciousness associated with seizures is usually instantaneous rather than gradual.

Because pathophysiology and treatment differ radically, metabolic and structural causes of coma must be distinguished as quickly as possible. The history is helpful in making this separation if it reveals trauma or drug ingestion. Sudden onset of coma suggests a seizure or a vascular event (e.g., SAH, brainstem stroke). The onset of coma after minutes to hours of a focal deficit suggests supratentorial intracerebral hemorrhage with progressively increasing ICP. A slowly evolving focal deficit occurring over days to weeks before loss of consciousness suggests abscess, tumor, or subdural hematoma, whereas progression to coma over minutes to hours without a focal deficit favors a metabolic cause. The setting in which coma develops may suggest trauma or hyperthermia or hypothermia from environmental or toxic exposure (e.g., organophosphates, carbon monoxide). Medications found near the comatose patient are particularly helpful. For example, not only may the offending compound(s) be discovered, but medication containers bearing the name of the prescribing physician may allow further history to be obtained. At the very least, knowledge of a patient’s medications provides a forensic picture of underlying diseases. In patients with alcoholism, intoxication with ethanol, ethylene glycol, methanol, or isopropyl alcohol should be suspected. In patients with diabetes, hypoglycemia and diabetic ketoacidosis (DKA) are common causes of coma. Underlying medical problems such as hypothyroidism, renal failure, cirrhosis, or psychiatric illness also increase the likelihood of a metabolic etiology, whereas a history of falling, previous stroke, brain tumor, extracranial neoplasm, or atrial fibrillation favors structural or vascular problems. Patients known to have malignant tumors are subject to both structural lesions (e.g., metastases and hemorrhage) and metabolic causes (e.g., hyponatremia, hypercalcemia). Similarly, uncontrolled hypertension can induce metabolic (e.g., hypertensive encephalopathy) or structural (e.g., intracerebral hemorrhage) coma. Immunocompromised patients, especially those with human immunodeficiency virus (HIV) infection are at higher risk for structural causes of coma including, CNS infections and lymphoid malignancies.

Physical examination is most helpful in differentiating structural from metabolic causes of coma when it reveals evidence of focal or lateralizing signs. In such patients, a metabolic etiology is uncommon. (Exceptions to this rule occur in patients with hepatic failure, hypoglycemia, prior stroke, and postictal patients.) Comatose patients should always be fully disrobed and examined for evidence of occult trauma. Although physical evidence of head trauma suggests a structural cause, up to 50% of trauma patients also suffer from intoxication, oftentimes sufficient to produce coma. Boggy areas of the skull suggest depressed skull fracture, while the Battle sign (postauricular hematoma), “raccoon eyes,” and bloody nasal or aural discharge suggest basilar skull fracture. In traumatized patients, it is critical to exclude cervical spine instability before the neck is manipulated because serious spinal injuries commonly accompany cranial lesions severe enough to cause coma. Echymoses, mucosal bleeding, or petechiae may implicate coagulopathy as the cause of intracranial bleeding. Incontinence of stool or urine or tongue laceration strongly suggests recent seizure. Atrial fibrillation, a large heart, and history of recent myocardial infarction are all associated with cerebral embolic disease. (In general, embolic disease is an uncommon cause of coma because of the limited area of cerebral infarction caused by emboli.) Cardiac murmurs should raise suspicion of endocarditis-induced septic embolism or brain abscess. Arrhythmias only result in coma when they cause hypotension or cerebral emboli. In this setting, isolated carotid bruits are of little significance because occlusive carotid disease is a rare cause of coma. Nuchal rigidity suggests meningitis, encephalitis, or SAH.

Vital signs provide additional clues to diagnosis. Although hypertension may accompany any cause of increased ICP, severe hypertension suggests intracerebral or SAH, particularly if accompanied by nuchal rigidity or focal neurological signs, respectively. Hypertensive encephalopathy alone is less likely to produce coma and is usually characterized by a nonfocal examination and blood pressures greater than 240/130 mm Hg. Stimulant intoxication with amphetamines, cocaine, phencyclidine, or phenylpropanolamine, should also be
considered in patients with altered mental status and hypertension. Cocaine-induced hypertension alone may cause delirium but if coma is present, intracranial hemorrhage is likely. Although young patients without underlying vascular or cerebral disease may remain awake with very low (40 to 50 mm Hg) MAPs, the elderly, patients with chronic hypertension, and those with concurrent metabolic encephalopathy or structural lesions tolerate hypotension less well.

Heatstroke, serotonin syndrome, neuroleptic malignant syndrome, malignant hyperthermia, stimulant intoxication, and any number of infections may cause fever sufficient to impair consciousness. Patients with hyperthermia or hypothermia frequently have an infection accompanying the primary temperature disorder that may itself disturb consciousness (e.g., pneumonia, brain abscess, or meningitis). Although primary aberrations of body temperature can directly cause coma, they rarely do so until core temperatures exceed 105°F or fall below 80°F (see Chapter 28). Bradypnea and hypoventilation most often result from the sedative effects of drugs or alcohol, accumulated hepatic or renal toxins, hypothyroidism, or far advanced brainstem compression. Tachypnea is a nonspecific finding but usually arises from one of four basic causes: (a) inappropriate ventilatory control, (b) hypoxemia, (c) compensation for metabolic acidosis, or (d) reduced lung or chest wall compliance. Contrary to popular teaching, specific “pathognomonic” respiratory patterns have little localizing or prognostic value, with one notable exception— uncoordinated, irregular (ataxic) respiration usually indicates severe medullary impairment and impending respiratory collapse.