Initial Diagnosis and Management of Coma

Coma represents a true medical emergency. Drug intoxications are a leading cause of coma; however, other metabolic disturbances and traumatic brain injury are also common causes. The general emergency department approach begins with stabilization of airway, breathing, and circulation, followed by a thorough physical examination to generate a limited differential diagnosis that is then refined by focused testing. Definitive treatment is ultimately disease-specific. This article presents an overview of the pathophysiology, causes, examination, and treatment of coma.

Key points

  • Coma is a life-threatening process that requires immediate stabilization and a structured approach to diagnosis and management.

  • The differential diagnosis for coma is long, but is often divided into structural vs. diffuse neuronal dysfunction; the latter is subdivided into toxic vs. metabolic.

  • When available, historical information may be of great use in determining the etiology of coma; in all cases, a focused physical examination can help greatly refine the differential diagnosis.

  • The definitive treatment of patients with coma is ultimately disease-specific.


Many patients present to the emergency department with an alteration in mental status simply as a complication of many serious illnesses. A subset of these patients will present comatose, a clinical state that is a true medical emergency. Although coma is a relatively rare presenting condition in the emergency department, patients who present with coma are often in extremis and necessitate immediate evaluation and stabilization.

The approach to coma by the emergency physician is described, beginning with a discussion of pathophysiology and cause. Then, the practical clinical aspects of coma are addressed, including initial stabilization, obtaining the correct historical information, performing a thorough physical examination, ordering appropriate testing and imaging studies, and providing appropriate treatment.


Many patients present to the emergency department with an alteration in mental status simply as a complication of many serious illnesses. A subset of these patients will present comatose, a clinical state that is a true medical emergency. Although coma is a relatively rare presenting condition in the emergency department, patients who present with coma are often in extremis and necessitate immediate evaluation and stabilization.

The approach to coma by the emergency physician is described, beginning with a discussion of pathophysiology and cause. Then, the practical clinical aspects of coma are addressed, including initial stabilization, obtaining the correct historical information, performing a thorough physical examination, ordering appropriate testing and imaging studies, and providing appropriate treatment.


A neuronal network in the dorsal pons and midbrain give rise to the ascending reticular activing system (ARAS), which is responsible for arousal. Neurons from these centers run together through the thalamus and then to the bilateral cerebral cortex; the cortex controls sensory processing and understanding, which generates awareness. Coma results from an impairment of this axis by a process that affects the brain’s arousal center, consciousness center, the tracts that connect them, or some combination thereof. Patients are, therefore, not aware and not awake. Importantly, coma from cortical impairment can only result from a bilateral insult; unilateral cortical deficits do not cause coma. Prolonged coma may result in awakening cycles (eyes open coma) without awareness. Because the comatose state is difficult to quantify, some patients diagnosed as comatose may be minimally aware (minimally conscious state) and others may be more aware than can be assumed or tested.

Although the final common physiologic pathway of coma is neuronal dysfunction in the ARAS-thalamic-cortical pathway, it is useful to subdivide the pathophysiology into structural versus diffuse neuronal dysfunction. Structural causes of coma are defined as those that precipitate cellular dysfunction through a mechanical force, such as pressure on key area or a blockade of delivery of critical cellular substrate. Diffuse neuronal dysfunction precipitates coma by abnormalities only at the cellular level and may be further divided into two general categories: toxic and metabolic. In a toxin-induced coma, an exogenous substance is responsible for the clinical findings; in a metabolic coma, a perturbation of an endogenous process, such as temperature or sodium regulation, has gone awry.

This classification, although useful, does have limitations. A metabolic process, such as hypoglycemia or hypoxia, may initially produce coma through diffuse neuronal dysfunction; however, if the process is uncorrected and cell death occurs, the cause of coma becomes structural. Similarly, a diffuse neuronal process, such as cerebral edema, may become a structural problem if the edema occludes vessels in the posterior circulation and produces brainstem ischemia.


A causal overview of coma is presented in Table 1 , categorized based on this logic, and includes coma mimics, which are several disorders that may be easily mistaken for coma but do not involve interruption of the ARAS-thalamic-cortical pathway. For the purposes of this article, the focus is on relatively common entities that may present with coma, rather than those that are uncommon or in which coma is a late finding.

Table 1

Causal overview of coma and coma mimics

Coma Coma Mimics
Structural Diffuse Neuronal Dysfunction
Toxic Metabolic
Intracranial hemorrhage
Vascular occlusion
Sedative-hypnotics agents
Dissociative agents
Carbon monoxide
Toxic alcohols
Agents of histotoxic hypoxia
Simple asphyxiants
Serotonin syndrome
Neuroleptic malignant syndrome
Respiratory insufficiency
Electrolyte disorders
Thiamine deficiency
Nonconvulsive status epilepticus
Locked-in syndrome
Neuromuscular paralysis
Akinetic mutism
Psychogenic unresponsiveness

Structural causes of coma


Tumors may cause coma by exerting pressure on either a key area (eg, the brainstem) or by causing a diffuse increase in intracranial pressure. More commonly, however, patients with tumors have a slow progression of neurologic findings. Abrupt onset of coma in such patients often results from hemorrhage into an expanding mass. Even small tumors, however, may cause obstructive hydrocephalus or focal infarctions, each of which may in turn lead to the relatively abrupt onset of coma.

Acute Hydrocephalus

There is approximately 100 to 150 mL of cerebrospinal fluid (CSF) in the adult brain. CSF is produced predominantly in the choroid plexus, circulates through the ventricular system, and empties into the subarachnoid space where it is absorbed predominantly into the venous system through the arachnoid villi. Occlusion of this flow via tumor, clotting of intraventricular blood, or dysfunction of the arachnoid villi may lead to an increase in intraventricular CSF, with a concurrent increase in intracranial pressure and resultant coma.

Intracranial Hemorrhage

Central nervous system (CNS) hemorrhage resulting in coma may have 1 of 4 causes.

Spontaneous subarachnoid hemorrhage

Spontaneous subarachnoid hemorrhage (SAH) usually results from the rupture of an aneurysm in the Circle of Willis (often referred to as a berry aneurysm). Thunderclap headache on presentation is present in more than 95% of patients. Coma in the setting of SAH may be due to acute hydrocephalus or anoxic-ischemic injury.

Subdural hemorrhage

Subdural hemorrhage (SDH) is an accumulation of blood between the dura and the arachnoid membrane. SDH is often associated with a trauma but may also be associated with low intracranial pressure, as occurs after lumbar puncture. SDH may occur because of either shearing of bridging veins or arterial interruption. The use of both antiplatelet agents and anticoagulants increase the risk of SDH. SDH may produce a rapid shift of brain parenchyma, resulting in compression of the thalamus and pressure on the brainstem. Seizures, including nonconvulsive status epilepticus (NCSE), may mimic structural injury and are more often seen after hematoma evacuation.

Epidural hemorrhage

Epidural hemorrhage (EDH) is most often due to blunt force trauma that disrupts an epidural artery, with blood collecting in the potential space between the dura and the skull. Patients may present with initial confusion or loss of consciousness from which they recover, only to subsequently “talk and deteriorate.” This lucid interval occurs in approximately half of all EDH patients. Coagulopathy is associated with a poorer outcome in patients with EDH. Similar to SDH, brain parenchymal shift, brainstem pressure, and seizures may result.

Intraparenchymal hemorrhage

Intraparenchymal hemorrhage (IPH) is usually due to longstanding hypertension and associated vascular changes, although amyloid angiopathy and coagulopathy are other possible causes. Coma from an IPH may be caused by the disruption of key tracts or a general increase in intracranial pressure, depending on the location of the lesion.

Vascular Occlusion

Arterial vascular occlusion may be either thrombotic or embolic; both may produce coma if critical structures are affected. Of note, arterial vascular occlusion causing coma is usually a posterior circulation event, with occlusion in the vertebrobasilar system leading to hypoperfusion of crucial structures within the ARAS. Arterial occlusion in the anterior circulation is an uncommon cause of coma because bilateral cortical disruption is required to produce the requisite depression of consciousness. This may occur, however, in patients who have suffered a stroke on one side of the brain and subsequently suffer an acute arterial vascular occlusion on the other.

Diffuse neuronal dysfunction causes of coma: metabolic

Respiratory Insufficiency

Respiratory insufficiency may produce coma in two ways. First, the brain is particularly sensitive to the effects of hypoxia, with coma possible within minutes of acute oxygen deprivation. Second, hypercarbia may cause coma; the exact mechanism is unclear, but may involve an alteration in neurotransmitter levels or changes in intracranial pressure as increases in carbon dioxide levels are associated with increases in cerebral blood flow.


Extremes of body temperature may accompany other primary causes of coma or be a primary cause. Although the exact temperature at which coma occurs will vary by individual, loss of consciousness in hypothermic patients generally occurs around 28°C and hyperthermia-induced coma generally does not occur below a temperature of 40°C.


Rarely, severe hypertension may result in a loss of vascular epithelial integrity in small vessels of the brain, resulting in a patchwork pattern of vascular narrowing and vasodilation, resulting in cerebral edema. This condition, called posterior reversible encephalopathy syndrome, may present with significant alterations in consciousness.


Hypoglycemia may produce virtually any neurologic sign, symptom, or syndrome, including coma. Hypoglycemia is most common in diabetic patients who are taking hypoglycemic agents, such as insulin or sulfonylureas, and the rate of coma in such patients is about 1% to 2% per year. Hyperglycemia may also cause coma, most commonly in the setting of a hyperosmolar hyperglycemic state (HHS) in which glucose levels are greater than 600 mg/dL and osmolality greater than 320 mOsm/kg. Coma is more common in HHS than diabetic ketoacidosis (DKA). Serum osmolality is the driver of mental status changes in hyperglycemic states and HHS is associated with higher serum osmolality levels than DKA.

Electrolyte Disorders

Disorders of sodium hemostasis, particularly when they are acute, may produce coma. Hyponatremia produces an imbalance of intracellular versus extracellular osmolality, the flow of free water into the brain parenchyma, and the development of cerebral edema. Hypernatremia may also cause coma, and overly-rapid correction (particularly when the hypernatremia develops acutely) may lead to either demyelination or intracranial hemorrhage due to abrupt changes in intraparenchymal volume.

Hypercalcemia is common in patients with advanced malignancy, occurring in 10% to 20% of such patients. Although the most common neurologic presentations of hypercalcemia are confusion, delirium, or lethargy, coma is reported.


Coma in the setting of infection may be due to one of several CNS infections. Profound coma is a rare presentation of meningitis but is more commonly seen in fulminant cases. In one series, approximately 10% of subjects with encephalitis presented with coma (defined by the investigators as Glasgow Coma Scale [GCS] ≤8) and these subjects had poorer outcomes.

Systemic non-CNS infections, such as sepsis, may also produce coma. The myriad biochemical and microcirculatory changes involved in sepsis-induced coma are incompletely understood but seem to activate neuroinflammatory and ischemic pathways culminating in dysfunction of the brain parenchyma.

Thyroid Disorders

Myxedema coma is a severe form of hypothyroidism in which alterations in cerebral blood flow and glucose metabolism may lead to significant changes in mental status and coma. The alterations in mental status that accompany hyperthyroidism classically include nervousness and anxiety, but decreases in mental status (which may include coma) may occur and are more common in the elderly.

Renal Failure

Renal failure produces neurologic findings that include uremic encephalopathy, which in severe cases may manifest as coma. The molecular basis of uremic encephalopathy is not fully elucidated but it is likely a multifactorial process that includes the accumulation of false neurotransmitters.

Hepatic Failure

Hepatic failure may lead to an encephalopathic state caused by either an accumulation of endogenous toxins (including ammonia) or cerebral edema.


Although hyperammonemia is a common finding in hepatic failure, nonhepatic hyperammonemia may cause coma as well. Valproic acid therapy in the setting of carnitine deficiency, infection with urease-producing bacteria, recent surgery (particularly lung transplantation, bariatric surgery or ureterosigmoidostomy), hyperalimentation, and errors of metabolism are also potential causes.

Thiamine Deficiency

Thiamine deficiency is a common problem in malnourished patients. In the emergency department, thiamine deficiency is of particular concern in patients with alcohol-related presentations, not only in alcoholics but in binge drinkers as well. Severe thiamine deficiency, usually seen in the context of alcoholism, may lead to Wernicke encephalopathy (characterized by encephalopathy, oculomotor dysfunction, and gait ataxia) or Korsakoff psychosis (a chronic amnestic condition). Coma as a presenting symptom of thiamine deficiency, however, is very uncommon.

Nonconvulsive Status Epilepticus

NCSE is an epileptogenic condition in which the classic manifestations of seizure (eg, focal or general motor activity) are absent. NCSE may be mistaken for coma or unresponsiveness, and is an under-recognized cause of altered mental status in the emergency department.

Diffuse neuronal dysfunction causes of coma: toxins

Sedative-Hypnotic Agents

Sedative-hypnotic agents are a broad class of drugs that include ethanol, benzodiazepines, barbiturates, baclofen, gamma-hydroxybutyrate, and others. Most sedative-hypnotic agents act by facilitating the effect of the neurotransmitter gamma-aminobutyric acid (GABA), hyperpolarizing neurons either through an increase in chloride conductance (GABA A ) or through an increase in potassium conductance (GABA B ). Ethanol, in addition to interacting with the GABA system, also produces some effects via interference with the excitatory neurotransmitter N-methyl- d -asparate (NMDA).


Opioids (ie, heroin, morphine, oxycodone, hydrocodone, and others) may produce profound decreases in mental status, including coma, in addition to other clinical findings such as respiratory depression. Opioid receptors are coupled to G proteins, which may exert their effects via adenylate cyclase, calcium channels, or potassium channels. Opioids have multiple receptor subtypes, with the mu receptor responsible for coma.

Dissociative Agents

Phencyclidine and ketamine depress (and therefore interrupt) thalamic-cortical tracts, producing a temporary state in which cardiorespiratory functions are preserved but in which the patient is dissociated from his or her higher functions. Dissociative agents likely exert most of their effects via NMDA antagonism but also have effects on opiate receptors and sympathetic neurotransmission.

Carbon Monoxide

Carbon monoxide (CO) poisoning is alarmingly prevalent, accounting for approximately 50,000 visits per year to US emergency departments and, in severe cases, presenting with coma. CO is a complex toxin that affects oxyhemoglobin dissociation, increases oxidative stress, interrupts cellular respiration, and leads to the generation of reactive oxygen species. All of these may contribute to the development of neurologic impairment.

Serotonin Syndrome and Neuroleptic Malignant Syndrome

Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are distinct entities with overlapping presentations that, when severe, include profound alterations in mental status, muscular rigidity, and hyperthermia. SS results from an excess of central and peripheral serotonin activity, often when two or more serotonergic agents are used together NMS (although less well understood) likely results from central dopaminergic blockade.

Miscellaneous Toxins

Several other toxins may produce coma. Toxic alcohols, such as methanol and ethylene glycol, are CNS depressants that produce coma in a manner similar to ethanol. Psychiatric medications, such as tricyclic antidepressants and serotonin selective reuptake inhibitors, may produce coma as an exaggeration of their normal pharmacologic effects. Simple asphyxiants, such as nitrogen, act by displacing oxygen and producing hypoxia. Agents of histotoxic hypoxia, such as cyanide, interfere with aerobic metabolism and the generation of adenosine triphosphate. Clonidine alters central sympathomimetic neurotransmission.

Coma Mimics

Four conditions deserve mention as coma mimics. The locked-in syndrome describes paralysis of all voluntary muscles of the body save the eyes, usually as a result of ischemia or infarction to key CNS tracts often involving the pons, with preservation of consciousness and higher cortical functions. Neuromuscular paralysis may be iatrogenic, after the administration of succinycholine or curare-like drugs, or may arise from varied environmental sources, such as the toxin of Clostridium botulinum , the venom of elapid snakes, or tetrodotoxin-producing organisms such as the blue-ringed octopus. Akinetic mutism usually results from injury to the frontal or prefrontal motor cortex, in which patients cannot initiate voluntary motor movements. In all 3 of these diseases, consciousness is preserved. The fourth coma mimic is psychogenic unresponsiveness, a complex disorder in which there is no neurologic insult; the condition resolves spontaneously.

Initial stabilization

The initial stabilization of comatose patients is the same as that for that of all emergency department patients and consists of securing the patients airway (with attention to the cervical spine), breathing, and circulation.

Decisions regarding airway management are often very difficult, driven by gestalt rather than algorithmic decision making, and are based on several factors. Mechanism of coma is important; although a GCS of 8 or less in a trauma patient is often viewed as an indication for intubation, poisoned patients with such GCS levels can be managed without intubation and with low levels of complications. Monitoring concerns may also enter into the decision-making process. Patients who require significant time out of the department for diagnostic imaging, as may occur during a computerized tomography (CT) scan, may require intubation; whereas patients who remain in an acute care area might be managed expectantly, even at the same level of consciousness. Expected clinical course, particularly in poisoned patients, is also a factor. The patient with an isolated alprazolam ingestion will likely do well without intubation, whereas a patient with carbamazepine ingestion is more likely to have a complicated course and require airway intervention.

Concurrently with airway management, the cervical spine must be stabilized whenever there is a possibility that the patient’s alteration in mental status has a traumatic cause. Cervical spine injuries are commonly associated with alterations mental status of traumatic cause, occurring in 5% or more of such patients.

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Dec 13, 2017 | Posted by in Uncategorized | Comments Off on Initial Diagnosis and Management of Coma

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