Consciousness has two components, arousal or wakefulness and content or awareness. Deficits in arousal are the result of either a diffuse, bihemispheric insult to the cerebral cortices or a focal injury to the ascending reticular activating system (ARAS) (see Figure 48A–1). Categories of arousal, in decreasing order, include awake, drowsy, obtunded or lethargic, stuporous, and comatose. Drowsy implies that the patient is prone to long bouts of sleep and hypoactivity during hours when normally expected to be awake and engaged, but they are easily aroused and awake with simple stimulation, such as speaking to them. An obtunded or lethargic patient requires a greater degree of stimulation to maintain their engagement. They often require a loud voice or gentle tactile stimulation to arouse them to participate in conversation or perform requested tasks. Once engaged, they tend to respond slowly and are prone to disengagement once stimulation is no longer maintained. A stuporous patient will require more substantial stimulation to arouse them, such as rigorous tactile or noxious stimulation. At best, they are able to follow simple commands, but more complex tasks are not possible, and may only be capable of localizing to painful stimulation. A comatose patient is unable to purposefully engage their environment regardless of the degree of stimulation provided. The best response seen will be a facial grimace and/or stereotyped, posturing, or reflexive movements of the extremities to noxious stimulation. In those with a TBI, a Glasgow Coma Scale (GCS) score of less than 9 (see “Physical Examination,” and Table 48A–1A) is often consider to be “coma” despite the possibility that the patient may be able to engage their environment (eg, motor GCS score of 5).
Arousal structure and main neurotransmitter.
Table 48A–1AGlasgow coma scale. |Favorite Table|Download (.pdf) Table 48A–1A Glasgow coma scale.
|Eye Opening (E) ||Verbal Response (V) ||Motor Response (M) |
|4—Opens spontaneouslya ||5—Alert and oriented ||6—Follows commands |
|3—Opens to voice ||4—Disoriented and confused ||5—Localizes to painb |
|2—Opens to pain ||3—Incoherent words ||4—Withdraws from pain |
|1—None ||2—Incomprehensible sounds, moaning ||3—Flexion posturing |
| ||1—None ||2—Extension posturing |
| ||“T” or “I”—If patient is intubated or has tracheostomy ||1—None |
Awareness is a product of the entire neurologic system, both peripheral and central, and whose assessment is a composite of several neurologic functions, including motor, sensory, visual, language, concentration, attention, cognitive, executive, social, behavioral, and emotional functions. Deficits in awareness are the result of focal neurologic injuries (eg, AIS or NMDz) or diffuse processes that disrupt neural networks (eg, TBI or hypoxic-ischemic encephalopathy after CA). Impairments in arousal, attention, or concentration can adulterate the assessment of awareness, which is most accurately performed in the awake, attentive, and focused patient.
Encephalopathy is a nonspecific term applied to patients with cerebral dysfunction and encompasses scores of possible diagnoses, each with their own requisite diagnostics and therapeutics. Other colloquialisms used to describe encephalopathic patients with overall lesser degrees of precision include “altered mental status,” “altered,” “delta MS,” “changed from baseline,” “clouded,” or “confused.” Clinical features of encephalopathy include abnormalities in arousal ranging from drowsy to hyperactive, with impairments in attention or concentration. A subset of encephalopathic patients will be delirious, which is best described as a heterogeneous acute confusional disorder that develops over several hours to days, fluctuates with time, is not attributed to a neurocognitive disorder, and is the result of the exposure to xenobiotics, drug withdrawal, or an acute medical disorder. Disturbances in attention, awareness, and orientation that tend to worsen in the evening and nighttime are hallmark features of delirium. The diagnosis is clinical and outlined in the American Psychiatric Association's Diagnostic and Statistical Manual, 5th edition. Further diagnostic considerations include the delirium etiology, duration of symptoms, and level of psychomotor activity (see Table 48A–1B). Please refer to other chapters in this textbook for a more in-depth discussion of delirium.
Table 48A–1BDelirium diagnostic criteria, diagnostic and statistical manual, 5th ed. |Favorite Table|Download (.pdf) Table 48A–1B Delirium diagnostic criteria, diagnostic and statistical manual, 5th ed.
|Diagnostic criteria || |
A disturbance in attention (ie, reduced ability to direct, focus, sustain, and shift attention) and awareness (reduced orientation to the environment).
The disturbance develops over a short period of time (usually hours to a few days), represents a change from baseline attention and awareness, and tends to fluctuate in severity during the course of a day.
An additional disturbance in cognition (eg, memory deficit, disorientation, language, visuospatial ability, or perception).
The disturbances in Criteria A and C are not better explained by another preexisting, established, or evolving neurocognitive disorder and do not occur in the context of a severely reduced level of arousal, such as a coma.
There is evidence from the history, physical examination, or laboratory findings that the disturbance is a direct physiological consequence of another medical condition, substance intoxication or withdrawal (ie, due to a drug of abuse or to a medication), or exposure to a toxin, or is due to multiple etiologies.
|Etiology || |
|Duration of symptoms || |
|Activity level || |
Mixed level of activity
When evaluating patients with a change in their neurologic status, it is crucial that a broad differential be maintained that includes both primary medical and neurologic etiologies. As discussed further later, stupor or coma can be the result of many metabolic, toxic, infectious, and inflammatory conditions. Additionally, it is not uncommon for a patient with a primary neurologic insult (eg, AIS) to also be suffering from an acute medical issue (eg, endocarditis or acute kidney injury). If a diagnosis still exists that can explain the patient's presentation and would require time-dependent treatment, it is important that it be definitively excluded via the expeditious conduction of the appropriate diagnostics.
Encephalopathy and coma are not a specific disease or syndrome. They are a physical finding signifying central nervous system (CNS) dysfunction requiring a diagnosis. For acute changes, the last known normal time or last known well time must be established and distinguished from the time that the change was noticed or the patient was found to be abnormal. Dramatic neurologic changes (eg, acute coma) do not preclude preceding subtle changes or stuttering symptoms that should be actively pursued. Historical information should also be sought from a variety of resources including family, friends, neighbors, Emergency Medical Service (EMS) personnel, 911 communication specialists, police, and patient belongings (eg, timed and dated receipts, cell phone text messages, emails, calls, or social media interactions). Clues at the scene of patient discovery should also be sought for consideration of environmental, traumatic, or pharmacologic etiologies.
A catalog of prior medical problems, medications (and compliance), social habits, and hobbies, should be performed. Specific inquiries about use of anticoagulant, antiplatelet, and antiepileptic medications should be made, particularly with the widespread use of target specific oral anticoagulation, such as dabigatran, rivaroxaban, and apixaban. EMS interventions (eg, naloxone) and the patient's response should as be gathered.
The physical exam commences with observation of the patient prior to interaction to assess for spontaneous movements and general physical condition (eg, healthy, chronically ill, ashen, wasted, cachectic, and disheveled). Violent spontaneous clonic movements may resemble the tonic-clonic activity seen in generalized seizures, but consideration must be given as to whether it is extensor posturing resulting from an acute brainstem injury (eg, basilar thrombosis). Detection of certain odors can provide clues to neurotoxin exposure (Table 48A–1C). Exposure of the patient will allow for the identification of occult injury, illness, or paraphernalia associated with or causative of the presentation.
Table 48A–1COdors suggestive of neurotoxin exposure. |Favorite Table|Download (.pdf) Table 48A–1C Odors suggestive of neurotoxin exposure.
|Odor ||Neurotoxin |
|Mothballs ||Camphor |
|Garlic ||Organophosphates, arsenic, thallium |
|Peanuts ||Vacor |
|Carrots ||Cicutoxin (water hemlock) |
|Wintergreen ||Methyl salicylates |
|Fruity ||Chlorinated hydrocarbons |
|Glue ||Solvents, toluene |
|Rotten eggs ||Dimercaptosuccinic acid, hydrogen sulfide |
|Shoe polish ||Nitrobenzene |
|Smoke or fire ||Carbon monoxide or cyanide |
Vital signs including heart rate, blood pressure (BP), respiratory rate (RR), and pattern, oxygen saturation (SpO2), quantitative waveform capnography (wPetCO2), core temperature, and blood glucose should be acquired. Bradycardia may indicate elevated supratentorial pressure in children and infratentorial (posterior fossa) pressure in adults. Tachycardia should be evaluated for possible cardioembolic inducing arrhythmias (eg, atrial fibrillation), which may be the cause or result of a cerebral insult. Hypertension is quite nonspecific, as it may be seen with pain, anxiety, anatomic irritation of the forebrain, insula, limbic system, hypothalamus, descending sympathoexcitatory pathway rostral to the medulla, or intracranial hypertension. Hypotension is suggestive of an injury to the descending sympathoexcitatory pathway (which is anywhere from rostral medulla through the upper thoracic spine). However, if the MAP is less than 60 mm Hg, hypovolemia, neurogenic stunned myocardium, or systemic illness should be considered. wPetCO2 can detect hypercapnia (albeit with limited sensitivity), while providing a continuous RR and tracing allowing for the demonstration of respiratory patterns localizable to specific cerebral anatomic locations (Table 48A–1D). Cushing's triad of irregular breathing, bradycardia, and hypertension is an unreliable sign of elevated ICP in adults. If observed, it is much more likely to represent a posterior fossa process or an exceptionally progressed supratentorial process. Hyperthermia may be environmental, suggest infection or signify a toxidrome, such as neuroleptic malignant syndrome, serotonin syndrome, or thyrotoxicosis. Hypothermia may be environmental, or can be seen in sepsis, various intoxications, hypothyroidism, or pituitary apoplexy. A finger stick blood sugar should be obtained immediately to exclude (and potentially emergently treat) symptomatic hypoglycemia.
Table 48A–1DRespiratory patterns in CNS disease. |Favorite Table|Download (.pdf) Table 48A–1D Respiratory patterns in CNS disease.
|Pattern ||Description ||Localization ||Examples of CNS Disease |
|Cheyne-Stokes ||Several large tidal volume breaths alternating with periods of apnea last 12-30 seconds ||Bihemispheric or diencephalon ||Bilateral cerebral infarcts, diencephalic shift, early transtentorial herniation, encephalopathy |
|Hyperventilation ||Persistently elevated RR in the absence of metabolic demands, pulmonary disease, or stimulation xenobiotic ||Bihemispheric ||Bilateral infarcts, encephalopathy |
| || ||Brainstem chemoreceptors ||SAH or meningitis |
| || ||Brainstem (rare) ||Glioma or lymphoma |
|Apneusis ||Large tidal volume breaths with breathing holding for 2-3 seconds at end-inspiration and end-expiration ||Pons ||Basilar artery stroke, transtentorial herniation |
|Cluster or ataxic ||Frequent irregular breaths of varying regularity and tidal volume ||Rostral medulla ||Transtentorial herniation, cerebellar mass, hemorrhage, swelling |
|Apnea ||No spontaneous breathing ||More extensive medullary injury ||Late transtentorial herniation, cerebellar mass, hemorrhage, swelling |
The following will emphasize the crucial aspects of the neurologic exam in the stuporous or comatose patient. Patients with mild impairments in arousal should undergo a usual neurologic assessment to include visual fields, cranial nerves, motor, language, coordination, reflexes, tone, and attention (eg, counting backward from 20 to 1 or reciting the months of the year backward).
Level of Arousal (or Wakefulness)
As outlined earlier, a patient's wakefulness can be placed into one of several categories. Clinically, the patient should be described by what they are able to do with a specific type of stimulation, rather than just the category of arousal. This is elicited by progressively escalating the stimulation by first speaking in a normal tone, then a loud voice, then tactile stimulation, then vigorous tactile stimulation (eg, jostling the patient), and finally applying noxious stimulation, and assessing for a response to verbal commands. During this evaluation, one must not assume that the patient is unconscious (eg, they may be locked in). Options for noxious stimulation include a trapezius pinch, nasopharyngeal irritation with a cotton swab, jaw thrust (if not prohibited by a traumatic injury), supraorbital pressure, sternal rub, or nail bed pressure. Grabbing and twisting of the skin or tissue folds is highly discouraged as this may lead to bruising, hematomas, and skin tears. Prior to providing noxious stimulation, be sure to lift the patient's eyelids and ask him or her to look up/down, left/right to carefully evaluate for a locked-in state.
In acute trauma, the GCS is a validated score of arousal that can be rapidly calculated, with values ranging from 3 to 15. It has three components; eye opening, verbal, and motor function (see Table 48A–1A). A more recently introduced and validated coma scale is the FOUR (Full Outline of UnResponsiveness) Score, which ranges from 0 to 16 and include assessments of eye movements, motor function, respiratory pattern, and brainstem function (Table 48A–1H).
Several months to a year after cerebral injury patients may transition from states of depressed arousal to those with near intact arousal, but varying degrees of awareness impairment, such as vegetative state and minimally consciousness state (Figure 48A–2). These terms can be applied three months after a non-traumatic brain injury (eg, CA) and 1 year after a traumatic brain injury.
State of consciousness by arousal and content.
The motor exam in comatose patients assesses appendicular movement, tone, and reflexes to identify asymmetry and/or localize CNS injuries. It occurs simultaneous with the evaluation of arousal. Localization is produced via activation of the cortical inputs to the corticospinal tracts. Therefore, absence of localization is suggestive of cerebral hemispheric dysfunction or an injury along the corticospinal tracts. The careful inspection of nonlocalizing movements provides clues to the presence or absence of a diencephalic or brainstem lesion (Table 48A–1E). To elicit such movements, the stimulus should be sustained until it is clear that the full extent of movement has been observed. Failure to do so may falsely localize the lesion and mischaracterize the problem. If pathologic posturing is observed, the descriptors “flexor” and “extensor” are preferred over “decorticate” and “decerebrate” posturing, respectively.
Table 48A–1EPhysical exam findings in a comatose patients with brainstem dysfunction. |Favorite Table|Download (.pdf) Table 48A–1E Physical exam findings in a comatose patients with brainstem dysfunction.
|Anatomic Level ||Mental Status ||Pupillary Size and Position ||Eye Movement ||Motor Responses ||Respiration |
|Diencephalon ||Drowsy ||Small (1-2 mm) ||Normal ||Abnormalities of flexion ||Cheyne-Strokes |
|Midbrain ||Coma ||Fixed in mid position (4-5 mm)a ||Dysconjugate ||Abnormalities of extension ||Hyperventilation |
|Pons ||Coma ||1 mm in primary pontine injury; fixed and 4-5 mm with prior midbrain injurya ||Complete paralysis ||Abnormalities of extension ||Hyperventilation or apneusis |
|Medulla ||Variable ||Variable ||Variable ||Flaccid ||Cluster, ataxic, or apnea |
Repeated identical movements (stereotyped) induced by a variety of stimuli are typical of those with dysfunction of the cerebral hemispheres or diencephalon. More extensive diencephalic lesions or rostral midbrain injury will produce flexor posturing in the upper extremities (ie, flexion of the fingers and wrist, forearm supination, elbow flexion, and shoulder adduction) and extensor posturing of the lower extremities (ie, extension of the knee, internal rotation and extension of the hip, and plantar flexion of the ankle). More caudal injuries will produce extensor posturing of the upper extremities (ie, shoulder adduction, elbow extension, and wrist pronation and flexion) and lower extremities. Extensor posturing can be elicited by trivial internal or external stimulation (eg, distended bladder or ventilator delivering a tidal volume), giving the appearance of spontaneous clonic movements, leading the clinician to falsely suspect they are epileptic in origin. Medullary brainstem lesions will produce flaccidity in all extremities. Opisthotonic posturing (ie, clenched teeth, arching of the spine) is an infrequently encountered manifestation of severe brainstem injury.
Tone and reflexes should be examined to discern between upper and lower motor neuron impairment (Table 48A–1F). Upper motor dysfunction leads to increased tone and reflexes, with upgoing toes and clonus, while hypotonicity, hyporeflexia, fasciculations, and mute toes are hallmarks of lower motor neuron dysfunction.
Table 48A–1FNeurologic exam findings in lower versus upper motor neuron lesions. |Favorite Table|Download (.pdf) Table 48A–1F Neurologic exam findings in lower versus upper motor neuron lesions.
|Finding ||Upper motor Neuron ||Lower Motor neuron |
|Reflexes ||Increased ||Decreased |
|Clonus ||+ ||– |
|Tone ||Increased ||Decreased |
|Fasciculations ||– ||+ |
|Atrophy ||–/late ||+ |
The value of fundoscopy in the evaluation of coma is to assess for intracranial hypertension (IC-HTN) and retinal ischemia. IC-HTN slows axoplasmic flow in the optic nerve producing axonal swelling. When sustained over several hours or longer, this is seen on fundoscopy as papilledema. Optic nerve demyelination or infarction (ie, papillitis), will also be seen as papilledema, as thus should be included in the differential. Dampening or loss of retinal venous pulsations can be seen when ICP exceeds systemic venous pressure. This finding is present in 20% of the population, limiting its specificity for IC-HTN.
The brainstem examination allows for the identification of herniation syndromes, acute treatable lesions of the brainstem (eg, acute basilar thrombosis), and is the crux of brain death examination. The components are pupillary assessment, oculomotor examination, and elicitation of the corneal, gag, and cough reflexes.
Components of the pupillary exam include assessment of size and symmetry in ambient light, followed by dim lighting, direct and consensual reactions to bright light, and the ciliospinal response. Pupillary responses in stuporous and comatose patients are often subtle and difficult to detect with the naked eye. The exam can be aided by an ophthalmoscope or otoscope for magnification, or a pupillometer.
An understanding of pupillary innervation is critical to the interpretation of the exam. Parasympathetic innervation, which control pupillary constriction, begins in the medial midbrain at the Edinger-Westphal nucleus (EWN) and runs superficially on the dorsal aspect of the third cranial nerve (CN3). Light detected by the retina sends a signal through the optic nerve to the EWN, producing pupillary constriction. Lesions that stretch or injury CN3, such as a herniating medial temporal lobe or expanding posterior communicating artery aneurysm, impair parasympathetic innervation and produce a unilateral pupillary dilation.
Sympathetic innervation takes a longer and more complicated course. It begins in the hypothalamus, projecting caudally through the brainstem where it receives inputs from several other pathways, proceeds to the upper thoracic spine where it exits and joins the superior cervical ganglion, then branches to the internal carotid artery and finally courses through the cavernous sinus to the pupil. Assessing for the presence of the ciliospinal reflex challenges the integrity of the sympathetic pathway. This is done by pinching the face or neck and observing for a 1 to 2 mm dilation of the pupils bilaterally. The painful stimulus is received in the lower brainstem, where it triggers autonomic pathways that produce a sympathetic discharge. The presence of a ciliospinal reflex implies that if a brainstem lesion is present, it is in the rostral pons or higher, and that the lower brainstem is spared.
Pupils are often observed to be small and reactive in diencephalic dysfunction and metabolic coma/encephalopathy. Notable exceptions to the later are some drug-induced comas (Table 48A–1G). Midbrain dysfunction, whether via a primary lesion or downward or laterally compressive forces, produced 4 mm, mid-position, fixed pupils. If the lesion affects the more dorsal pretectal midbrain (eg, pineal gland mass, enlarged third ventricle, or dorsal midbrain stroke [Parinaud's syndrome]), the pupils tend to be slightly larger (~5 mm) and a downward gaze is observed (sunset eyes). Compressive midbrain lesions that also stretch the CN3 will produce fully dilated (~8 mm) and nonreactive pupils.
Further progressive downward injury or primary pontine injury will produce nonreactive pinpoint (1 mm) pupils. Table 48A–1E summarizes the neurologic exam findings in various brainstem lesions.
Table 48A–1GPhysical findings in drug-induced coma. |Favorite Table|Download (.pdf) Table 48A–1G Physical findings in drug-induced coma.
|Drug class ||Pupils ||Other changes |
|Opioids ||Miotic ||Hypopnea/apneic |
|Barbiturates and benzodiazepines ||Reactive ||Hypopnea, mild hypotension |
|Anticholinergics (scopolamine, etc) ||Mydriasis ||Tachycardia, seizures |
|Anticholinesterases (organophosphates) ||Miotic ||Bradycardia, sweating, salivation, lacrimation, diarrhea, vomiting, urination |
|Cocaine and amphetamine ||Mydriasis ||Tachycardia, hypertension, hypotension, arrhythmia |
|Neuroleptics ||Variable ||Motor rigidity, hypotension, hyperthermia |
|Antidepressants ||Mydriasis ||Rarely seizure |
Gaze palsies result from injury to the frontal eye fields (frontal lobes), CN3, sixth cranial nerve (CN6), or the brainstem connections between the CN3 and CN6 nuclei (ie, pontine paramedian reticular formation [PPRF], medial longitudinal fasciculus [MLF]). Symmetric lateral gaze is accomplished by signaling the ipsilateral CN6 via PPRF, and the contralateral CN3 through the MLF. Integrity of this system is assessed in conscious patients by having the patient follows the examiner's finger through all extremes of eye movement. The oculocephalic (doll's eyes) reflex is used to assess the oculomotor system in stuporous and comatose patients that are unable to follow commands. It is performed with the patient's neck in 30° of extension and by gently rolling the patient's head from side to side while observing eye movements. The patient's eyes should attempt to move in the opposite direction of head. If this maneuver fails to produce a response or if it cannot be done because of concern for a cervical spine injury, then caloric oculovestibular testing (ie, cold calorics) can be performed by injecting 30 to 60 mL of cold saline on the tympanic membrane (TM), then observing for 1 to 2 minutes for tonic eye deviation toward stimulus. Before performing this maneuver, be certain that the TM is intact and unobstructed (eg, cerumen impact or hemorrhagic debris in the external auditory canal).
Corneal Reflex, Gag, and Cough
The corneal reflex (CR) is examined by stimulating the cornea with either saline drops or by gently touching the delicate corneal with a cotton swab and observing for a blink and/or elevation of the eye. The CR evaluates CN3, CN5, CN7, the midbrain, and pons. Contact lens wearers will have a suppressed CR. It should not be performed in conscious patients. The gag reflex, which assesses CN9, CN10, and CN12, is assessed by stimulating the posterior pharynx with a tongue blade or a similar object and visually observing for elevation of the ipsilateral soft palate and depression of the tongue. A cough is elicited by carefully advancing the endotracheal suction catheter to the greatest possible depth.
Patients with loss of all cerebral function due to an irreversible cerebral insult can be evaluated for brain death. The examination components include an assessment of motor function, pupil reactivity, caloric oculovestibular testing, corneal, gag, cough, and oculocephalic reflexes, in the absence of any neuromuscular blockers (NMBs), CNS depressants, metabolic derangements, or physiologic abnormalities. If there is no evident neurologic function, apnea testing is performed to pronounce brain death. Apnea is diagnosed if the PaCO2 rises from a normal level (35-45 mm Hg) to more than 60 mm Hg or by more than 20 mm Hg without evidence of respiratory effort over at least 8 minutes while patient's endotracheal tube is disconnected from the ventilator. A RR greater than the set rate on the ventilator does not imply the patient is not apneic; cardiac pulsations are capable of triggering tidal volumes. Table 48A–1I summarizes the brain death examination conditions and components.
Table 48A–1HFull outline of unresponsiveness (FOUR) score. |Favorite Table|Download (.pdf) Table 48A–1H Full outline of unresponsiveness (FOUR) score.
|Score ||Eye ||Motor ||Brainstem ||Respiration |
|4 ||Open and tracks or blinks to command ||Follows commanda ||PR and CR present ||Not intubated, normal RP |
|3 ||Open, no tracking ||Localize ||One pupil fixed and dilated ||Not intubated, C-S RP |
|2 ||Open to loud voice ||Flexes to pain ||PR or CR present ||Not intubated, irregular breathing |
|1 ||Open to pain ||Extensor posture ||PR and CR absent ||Breathers over ventilator |
|0 ||Do not open ||No response or myoclonic status ||PR, CR, and cough absent ||Breathes at ventilator rate or apnea |
Table 48A–1ICritical elements of brain death declaration. |Favorite Table|Download (.pdf) Table 48A–1I Critical elements of brain death declaration.
|Metabolic or Pharmacologic Disturbances Prohibiting Brain Death Assessment ||Examination Components |
Severe acid-base abnormalities
Significant electrolyte disturbances
Hypo- or hyperthermia
Hypo- or hypercarbia
Sedative and paralytics drugs or intoxicants
|Apnea Test Prerequisites ||Conditions Mandating Abortion of Apnea Test ||Empiric Hypothalamic Hormonal Replacement |
Temperature > 96°F
sBP > 100 mm Hg
PaCO2 35-45 mm Hg
PaO2 > 200 mm Hg
sBP < 100 mm Hg
Hypoxia (SpO2 < 90%)
If select components of the neurologic exam cannot be performed (eg, caloric oculovestibular testing due to traumatic TM perforation) or the patient's physiology cannot tolerate at least 8 minutes of apnea, then a confirmatory test can be completed instead. Options include a digital subtraction angiography, CT angiography of the head, cerebral scintigraphy (preferred in most centers), transcranial Dopplers, or electroencephalography (EEG).
The brain death process is prone to institutional idiosyncrasies due to local and state policies. Your institutional policy and state laws should be consulted when pronouncing brain death. Movements in the brain dead have been observed, such as “the undulating toe,” lower extremity reflexes, such as “triple flexion” and the “Lazarus sign” (ie, arms raised, then crossed on the chest). These require interpretation. If there is ambivalence, confirmatory testing should be pursued.
Once brain death is pronounced, an organ donation representative may approach the family of the deceased. The clinician should not engage organ donation discussions with patient's surrogate/proxy. If the surrogate/proxy inquires about donation, they should be referred to the organ donation representatives. Leading up to and following brain death declaration, the clinician should continue to optimize the deceased's physiology, as this has been shown to improve the success of transplantation. Physiologic replacement of hypothalamic hormones can help achieve hemodynamic stability, including vasopressin, levothyroxine, and methylprednisolone. A recent randomized trial found that delayed graft function was decreased in recipients of kidneys from deceased donors that were cooled to 34°C to 35°C.
Pathophysiology and Differential Diagnosis
CNS dysfunction may occur for several reasons. Table 48A–1J breaks them into 7 mechanistic categories that provide a structure for a differential diagnosis. It is not uncommon for multiple etiologies to coexist and synergistically impair CNS function. Asymmetric or lateralizing neurologic findings often suggest a primary CNS disorder, but they can also be seen with systemic illness in patients with a prior CNS insult. Above all, the identification and treatment of etiologies that will lead to irreversible CNS injury with delays in care must be prioritized. This includes failure of systemic substrate delivery, impairment in the local delivery of substrate (eg, AIS or vasospasm), rapidly expanding intracranial masses (eg, ICH), unmitigated deranged physiology (eg, status epilepticus), anatomic neuronal distortion (eg, cerebral herniation), and failure of global or focal cerebral perfusion (eg, intracranial hypertension, collapse of perforating vessels causing focal infarction).
Table 48A–1JPathophysiologic mechanisms of encephalopathy, stupor, and coma. |Favorite Table|Download (.pdf) Table 48A–1J Pathophysiologic mechanisms of encephalopathy, stupor, and coma.
|Mechanism ||Examples |
|Failure of substrate delivery ||Hypoxemia, severe anemia, hypoglycemia, hypotension, cardiogenic shock |
|Metabolically or pharmacologically induced neuronal dysfunction ||Uremia, hyponatremia, liver failure, hypercarbia, drug ingestion, toxidrome, hypothermia |
|Primary disturbance in neuronal function or physiology ||Seizures, convulsive or nonconvulsive status epilepticus |
|Primary diffuse, bihemispheric cortical pathology ||Encephalitis, acute demyelinating Encephalomyelitis, CNS vasculitis |
|Focal lesion of the ARAS ||Acute basilar thrombosis, brainstem intracerebral hemorrhage |
|Anatomic distortion or compression of the ARAS ||Hydrocephalus, SDH with uncal herniation, pineal gland tumor with dorsal midbrain compression |
|Intracranial hypertension ||Acute aSAH, dural sinus thrombosis, meningitis |
Hypotension, hypoxemia, and hypoglycemia warrant immediate exclusion and treatment. Those with evidence of or risk factors for malnutrition should receive thiamine intravenously. wPetCO2 may fail to detect hypercarbia in hypopneic patients; therefore, a blood gas is warranted. Table 48A–1K summarizes theses as well as other metabolic, environmental, and toxicologic processes that require immediate consideration. Table 48A–1G outlines findings in some common toxidromes. Other chapters in this text cover toxicologic and environmental emergencies in greater detail.
Table 48A–1KAcute undifferentiated encephalopathy, stupor, and coma: substrate delivery and initial metabolic and environmental considerations. |Favorite Table|Download (.pdf) Table 48A–1K Acute undifferentiated encephalopathy, stupor, and coma: substrate delivery and initial metabolic and environmental considerations.
|Condition ||Diagnostics and considerations |
|Hypoglycemia ||FSBG |
|Hypoxia ||Pulse oximetry, arterial blood gas, CO-oximetry |
|Severe anemia ||CBC, inspect conjunctiva, mucus membranes |
|Hypercarbia ||Blood gas (venous or arterial) |
|Hypotension (absolute or relative) ||Palpate pulse, sphygmomanometry, arterial line |
|Cardiogenic shock ||Capillary refill, pulse quality, bedside echocardiography |
|Severe sepsis or septic shock ||Core temperature, physical evidence of infection, WBC, lactate, lipase, U/A |
|DKA/HONC ||BMP, VBG, serum ketones, U/A, serum osm, fruity breath, severe tachypnea without respiratory illness |
|Myxedema coma/thyrotoxicosis ||TSH, free T4, T3; bradycardia, hypothermia or tachycardia, hyperthermia, hypertension |
|Uremia ||BMP |
|Beriberi/Wernicke's encephalopathy ||Evidence or risk factors for malnourishment, empirically treat |
|Electrolyte derangement ||BMP, iCa, PO4, Mg |
|Hepatic encephalopathy ||NH3, LFTs |
|Carbon monoxide ||CO-oximetry, appropriate environmental setting |
|Methemoglobinemia ||CO-oximetry |
|Cyanide ||Lactate, building fire victim, initiate hydroxocobalamin |
|Hypo- or hyperthermia ||Core temperature (bladder, rectal, and esophageal). If hyperthermia considers sepsis, serotonin syndrome, NMS, MH, heat stroke. If hypothermia, consider myxedema, pituitary apoplexy, Addison's disease |
|Intentional ingestion (suicide attempt) ||Serum tylenol, salicylates, toxic alcohols, ethanol, serum Osm, Urine drug screen, evidence of prior or recent self-harm |
|Electrocution/lightning strike ||Total CPK, ferning, entry and exit burns, charred clothing |
Delays of as little as 15 minutes in the diagnosis and treatment of acute primary neurologic emergencies have been associated with worse outcomes. Acute disorders and their corresponding diagnostic tests are found in Table 48A–1L. Neuroimaging, cerebrospinal fluid (CSF) analysis, and EEG will capture nearly all of these conditions. Table 48A–1M lists etiologies of stupor and coma that will require more sophisticated diagnostics, consultative services, and/or unique therapies.
Table 48A–1LPrimary neurologic process and preferred diagnostic tests. |Favorite Table|Download (.pdf) Table 48A–1L Primary neurologic process and preferred diagnostic tests.
|Neurologic Process ||First Line Diagnostics |
|Acute Ischemic stroke ||NCHCT (insensitive acutely), CTA head and neck, MRI w/DWI + ADC sequences (difficult to obtain emergently) |
|Intracerebral hemorrhage ||NCHCT |
|Traumatic brain injury ||NCHCT |
|Extra-axial hemorrhage ||NCHCT |
|Meningitis/encephalitis ||LP with CSF analysis |
|Acute hydrocephalus ||NCHCT |
|Aneurysmal subarachnoid hemorrhage ||NCHCT |
|Dural sinus thrombosis ||CTV vs MRV |
|Status epilepticus ||Scalp EEG |
|Posterior reversible encephalopathy syndrome ||NCHCT (limited sensitivity), MRI with FLAIR sequence |
|Brain abscess/empyema ||Head CT with contrast; MRI ± contrast |
Table 48A–1MLess common etiologies of stupor and coma. |Favorite Table|Download (.pdf) Table 48A–1M Less common etiologies of stupor and coma.
Posthypoxic ischemic encephalopathy
Acute disseminated encephalomyelitis
Marburg variant of multiple sclerosis
Central pontine myelinolysis
CNS vasculitis or vasculopathies
Chronic meningitis/CNS infections
Progressive multifocal leukoencephalopathy
Several nutritional deficiencies
Inherited metabolic disorders
In adults, the cranial vault is a rigid, noncompliant structure filled with brain tissue, blood, CSF, and meninges. The brain is divided into supratentorial and infratentorial compartments by a dural fold, the tentorium cerebelli. The brainstem passes through an opening in the tentorium, called the tentorial incisure or notch. Another dural fold, the falx cerebri, similarly divides the brain into the left and right hemispheres and importantly contains the superior and inferior sagittal sinuses. Cisterns filled with CSF, cranial nerves, and large intracranial arteries surround the brainstem.
Pressure is a function of the amount of mass occupying a fixed amount of space (eg, the human cranium) and is expressed in force per unit area. Alternatively, it is reported in either centimeters of water (cm H2O) or millimeters of mercury (mm Hg). Literally, it is the amount of force applied by a column of either H2O or Hg, with the height of the column being cm with H2O or mm with Hg. When pressures vary at different locations (ie, there is a pressure gradient), objects are liable to be moved from their position by these differences in force. In the brain, pressure gradients cause cerebral tissue to herniate, nerves to stretch, and vascular and ventricular structures to be compressed, displacing CSF and blood and eventually disrupting the circulation of CSF and/or flow of blood. Initial elevations in ICP cause CSF to shift from the ventricles to the spinal subarachnoid space. Next, venous outflow is accelerated when ICP exceeds right atrial pressure. With further increases, cerebral tissue is displaced (herniated) and arterial perfusion pressures are exceeded, producing ischemia and infarction. The infarcted tissue then swells, leading to further herniation and compromise of arterial blood flow. Once compensatory mechanisms are exhausted (ie, the displacement of CSF and/or venous blood), larger pressure increases occur with small increases in volume (ie, compliance worsens). These are the principles of the Monro-Kellie doctrine (Figure 48A–3). When measured via intraparenchymal fiberoptic monitors or intraventricular catheters, ICPs of greater than 20 mm Hg have been associated with worse outcomes. It is important to note that most intracranial disease processes do not lead to global symmetric increases in pressure. Instead, the aforementioned concepts are frequently localized phenomena that may be under-appreciated by monitors placed in nondiseased tissue (Table 48A–1N). Further details on ICP monitoring, indications, waveforms, and their interpretation can be found in Chapter XY.
Monroe-Kellie hypothesis. An increase in cranial volume will lead to an increase in pressure unless an equal amount of volume in cerebrospinal fluid and/or blood is displaced.
Table 48A–1NRegional mass lesion and increasing ICP difference with focal hemispheric lesion.
Cerebral Herniation Syndromes
Cerebral herniation tends to follow one of several anatomic trajectories, which are accompanied by an expected constellation of neurologic changes, termed herniation syndromes (Table 48A-1O and Figure 48A–4). Supratentorial syndromes include subfalcine, diencephalon shift, uncal, and central, while infratentorial syndromes include tonsillar and upward.
Table 48A–1OHerniation syndromes. |Favorite Table|Download (.pdf) Table 48A–1O Herniation syndromes.
|Herniation Syndrome ||Level of arousal ||Motor Exam ||Pupillary Exam ||Other Findings |
|Subfalcine, early ||Drowsy to lethargy ||Normal to CL LE paresis, paratonia ||Normal || |
|Subfalcine, late ||Stupor to coma ||CL LE paresis, FP CL > IL ||Small, minimally reactive || |
|Diencephalon shift, early ||Drowsy to lethargy ||Possible CL HP, paratonic ||Small, minimally reactive || |
|Diencephalon shift, late ||Stupor to coma ||FP CL > IL to QP ||Mid-position, NR, maybe irregular || |
|Uncal, early ||Lethargy to stupor ||Localizes IP, paratonic CL ||IP Mydriasis, NRa || |
|Uncal, late ||Stupor to coma ||CL FP/EP to HP (IP ~ 25%) ||IP Mydriasis, NR ||IP eye is abducted and depressed w/ptosisa |
|Central (transtentorial), diencephalon stage ||Lethargy to stupor ||Localizes to withdrawal ||Small, minimally reactive || |
|Central (transtentorial), midbrain stage ||Coma ||FP to EP ||Mid-position, NR, maybe irregular ||DC gaze w/impaired adduction on VOR |
|Central (transtentorial), pontine stage ||Coma ||QP, ± TF of LEs ||Miotic ||No VOR |
|Central (transtentorial), medullary stage ||Coma ||QP, ± TF of LEs ||Miotic or Mydriatic and NR ||Hypotension and apnea |
|Tonsillar ||Coma ||QP, ± TF of LEs ||Miotic ||Hypotension and apnea |
|Upward, early ||Lethargy ||Quadraparesis to QP ||Mid-position, NR, maybe irregular ||Impaired upward gaze |
|Upward, late ||Coma ||EP to QP, ± TF of LEs ||Mid-position, NR, maybe irregular ||No VOR |
Herniation syndromes. (a) Subfalcine, (b) uncal, (c) central transtentorial, (d) external, and (e) tonsillar. (Adapted with permission from Knoop KJ, Stack LB, Storrow AB, et al: The Atlas of Emergency Medicine, 3rd edition. New York: McGraw-Hill, Inc; 2010.)
Subfalcine herniation and diencephalon shift are the result of lateral pressure gradients across the hemispheres. In subfalcine herniation, the cingulate gyrus is forced against and eventually under the inferior margin of the falx cerebri, where the pericallosal branches of the anterior cerebral artery can be compressed, leading to infarction and impaired motor function in the contralateral leg. They are radiographically quantified by the amount of midline shift (MLS) at the septum pellucidum (subfalcine) or pineal gland (diencephalon shift) on axial sequences. Clinically, the level of arousal is depressed in proportion to the degree of MLS.
Uncal herniation occurs when the medial aspect of the temporal lobe is forced over the tentorial edge into the basal cisterns, eventually compressing and pushing the midbrain laterally. The first manifestation is typically impaired consciousness with ipsilateral pupillary dilation due to stretching of the CN3 as it course through the cisterns, followed by contralateral hemiparesis from compression of the midbrain. Approximately 25% of the time, ipsilateral hemiparesis occurs when the midbrain is forced against the contralateral free edge of the tentorium. Arousal is impaired from stretching of the elements of the ARAS. The posterior cerebral artery territory is subject to compression by the uncus with subsequent infarct of its territory.
Central transtentorial herniation begins with compression of the diencephalon, followed by the midbrain, then the pons, and finally the medulla. It is often the result of obstructive hydrocephalus or other mass located in the midline. Clinically, a rostrocaudal deterioration of brainstem function can be appreciated. Initially, compression of the diencephalon causes a depression in arousal with small, minimally reactive pupils. Untreated, midbrain compression ensures, where the pupils enlarge to approximately 4 to 5 mm (mid-position) or dilated and nonreactive, often with flexor posturing. Further progression yields miotic pupils and/or extensor posturing. Finally, once the medulla is compressed, the patient becomes quadriplegic and hypotensive. Neuroendocrine functions can become disturbed at various points along this deterioration as a result of pituitary ischemia or avulsion of the stalk. Additionally, both posterior cerebral arteries are at risk for compression and infarction in this syndrome.
Tonsillar herniation can result from posterior fossa masses or advanced transtentorial herniation (uncal or central). The cerebellar tonsils are forced through the foramen magnum, compressing the caudal medulla, causing apnea, hypotension (but often initially hypertension), miotic pupils, and quadriplegia. The fourth ventricle is commonly compressed, leading to obstructive hydrocephalus. In this setting, treating the hydrocephalus first with an external ventricular drain can cause the brainstem to herniate upward, causing the brainstem to buckle and bend, compressing its perforating arterial supply, leading to infarction. Therefore, it is often prudent to prioritize or simultaneously perform a suboccipital decompression while establishing diversion of CSF.
Neurologic Resuscitation: Treatment of Acute Stupor and Coma
The early treatment goals in undifferentiated acute disturbances in anchor on the empiric optimization of cerebral blood flow (CBF) and delivery of critical substrates, such as oxygen and glucose. To do so, the clinician needs to have a firm understanding of the relationships between MAP, ICP, ventilation, oxygenation, CBF as well as the effects of airway management on ICP. Immediate actions are to correct hypoxia, hypoglycemia, hypotension, hypoperfusion, and hypo, or hypercarbia. Prolonged hyperoxia should be avoided, as this is associated with harm. BP reduction and goals are tailored to the etiology of the neurologic change. Prior to definitive diagnostics, it is likely unclear whether the brain is in a hypoperfused state (eg, critical carotid stenosis) or would benefit from aggressive BP reduction (eg, ICH). In those with a diastolic blood pressure (dBP), more than 120 mm Hg or systolic blood pressure (sBP) more than 230 mm Hg, gentle BP reduction to a sBP less than 220 mm Hg and/or dBP less than 120 mm Hg are reasonable, but it represents a low priority therapeutic target, with more risk than reward in the undifferentiated patient. Mildly hypothermic states may not warrant immediately, rapid correct; if ICP proves to be an issue, as rapid normalization can produce herniation. Suggested initial empiric diagnostic and therapeutic targets are summarized in Table 48A–1P.
Table 48A–1PEmpiric diagnostics and therapeutic targets in the patient with undifferentiated disturbance in consciousness. |Favorite Table|Download (.pdf) Table 48A–1P Empiric diagnostics and therapeutic targets in the patient with undifferentiated disturbance in consciousness.
|First-Tier Diagnostics ||Second-Tier Diagnostics ||Therapeutics |
BMP, Mg, Phos, iCa
Coagulation panel, fibrinogen
Type and screen
Blood gas, CO, lactate
Drug levels (eg, AEDs, digoxin)
NCHCT, CTA, head and neck
CSF Analysis and OP
Brain MRI ± gadolinium
Head CT Venography/MR Venography
The PaCO2 heavily influences CBF due to its powerful effects on cerebral vessel diameter. About 1 mm Hg increase in the PaCO2 will increase the CBF by 2% to 4% (and vice versa). Beyond this physiologic relation, hypo- and hypercarbia have been associated with worse outcomes in several neurologic emergencies. Therefore, vigilant ventilator management is crucial. End-tidal capnography (ETCO2) is a valuable tool to accomplish this, noting that it may prove inaccurate if there is upper airway obstruction, hypopnea, pulmonary disease, hypotension, metabolic acidosis, and/or thoracic trauma. One caveat is the patient with hypocarbia as a compensation for a metabolic acidosis; this patient should have their PaCO2 forcibly normalized, as it will worsen the underlying acidosis and potentially produce cardiovascular collapse.
Via autoregulatory feedback, systemic hypotension will produce cerebral vasodilation, increasing the cerebral blood volume (CBV) (Figure 48A–5). A minimal mean arterial blood pressure (MAP) target of more than 65 mm Hg may be inadequate for those with flow limiting cervical or cerebral vessel stenosis and many not produce the desired cerebral perfusion pressure (CPP) of more than 60 mm Hg in those with IC-HTN (CPP = MAP – ICP); therefore, an initial target MAP of more than 80 mm Hg is often selected. Ensuring euvolemia through clinical intravascular volume assessment and provision of isotonic crystalloids initially pursues MAP targets. Albumin and synthetic colloids have not found a place in the neurologic resuscitation. In fact, a subgroup analysis of the SAFE trial found albumin to be associated with increased mortality in TBI patients, when compared to crystalloids. Bedside echocardiography is a valuable tool to screen for acute cardiac dysfunction and neurogenic stunned myocardium.
As discussed earlier, ICP is a product of the amount of mass in the intracranial vault. Actions that increase CBV can increase ICP. Hypermetabolic states, such as agitation, seizures, or hyperthermia will increase CBF. Cerebral venous drainage can be impaired when the patient's head is falling to one side or if their cervical collar is tight fitting, causing ICP elevations.
Acute intracranial hemorrhage should remain high on the differential. Inquiries regarding anticoagulant use and serologic assessment of the patient's coagulation status must occur. If intracranial hemorrhage is identified, rapid, immediately correction of any coagulopathy is mandatory and must be conducted with the highest sense of urgency, regardless of any perceived transient stability.
Hypoxia, hypercarbia, hypertension, IC-HTN, and hypotension are all known complications of endotracheal intubation (ETI). As described earlier, many acute neurologic conditions are worsened by these physiologic perturbations and must be avoided.
Hypoxia can be avoided with optimal preoxygenation and utilizing techniques, strategies, and equipment that optimize the probability of first pass success. Similarly, hypercarbia will be minimized with short paralysis to intubation times. The PaCO2 rises by 6 to 7 mm Hg in the first minute of apnea, followed by a 3 to 4 mm Hg rise for every minute thereafter, with greater jumps in those increased metabolism (eg, hyperthermia) and likely with depolarizing NMBs, such as succinylcholine. Hypotension can be avoided via intravascular volume loading with isotonic crystalloids, selection of induction agents with hemodynamic stability (eg, etomidate and ketamine, KET), and using lower doses of induction agents in comatose patients.
Laryngoscopy and endotracheal suctioning are known to increase in ICP via several hypothesized pathways. Weak evidence suggests that administering 1.5 mg/kg of lidocaine IV (up to 150 mg) 3 minutes prior to intubation may mitigate this increase. If provided, note that systemic BP decreases can be seen and the fasciculations normally seen after succinylcholine administration will be blunted or absent. Alternatively, fentanyl (1-3 mcg/kg) IV can be provided to blunt the sympathetic response to laryngoscopy that is blamed for some of the ICP rise.
KET has been reported to dramatically increase ICP and has been contraindicated into those with IC-HTN. More recently, several small, randomized trials have not observed this increased when KET is used in combination with propofol (PRO), benzodiazepines, or barbiturates, although none of these studies used KET for ETI. The overall safety of bolus KET in patients with IC-HTN is still not entirely clear, but its hemodynamic stability makes it an appealing option for those with hypotension or assessed to be high risk for hypotension during intubation.
Extraglottic devices (EGDs) in the acute management of CA have been associated with inferior outcomes, possibly due to compression of the carotid arteries, reducing CBF and exacerbating brain injury. Randomized evidence is lacking to definitely inform the EGD versus ETI decision, but these observations are worth considering with ETI is an option.
Despite some of the speculative physiologic limitations, succinylcholine is the preferred paralytic in these patients, assuming the absence of other contraindications to its use, as its short duration action allows for immediate recovering of the neurologic exam, which is absolutely needed for decisions on further diagnostics and therapeutics. The recent approval of sugammadex (a reversal agent for rocuronium) in the United States does trump this concern, making rocuronium the preferred NMB where sugammadex is available.