Alterations in Consciousness

General Principles

Definition

  • Coma: A state of complete behavioral unresponsiveness to external stimulation. Evaluation and treatment should be performed concurrently and expeditiously as multiple etiologies can lead to irreversible brain damage.
  • Delirium: An acute state of confusion that can result from diffuse or multifocal cerebral dysfunction and is characterized by relatively rapid reduction in the ability to focus, sustain, or shift attention. Changes in cognition, fluctuations in consciousness, disorientation, and even hallucinations are common.

Epidemiology

  • Between 14% and 56% of all hospitalized patients and as high as 82% of mechanically ventilated patients develop delirium.1
  • Delirious patients often have prolonged stays and are at greater risk for subsequent cognitive decline.

Etiology

  • Coma results from diffuse or multifocal dysfunction that involves both cerebral hemispheres or the reticular activating system in the brainstem.
  • Etiologies of altered mental status are listed in Table 27-1.
  • Mild systemic illness (e.g., urinary tract infections), introduction of new medications, fever, and/or sleep deprivation are common causes of delirium in the elderly and patients with chronic central nervous system (CNS) dysfunction of any etiology.
Table 27-1: Causes of Altered Mental Status
Metabolic derangements/diffuse etiologies
  • Hypernatremia/hyponatremia
  • Hypercalcemia
  • Hyperglycemia/hypoglycemia
  • Hyperthyroidism/hypothyroidism
  • Acute intermittent porphyria
  • Hypertensive encephalopathy/reversible posterior leukoencephalopathy
  • Hypoxia/hypercapnia
  • Global cerebral ischemia from hypotension
Infections
  • Meningitis/encephalitis
  • Sepsis
  • Systemic infectious with spread to CNS
Drugs/toxins/poisons
  • Prescription medications and side effects of medications
  • Drugs of abuse
  • Withdrawal situations
  • Medication side effects
  • Inhaled toxins
Inborn errors of metabolism
Nutritional deficiency (i.e., thiamine)
Seizures
  • Subclinical seizures
  • Postictal state
Head trauma
Vascular
  • Ischemic stroke (only certain stroke locations cause altered mental status)
  • Hemorrhage
Structural
  • Hydrocephalus
  • Tumor
Systemic organ failure
  • Hepatic failure
  • Renal failure
Psychiatric
Autoimmune/inflammatory
  • Vasculitis (primary CNS or systemic)
  • Encephalitis
  • Autoantibody-mediated encephalopathies (e.g., anti–voltage-gated potassium channel complex antibodies like anti-LGI1 and anti-Caspr2)

CNS, central nervous system.

Diagnosis

  • Initial assessment should focus on recognizing the development and progression of altered consciousness. Query for history of trauma, seizures, stroke, medication changes, and alcohol or drug use as possible etiologies. A collateral source is often necessary.
  • The AWOL tool is a quick bedside measure that can be used to assess patients’ risk of delirium at the time of admission.2 The AWOL score is derived from assigning one point for each of the following variables (age ≥80, inability to spell the word “world” backward, disorientation to location, and nurse-rated illness severity [with a point given for patients considered to be at least moderately ill]). In the pilot study describing this tool, 2% of patients with a score of 0 went on to develop delirium, whereas 64% of patients with a score of 4 went on to develop delirium.

Clinical Presentation

  • Search for signs of systemic illness associated with coma (e.g., cirrhosis, hemodialysis fistula/graft, rash of meningococcemia) or signs of head trauma (e.g., lacerations, periorbital or mastoid ecchymosis, hemotympanum). The physical and neurologic examination may reveal systemic illness (e.g., pneumonia or elevated temperature) or neurologic signs (meningismus or paralysis) that can help narrow the differential diagnosis.
  • Herniation occurs when mass lesions or edema cause shifts in brain tissue. The diagnosis of brain herniation requires immediate recognition and treatment. If a risk of herniation is present, the patient should be monitored in a neurosurgical/neurologic critical care unit, and frequent (q1-2 hour) “neuro checks” should be performed to evaluate for signs of impending herniation.
    • Nonspecific signs and symptoms of increased intracranial pressure include headache, nausea, vomiting, hypertension, bradycardia, papilledema, and sixth nerve palsy. Alteration in consciousness is a late finding.
    • Uncal herniation is caused by unilateral supratentorial lesions. The earliest sign is diminished consciousness, followed by a dilated pupil ipsilateral to the mass, then hemiparesis, first contralateral to the mass and later ipsilateral to the mass (Kernohan notch syndrome).
    • Central herniation is caused by medial or bilateral supratentorial lesions. Signs include progressive alteration of consciousness, Cheyne–Stokes or normal respirations followed by central hyperventilation, midposition and unreactive pupils, loss of upward gaze, and posturing of the extremities.
    • Tonsillar herniation occurs when pressure in the posterior fossa forces the cerebellar tonsils through the foramen magnum, compressing the medulla. Signs include altered level of consciousness and respiratory irregularity or apnea.
  • In general, the neurologic assessment should ascertain the patient’s ability to focus, sustain, and shift attention appropriately. Due to fluctuations, repeated examinations are often necessary.
  • Level of consciousness can be semiquantitatively assessed and followed by using the Glasgow coma scale (GCS). Scores range from 3 (unresponsive) to 15 (normal).
  • Respiratory rate and pattern
    • Cheyne–Stokes respirations (rhythmic crescendo–decrescendo hyperpnea alternating with periods of apnea) are seen in metabolic coma, supratentorial lesions, chronic pulmonary disease, and congestive heart failure (CHF).
    • Hyperventilation is seen in metabolic acidosis, hypoxemia, pneumonia, or other pulmonary diseases but can also occur with an upper brainstem injury.
    • Apneustic breathing (long pauses after inspiration), cluster breathing (breathing in short bursts), and ataxic breathing (irregular breaths without pattern) are signs of brainstem injury and are commonly associated with impending respiratory arrest.
  • Pupil size and light reactivity
    • Anisocoria (asymmetric pupils) in a patient with altered mental status requires immediate diagnosis (i.e., stat head CT) for exclusion and treatment of possible herniation.
    • Anisocoria may be physiologic or produced by mydriatics (e.g., scopolamine, atropine) and therefore requires well-documented serial examinations.
    • Small but reactive pupils are seen in narcotic overdose, metabolic encephalopathy, and pontine lesions.
    • Fixed midposition pupils imply midbrain lesions or transtentorial herniation.
    • Bilaterally fixed and dilated pupils occur with severe anoxic encephalopathy or drug intoxication (e.g., scopolamine, atropine, glutethimide, or methanol).
  • Eye movements
    • To test the oculocephalic reflex (“doll’s eyes” maneuver, assuming no cervical injury is present), the examiner quickly turns the head laterally or vertically (head impulse test). Intact brainstem oculomotor function, in the setting of coma, will result in conjugate eye movements opposite to the direction of head movement (back to the examiner).
    • In the absence of a history to suggest a drug-induced cause (e.g., barbiturates, phenytoin, paralytics) or a preexisting disorder such as progressive external ophthalmoplegia, absence of all eye movements indicates a bilateral pontine lesion.
    • A conjugate gaze preference to one side suggests a unilateral pontine or frontal lobe lesion.
    • Impaired vertical eye movement occurs in midbrain lesions and central herniation. Conjugate depression and impaired elevation suggest a tectal lesion (e.g., pinealoma) or hydrocephalus.
  • Motor responses also help with localization. Asymmetric motor responses (spontaneous or stimulus induced, including noxious stimuli if necessary) also have localizing value.

Diagnostic Testing

Laboratory Studies

Obtain serum electrolytes, creatinine, glucose, calcium, complete blood count (CBC), and urinalysis. Drug levels should be ordered if appropriate. An accurate medication list and any history to suggest intoxication are critical features of the evaluation. Toxicology screen of blood and urine should be considered.

Imaging

A head CT should be obtained to evaluate for structural abnormalities. Brain MRI can be useful if head CT is nondiagnostic and there is suspicion for an ischemic or parenchymal lesion (especially of the posterior fossa).

Diagnostic Procedures

  • Lumbar puncture (LP) should be considered in patients with fever and/or new headache or those with high risk of infection. A funduscopic examination and/or head imaging should be performed prior to performing the LP to assess risk of herniation. Patients with focal neurologic symptoms, altered mental status, a history of CNS disease (e.g., stroke or tumor), or recent seizures should undergo head CT prior to LP. Basic cerebrospinal fluid (CSF) studies include protein, glucose (with concurrent serum glucose), cell count, Gram stain, and aerobic culture. Additional studies should be obtained depending on the possible etiology (e.g., viral polymerase chain reactions, immune markers).
  • Electroencephalography (EEG) can be considered to rule out seizures. Nonconvulsive status epilepticus (NCSE) is a common cause of unexplained encephalopathy in the critically ill population. Interictal abnormalities can be suggestive of specific etiologies (e.g., periodic lateralized epileptiform discharges in herpes simplex virus [HSV] encephalitis, triphasic waves in hepatic or uremic encephalopathy, and β activity or voltage suppression in barbiturate or other sedative intoxications).

Treatment

Delirium

  • Repeated attempts should be made to reorient the patient and possibly have a sitter present if necessary.
  • A quiet room with close observation is necessary. Patients should have a well-lit environment with familiar objects during the day and dark, quiet (minimize stimulation if possible) environments at night.
  • Physical and pharmacologic restraints should be used only as a last resort and with appropriate documentation in the medical record. If restraints are needed, they should be carefully adjusted and checked periodically to prevent excessive constriction.
  • Ramelteon may be used in patients at risk for delirium.3

Coma

  • Ensure adequate airway and ventilation, administer oxygen as needed, and maintain normal body temperature.
  • Establish secure IV access and adequate circulation.
  • Neurosurgical consult may need to be obtained for intracranial pressure monitoring and treatment, if applicable.

Medications

  • IV thiamine (100–500 mg), followed by dextrose (50 mL of 50% dextrose in water = 25 g dextrose), should be administered. Thiamine is administered first because dextrose administration in thiamine-deficient patients may precipitate Wernicke encephalopathy.
  • IV naloxone (opiate antagonist), 0.01 mg/kg, should be administered if opiate intoxication is suspected (coma, respiratory depression, small reactive pupils).
  • Flumazenil (benzodiazepine antagonist), 0.2 mg IV, may reverse benzodiazepine intoxication, but its duration of action is short, and additional doses may be needed. Flumazenil should be used with caution in certain patient populations (e.g., epileptics) because it reduces the seizure threshold.
  • In delirious patients, sedatives should be avoided if possible. If necessary, low doses of quetiapine (12.5–25 mg) or lorazepam (1 mg) can be used. Remember to always consider comorbidities before administering these medications.

Other Nonpharmacologic Therapies

If herniation is identified or suspected, treatment consists of measures to lower intracranial pressure while surgically treatable etiologies are identified or excluded. All of the listed measures are only temporizing methods. Consultation with neurosurgery should be performed concurrently.

  • Elevate the head of the bed to at least 30 degrees.
  • Endotracheal intubation is usually performed to enable hyperventilation to a partial pressure of carbon dioxide (PCO2) of 25–30 mm Hg. This reduces intracranial pressure within minutes by cerebral vasoconstriction. Bag mask ventilation can be performed if manipulation of the neck is precluded by possible or established spinal instability. Reduction of PCO2 below 25 mm Hg is not recommended because it may reduce cerebral blood flow.
  • Administration of IV mannitol (1–2 g/kg over 10–20 minutes) osmotically reduces free water in the brain via elimination by the kidneys and does not require a central line for administration. Remember that, given its potent diuretic effect, mannitol can precipitate renal failure if volume is not adequately replaced. Hypertonic saline (5% or 23.4% saline) is an alternative option but also has side effects and requires central venous access.
  • Dexamethasone (10 mg IV, followed by 4 mg IV q6h) reduces the edema surrounding a tumor or an abscess but is not indicated for diffuse cerebral edema or the mass effect associated with malignant cerebral infarcts.
  • Coagulopathy should be corrected if intracranial hemorrhage is diagnosed and before surgical treatment or invasive procedures (e.g., LP) are performed. Each patient’s circumstances should be carefully assessed before therapeutic anticoagulation is reversed.

Surgical Management

Surgical evacuation of epidural, subdural, or intraparenchymal (e.g., cerebellar) hemorrhage and shunting for acute hydrocephalus should be considered in the appropriate clinical circumstances. However, some structural lesions are not amenable to surgical treatment.

Autoimmune Encephalitis

Autoimmune encephalitis is increasingly recognized as an etiology of subacute confusion in certain patients. It is characterized by subacute onset of confusion, often with other neurologic signs/symptoms (e.g., seizures, movement disorders, psychosis).

Diagnostic Testing

  • Patients in whom autoimmune encephalitis is suspected should undergo evaluation with LP, EEG, and MRI. A thorough investigation aimed at identifying other possible etiologies should also be pursued.
    • CSF often demonstrates findings consistent with inflammation (protein >50 mg/dL or lymphocytic pleocytosis >5 cells/μL) but can be normal.
    • MRI features consistent with encephalitis include T2/FLAIR hyperintensities restricted to one or both medial temporal lobes or multifocal in gray and/or white matter compatible with demyelination or inflammation with our without contrast enhancement.
    • Interictal EEG may demonstrate focal discharges or slowing in a patient with seizures.
  • The Antibody Prevalence in Epilepsy and Encephalopathy (APE2) score (Table 27-2) is used to predict neural-specific antibody positivity. An APE2 score ≥4 is 99% sensitive and 93% specific in this regard.4
  • The Mayo autoimmune encephalitis (not paraneoplastic) panel should be sent from both serum and CSF if an autoimmune encephalitis is suspected.
Table 27-2: APE2 Score

Value
New-onset, rapidly progressive mental status changes that developed over 1–6 wk or new-onset seizure activity (within 1 y of evaluation)+1
Neuropsychiatric changes; agitation, aggressiveness, emotional lability+1
Autonomic dysfunction (sustained atrial tachycardia or bradycardia, orthostatic hypotension [≥20 mm Hg fall in systolic pressure or ≥10 mm Hg fall in diastolic pressure within 3 min of quiet standing], hyperhidrosis, persistently labile blood pressure, ventricular tachycardia, cardiac asystole or gastrointestinal dysmotility)+1
Viral prodrome (rhinorrhea, sore throat, low-grade fever) to be scored in the absence of underlying systemic malignancy within 5 y of neurological symptom onset+2
Faciobrachial dystonic seizures+3
Facial dyskinesias, to be scored in the absence of faciobrachial dystonic seizures+2
Seizure refractory to at least to two antiseizure medications+2
CSF findings consistent with inflammation (elevated CSF protein >50 mg/dL and/or lymphocytic pleocytosis >5 cells/µL, if the total number of CSF RBCs is <1000 cells/µL)+2
Brain MRI suggesting encephalitis (T2/FLAIR hyperintensity restricted to one or both medial temporal lobes or multifocal in gray matter, white matter, or both compatible with demyelination or inflammation)+2
Systemic cancer diagnosed within 5 y of neurological symptom onset (excluding cutaneous squamous cell carcinoma, basal cell carcinoma, brain tumor, cancer with brain metastasis)+2

APE2, Antibody Prevalence in Epilepsy and Encephalopathy; CSF, cerebrospinal fluid; RBCs, red blood cells.

Principles of Treatment

  • The initial treatment of choice, which is also used to determine response to immunotherapy, is IV methylprednisolone 1000 mg/d for 3 days.
  • Other treatment considerations include IV immunoglobulin (IVIG), plasma exchange, azathioprine, mycophenolate mofetil, rituximab, and cyclophosphamide.

Severe Brain Injury

  • Brain death occurs from irreversible brain injury sufficient to permanently eliminate all cortical and brainstem functions. Because the vital centers in the brainstem sustain cardiovascular and respiratory functions, brain death is incompatible with survival despite mechanical ventilation and cardiovascular and nutritional supportive measures. Brain death is distinguished from persistent vegetative state (PVS) in which the absence of higher cortical function is accompanied by intact brainstem function. Patients in a PVS are unable to think, speak, understand, or meaningfully respond to visual, verbal, or auditory stimuli, yet with nutritional and supportive care, their cardiovascular and respiratory functions can sustain viability for many years.
  • Brain death criteria vary by institution. Refer to your institution’s policy for details. AAN prerequisite guidelines are summarized below5:
    • Declaration of brain death requires presence (clinical and radiographic) of CNS catastrophe.
    • CNS depressant effect must be absent.
    • Acid–base disturbances must be corrected.
    • Patient must be normothermic.
    • Systolic blood pressure must be >100 mm Hg.
  • Prognostication after cardiac arrest utilizes a multimodal assessment including the clinical examination, EEG, somatosensory evoked potentials, and serum neuron-specific enolase (NSE).6
    • Key features of the clinical examination include pupillary response, corneal reflex, motor reaction to pain, and presence of early myoclonus.
    • EEG is used to identify certain patterns (such as burst suppression), but also to identify the presence of status epilepticus, which should be treated.
    • Serum NSE is not widely used given slow turnaround time and lack of availability.

Alcohol Withdrawal

Alcohol withdrawal typically occurs when illness or hospitalization interrupts continued alcohol intake.

  • Tremulousness, irritability, anorexia, and nausea characterize minor alcohol withdrawal. Symptoms usually appear within a few hours after reduction or cessation of alcohol consumption and resolve within 48 hours. Treatment includes supportive care with hydration and reassurance. Thiamine, 100–500 mg IM/IV, followed by 100 mg PO daily; multivitamins containing folic acid; and a balanced diet as tolerated should be administered. Serial evaluation for signs of major alcohol withdrawal is essential.
  • Alcoholic hallucinosis occurs within 8–48 hours after cessation of alcohol and is distinguished from delirium tremens (DTs) by a clear sensorium.
  • Alcohol withdrawal seizures, typically one or a few brief generalized convulsions, occur 12–48 hours after cessation of ethanol intake. Antiepileptic drugs (AEDs) are not indicated for typical alcohol withdrawal seizures. Other causes for seizures (see “Seizures” section) must be excluded. If hypoglycemia is present, thiamine should be administered before glucose.
  • Severe withdrawal or DTs consists of tremulousness, hallucinations, agitation, confusion, disorientation, and autonomic hyperactivity (fever, tachycardia, diaphoresis), typically occurring 48–72 hours after cessation of drinking. DTs complicates 5%–10% of cases of alcohol withdrawal, with mortality up to 15%. Other causes of delirium must be considered in the differential diagnosis (see Table 27-1).7
  • Mild withdrawal symptoms can be managed with chlordiazepoxide PO 25–50 mg q6–8h (maximum total daily dose 300 mg) with a subsequent dose taper or, preferably, with a symptom-triggered treatment protocol. This medication is hepatically cleared and should be avoided in patients with liver disease. In patients with severe hepatic failure, oxazepam (15–30 mg PO, q6–8h as needed), which is excreted by the kidney, is preferred. For patients with severe withdrawal symptoms, seizures, and/or DTs, diazepam or lorazepam IV are effective agents. Diazepam 10 mg IV every 5–20 minutes or lorazepam IV 2–4 mg every 15–20 minutes should be given until symptom control is achieved. Treatment can then be transitioned to a symptom-triggered or scheduled regimen.
  • Maintenance of fluid and electrolyte balance is important. Alcoholic patients are susceptible to hypomagnesemia, hypokalemia, hypoglycemia, and fluid losses, which may be considerable due to fever, diaphoresis, and vomiting.

References

  1. Douglas VC, Josephson SA. Delirium. Continuum (Minneap Minn). 2010;16(2):120-134.  [PMID:22810284]
  2. Douglas V, Hessler CS, Dhaliwal G, et al. The AWOL tool: derivation and validation of a delirium prediction rule. J Hosp Med. 2013;8(9):492-499  [PMID:23922253]
  3. Hatta K, Kishi Y, Wada K. Preventative effects of ramelteon on delirium: a randomized placebo-controlled trial. JAMA Psychiatry. 2014;74(4):397-403.  [PMID:24554232]
  4. Dubey D, Kothapalli N, McKeon A, et al. Predictors of neural-specific autoantibodies and immunotherapy response in patients with cognitive dysfunction. J Neuroimmunol. 2018;323:62-72.  [PMID:30196836]
  5. Wijdicks EF, Varelas PN, Gronseth GS, Greer DM; American Academy of Neurology. Evidence-based guideline update. Determining brain death in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2010;74(23):1911-1918.  [PMID:20530327]
  6. Rossetti AO, Rabinstein AA, Oddo M. Neurological prognostication of outcome in patients in coma after cardiac arrest. Lancet Neurol. 2016;15(6):597-609.  [PMID:27017468]
  7. Sarff M, Gold JA. Alcohol withdrawal syndromes in the intensive care unit. Crit Care Med. 2010;38(9):S494-S501.  [PMID:20724883]

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