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    CoreGERIATRICSNeurology

    Delirium: Clinical Manifestation and Management In The Emergency Department

    Shahriar Lahouti
    November 23, 2023
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    58 min read

    23 November 2023, by Shahriar Lahouti.

    CONTENTS

    Key points

    Delirium is a geriatric syndrome characterized by an acute change in attention, awareness, and cognition that may last in a subacute form for weeks or even months, resulting in significant morbidity and mortality. It not only increases the risk of falls and prolonged hospitalization but also may result in irreversible cognitive decline and even death. Delirium is a manifestation of an underlying medical condition(s) that cannot be better explained by a pre-existing neurocognitive disorder and is often considered multifactorial. Multiple predisposing factors (e.g. pre-existing dementia) and precipitating factors (for example, infections, urinary retention, pain) for delirium have been described, with most patients having both types. There is no single treatment for delirium. Once it is diagnosed, finding and treating the underlying causes are key to resolving delirium. If the patient is dangerously agitated, pharmacologic agents such as antipsychotic medications should be used.

    Introduction

    Delirium is a common severe neurocognitive disorder characterized by the acute onset of inattention and other cognitive dysfunction (e.g. disorientation). They may also experience distressing symptoms of psychosis (e.g. hallucinations) and altered mood. Patients often have altered arousal, from reduced responsiveness at a near-coma level to severe agitation *.

    Delirium is known by a variety of different terms, including altered mental status, acute mental status change, encephalopathy, agitation, altered level of consciousness, brain failure, and even psychosis *. Although these terms are descriptive of symptoms, they can be confusing to healthcare providers and can negatively affect clinical management *. For example, the use of the term ‘delirium’ may trigger specific management, whereas ‘septic encephalopathy’ may overlook mechanisms other than sepsis, such as metabolic alterations or drug side effects.

    Nomenclature and definition

    The consensus statement on nomenclature advocates using only two terms: acute encephalopathy and delirium *.

    • They suggest that the terms acute confusional state, acute brain dysfunction, and acute brain failure should NOT be used in addition to the terms delirium and acute encephalopathy.
    • The term altered mental status is not synonymous with delirium and should NOT be used.
    Acute Encephalopathy
    • This is a broad term, referring to a rapidly developing (usually within hours to a few days), diffuse pathobiological process that can lead to a clinical presentation of delirium, or coma, and may have additional features, such as seizures or extrapyramidal signs.
      • Therefore, acute encephalopathy refers to the brain disorder underlying the delirium.
    Coma
    • Refers to a clinical state of severely depressed responsiveness defined by diagnostic systems such as the GCS * or FOUR score *.
    Delirium
    • Delirium is acute, generalized brain dysfunction leading to a clinical state characterized by a combination of features defined by DSM-5 *. The presence of delirium requires all the criteria to be met:
      • Disturbance in attention (reduced ability to direct, focus, sustain, and shift attention) and awareness (reduced orientation to the environment or altered arousal).
      • Disturbance develops acutely (in contrast to dementia) and tends to fluctuate in severity.
      • At least one additional disturbance in cognition; “disorganized thinking” (memory deficit, disorientation, language, visuospatial ability, or perception).
      • Not better explained by preexisting dementia.
      • Not due to a severely reduced level of arousal or coma.
      • Evidence of an underlying organic cause or causes.
    1.  
    Subclinical Delirium
    This term is used to describe patients who have some delirium features but do not fulfill all criteria for a delirium diagnosis *,*.

    Additional features of delirium

    Subtypes: Based on psychomotor behavioral disturbances, delirium is sub-typed into *:

    • Hypoactive/quiet delirium
      • Hypoactive symptoms: Apathy, staring, slowed movements and speech, ↓alertness, unawareness, and lethargy.
      • Psychotic features are present in more than half of patients.
      • Hypoactive delirium is the most common subtype in the emergency department *.
      • It has a higher morality relative to the hyperactive subtype.
      • In particular, this type may be easily missed or misdiagnosed *.
    • Hyperactive/agitated delirium 
      • Hyperactive symptoms: Hypervigilance, restlessness, irritability, anger, combativeness, euphoria, fast motor responses, and speech, increased sympathetic activity, and impairment in sleep duration and architecture.
      • The hyperactive subtype has the best prognosis *.
    • Mixed delirium
      • Periods of hyperactive and hypoactive delirium.
      • The mixed subtype of delirium seems to have the worst prognosis *.

    Other clinical features

    • Emotional disturbances, including fear, depression, euphoria, or perplexity.
    • Psychotic symptoms (hallucinations, delusions, paranoia).
    • Sundowning (day-night reversal with hyperactivity at night) *.

    Epidemiology

    Delirium has primarily been studied in hospital settings. Nearly 30% of older medical patients experience delirium at some time during hospitalization. In general, delirium can be found wherever there are sick patients.

    • Among critically ill patients in ICU (70-80%)*
    • Hospice units (42%) *
    • Postacute care settings (16%) *
    • Emergency department (10%) *

    Prognosis and outcomes

    • Patients who develop delirium are at increased risk for a variety of poor outcomes including falls, debility, prolonged hospital stay, and increased risk of death *,*.
    • Features of delirium that predict worse outcomes include:
      • Older age
      • Frailty
      • Hypoactive subtype
      • Delirium severity *.
      • Delirium duration
        • Persistent delirium (that is, lasting for weeks or months), even with partial recovery, is strongly associated with poor outcomes *.

    Pathophysiology and mechanism

    Background: Neurobiology of arousal and attention

    • Key structures in maintaining an awake state and awareness involve the ascending reticular activating system (ARAS) from the mid-pontine tegmentum rostrally to the thalamus and the anterior cingulate regions, and cortical association area (precuneus and cuneus) *.
      • The results of brainstem auditory evoked potential, somatosensory evoked potentials, and neuroimaging studies have supported an important role for subcortical (eg, thalamus, basal ganglia, and pontine reticular formation) as well as cortical structures in the pathogenesis of delirium *.
      • These findings correlate with clinical reports that patients with subcortical strokes and basal ganglia abnormalities (including Parkinson’s disease) have a higher susceptibility to delirium.

    Neurotransmitter imbalance

    • Neurotransmitters such as acetylcholine, serotonin, gamma-aminobutyric acid (GABA), and dopamine become imbalanced in delirium, which results in the inability of delirious patients to process information and respond appropriately *.
    • Acetylcholine
      • It plays a key role in the pathogenesis of delirium *. Several studies support the cholinergic hypothesis of delirium.
        • Anticholinergic drugs can cause delirium when given to healthy volunteers *.
        • There is a correlation between cognitive impairment and anticholinergic drug serum levels. Elevated serum anticholinergic levels decrease when the delirium resolves *.
        • Alzheimer’s disease, which is characterized by a loss of cholinergic neurons, increases the risk of delirium due to anticholinergic medications.
        • Medical conditions precipitating delirium, such as hypoxia, hypoglycemia, and thiamine deficiency, decrease acetylcholine synthesis in the CNS *,*.
      • Keep in mind the anticholinergic mechanism, since many drugs used by older adults (including several not traditionally viewed to have “anticholinergic effects”) can lead to detectable serum anticholinergic activity *.
        • Psychotropic drugs, in particular, are likely to cause detectable serum anticholinergic activity at doses typically administered to older patients.
    • GABA
      • GABA is the predominant inhibitory neurotransmitter in the CNS *.
      • ⬆️GABAergic activity has been implicated in
        • Hepatic encephalopathy (HE)*
          • Elevated serum ammonia levels in HE contribute to ↑glutamate and glutamine levels; these amino acids are precursors to GABA.
        • Withdrawal from benzodiazepine, and alcohol.
    • Dopamine
      • ⬆️ Dopaminergic activity has been implicated in causing delirium associated with bupropion toxicity.
      • Symptomatic relief of delirium occurs with haloperidol, a potent dopamine blocker.
    • Other
      • Cerebrospinal fluid studies of patients with delirium reveal alterations in neuropeptides (eg, somatostatin), endorphins, and serotonin among others *, however, it is difficult to exclude the confounding effects of underlying illness or dementia.

    Cerebral metabolic insufficiency

    • The brain requires a large amount of energy, as either oxygen or glucose deficiency can markedly constrain brain function.
    • Acute illnesses (precipitators of delirium) such as respiratory distress, and hemodynamic shock might impair brain metabolism in multiple ways.

    Systemic inflammation

    • Peripheral inflammation is a well-established trigger of delirium, but the precise mechanisms by which it disrupts brain function are not clearly understood.
    • Several processes have been proposed in the pathogenesis of delirium in septic patients (sepsis-associated encephalopathy, “SAE”) shown in the figure below *.
      • Moreover, inflammation may also contribute to delirium through the promotion of coagulation, which is common in sepsis.

    Impaired neuronal network connectivity

    • Neurochemical influences on the brain’s functional state are dependent on the neuroanatomical networks in which these neurotransmitters operate.
    • Structural connectivity studies show that loss of integrity in the inter-hemispheric corpus callosum is associated with increased delirium duration *.

    Risk factors

    Delirium is a multifactorial disorder. Factors that increase the risk for delirium (figure below) can be classified into *:

    • Predisposing factors: Premorbid conditions (i.e. patient’s characteristics) that increase baseline vulnerability to delirium.
    • Precipitating factors: Factors relating to the presenting illness (i.e. causes of delirium, e.g. acute insult, injury, drugs).
    Delirium

    Predisposing risk factors

    • Advanced age >65 *
    • History of delirium
    • Frailty: Immobility, impairment in activities of daily living *
    • Baseline cognitive impairment such as dementia, stroke, or Parkinson’s disease.
    • Sensory impairment (e.g. hearing, visual impairment) *.
    • Decreased oral intake: Dehydration, malnutrition *
    • Depression and other psychiatric illnesses.
    • Comorbidities (e.g. cardiovascular and renal disease).
    • Illness severity (especially intubation).
    • Alcohol abuse, illicit drugs, opioids, or benzodiazepine use.

    Causes

    Factors that may precipitate delirium are numerous and varied. Some common causes are listed below.

    Medication: Especially pay attention to:
    🔸Drug-drug interaction
    🔸New medications
    🔸Polypharmacy (≥5 medications)
    🔸Renally cleared medications plus acute kidney injury.
    • Medications with “predominant” anticholinergic effects *:
      • Atropine
      • Antisialagogue: Glycopyrrolate.
      • Bladder antispasm: Oxybutynin, tolterodine, flavoxate.
      • Used for irritable bowel syndrome: Dicyclomine, hyoscyamine.
      • Antiemetic or antisialagogue: Scopolamine (hyoscine)
      • Used for Parkinson’s disease: Benztropine, trihexyphenidyl *
      • Anticholinergic eye drops: Atropine, cyclopentolate, homatropine.
      • Inhaled bronchodilator: Ipratropium, tiotropium.
    • Medications with “mixed” effects including anticholinergic effects *:
      • First generation antihistamines: Chlorpheniramine, promethazine, cyproheptadine, dimenhydrinate, diphenhydramine, doxepin, hydroxyzine, clemastine, meclizine).
      • TCA antidepressants: Amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline.
      • Muscle relaxants: (e.g. cyclobenzaprine, orphenadrine).
      • Antipsychotics, especially:
        • Low-potency typical antipsychotics e.g. chlorpromazine, fluphenazine, thioridazine.
        • Atypical agents: Olanzapine, quetiapine.
    • Dopamine agonists (antiparkinson): Amantadine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole.
    • Metoclopramide
    • Sedative-hypnotics: Benzodiazepines, zolpidem, barbiturates.
    • Analgesics: Opioid (esp. meperidine), NSAID.
    • Skeletal muscle relaxers: Baclofen, cyclobenzaprine, tizanidine.
    • Antiseizure medications: Carbamazepine, levetiracetam, phenytoin, valproate, vigabatrin.
    • Other CNS-active agents: Phenothiazines, lithium, cholinesterase inhibitors (eg, donepezil), Interleukin 2, and disulfiram.
    • Cardiovascular & hypertensive drugs: Digoxin, dihydropyridines calcium channel blockers e.g. amlodipine *, antiarrhythmic, β-blockers, clonidine, diuretics, methyldopa.
    • Antimicrobial: Acyclovir, aminoglycosides, cefepime, fluoroquinolones, isoniazid, metronidazole, macrolide, rifampin, sulfonamides.
    • Steroids.
    • Medication side effects (e.g. hyperammonemia from valproic acid *,*, confusion from quinolones, serotonin syndrome *)
    • Hypoglycemic agents.
    Toxicologic
    • Intoxication
      • Almost any substance, including:
        • Cardiovascular: Digoxin, antiarrhythmic, sympathomimetic, β-blocker, ⍺-2 adrenergic agonists (e.g. clonidine)
        • Toxic alcohols (ethylene glycol, methanol), lithium, bupropion (norepinephrine/dopamine reuptake inhibitor), inhaled toxins e.g. carbon monoxide, cyanide, hydrogen sulfide, and salicylate intoxication.
    • Withdrawal from:
      • Benzodiazepines, ethanol, opioids, gabapentin, baclofen, dexmedetomidine, serotonin-norepinephrine receptor inhibitors, e.g. duloxetine, venlafaxine.
    Infection
    • Sepsis (septic encephalopathy) *.
    • Systemic infections
    • Fever-related delirium
    Metabolic derangement
    • Electrolyte disturbance (⬆️ or ⬇️): Na, Ca, Mg, Phos.
    • Endocrine disturbance (⬆️ or ⬇️): Thyroid, Parathyroid, Pancreas, Pituitary, Adrenal.
    • Hypercarbia
    • Hypoxemia
    • Hypoglycemia, hyperglycemia including DKA, and hyperosmolar hyperglycemic state (HHS).
    • Hyperosmolar and hypoosmolar states
    • Inborn errors of metabolism: porphyria, Wilson disease, etc.
    • Nutritional: Wernicke encephalopathy, vitamin B12 deficiency, possibly folate and niacin deficiencies
    Systemic organ failure
    • Cardiovascular
    • Hematologic
      • Thrombocytosis
      • Hypereosinophilia
      • Leukemic blast cell crisis
      • Polycythemia
      • Thrombotic thrombocytopenic purpura (TTP).
    • Liver failure: acute, chronic.
      • Pathogenesis: 
    • Pulmonary: Including hypercarbia and hypoxemia.
    • Renal failure: acute, chronic.
      • Pathogenesis:
        • Uremia
        • Electrolyte disturbance
        • Accumulation of renally cleared medications e.g. digoxin.
        • Dialysis disequilibrium syndrome (onset of toxic metabolic encephalopathy after dialysis)
    Brain disorder
    • CNS infections: encephalitis, meningitis, brain or epidural abscess.
    • Autoimmune encephalitis.
    • Ischemic stroke.
      • Risk factors for delirium in the setting of stroke include preexisting cognitive impairment, infection, right hemispheric stroke, anterior circulation large vessel stroke, and greater stroke severity *.
    • Space occupying lesions: Intracranial hemorrhage, tumor.
    • Traumatic brain injury.
    • Epileptic seizures, especially nonconvulsive status epilepticus (NCSE) *. More on this here.
    Physical
    • Pain (insufficient pain management, urinary retention, fecal impaction, etc. ) *
    • Physical restraints, prolonged immobilization
    • Sleep disruption, visual/hearing impairment.
    • Surgery
    • Trauma: trauma with systemic inflammatory response syndrome, fat embolism.
    • Sleep deprivation: Frequent blood pressure or neurologic checks, uncontrolled pain, noisy environment.
    • Bladder catheters.
    • Hyperthermia, hypothermia.

    Differential diagnosis (delirium mimics)

    • Dementia
      • Key features of patients with dementia that could differentiate them from delirious patients *:
        • Intact attention and remote memory especially in the earlier stages of dementia.
          • In practice, patients with dementia should be able to converse and perform some tests of attention such as counting backward from 20 or naming the months of the year or days of the week in reverse.
        • Insidious and progressive, occurring over a much longer time (months to years).
        • Not much fluctuation.
      • Dementia with Lewy bodies (DLB) is similar to Alzheimer’s disease but can be more easily confused with delirium because fluctuations and visual hallucinations are common and prominent *.
    • Primary psychiatric illnesses
      • Depression: The presence of dysphoria and absence of much fluctuation in severity are helpful distinguishing features of depression.
      • Mania: is usually associated with a history of previous episodes of mania or depression.
      • Schizophrenia: The delusions are usually highly systematized, the history is longer, and the sensorium is otherwise clear.
    • Catatonia
      • Catatonia is a motor dysregulation syndrome involving difficulty initiating or terminating actions *.
        • This causes periods of physical rigidity, negativism, or stupor, although psychomotor hyperactivity may also occur *.
      • Causes: It happens in the context of many underlying psychiatric and general medical disorders, e.g. anti-dopaminergic medications, viral encephalitis, multiple sclerosis, and Parkinson’s disease *, *.
      • Catatonia may appear similar to delirium, however, these are fundamentally distinct processes:
        • Delirium is predominantly an abnormality of attention, which largely reflects dysfunction of the cerebral cortex.
          • 💡Psychomotor features of catatonia will be absent. The waxing and waning in delirium describes arousal/ orientation, whereas in catatonia it refers to motoric dysregulation *.
        • Catatonia is predominantly an abnormality of motor regulation, which largely reflects dysfunction of the basal ganglia.
      • 💡Generally, catatonia has 3 types: Hypokinetic catatonia (causing stupor), hyperkinetic catatonia (causing agitation), and malignant catatonia (media below).
        • Either hypokinetic or hyperkinetic catatonia may lead to autonomic instability, if severe enough. Catatonia which causes autonomic instability is defined as malignant catatonia.
    • Stupor and coma
    • Abulia/akinetic mutism
      • Profound failure of executive function (e.g. failure to speak, move, or eat), “lack of spontaneity”.
      • Patients may respond to questions, but only in a very delayed fashion.
      • Visual tracking may occur, with conjugate eye movements.
      • Causes
        • Damage to the medial frontal lobe(s) e.g. by tumor or trauma.
        • Infarction of the ACA 📖
    • Aphasia (various types especially Wernicke’s aphasia).
    • Acute ischemic stroke can rarely mimic delirium:
      • PCA (posterior cerebral artery) stroke 📖
        • Bilateral infarctions involving the occipital region (Anton syndrome).
          • Cortical blindness and confabulation might be confused with delirium. Careful examination will reveal a lack of vision.
        • Inferomedial temporal lobe infarction may cause global amnesia in which the deficit is restricted to memory.
      • Inferior-division MCA stroke
        • Patients may appear delirious in that they do not comprehend or obey and seem confused.
          • In Wernicke’s aphasia, the problem is restricted to language, while other aspects of mental function are intact.
          • In the inferior-division MCA stroke contralateral superior quadrantanopia is present. 📖
    • Nonconvulsive status epilepticus (NCSE)
      • Patients with NCSE show no classic ictal features, but the following features should suggest the possibility of seizures *:
        • Prominent bilateral facial twitching.
        • Unexplained nystagmoid eye movements during obtunded periods.
        • Spontaneous hiccups.
        • Prolonged “postictal state”
        • Automatisms (lip-smacking, chewing, or swallowing movements).
        • Acute aphasia or neglect without a structural lesion.
      • Diagnosis of NCSE requires an electroencephalogram (EEG). More on this here.
        • NCSE should also be considered in the absence of these findings when the etiology of a confusional state remains obscure *.

    Diagnostic evaluation

    There are two important aspects to the diagnostic evaluation of delirium:

    1. Recognizing that delirium is present.
    2. Identifying the underlying medical illness that has caused delirium.

    Recognizing delirium

    • First, a patient’s level of arousal and content of consciousness need to be examined to evaluate for delirium.
      • This can be performed through the use of the Glasgow Coma Scale, Four score, or a sedation scale.
      • The Richmond Agitation-Sedation Scale 🧮 and the Riker Sedation-Agitation Scale 🧮 are commonly used tools that can be used to assess the level of arousal, including in patients on mechanical ventilation.
      • If the patient is determined to be unresponsive, then he or she is in a comatose state and cannot be assessed for delirium.
    • Second, assess for delirium using tools such as the Confusion Assessment Method (CAM), If the patient is responsive to verbal stimuli
      • Evidence of acute change from baseline attention and awareness, which may fluctuate in presence and severity, is sought from the patient, caregivers, or staff who know the patient, from medical records, or, less commonly, from the clinician’s knowledge of the patient.
      • Assessment tools
        • The 4A’s test (4AT) is a 4-item test used in general hospital settings. A score ≥4 indicates delirium is likely. 🧮 MDCalc.
          • A meta-analysis of 17 diagnostic test accuracy studies reported a pooled sensitivity and specificity of 88% *.
        • Confusion Assessment Method (CAM)-based tools, such as the CAM, CAM- Intensive Care Unit (ICU) assess 4 features ( acute onset and fluctuating course, inattention, disorganized thinking, altered level of consciousness). 🧮MDCalc: CAM-ICU 
          • For delirium to be present according to CAM-based tools, features 1 and 2 must be present, plus either features 3 or 4.
          • In a meta-analysis of 9 studies including 969 patients, the CAM-ICU had a pooled sensitivity of 80% and a pooled specificity of 96% *.
      • After diagnosis, further assessment of the patient to obtain more details about the individual profile of delirium, including features such as delusions, hallucinations or mood changes is crucial because this information influences the specific management plan.
    • Third: Diagnosis of delirium should prompt a thorough investigation into the potential etiology of the “acute brain dysfunction” that includes a detailed history, physical exam, and further laboratory and/or neuroimaging (if indicated). This is discussed below.

    Identifying the underlying cause of delirium

    Historical clues

    • Helpful historical clues to identify the underlying etiology of delirium and confusion can be obtained from relatives:
      • Recent febrile illness
      • History of organ failure
      • A medication list 💊
      • History of alcoholism or drug abuse
      • Recent depression.
      • Recent events & procedures
    • It is otherwise often difficult to impossible to obtain a history in the confused or uncooperative patient. As an example, myocardial infarction may cause sufficient confusion that the patient cannot relate to a history of chest pain.

    Examination

    • General exam
      • Vital signs.
      • Helpful findings in the general exam that may be suggestive of specific underlying causes of delirium
        • Cyanosis: Chronic pulmonary disease
        • Jaundice/ascites: Hepatic failure
        • Cherry-red lips: CO poisoning
        • A bitten tongue or posterior fracture-dislocation of the shoulder, signs of head injury: Epileptic seizures, nonconvulsive status epilepticus.
        • Look for foci of infection
          • 💡Note that sepsis may present as delirium without obvious fever (sometimes even with hypothermia) or localizing signs (eg, rebound tenderness from a perforated viscus).
    • Neurologic exam
      • The neurologic examination is often confounded by inattention and altered consciousness in patients with delirium.
      • Pay attention to certain aspects of the neuro exam:
        • Level of consciousness.
        • Degree of attention or inattention.
        • Visual fields, pupil exam.
        • Cranial nerve and motor deficits.
      • Note that the absence of a focal neurologic deficit does not exclude the possibility of focal or multifocal neurologic lesions as the cause of delirium
        • Posterior cortical strokes, for example, can present as delirium with few findings other than hemianopia, and in some cases may present with no focal symptoms or signs.
        • In the absence of an obvious cause for delirium, further testing including neuroimaging, LP, and EEG is indicated.
      • The physical signs of metabolic/toxic delirium include multifocal myoclonus, asterixis, and postural action tremor.
        • However, these are nonspecific findings and do not help establish any particular medical etiology within the metabolic/toxic category.
    • Physical findings suggestive of drug exposure may be useful.
      • For example, anticholinergic exposure would reveal increased temperature, flushed dry skin, tachycardia, and pupillary dilation on the exam (More on this 👉appendix)

    Indications for more comprehensive investigations

    • Delirium is common among critically ill patients, but not every patient requires an exhaustive workup.
    • Some indications for more aggressive evaluation include:
      • A rapid and major change in mental status.
      • Delirium was the presenting problem at the hospital.
        • It is important to note that most patients with delirium have more than one etiology. There are multifactorial etiologies contributing to delirium *.
      • No obvious cause for delirium.
      • No history of prior delirium/dementia.

    Basic labs *

    • Fingerstick glucose (STAT).
    • CBC with differential (anemia, leukocytosis)
    • Basic metabolic panel: (Hypo-/hypernatremia, hypercalcemia, uremia?) *
    • ECG: Ischemic changes, arrhythmia, electrolyte abnormality

    Further lab tests may be considered depending on context *:

    • Liver function tests.
    • Ammonia
    • TSH.
    • ABG/VBG (if hypercarbia is suspected).
    • Infectious workup (e.g. urinalysis, blood cultures, chest X-ray).
      • 💡Urine analysis frequently shows pyuria and bacteriuria in older adults. Consider alternative etiologies, especially in the absence of symptoms of UTI, pyelonephritis, or absence of signs of infection such as fever or leukocytosis *.
    • Levels of medications the patient is on (e.g. lithium, digoxin, phenytoin, theophylline, valproic acid, phenobarbital).
      • 💡Keep in mind that delirium can happen even with “therapeutic” levels of such agents as digoxin, lithium, or quinidine.
    • Toxicologic workup {e.g. carboxyhemoglobin (CO poisoning), salicylates, acetaminophen, ethanol level}.

    Neuroimaging

    • Nonenhanced CT head may be considered for *:
      • Patients presenting with delirium with unclear history.
      • History of trauma.
      • Significant anticoagulation *.
      • Focal neurologic abnormality (note however that subdural hematoma can depress mental status without focal findings).
      • Substantially reduced level of consciousness.
    • MRI may provide additional information about a variety of conditions (especially CVA). Furthermore, brain MRI may suggest the underlying cause of toxic metabolic encephalopathy (shown below) *.

    Lumbar puncture (LP) may be considered if

    • Delirium is the chief complaint on admission to the hospital.
    • Evidence of infection (fever, leukocytosis, nuchal rigidity).
    • The presence of an obvious precipitating factor for CNS infection such as endocarditis or a history of neurosurgery *.

    🔴Neuroimaging should be obtained before LP in patients with coma, focal signs, papilledema, or suspicion of increased ICP because of the very low but real risk of precipitating transtentorial herniation.

    EEG should be considered if:

    • History of seizure or active neurologic disorder that predisposes to seizure.
    • Exam findings concerning for nonconvulsive status epilepticus, e.g. a bitten tongue or posterior fracture-dislocation of the shoulder, signs of head injury.
    • Unexplained delirium despite other investigations.

    Management

    Delirium is an urgent medical condition, and prompt review of possible causes or inciting factors should be performed. Underlying causes such as pain, metabolic derangements, infection, and hypoxemia should be sought and treated. The management of delirium encompasses two broad categories:

    • Prevention
    • Pharmacologic treatment of dangerous agitation

    An overview of diagnostic and therapeutic approaches to delirium is shown below.

    delirium
    Prevention and Treatment of Delirium

    Preventive measures

    • Avoid and remove factors known to cause or aggravate delirium:
      • Avoid deliriogenic medications
        • ⚠️Benzodiazepines, in particular, are often implicated.
          • In one systematic review, the authors concluded that benzodiazepines should be avoided in high-risk patients, while caution should be used in prescribing opioids, dihydropyridines, and antihistamines *.
      • Maintain hydration.
      • Environmental and supportive measures.
        • Reduce noise, avoid restraints and disruption of the sleep-wake cycle, and early mobilization.
      • Prevent and treat pain and discomfort (more on this below).
        • Pain is a significant risk factor for delirium *,*.
        • Remove unnecessary invasive devices.
        • Treat urinary or fecal disorders.
          • Assess for and treat urinary retention (so-called cystocerebral syndrome) and fecal impaction *.
      • Promote sleep and circadian rhythm
        • Prevention *
          • Stimulate during the day:
            • Use the patient’s glasses and hearing aids if needed.
            • Physical therapy.
            • Open window shades.
          • Limit stimulation at night:
            • Using earplugs at night has been shown to avoid delirium.
            • Decrease the frequency of vital sign monitoring at night if possible (especially blood pressure cuff cycling).
            • Night-time noise should be reduced.
            • Nursing and medical procedures, including the administration of medications, should be avoided during sleeping hours when possible.
            • Use of single ICU rooms that are quieter.
        • Treat insomnia. Preferred medications are:
          • Quetiapine 12.5-25 mg PO QHS might be the best agent.
          • Trazodone 25-100 mg PO QHS
            • Contraindications/side effects of note: QT prolongation, torsade de pointes, orthostatic hypotension, promotion of serotonin syndrome.
          • Dexmedetomidine: Low-dose, nightly dexmedetomidine is probably the most effective agent to promote sleep and daytime wakefulness.
            • If dexmedetomidine is used for insomnia or nocturnal agitation, it should be discontinued or aggressively down-titrated the following morning. Reserving dexmedetomidine for nocturnal use may promote the preservation of a normal circadian rhythm.
          • Oral clonidine (0.2-0.3 mg QHS) may be considered as an alternative to dexmedetomidine for mild insomnia.
          • Melatonin may still be utilized for the management of insomnia.
          • ⚠️Avoid using of deliriogenic sedatives (e.g. benzodiazepine, diphenhydramine, or zolpidem).

    Treatment strategy once delirium is established:

    • Identify and treat the underlying cause of delirium.
    • Fever treatment.
    • Management of pain & discomfort
      • Appropriate sedation regimens.

    Identify and treat the underlying cause of delirium

    • Drugs
      • Consider the etiologic role of newly initiated drugs, increased doses, interactions, over-the-counter drugs, and alcohol.
      • Consider especially the role of high-risk drugs: lower the dose.
      • Discontinue the deliriogenic drugs, or substitute a less psychoactive medication.
    • Correct metabolic/electrolyte disturbances, especially:
      • Hypoglycemia 📖
      • Sodium disturbance: Hypernatremia, Hyponatremia 📖
      • Hypercalcemia 📖
      • Hepatic encephalopathy: If this is probable, empiric treatment may be reasonable. 📖
      • Wernicke encephalopathy: If this is possible, empirically give thiamine 500 mg IV q8hr.
      • Hypoxemia/hypercarbia
      • Uremic encephalopathy 📖
    • Infections: Evaluate and treat, especially urinary tract, respiratory tract, skin, and soft tissue.
    • Intoxication/Withdrawal
      • Treat intoxication, especially, digoxin 📖, lithium 📖, antidote for specific drug-poisoning syndromes.
      • Withdrawal from alcohol and sedatives.

    Fever treatment

    Background

    • Fever in the ICU is defined as a temperature >38.3C *. However, a lower threshold for fever (>38/100.4) may be appropriate in some patients
      • Immunocompromised patients (e.g. neutropenic).
      • Elderly patients.
      • Patients on scheduled acetaminophen or NSAIDs.
      • Patients on ECMO or continuous renal replacement therapy.
    • Hyperpyrexia: This is the term used for an extraordinarily high fever (>41.5°C), which can be seen in patients with severe infections but can also occur in patients with central nervous system (CNS) hemorrhages.
    • Hyperthermia is defined as elevated temperature resulting from excess heat generation, rather than from an alteration of the hypothalamic set point and is suggested by the following clinical features:
      • Extreme temperature elevation (temperatures >41C).
      • Lack of rigors (in contrast to fever, that rigors can precede temperature spikes).
      • Skin may be hot and dry (but not always).
      • Antipyretics are ineffective.
    Causes of fever (expand to view)

    🔴Infectious: Pneumonia, urinary tract infection, line infection, surgical site infection, etc.

    🔴Non-infectious
    1. Procedure-related: Febrile transfusion reaction, bronchoscopy, hemodialysis, postoperative fever (1-3 days post-surgery, usually <39C).
    2. Medication-related: a)Drug fever. b)Medication-induced hyperthermia: Serotonin syndrome, neuroleptic malignant syndrome, malignant hyperthermia.
    3. Sterile inflammation (pancreatitis, aspiration pneumonitis, ARDS).
    4. Pulmonary embolism (usually low-grade fever, <39/102 *
    5. Neurogenic fever (a.k.a. central fever): Subarachnoid hemorrhage, intracranial hemorrhage, traumatic brain injury *
    6. Toxicologic a) Salicylate, tricyclic antidepressant, anticholinergic, sympathomimetic toxicity, thyroid hormones b)Withdrawals: Alcohol, benzodiazepines, baclofen
    7. Miscellaneous
    a)Malignancies (e.g. leukemia, lymphoma)
    b)Systemic inflammatory disease (e.g. Polyarteritis nodosa, giant cell arteritis, inflammatory bowel disease)
    c)Adrenal insufficiency
    d)Thyroiditis

    Deciding whether to treat fever in adults.

    • Whether to treat fever and hyperpyrexia is often debated.
      • Unlike fever and hyperpyrexia, there is no debate that hyperthermia should always be treated to rapidly reduce core temperature.
    • When deciding whether to treat patients with fever, consideration of the adverse effects of pharmacologic and nonpharmacologic treatments must also be considered, as well as the possibility of masking temperature fluctuations that may provide valuable diagnostic or treatment-related information.
    • It’s generally best to avoid antipyretics, as these will obscure the true fever curve in hospitalized adult patients.
    • Indications for antipyretics:
      • Severe fever (e.g. >40C).
      • Neurologic injury (e.g. stroke, anoxic brain injury).
      • Fever in patients with advanced age, underlying cardiac or pulmonary disease, or those on chemotherapy or checkpoint inhibitor therapy.
      • Fever appears to cause clinical deterioration (fever can cause some patients to become delirious or tachycardia).

    Treat pain & discomfort

    Multimodal therapy

    Multimodal therapy is a useful principle that can be applied to treat a variety of topics (e.g. pain, anxiety, hemodynamic support).

    • It refers to using moderate doses of several different agents, in order to maximize efficacy while minimizing toxicity *.
      • Using lower doses avoids toxicity from each medication, while the use of several medications provides synergistic efficacy.
        • Different agents frequently work in a synergistic fashion (i.e. 1+1 = 3). Synergy allows moderate doses of several different agents to have a large combined impact.

    Target of treatment

    • Ideally, an uncomfortable patient should be evaluated to determine the source of discomfort. This should be treated appropriately:
      • Pain should be treated with an analgesic agent.
      • Anxiety refers to fear or uneasiness in the absence of confusion. If medication is required, the optimal medication is a sedative (e.g. propofol or dexmedetomidine).
      • Agitated delirium refers to an acute confusional state marked by agitation. If medication is required, the optimal therapy is an antipsychotic.
    • However, in practice, it may be impossible to differentiate precisely between pain, anxiety, or agitated delirium.
      • The ultimate goal is to keep the patient comfortable and calm while avoiding iatrogenic harm from medications.

    Multimodal analgesia

    • Multimodal analgesia has been shown to significantly reduce morbidity and mortality and the use of opioids in critically ill patients *.
    • The analgesia should be targeted specifically at pain.
      • Analgesics shouldn’t be used as nonspecific “calm down” medication for any agitated patient.
    • The multimodal analgesia protocol involves systematic and periodic pain assessment of all patients, using validated and standardized pain scales:
      • A numerical rating scale (NRS) or visual analog scale (VAS) for patients able to communicate
      • A behavioral pain scale (BPS) for patients who could not be evaluated otherwise can help determine whether the patient is in pain.
    • The use of analgesia is titrated to pain intensity.
    • There are many regimens and designs for multimodal analgesia, however, there is no one-size-fits-all design for analgesia in critical patients. For example, patients with neuropathic pain may benefit from up-front initiation of a gabapentinoid, whereas most other patients probably won’t.
    • The most popular strategy for critically ill patients is shown below:

    Step 1: Acetaminophen

    • Pharmacology
      • Acetaminophen (aka. paracetamol), is a centrally acting non-competitive reversible inhibitor of cyclooxygenase (COX) enzymes with analgesic and antipyretic effects but lacks anti-inflammatory activity compared to other COX inhibitors *.
      • Metabolized hepatically
    • Advantages: Both analgesic and antipyretic effects, safety profile, effective analgesia in a variety of contexts with benefits which may include reduced opioid requirements, reduced delirium, and avoidance of nausea/vomiting *,*,*.
    • Contraindications and cautions
      • Contraindicated in acute liver injury or decompensated cirrhosis.
      • Dose reduction of up to 2 grams/day in patients with alcoholism, chronic liver disease, or low body weight (<50 kg) *.
      • In neutropenia, acetaminophen might be avoided, to allow for early detection of neutropenic fever.
      • It’s not a very potent analgesic.
    • Indications / Usage
      • Antipyretic (when indicated)
      • Analgesia: It is used as the first level of the analgesic in the multimodal analgesic protocol (due to its safety, rather than its efficacy).
    • Dosage
      • The usual dose is 650-1,000 mg q6hr (up to 4 grams/day). For patients with ongoing pain this should be scheduled, to provide a baseline level of analgesia.

    Step 2: Opioids PRN

    • They are often used as second-line therapy, mostly due to convenience.
    • For more stable patients with moderate pain who can take oral medications, oral opioids may be preferable.
    • The most important aspect of opioid administration is dose titration, rather than the selection of any particular drug.
    • PRN bolus-dose opioids will often be required for the management of critically ill patients.
    • Opioid toxicity increases substantially with the use of a continuous opioid infusion, so these should be avoided whenever possible.
    • Agents
      • The most commonly used IV opioids in critically ill patients: Fentanyl 💉, hydromorphone 💉, and morphine 💉.
      • Other opioids, especially tramadol, and meperidine, have numerous side effects and no role in managing critically ill patients.
    • Complications
      • Delirium
      • Respiratory suppression
      • GI: Nausea/vomiting, gastroparesis, ileus, and colonic pseudo-obstruction which may lead to colonic perforation.
      • Opioid dependence and withdrawal.

    Step 2: Ketamine infusion +/- clonidine/dexmedetomidine

    • Ketamine
      • Pain-dose ketamine provides a mild-moderate amount of analgesia.
      • Ketamine has been shown to reduce opioid requirements and decrease the incidence of nausea/vomiting *,*.
      • Ketamine may also attenuate the development of opioid tolerance and opioid-induced hyperalgesia, thereby making co-administered opioids safer and more effective*,*.
      • Dose: The typical dosing range is 0.1-0.3 mg/kg/h.
        • However, guidelines suggest that doses up to 1 mg/kg/h may be used, with close monitoring for psychomimetic side effects *.
    • Dexmedetomidine/clonidine
      • Dexmedetomidine or clonidine synergizes with ketamine to improve analgesia *.
      • Dexmedetomidine or clonidine also prevents the psychomimetic side effects of ketamine, thereby further enhancing the safety of ketamine *,*.
      • Contraindications: Patients with bradycardia, heart block, or hypotension.
      • Dexmedetomidine dose:
        • Do not give bolus doses. Start the infusion at a high rate (e.g. 1-1.4 mcg/kg/min) and down-titrate as the drug takes effect (within an hour). Infusion rate at 0-1.4 mcg/kg/hr.
      • Clonidine dose
        • Multimodal analgesia: Start at 0.1-0.2 mg q12h. May increase to 0.3-0.4mg q8h.

    Step 3: NSAIDs

    • NSAIDs are generally not preferred in critically ill patients due to risks of renal failure, GI hemorrhage, and platelet dysfunction.
    • NSAIDs may be considered selectively for patients who meet all the following criteria:
      • The patient is on no other nephrotoxic medications.
      • Renal function is good and stable.
      • No sources of hemodynamic instability or impaired perfusion.
      • Absence of cirrhosis or inflammatory bowel diseas
      • No history of GI ulceration/bleeding.
      • No active hemorrhage or severe coagulopathy.
    • IV ketorolac 💉 takes effect faster than oral agents.

    Step 3: Gabapentinoids

    • Pharmacology
      • These drugs don’t actually interact with GABA receptors (they function to inhibit voltage-dependent calcium channels).
      • Gabapentin has a half-life of 5-7 hours, which is prolonged in renal dysfunction.
      • Pregabalin may have a faster onset, with 90% bioavailability and peak concentration within an hour.
    • Indications: Predominantly for neuropathic pain e.g. Guillain-Barre Syndrome, diabetic neuropathy, spinal cord injury, post-herpetic neuralgia, pain due to subarachnoid hemorrhage; post-stroke central pain.
    • Contraindications and cautions
      • Side effects include somnolence, respiratory depression, hypoactive delirium, and myoclonus.
      • Risks are compounded by renal dysfunction and other CNS-suppressive medications.
      • Rapid discontinuation of gabapentinoids can cause withdrawal.
        • Patients who were on these medications prior to ICU admission should generally be continued on them (with dose adjustment as needed based on renal function).

    Step 4: Fentanyl infusion

    • Fentanyl infusions should be avoided whenever possible, for many reasons:
      • Over several days patients will become tolerant to opioids, which may subsequently cause withdrawal when fentanyl is discontinued *.
      • Fentanyl accumulates in adipose tissue, causing the drug to remain after the infusion is stopped, leading to delayed awakening *.
      • A 25 mcg/hr fentanyl infusion is equivalent to 120 mg of oxycodone per day.
        • Unless the patient has some extraordinary source of pain, 25-50 mcg/hr of fentanyl should be sufficient.
        • High-dose fentanyl infusions can exacerbate pain, a phenomenon known as opioid-induced hyperalgesia*.
    • If a fentanyl infusion is used, attempts should be made on a regular basis to reduce the dose.

    Sedation for intubated patients

    • Intubated patients will generally require a sedative infusion
      • Sedative regimens that focus on targeted arousal levels and light sedation have positively affected the rates of delirium.
      • In contrast, exposure to sedative medications and deeper levels of sedation have been associated with an increased risk of delirium.
    • Sedation should therefore be titrated to the minimal required amount to keep the patient comfortable and safe but awake.
    • Choosing a sedative regimen for an intubated patient may involve the following steps
      • Step 1:Initiate a cornerstone sedative infusion.
        • Agent of choice: Propofol or dexmedetomidine.
      • Step 2: Addition of a basal adjunctive agent(s)
        • Fundamental concept
          • Basal agents may be used to reduce the required dose of propofol or dexmedetomidine.
            • Decreasing the dose of propofol or dexmedetomidine may avoid complications with these agents (e.g. hemodynamic instability, propofol infusion syndrome, or dexmedetomidine tolerance/withdrawal).
          • Basal agents are required to achieve control of refractory agitation.
        • Agents: Atypical antipsychotics (quetiapine or olanzapine), phenobarbital, oral ⍺-2 agonist (e.g. clonidine), valproic acid.
      • Step 3: Switching to dissociative ketamine infusion (when all above medications fail)
        • A dissociative-dose ketamine infusion (e.g. 1-5 mg/kg/hour) is an option when all above medications fail (esp. in patients with profound hypotension, which limits the ability to give sedatives (e.g., propofol, alpha-2 agonists, or phenobarbital) *.

    Dexmedetomidine: Sedalgesics (sedation > analgesia)

    • Pharmacology
      • It is a highly selective, centrally acting ⍺-2-agonist with anxiolytic, sedative, and some analgesic effects.
      • Infusion takes ~30-60 min to reach equilibrium levels.
      • Excretion is mostly renal.
    • Advantages
      • When used for sedation during mechanical ventilation, it has improved delirium outcomes in RCT when compared to lorazepam *, midazolam *, propofol, and morphine.
      • Lack of respiratory depression.
        • Therefore it is safe to use in non-intubated patients as well as throughout the weaning process (unlike propofol, which must be shut off before extubation). This is an excellent option for patients who develop anxiety and tachypnea whenever sedation is lifted, making it difficult to extubate them *.
      • Titratable infusion, which can be discontinued easily.
      • Patients often remain arousable while on dexmedetomidine (so this may be used in situations requiring frequent neurologic examinations) *.
    • Disadvantages
      • It may cause hypotension due to bradycardia (especially when bolused).
        • This issue can be circumvented with an infusion of low-dose epinephrine or dobutamine if the use of dexmedetomidine is critical.
        • Avoid boluses of dexmedetomidine, as these can cause bradycardia and hemodynamic instability.
        • Rather, the infusion may be started at a high rate (e.g. 1-1.4 mcg/kg/min) and down-titrated as the drug takes effect (within an hour).
      • Prolonged uninterrupted use (>3-5 days) may cause tolerance and subsequent withdrawal after dexmedetomidine is discontinued *.
        • Using lower doses of dexmedetomidine (e.g., 0.8 mcg/kg/hr or less) might help avoid withdrawal *.
        • If tolerance occurs, dexmedetomidine may be transitioned to oral clonidine *.
      • It does not provide very deep levels of sedation.
        • However, deep sedation isn’t usually preferred among critical patients, it may be desirable in some situations such as patients undergoing intubated prone ventilation.
      • Delayed onset of action, so it’s not a good option for acute, dangerous agitation.
    • Indications
      • Sedation of intubated patients who are close to extubation (e.g. within 2-4 days of extubation) *.
      • Sedation of patients who aren’t intubated (e.g. BiPAP).
      • Management of nocturnal agitation (may promote physiological sleep and reduce delirium) *.
    • Dosing 💉
      • Do not give boluses of dexmedetomidine as it may cause bradycardia and hemodynamic collapse.
      • Rather, the infusion may be started at a high rate (e.g. 1-1.4 mcg/kg/min) and down-titrated as the drug takes effect (within an hour).
      • Infusion rate at 0-1.4 mcg/kg/hr.

    Propofol: Pure sedative

    • Pharmacology
      • Propofol is a GABA-receptor agonist. Pure sedative with anticonvulsant properties.
    • Advantages
      • Pharmacokinetic profile, with fast recovery even after prolonged sedation *.
      • Anticonvulsive
      • Dose-dependent reduction of ICP
    • Disadvantages
      • Hemodynamic instability (↓MAP)
        • This can be counteracted with an infusion of low-dose phenylephrine (e.g. ~0-80 mcg/min) or norepinephrine (e.g. ~0-8 mcg/min).
      • Lack of analgesic effect
      • Risk of propofol infusion syndrome 📖.
      • Hypertriglyceridemia
    • Indications
    • Dosing 💉
      • Sedation for intubated patients
        • Initial: 5 mcg/kg/min; increase by 5 to 10 mcg/kg/min q10 min until goal sedation level is achieved.
        • Usual maintenance dose: 5 to 50 mcg/kg/min
    Pharmacologic Treatment of Dangerous Agitation

    The principle of delirium treatment involves a multimodal approach.

    • Treat the underlying cause(s) of delirium
    • Active management of delirium requires consideration of both non-pharmacological and pharmacological options.
      • Pharmacologic treatment of delirium is indicated to manage symptoms that are acutely dangerous (dangerous agitation).
      • Generally, when pharmacologic treatment is indicated, the use of low-dose, short-acting agents is recommended.

    Antipsychotic drugs

    • Antipsychotic drugs interact with several different receptors, causing variable different side effects (table in appendix).
    • Antipsychotic classes:
      • Typical antipsychotics such as haloperidol, predominantly block the D2 dopamine receptor.
        • They have most strong antagonistic effect on D2 dopamine receptors among antipsychotics and a relatively high risk of extrapyramidal symptoms.
          • They can cause dystonia or akathisia (disturbing restlessness).
          • Prolonged administration can cause tardive dyskinesia, so these aren’t preferred as maintenance antipsychotics.
          • The neuroleptic malignant syndrome can occur (rarely).
      • Atypical antipsychotics (e.g. quetiapine, risperidone, olanzapine) block the 5-HT-2A receptor, with less pronounced blockade of the D2 dopamine receptor.
        • A balance of activity against 5-HT2a receptors and D2 receptors reduces the risk of extrapyramidal side effects among atypical antipsychotics.
        • Anticholinergic effects may further reduce the rate of extrapyramidal side effects.
    • General concepts on antipsychotic use
      • Indications for use in the context of delirium:
      • 💡Antipsychotics are not beneficial in patients with hypoactive delirium *.
      • Response variability
        • Patients may respond variably to different agents.
        • If a patient isn’t responding favorably to one agent, it may be better to switch to another agent rather than continuing to up-titrate the dose.
      • Dosage
        • The dose and duration should be limited as much as possible.
        • Optimal dose ranges for ICU patients are largely undefined. Overly aggressive up-titration may increase the risk of neuroleptic malignant syndrome.
          • Among outpatients or patients in the general ward, antipsychotics are generally started at a low dose and up-titrated. This may be a rational approach among critically ill patients as well.
          • Overly aggressive up-titration may increase the risk of neuroleptic malignant syndrome.
          • In a controlled setting (e.g. ICU), higher doses can be used especially for younger patients with more severe agitation.
        • Antipsychotic Dose Conversion Calculator🧮
    EPS/TDSedationAnticholinergic side effectOrthostatic hypotensionQTc prolongationConsideration
    Haloperidol+++++/-–PO: ++
    IV:+++    		⛔️CI: PD, LBD, known QTc prolongation
    Quetiapine -/+++++++++++✅Advantage: Lowest risk of EPS, low risk of TdP.
    ✅Can be used for PD.
    ✅Can be used as a long-term maintenance agent.
    ⚠️Dose adjustment for hepatic dysfunction.
    👉May cause orthostatic hypotension.
    Risperidone+++++++++⛔️CI: PD, LBD, known QTc prolongation
    ⚠️Highest risk of EPS among atypical antipsychotics
    ⚠️Dose reduction in hepatic or renal insufficiency.
    ✅Less sedating among atypical antipsychotics.
    Olanzapine++++++++✅Advantage: No risk of TdP.
    ⚠️Relative CI: Parkinson, DLB
    ⚠️Dose adjustment in renal, hepatic dysfunction
    CI, contraindication; EPS, extrapyramidal symptoms; LBD, Lewy Body Dementia; PD, Parkinson’s disease; TD, tardive dyskinesia; TdP, Torsades de Pointes.

    Butyrophenones (haloperidol & droperidol)

    Advantages

    • Immediately available on most units
    • Can be administered IV/IM.
    • More easily dose-titrated than most other antipsychotics.
    • Hemodynamically stable agents.
    • Do not suppress respiration (allowing them to be used for non-intubated patients).

    Contraindications and toxicity

    • ⚠️QTc prolongation and torsade de pointes can occur.
      • ⛔️These agents are contraindicated in patients with known QTc prolongation. (If this is a problem, consider using olanzapine, which doesn’t affect QT).
    • ⚠️Extrapyramidal symptoms can occur.
      • ⛔️These agents are contraindicated in patients with Parkinson’s disease, or Lewy Body Dementia (LBD).
      • Butyrophenones can cause dystonia or akathisia (disturbing restlessness). This generally isn’t a major problem but must be identified and treated appropriately. Akathisia must not be misdiagnosed as “agitation” and treated with escalating doses of antipsychotic agents.
    • Prolonged administration can cause tardive dyskinesia, so these aren’t preferred as a maintenance antipsychotic (consider quetiapine or olanzapine instead).
    • Neuroleptic malignant syndrome can occur (rarely).

    Use in agitated delirium

    • These agents are a traditional mainstay of initial therapy for dangerous agitation *.
    • These agents may not be ideal for longer-term management of delirium, due to a relatively high risk of extrapyramidal symptoms.
      • If ongoing maintenance therapy is needed, an atypical antipsychotic (e.g. quetiapine or olanzapine) is generally preferable, with IV haloperidol or IV droperidol utilized for PRN management of breakthrough agitation.
      • Continuous or prophylactic dosing is not recommended.

    Haloperidol

    • Route
      • IV route is usually utilized and preferred among the critically ill.
        • This carries a lower risk of dose-stacking or extrapyramidal side effects, though with a higher risk of torsade de pointes.
      • With IV administration, onset occurs in ~5-20 minutes.
      • IM route can be used.
    • Dosage for agitation
      • The initial dosage depends on the severity of agitation, the patient’s age (young vs. elderly group), and the setting in which medication is given, for example, a higher dosage may be used in a closely monitored setting e.g. ICU where the goals and sedation needs are different.
        • The severity of agitation can be assessed 🧮
        • For moderate to severe agitation or psychotic symptoms 0.5 to 1 mg be used as needed, up to a maximum dose of 5 mg per day.
        • Higher doses might be used in ICU: 💉
        • Wait ~20 minutes before re-dosing.

    Droperidol

    • Droperidol is ~2-3 times more potent than haloperidol *. Rapid onset of 3 to 10 minutes, is advantageous in severely agitated violent patients.
    • Onset begins within ~10 minutes when given IM. Half-life is ~2 hours, with a duration of action of ~2-4 hours.
    • Metabolized in the liver.
    • Route: IM or IV
    • Dosage: 💉
      • Wait ~20 minutes before re-dosing.

    Sedating atypical antipsychotics

    (Quetiapine, olanzapine, risperidone)

    General advantages

    • Generally, less extrapyramidal side effects (as compared to prolonged, high-dose haloperidol).  
      • Thus, gradual escalation of scheduled atypical antipsychotics as a haloperidol-sparing agent may lead to an overall safer antipsychotic regimen.
      • May be continued outside of the ICU (for patients with ongoing delirium).
    • A useful combination is often PRN IV haloperidol plus scheduled atypical antipsychotics.

    Olanzapine 💉

    • Route: PO, or IM, or IV
    • The typical starting dose for agitation is 2.5–5 mg IM/IV. May use higher doses for younger and more severe agitation, e.g. 10mg IV.
    • Olanzapine is the preferred agent for managing agitation associated with thyroid storm *.
    • Maintenance therapy for agitated delirium: 5-20 mg PO daily, in the early evening.
    • Advantages
      • Olanzapine doesn’t cause torsade de pointes. So it can be used in patients with prolonged QTc.
      • PO olanzapine can be used as maintenance therapy for agitated delirium.
    • Contraindication, cautions
      • Olanzapine can cause extrapyramidal symptoms (though with a lower risk than typical antipsychotics).
        • ⚠️Thus, Parkinson’s disease and Lewy Body Dementia are a relative contraindication.
      • ⚠️Dose adjustment in elderly, or patients with hepatic and/or renal dysfunction.

    Quetiapine 💊

    • Advantages
      • Lowest risk of extrapyramidal side effects (compared to other antipsychotics).
        • For patients with Parkinson’s disease, quetiapine may be the antipsychotic of choice.
      • Quetiapine can slightly prolong the QTc interval, but the risk of torsade de pointes seems to be extremely low.
    • Contraindications, cautions
      • ⚠️Adjust for hepatic dysfunction.
      • Quetiapine may cause hypotension due to the antagonism of alpha-adrenergic receptors (more so than olanzapine).
        • This may cause orthostatic hypotension for mobile patients.
      • Quetiapine is very sedating, which could be useful for patients on mechanical ventilation.
    • Indication and usage
      • Insomnia: Seven-hour half-life allows effects to wear off overnight.
      • Longer-term maintenance agent for agitation (especially during mechanical ventilation)
        • Quetiapine is very sedating, which could be useful for patients on mechanical ventilation.
    • Dosage
      • Typical starting dose for agitation is 25–50 mg PO q12 hours.
        • Can be used as a long-term maintenance agent for agitation.
      • Typical starting dose for insomnia is 12.5–25 mg PO QHS.

    Risperidone 💊

    • Contraindication and cautions
      • The highest risk of extrapyramidal symptoms among atypical antipsychotics.
        • ⛔️Contraindicated in patients with Parkinson’s disease or Lewy Body Dementia.
      • QTc prolongation and torsade de pointes can occur.
        • ⛔️Risperidone is contraindicated in patients with known QTc prolongation.
      • ⚠️Dose reduction in hepatic or renal insufficiency.
    • Advantage and usage
      • It can be used as an oral maintenance agent in agitated delirium, perhaps as a second-line agent.
      • Less sedating effect than other atypical antipsychotics (e.g. quetiapine, olanzapine).
        • This could be useful in non-intubated patients with intermittent agitation due to an underlying psychiatric disorder.
    • Typical starting dose: ≤ 1 mg PO

    Dexmedetomidine

    • This is a centrally acting alpha-2-agonist with anxiolytic, sedative, and some analgesic effects.
    • Dexmedetomidine is an easily titratable agent with a short half-life.
    • Use in delirious patients
      • Controlling nocturnal agitation (“sundowning”) and promoting sleep at night.
        • It can be used to treat nocturnal agitation and promote sleep at night. The following day, dexmedetomidine can be titrated off, thereby promoting wakefulness during the day *
        • The short half-life of dexmedetomidine avoids the sundowning cycle wherein a patient gets tons of medications for agitation at 2 AM, sleeps for 18 hours, and then wakes up and gets agitated the following night.
    • More on this above.

    Benzodiazepines

    • They are primarily metabolized by the liver, and many have active metabolites prolonging their duration of action.
    • Disadvantages
      • Benzodiazepines might be the most deleriogenic sedative agent.
        • The use of benzodiazepine in particular by infusion, is an independent risk factor for the development of delirium and posttraumatic stress disorder *,*.
      • Benzodiazepines have been shown to increase the duration of mechanical ventilation (when compared to dexmedetomidine or propofol) *.
      • Benzodiazepines may cause paradoxical agitation *,*.
        • This may lead to a vicious spiral of increased benzodiazepine use, leading to obtundation.
      • Ongoing exposure to benzodiazepines may lead to tolerance, with subsequent withdrawal.
      • Lorazepam infusions tend to cause propylene glycol intoxication.
      • Midazolam may accumulate over time in adipose tissue, especially in patients with renal or hepatic dysfunction or due to various drug-drug interactions.
    • Advantages
      • More favorable hemodynamic profile (hemodynamically stable).
      • Anticonvulsive properties.
    • They have a very limited role in the treatment of delirium. Possible indications of benzodiazepine may be limited to
      • Agitation caused by alcohol or substance abuse.
      • Management of moderate-severe alcohol withdrawal.
      • Bupropion intoxication
      • Ketamine re-emergence, procedural sedation.
      • Patients who are chronically on benzodiazepines as a home medication.
      • Palliative sedation
      • Status epilepticus
      • When antipsychotic medications are contraindicated:
        • History of seizure: Antipsychotics lower the seizure threshold.
        • Anti-cholinergic intoxication.
        • Neuroleptic malignant syndrome.
        • Prolonged QTc: Benzodiazepines are the first choice. Olanzapine is the second choice.
    • 🧮Equivalent Benzodiazepine Calculator

    Specific condition

    Agitation associated with sympathomimetic intoxication

    • The traditional belief that antipsychotics may promote hyperthermia or seizures is debunked.
      • Sympathomimetic intoxication increases brain dopamine activity, therefore antipsychotics may work to antagonize dopamine signaling and clear the agitation.
      • Available evidence suggests that antipsychotics are safe and effective *, *.
      • In an RCT involving 92 emergency department patients with methamphetamine-related agitation, who were randomized to treatment with 10 mg droperidol, 10 mg olanzapine, or a combination of 5 mg droperidol plus 5 mg midazolam (all administered intravenously). The droperidol/midazolam combination therapy was more rapidly effective. However, there were more adverse events in the combination therapy group (although they were generally minor) *.
    • Possible treatment options
      • Antipsychotic monotherapy strategy
        • Droperidol or olanzapine 10 mg IV, or IM, followed by an additional 5-10 mg as needed.
        • Haloperidol might work as well, but haloperidol is about half as potent as droperidol/olanzapine. So this would require higher doses of haloperidol to be effective.
      • Antipsychotic/benzodiazepine combination strategy
        • This will work more rapidly to control the agitation.
        • Midazolam 5mg + Droperidol 5mg (or haloperidol 10mg, if droperidol isn’t available) *.
          • Lorazepam should be avoided here due to a slow onset of action.

    Agitation associated with serotonin syndrome

    • Front-line agents are theoretically cyproheptadine and dexmedetomidine.
    • Benzodiazepines are the first choice in patients with seizures.
      • For patients with very mild agitation who can take oral medication, cyproheptadine may be trialed (with the understanding that it takes a while to work).
      • For patients who are unable to take oral medication or need more immediate sedation, dexmedetomidine may be preferable.
      • For patients with seizures who aren’t intubated, benzodiazepines make sense.
      • For an intubated patient, dexmedetomidine or propofol could be used.

    Agitation due to neuroleptic malignant syndrome (NMS)

    • NMS with malignant catatonia: Benzodiazepines may help control agitation and also promote muscle relaxation.
      • A usual dose may be ~2 mg IV q8hr of lorazepam.
      • There is a risk that benzodiazepines could cause or promote the development of delirium.
    • Management of agitation
      • Treatment options may include:
        • Central alpha 2 agonists (e.g.dexmedetomidine, clonidine).
        • Valproate is probably a reasonable treatment for hyperactive delirium in this context.
      • ⛔️Avoid antipsychotics.

    Delirium due to salicylate intoxication

    • CNS glucose levels are often lower than the blood level.
    • Glucose should be given to patients with altered mental status, even if their serum glucose levels are normal (e.g. 1-2 ampules of D50W).
    • The target glucose level is unclear, but it may be reasonable to maintain the glucose >80-100 mg/dL (>4.4-5.5 mM).
    • Glucose infusion should be considered in severe intoxication.
      • Most patients will receive an infusion of isotonic bicarbonate which is formulated in D5W, which should suffice.

    Agitation due to anti-cholinergic intoxication

    • Non-medication therapies
      • If bladder distension is driving agitation, this should be managed with Foley catheter placement.
      • Consider dimming the room lights, as pupil dilation may cause photophobia.
    • Physostigmine 💉
    • Benzodiazepines

    Agitation due to bupropion intoxication

    • Benzodiazepines are front-line therapy (which could also potentially reduce the risk of seizure).

    Appendix

    Receptor-binding profile of antipsychotic medications

    Common Toxidromes

    Media

    Catatonia

    References

    Expand to view the reference list

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    Shahriar Lahouti

    Founder, Chief Editor
    I am Shahriar Lahouti and RECAP EM is my primary FOAMed project. The philosophy of RECAP EM is to promote critical thinking and enlightening the mindsets with most rational, current evidence towards a safer practice.

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