Clinical manifestations

Presentation and course

• Delirium is characterized by a reduction of the level of consciousness, which is manifested clinically by disorientation.

• Criteria for diagnosis of substance intoxication delirium have been defined.

Five criteria are listed in the Diagnostic and Statistical Manual of Mental Disorders V for the diagnosis of delirium. Criterion E includes drug-related causes.

Table 1. Diagnostic and Statistical Manual of Mental Disorders IV-TR Criteria for Substance Intoxication Delirium

(A) There is a disturbance in attention and awareness. (B) Delirium develops over a short period of time, typically hours to days. There is a change in baseline attention and awareness. It fluctuates throughout the day. (C) There is also another disturbance in cognition, such as in memory, orientation, language, and perception. (D) The disturbances in (A) and (C) are not better explained by another preexisting, established, or evolving neurocognitive disorder. (Having a neurocognitive disorder, however, increases the risk of the development of delirium.) (E) There must also be evidence that the delirium is due to a direct physiological consequence of another medical condition, substance intoxication or withdrawal, or exposure to a toxin, or it is due to multiple etiologies. There are many specifiers for delirium that clarify the cause. Those relevant to drugs are:
	(1) substance intoxication delirium (2) substance withdrawal delirium (3) medication-induced delirium
(02)

Manifestations of delirium include short-term memory deficits, misinterpretation of surroundings, and language difficulties. In addition to fluctuations of consciousness and cognition, the affective and psychotic features may vary a great deal from time to time. Other features include insomnia, difficulty in concentration, restlessness, irritability, hypersensitivity to lights and sounds, and nightmares. Physical signs of delirium may include autonomic system activation, but these are blunted in elderly patients.

Prognosis and complications

The definition of delirium no longer requires reversibility as a criterion. Drug-induced delirium usually clears up on removal of the offending medication, but it may be slow to resolve and recovery may be only partial or may never occur at all. In the elderly, symptoms of delirium may persist even after the underlying condition is addressed and the patient is discharged from the hospital; about one fifth of patients may have residual symptoms of the delirium present even 6 months after discharge. Cognitive impairment may outlast the acute syndrome.

Overall mortality rates reported in the literature vary between 10% and 70%. The higher mortality reflects advanced age and severe underlying disease. Delirium is an important marker of risk for dementia and death in older people, even without prior cognitive or functional impairment.

Biological basis

Etiology and pathogenesis

• Delirium is a diffuse brain disturbance that involves both cortical and subcortical structures.

• Multiple factors are involved in the pathomechanism of delirium, but medications are considered the most common cause of delirium in the hospital setting.

• Anticholinergic medications produce classic delirium that can be reversed with cholinesterase inhibitors.

Because multiple factors are implicated in the etiology of delirium, several neurobiological processes may contribute to delirium pathogenesis, including neuroinflammation, cerebrovascular dysfunction, altered brain metabolism, neurotransmitter imbalance, and impaired neuronal network connectivity (60).

DSM-V recognizes substance related disorders resulting from the use of 10 separate classes of drugs: alcohol, caffeine, cannabis, hallucinogens (phencyclidine or similarly acting arylcyclohexylamines), other hallucinogens such as LSD, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants (including amphetamine-type substances, cocaine, and other stimulants), tobacco, and other or unknown substances. Drugs reported to be associated with delirium are listed in Table 2. Most of the information about drugs causing delirium is based on anecdotal information; sometimes this information is based on single case reports. Because of the complicating background factors, association of delirium with drugs is difficult to investigate by controlled studies. In some cases, the drug's relationship with delirium has been established by "dechallenge," ie, clearing up of the adverse reaction after discontinuation of the suspected medication, and "rechallenge," ie, recurrence of the adverse effect after resumption of the suspected medication.

Table 2. Drugs Associated with Delirium

Analgesics
	• Nonsteroid anti-inflammatory drugs* • Opioid analgesics* • Intrathecal ziconotide*
Anticancer drugs
	• Chemotherapeutics • Cytokines: Interferon-alpha, interleukin-2*
Anticholinergic agents*
	• Antimuscarinic agents, eg, atropine, tricyclic antidepressants • Antinicotinic agents, eg, bupropion
Anticonvulsants
	• Levetiracetam (22)
Antidepressants
	• Tricyclic antidepressants • Selective serotonin reuptake inhibitors: fluoxetine • Noradrenergic and specific serotonergic antidepressants: mirtazapine • Serotonin and norepinephrine reuptake inhibitors: venlafaxine
Antimalarials: chloroquine, mefloquine Antimicrobials
	• Acyclovir • Amphotericin • Azithromycin • Clarithromycin • Ertapenem (57) • Fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin) • Gentamicin • Itraconazole • Nalidixic acid • Sulfonamides • Tobramycin
Antiparkinson drugs
	• Levodopa • Dopamine agonists • Amantadine • Benztropine • Trimethobenzamide
Antipsychotics
	• Chlorpromazine • Clozapine • Olanzapine • Lithium • Perphenazine • Risperidone • Thioridazine • Trifluoperazine • Benzodiazepines*
Cardiovascular drugs
	• Antihypertensives • Beta blockers • Clonidine
Antiarrhythmics: amiodarone Diuretics
	• Digitalis • Quinidine
CNS stimulants Drug abuse Drug interactions
	• Clozapine and lorazepam • Fluoxetine and clarithromycin • Ibuprofen and tacrine • Lithium and risperidone • Paroxetine and zolpidem • Tranylcypromine and disulfiram
Drug combinations
	• Valproic acid and lamotrigine • Diphenhydramine and linezolid
Corticosteroids Antihistaminics
	• Histamine H2-receptor antagonists*
Hypnotics-sedatives
	• Zolpidem
Miscellaneous drugs
	• Atropine • Baclofen • Bromides • Cyclobenzaprine • Disulfiram • Ergotamine-caffeine combination • Fentanyl transdermal • Metrizamide • Methazolamide • Niridazole • Omeprazole • Podophyllin • Procaine derivatives • Sodium nitroprusside • Theophylline
Drug withdrawal
	• Abrupt discontinuation of serotonin reuptake inhibitors (07) • Sudden discontinuation of sedative drugs* • Withdrawal from narcotic drugs* • Withdrawal from gamma hydroxyl butyrate • Abrupt cessation of baclofen and tizanidine
*Denotes established and frequent association

Anticholinergic agents. Anticholinergic agents, drugs that block the action of the neurotransmitter acetylcholine in the brain, are the leading cause of drug-induced delirium. These agents are also an important cause of drug-induced memory disorders. Anticholinergic agents include antidepressants, antipsychotics, antihistamines, antispasmodics, antiemetics, and antiparkinsonian agents. However, the relationship of anticholinergic drugs to delirium is difficult to establish in prospective clinical studies.

Antidepressants. Tricyclic antidepressants have a high affinity for antagonizing the histamine receptors, as well as the muscarinic acetylcholine receptors, which can induce delirium. SSRIs are associated with delirium as a side effect. Tianeptine, an atypical antidepressant that enhances serotonin reuptake, has been reported to induce delirium (56).

Antimicrobials. A retrospective study in a veteran population has shown that fluoroquinolones were associated with delirium when used in patients on typical antipsychotics and those of advanced age (47). Delirium occurred in 3.6% of patients treated with ciprofloxacin and 4.5% of those treated with moxifloxacin. Delirium associated with fluoroquinolones are rarely reported, eg, there are only 8 published cases of levofloxacin-induced delirium (40). This potentially fatal adverse effect of levofloxacin is more common in practice than reported.

Antiparkinsonian drugs. Varieties of neuropsychiatric disturbances (eg, psychoses, hallucinations, delirium) occur as a complication of the drug treatment of Parkinson disease (25). All drug categories including anticholinergic drugs, levodopa, and dopaminergic agonists have the potential to produce delirium. Older patients with dementia are particularly at risk when on anticholinergic drugs. Amantadine, originally discovered as an antiviral agent before it became an antiparkinson drug, is also used for the treatment of acute influenza. An elderly patient developed delirium with psychotic features 48 after initiation of standard dose of amantadine for influenza (39). Parkinson disease patients who tolerate amantadine well as long-term therapy can develop delirium when the drug is suddenly withdrawn due to therapeutic regimen change (16; 36). Gradual withdrawal can prevent this adverse effect.

Antipsychotics. Antipsychotics can induce delirium. Clozapine-induced delirium has been reported. Delirium is known with acute lithium intoxication but is rare with therapeutic doses of the drug. A case has been reported of a patient with schizophrenia who developed severe delirium shortly after initiation of a lithium-quetiapine combination therapy, although therapeutic doses of both drugs were used and resolved after discontinuation of lithium (37).

Benzodiazepines. Risk of delirium is increased in older hospitalized patients receiving benzodiazepines. Delirium may also occur in long-term users of benzodiazepines because of withdrawal. Short-acting agents such as alprazolam are more likely to produce withdrawal reactions.

Corticosteroids. Psychological, cognitive, and behavioral disturbances are well recognized side effects of glucocorticosteroids. Delirium, confusion, or disorientation have been reported to occur in 15.7 per 100 person-years at risk for all glucocorticoid courses of treatment, and 22.2 per 100 person-years at risk for first courses (27). Tapered withdrawal of the offending drug usually resolves the situation but if symptoms persist, treatment with antipsychotic drugs and benzodiazepines may be needed.

Interferons. Neuropsychiatric symptoms are a prominent feature of interferon syndrome, including an acute confusional state that develops rapidly after initiation of high-dose interferon alpha. Strategies for managing delirium should be employed, including treatment of contributing medical conditions, use of either typical or atypical antipsychotic agents, and avoidance of medications likely to worsen mental status.

Drug abuse. Cocaine-related delirium is now common and is likely due to disruption of dopaminergic function from chronic use of the drug, which, when coupled with recent cocaine use, may precipitate agitation, delirium, aberrant thermoregulation, rhabdomyolysis, and sudden death. Gamma-hydroxybutyrate withdrawal syndrome may progress to delirium.

Histamine H2-receptor antagonists. All drugs of this class have the potential to cause delirium. Cimetidine has the largest number of reported cases because it was the first drug of this class to enter the market. CNS toxicity generally occurs during the first 2 weeks of therapy and is seen mostly in intensive care patients, particularly in those patients with renal gland hepatic failure. The reaction usually resolves within a few days of drug withdrawal.

Nonsteroid anti-inflammatory drugs. There are several reports of the association of nonsteroid anti-inflammatory drugs with delirium. Because these are the most used drugs, the cognitive impact is considerable. Toxicity from aspirin frequently manifests as delirium.

Opioid analgesics. Of the opioid analgesics, meperidine (pethidine) poses the greatest risk for delirium because of the accumulation of its metabolite, norpethidine, which has anticholinergic properties. Because the clearance is by the kidney, the metabolite is more likely to accumulate in elderly subjects with impaired renal function. In a comparative study of the use of opioids as analgesics in cancer patients, fentanyl was associated with a much lower risk of delirium than morphine (55).

Drug withdrawal. Delirium due to withdrawal of narcotics and sedatives is well known, but it may also occur due to cessation of other drugs such as muscle relaxants. A case of delirium was reported due to abrupt cessation of baclofen and tizanidine and resolved in 24 hours after reintroduction of baclofen (28).

One case has been reported of delirium following withdrawal from gamma hydroxyl butyrate, a recreational drug, but the patient recovered in 11 days (29).

Little is known about pathophysiological mechanisms in delirium. Reduced severe oxidative metabolism may cause brain dysfunction due to abnormalities in various neurotransmitter systems. There is probably no final common pathway to delirium, but it is the final common symptom of multiple neurotransmitter abnormalities. One hypothesis of a final common pathway is based on neuroanatomical data derived from neuroimaging and lesion reports in prefrontal cortex, thalamus, posterior parietal cortex, and basal ganglia. Among the neurotransmitters implicated in delirium, acetylcholine deficiency and dopamine excess (as well as their interaction with each other) appear to be critical in the final common pathway of delirium.

Cerebrospinal fluid levels of somatostatin and beta-endorphin are low in patients with delirium, indicating disturbances in the chemistry of the brain. Another abnormality in delirium is cortisol excess, which seems to be abnormal “shut-off” of the hypothalamic-pituitary-adrenal axis as tested by the dexamethasone suppression test. Measurement of serum levels of anticholinergic activity in delirious states shows that these levels are raised and correlate it with delirium induced by drugs with cholinergic effect.

Pathogenesis of delirium. This is often multifactorial and may involve the interaction of precipitating factors with underlying patient vulnerability. Various risk factors for the development of delirium are shown in Table 3.

Table 3. Risk Factors for Development of Drug-Induced Delirium

Predisposing factors (vulnerability)
	• Advanced age • Sensory impairment: hearing and vision • Brain damage • Dementia • Psychiatric disorders • Addiction to alcohol or drugs
Precipitating factors
	• Multiple psychoactive drugs • Severe acute illness • Sleep deprivation • Major surgery • Intensive care setting • Immobilization • Stress • Sensory overstimulation

Three main risk factors for delirium are generally recognized: advanced age, brain damage, and addiction to alcohol or other drugs. Age is a significant risk factor for drug-induced delirium for the following reasons:

	• The elderly may be at greater risk of drug-induced confusion than younger people because of decreased functional reserve of the CNS and alterations in neurotransmitter systems.
	• Alzheimer disease and vascular dementia, which are more common in this age group, are predisposing factors for the development of drug-induced delirium.
	• Elderly patients taking multiple psychotropic drugs are at increased risk for developing delirium because of the cholinergic effects of these drugs. In a study of the 25 most prescribed drugs for the elderly, 14 were associated with detectable anticholinergic levels as measured by radioreceptor assay.
	• Age-associated changes or diseases of liver and kidney may interfere with drug clearance.

Among the precipitating causes of delirium, an acute febrile illness usually associated with infection is well recognized. Exposure to multiple noxious stimuli such as trauma, surgery, general anesthesia, and multiple psychoactive medications can induce delirium even in healthy individuals without predisposing risk factors. The following factors may play a part in postoperative delirium:

	• Physical stress of surgery may cause an increase in corticosteroids
	• Anesthesia required for major surgery
	• Disturbances of cerebral circulation and metabolism associated with cardiovascular and neurosurgical procedures
	• Immobilization following orthopedic procedures
	• Opioid analgesics used in the postoperative period

The use of benzodiazepines or opioids in the intensive care unit is associated with longer duration of a first episode of delirium, and these are modifiable risk factors for delirium.

Pathomechanism of drug-induced delirium. Among hospitalized patients, the leading drug-induced causes in descending order are as follows:

• Opioid analgesics • Benzodiazepines • Anticholinergics • Nonsteroidal anti-inflammatory drugs • Sedative withdrawal

Drugs can induce delirium in several ways such as:

	• Toxic concentrations of drugs due to overdose or impaired clearance
	• Pharmacodynamic changes may result in increased sensitivity to normal concentrations of centrally acting drugs
	• Drug-disease interaction such as in patients with dementia where the risk of delirium is enhanced due to diminished "cognitive reserve"
	• Drug-drug interactions in the case of polypharmacy

The actual mechanisms by which drugs cause delirium are poorly understood because the pathophysiology of delirium itself is not well understood. Delirium is a diffuse brain disturbance that involves both cortical and subcortical structures. Although multiple neurotransmitters are involved, most of the current evidence points to cholinergic failure. Anticholinergic medications produce classic delirium that can be reversed with cholinesterase inhibitors. Clinical conditions that cause delirium, such as thiamine deficiency and hypoglycemia, also impair acetylcholine synthesis. Radioreceptor assays, which measure muscarinic binding, enable a more precise determination of the mechanism of drug-induced delirium. Acute confusion can correlate with increased serum anticholinergic activity. Several drugs that are not traditional anticholinergics but cause delirium show measurable cholinergic receptor binding by this assay. Among the drugs currently in use, well over 600 have some anticholinergic effects. In addition to cholinergic deficiency, there may be an imbalance between acetylcholine and dopamine. Two types of delirium have been described: a hypo-reactive delirium due to tramadol (an opiate with anticholinergic effect), and a hyper-reactive delirium after administration of L-dopa (31).

Cases of delirium have been reported as side effects of selective serotonin reuptake inhibitors (SSRIs) used as antidepressants (30). There is a case report of lidocaine-induced delirium (01). The pathomechanism is not clear in these cases.

A study on patients has shown that delirium following fentanyl and midazolam is unrelated to midazolam and may be linked to inflammatory status, suggesting that iatrogenic coma and delirium are not mechanistically linked (51). Fluctuations in sedation levels may contribute to development of delirium, but this can be reduced by maintaining a stable sedation level (54).

An example of delirium due to drug-drug interaction is the addition of bupropion to duloxetine in an elderly patient with major depressive disorder that resulted in a high level of hydroxybupropion, as both drugs are cytochrome P450 2D6 inhibitors (34). Increase in level of hydroxybupropion further raises dopamine level, which is a risk factor for delirium, and this patient improved after discontinuation of bupropion and drop in the blood level of hydroxybupropion.

Epidemiology

• Prevalence rate of delirium in the community is low but high in hospitalized patients.

• One third of all cases of delirium are drug-induced.

Accurate data on incidence of, prevalence of, and mortality due to delirium are difficult to obtain and evaluate because of differences in definitions and methodology. Most information is based on hospitalized patients, but a community study, the Eastern Baltimore Mental Survey, found a point prevalence rate of 0.4% in the adult population, rising to 1.1% in those aged 55 or over (14).

In contrast to the low prevalence rate in the community, 10% to 30% of all hospitalized patients meet criteria for delirium at some point during their stay. Delirium occurs in up to 50% of patients after major surgery. This would make delirium the mental disorder with the highest incidence. Prevalence in nursing homes is even higher. In a study combining old patients at home, in nursing homes, and in hospitals, delirium was diagnosed in 43.9% of the patients, and 42.9% of the delirious patients had dementia as well (45). This high figure of prevalence of delirium is due to the coincident prevalence of dementia in the elderly population.

Delirium rates in the pediatric ICU are higher than 25% and are associated with prolonged mechanical ventilation and hospital length of stay (50).

Approximately one third of all cases of delirium are drug-induced. Postoperative delirium occurs in 7% to 52% of patients undergoing surgery, depending on patient population and clinical setting (08). Delirium develops in 44% to 55% of hip surgery patients versus 10% to 14% of general surgery patients (42). Delirium occurs in 25% to 40% of all patients with cancer and in up to 85% of patients who are in the terminal phase of the disease (58). This alteration in mental status may be attributable to both the underlying condition as well as to the cancer treatment utilized. Delirium develops in 43% of the patients undergoing hematopoietic stem cell transplantation (04). Delirium is associated with higher mortality in these patients.

In a prospective study of 1500 hospital neurologic consultations, delirium accounted for 7% of all cases and 19% of all iatrogenic neurologic disorders (38). Delirium was drug-induced in 17% of these cases, and drugs were suspected to have contributed to delirium in 47% of the cases in which no single cause was identified.

A survey of hospitalized patients in the United States during 1998 to 2005 recorded delirium in 0.54% of nonpsychiatric adult hospitalizations (32). Whereas the overall prevalence of dementia-associated delirium and nondrug, nondementia delirium decreased over time, drug-induced delirium prevalence increased. The presence of dementia and adverse drug effects had the strongest associations with dementia-associated and drug-induced delirium, respectively, in the cohort hospitalizations. The findings suggest that interventions focusing on adverse drug effects have the greatest potential for preventing delirium.

Prevention

• Close monitoring of the patient’s medications is the most important prevention against drug-induced delirium.

Multidisciplinary interventions to prevent delirium include the following: adjustment of medications, early detection and management of cognitive impairment, treatment of sleep disorders, mobilization of patients, aids for visual and hearing impairment, and correction of dehydration. To reduce the morbidity and mortality associated with drug-induced delirium, and to prevent it, patients' medications should be closely monitored.

Preventive measures against drug-induced delirium are:

	• Anticholinergic, sedative-hypnotic, and opioid medications should be used sparingly in the elderly.
	• Prevalence of delirium in children is lowered by reduction of benzodiazepine-based sedation.
	• Avoidance of combinations of drugs suspected to cause delirium. The combination of benzodiazepines and clozapine should be avoided if possible.
	• Clinicians caring for intensive care unit patients should carefully evaluate the need for benzodiazepines, opioids, and haloperidol, which are known risk factors for precipitating delirium. There is an association between cumulative dose of haloperidol and next-day delirium in older medical intensive care unit patients (43). Each additional cumulative milligram of haloperidol was associated with 5% higher odds and intubation with a 5-fold increase of next-day delirium. Haloperidol use to control delirium has been associated with development of neuroleptic malignant syndrome (11).

Differential diagnosis

Confusing conditions

Various conditions that have similar presentation and should be considered in the differential diagnosis of delirium are:

• Anticholinergic syndrome: delirium, hallucinations, dilated pupils, etc. • Serotonin syndrome: agitation, confusion, hyperreflexia, tremor, fever, diarrhea, etc. • Neuroleptic malignant syndrome: confusion, disorientation, muscle rigidity, fever, etc.

Associated or underlying disorders

Table 4. Underlying Disorders and Risk Factors for Stroke

(A) Drug withdrawal
	• Withdrawal of therapeutic drugs • Withdrawal of drugs of abuse • Alcohol withdrawal: delirium tremens
(B) Acute neurologic disorders that may present with delirium
	• Stroke • Meningitis • Traumatic brain injury • Epilepsy
(C) Viral infections of the brain
	NeuroCovid
	Viral encephalopathies
(D) Other conditions that are also risk factors for the development of delirium
	• Hypoglycemia • Hypoxia • Hepatic or renal insufficiency • Endocrinopathies, eg, hyperthyroidism
(E) Psychiatric disorders
	• Dementia • Confusion in elderly patients • Depressive stupor • Psychoses schizophrenia, mania
(F) The intensive care unit syndrome, which is an altered emotional state, occurs in a highly stressful environment and may manifest itself as delirium.

Drug-induced delirium. Anticholinergics, together with several different drugs, may significantly contribute to the delirium onset, especially in elderly, demented persons. Side effects such as delirium, induced by anticholinergic drugs, are particularly severe in aging brain.

Anticholinergic syndrome used to be common after general anesthesia because of the premedication with anticholinergic agents atropine and scopolamine. Because these agents are used infrequently, this syndrome occurs infrequently but may still occur due to anticholinergic effect of some general anesthetics. Therefore, this syndrome should still be considered in the differential diagnosis of delirium after anesthesia. It can be reversed by administration of physostigmine.

Dementia. After drug-induced disorders, the next most important differential diagnosis is dementia. Delirium has an acute onset, whereas dementia develops slowly over a longer period. In uncomplicated dementia, consciousness remains essentially intact, whereas its impairment is an important feature of delirium. One of the features of dementia is short-term memory deficit in the absence of an attentional deficit before the disease progresses to impair long-term memory as well. In delirium, short-term memory deficit does not occur in the absence of attentional deficits, and there is no clear-cut progression to long-term memory deficits. A higher-level term cognitive impairment that includes both dementia and delirium may be used if it is not possible to delineate delirium from dementia, which may coexist in a particular patient.

NeuroCovid. Delirium is frequently found in patients who test positive for COVID-19, even in the absence of respiratory symptoms (03). COVID-19 is associated with neuropsychiatric symptoms with a higher rate of agitation, myoclonus, abulia, and alogia.

Schizophrenia. Clinical features common to delirium and schizophrenia are incoherent speech, disturbances of affect, delusions, and hallucinations. Delusions form a part of abnormal beliefs in schizophrenic patients, and hallucinations are usually auditory. Hallucinations in delirium are usually visual. Consciousness, memory, and attention are relatively unimpaired in schizophrenia as compared to delirium. There may be a difficulty in differentiating between delirium and an acute psychotic state where the patient may be confused and show signs of altered consciousness.

Diagnostic workup

	• Careful history
	• Basic laboratory studies
	• Rating scales for delirium

The most important step in the diagnosis of delirium is a careful drug history, and noting the temporal relationship to any new medication at the onset of delirium. Delirium is often overlooked on initial examination.

Various rating scales are available. The Delirium Rating Scale is the most widely used instrument in research studies for rating the severity of delirium with validity, high interrater reliability and substantial sensitivity and specificity. The Delirium Rating Scale has been translated from English into many other languages, and the 10 items of the scale are:

(1) Temporal onset (2) Perceptual disturbances (3) Hallucinations (4) Delusions (5) Psychomotor behavior (6) Cognitive status (7) Physical disorder (8) Sleep-wake cycle disturbances (9) Lability of mood (10) Validity of symptoms

The Delirium Rating Scale has been revised to include separate items for each cognitive function and items for rating the severity of impairment of thought and language.

The Memorial Delirium Assessment Scale (MDAS) is a 10-item severity-rating instrument for delirium in patients with advanced cancer. A study has compared the revised Delirium Rating Scale (DRS-R98) and MDAS and found that the derived conversion rules demonstrated promising accuracy in this palliative care population (41).

A systematic review of the literature shows that Anticholinergic Risk Scale (ARS) is consistently associated with delirium due to Anticholinergic Drug Burden (ADB), but the association between its modified versions and Anticholinergic Cognitive Burden Scale and delirium needs confirmation. When ADB was assessed with other scales, the findings were inconclusive. The current findings suggest that the ARS might be a useful tool to identify patients at increased risk for delirium (13).

General investigations. These include basic laboratory studies: complete blood count, urine analysis, electrolytes, creatinine, blood urea nitrogen, arterial blood gases, liver enzymes, and calcium levels. Further tests are based on the results of the basic evaluation. In some cases, physical examination may give important clues to the nature of the drugs involved. Toxic screens and serum estimations of drugs are useful, but these may be within therapeutic range in elderly patients and still be the causative agent. Neurologic diagnostic procedures may include EEG, lumbar puncture, and brain imaging.

Management

	• Early recognition of the condition
	• Management of agitation
	• Identification and treatment of the underlying cause
	• General supportive care
	• Limited pharmacotherapy with caution

General measures. General principles of the clinical management of delirium are:

(1) Early recognition of the condition (2) Identification and treatment of the underlying cause
	(a) Discontinuation of the offending medication (b) Treatment of the primary disease process
		1. Correction of the electrolyte abnormalities and anemia 2. Correction of the hypoxemia 3. Treatment of heart failure 4. Pain relief in case of cancer and surgery
(3) Management of agitation
	(a) Behavioral control
		1. Reassuring communication 2. Provide orientation, eg, time, window view
	(b) Social restraint (try to avoid physical restraints) (c) Pharmacotherapy (only in other measures fail)
(4) General supportive care
	(a) Remove indwelling urinary catheter as soon as possible (b) Mobilize the patient as soon as possible
(5) Maintenance of adequate nutrition (6) In postoperative patients, judicious use of oxygen can treat delirium effectively (7) Pharmacotherapy
	(a) Limited use of drugs with caution

The causative role of newly initiated drugs, increased doses, interactions, over-the-counter drugs, and alcohol should be considered, especially the role of high-risk drugs, and measures should be to lower the dose, discontinue the drug, or substitute a less psychoactive medication (35).

Anticholinergic delirium. Anticholinergic delirium is the only form of delirium for which specific pharmacotherapy is available. Anticholinergic delirium is best managed by physostigmine, a cholinesterase inhibitor. It can reverse delirium due to anticholinergic toxicity for up to 1 hour following a 1 to 2 mg intravenous dose. Adverse effects of intravenous infusion are cardiotoxicity and signs of cholinergic excess such as seizures, nausea, and vomiting. The short duration of action and potential for serious cholinergic side effects, which requires close monitoring, are major limitations to its use. It can potentiate toxicity of tricyclic antidepressant overdose.

Cholinesterase inhibitor donepezil is an effective choice in the management of anticholinergic drug induced delirium.

Nonspecific pharmacotherapy. Few controlled studies of the pharmacological management of delirium have been performed. The major reported methods of treatment are antipsychotics or benzodiazepines. If the patient is aggressive or dangerous, intravenous diazepam may be used until the patient is fully sedated. Parenteral antipsychotics that have been used in this situation include haloperidol, trifluoperazine, and thiothixene. The major advantage of haloperidol is its lack of anticholinergic activity. Risperidone may prove to be an effective alternative to haloperidol in delirious patients, especially the elderly and the severely medically ill who are more prone to adverse effects.

Delirium in special disease groups and medical situations. There are special considerations for the treatment of delirium in various groups.

Postoperative delirium. There is no global guideline with standardized concepts of management of postoperative delirium. It is important to detect patients with high risk for postoperative delirium and to apply personalized measures based on correction of risk factors. The most important predisposing risk factors are a higher age, preexisting cognitive deficits, multimorbidity, and an associated pro-delirious polypharmacy. Multidisciplinary approaches to pharmacological and nonpharmacological management are highly recommended (12).

Delirium in critically ill patients. Patients in the intensive care unit often suffer sleep disturbances and abnormal circadian rhythms, which may increase delirium and lengthen stay. Monitoring should be done routinely. The best-validated intensive care unit bedside instruments are Conclusion Assessment Method of Intensive Care Unit and Intensive Care Delirium Screening Checklist, both of which also detect subsyndromal delirium (53). Both tools have some inherent limitations in the neurologically injured patients but provide valuable information about delirium. Aggravating factors include psychoactive medications, sensory deprivation through prolonged immobilization, uncorrected vision, hearing deficits, and poor sleep hygiene. These should be corrected as much as possible as a part of management.

Nonpharmacologic strategies are usually tried first, but a multimodal approach to care including pharmacotherapy is required. A large, double-blind, randomized, placebo-controlled trial found no evidence that use of the dopamine antagonists haloperidol or ziprasidone significantly altered the duration of delirium in the intensive care unit (17). The dose of haloperidol in the trial was less than 20 mg/day, as a dose higher than 25 mg per day can induce delirium. Despite the limited available data supporting their use, non-benzodiazepine medications such as melatonin, ramelteon, suvorexant, and dexmedetomidine may promote sleep and improve a variety of patient-centric outcomes such as delirium (15).

Delirium in intensive cardiac care units (ICCU). Severe consequences include longer times on mechanical ventilation, increased risks of mortality, cognitive impairment, and dependence at discharge. A protocol for delirium prevention and management in intensive cardiac care units includes a daily comprehensive assessment to improve detection by using validated scales. Preventive measures are amelioration of reversible risk factors, including sleep promotion, family support, communication, and adequate treatment of pain and dyspnea. Pharmacological prophylaxis is not indicated with the exception of patients at risk of withdrawal syndrome but should only be used in patients with confirmed delirium. Dexmedetomidine is the drug of choice in patients with severe agitation and those weaning from invasive mechanical ventilation (10).

AIDS. Symptoms of delirium in medically hospitalized AIDS patients may be treated efficaciously with few side effects by using low-dose neuroleptics (haloperidol or chlorpromazine). Lorazepam alone appears to be ineffective and associated with treatment-limiting adverse effects.

Cancer. Delirium precipitated by opioids and other psychoactive medications is frequently reversible with change of opioid or dose reduction and discontinuation of unnecessary psychoactive medication. Terminal cancer patients may experience acute delirium when treated with morphine but improve when the opioid is changed to oxycodone or fentanyl. This treatment allows patients to remain more comfortable and lucid in their final days. In cancer patients, opioid-induced delirium can improve with intravenous injection of the acetylcholinesterase inhibitor physostigmine.

Parkinson disease. Drugs used to treat Parkinson disease, such as levodopa, often have neuropsychiatric adverse effects, most prominently psychosis and delirium. Elderly patients and those with dementia are particularly vulnerable to these adverse effects. The treatment of drug-induced delirium begins with the manipulation of the antiparkinsonian drug regimen, but this frequently worsens patient motor function. Anticholinergics should be tapered first, as they are most likely to cause delirium. Levodopa should be tapered slowly and not abruptly as it may precipitate a neuroleptic-like syndrome. Atypical antipsychotics such as clozapine have been successfully employed to treat psychosis without worsening motor disability.

Drug withdrawal. There are no specific guidelines for the management of delirium after drug withdrawal. Sometimes the withdrawn drug needs to be resumed for the control of delirium.

Delirium after withdrawal of clozapine resolves rapidly with the resumption of low doses of clozapine. Severe withdrawal symptoms can probably be avoided by slowly tapering clozapine or simultaneously substituting another psychotropic with high anticholinergic activity, such as thioridazine.

Intravenous benzodiazepines are the recommended treatment when delirium is associated with withdrawal from alcohol or delirium tremens. Intravenous or intramuscular lorazepam may be given up to once every 4 hours. There is a risk associated with the use of drugs in this situation as it may aggravate delirium. Benzodiazepines are also causally associated with delirium. Excessive sedation or respiratory depression from benzodiazepines is reversible with flumazenil. Flumazenil can also reverse lorazepam-induced acute delirium if it should occur.

Special considerations

Geriatric age group

Elderly persons are more likely than younger adults to develop drug-induced cognitive impairments, as their renal and liver functions are often impaired (48). Antipsychotics, although not approved for drug-induced delirium, are effective in treating delirium of the elderly in a hospital setting.

Pediatric age group

Intravenous physostigmine, despite a concern for toxicity, has been used successfully as intermittent intravenous injections for control of delirium in a 6-year-old boy who had accidently ingested olanzapine (19).

Anesthesia

Delirium may result from some anesthetics, particularly during recovery from short-acting anesthetics. Preoperative benzodiazepines, breast and abdominal surgery, and surgery of long duration are risk factors for emergence of delirium in the postanesthetic period. In a randomized, double-blind, placebo-controlled trial in children, intravenous administration of 0.03 mg/kg of midazolam just before the end of surgery reduces emergence of agitation without delaying the emergence time in children having surgery with sevoflurane anesthesia (09). Limiting intraoperative sedation depth during spinal anesthesia for surgery in elderly patients can decrease the prevalence of postoperative delirium. The use of light propofol sedation decreased the prevalence of postoperative delirium by 50% compared with deep sedation (49). In a randomized clinical trial on older adults undergoing major surgery, EEG-guided anesthetic administration compared with usual care did not decrease the incidence of postoperative delirium (59). Because of the limited treatment options available for treatment of delirium, risk assessment and perioperative risk reduction may be the most effective approaches in managing postoperative delirium (26).

The American Society for Enhanced Recovery and Perioperative Quality Initiative joint consensus statement on postoperative delirium prevention includes the following strategies (20):

	• Use of multicomponent nonpharmacologic interventions for the prevention of postoperative delirium in older high-risk patients.
	• Minimization of medications known to be associated with an increased risk of postoperative delirium in older high-risk surgical patients.
	• Optimization of postoperative pain control to reduce the risk of postoperative delirium.
	• There is insufficient evidence to recommend administration of prophylactic medications to reduce the risk of postoperative delirium.
	• Intensive care units’ protocol should include sedation with dexmedetomidine to reduce the risk of postoperative delirium in patients requiring postoperative mechanical ventilation.