Understanding and Treating Delirium

Table 1 – Common signs and symptoms of delirium

Table 2 – Differentiating delirium from dementia

Table 3 – A useful mnemonic for remembering possible causes of delirium

Premiere Date: December 20, 2014
Expiration Date: December 20, 2015

This activity offers CE credits for:
1. Physicians (CME)
2. Other

ACTIVITY GOAL

This article reviews the pathophysiology and epidemiology of delirium and provides strategies for assessment, prevention, and management of this syndrome.

LEARNING OBJECTIVES

At the end of this CE activity, participants should be able to:

1. Understand the causes and manifestations of delirium.

2. Understand the different hypotheses ascribed to the pathophysiology of delirium.

3. Explain the epidemiological factors associated with delirium.

4. Define strategies for assessing, preventing, and managing delirium.

TARGET AUDIENCE

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

CREDIT INFORMATION

CME Credit (Physicians): This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of CME Outfitters, LLC, and Psychiatric Times. CME Outfitters, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

CME Outfitters designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Note to Nurse Practitioners and Physician Assistants: AANPCP and AAPA accept certificates of participation for educational activities certified for AMA PRA Category 1 Credit™.

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Alan T. Bates, MD, PhD, has no disclosures to report.

Yesne Alici, MD, has no disclosures to report.

Sandeep Grover, MBBS, MD (peer/content reviewer), has no disclosures to report.

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Delirium is a psychiatric illness to which no one is immune. The right set of unfortunate medical circumstances could induce disturbed attention, disorientation, and even psychosis in any of us. Yet despite the universal risk, relatively high incidence, and potential long-term consequences, delirium is largely without associated advocacy groups or public awareness programs. Even within medicine, delirium struggles to find a home. Describing delirium’s sometimes awkward position somewhere between internal medicine and psychiatry, Engel and Romano¹ wrote in 1959 that “the unfortunate patient’s malfunctioning brain rests in limbo, an object of attention and interest neither to the medical man nor to the psychiatrist.”

It can be argued that relatively little has changed over the decades, but now the modern evolution of psychosomatic medicine as well as greater recognition of the negative effects of delirium by medical and surgical services is creating more rapid progress. The American Delirium Society and the European Delirium Association are examples of organizations working to bridge the gap between medical specialties. Advances in prevention and management of delirium cannot come soon enough, with the “silver tsunami” threatening to overburden health care systems with dementiaassociated costs. Evidence is quickly accumulating for Engel and Romano’s seemingly prophetic assertion that delirium “carries the serious possibility of permanent irreversible brain damage.”

Diagnosis: from DSM-IV to DSM-5

DSM-IV diagnostic criteria for delirium can be summarized as a disturbance in consciousness (eg, changes in awareness or attention) associated with other cognitive changes (eg, memory, language) that is not the result of dementia. Moreover, onset is relatively acute with fluctations in severity throughout the day, and it must be caused by a medical condition (eg, pneumonia).

As with many diagnoses, there was spirited debate about what changes should be made for DSM-5. In the end, the differences between the editions are fairly minimal. DSM-5 drops the more nebulous term “consciousness” and puts the focus squarely on disturbance of attention and awareness. It is also more explicit about differentiating delirium from coma while being less explicit about differentiating it from dementia, a condition that commonly overlaps with delirium.

Delirium as a syndrome

Meagher and colleagues² attempted to better characterize delirium as a syndrome in a sample of 100 palliative care patients exhibiting the disorder. A number of the most common signs and symptoms that they identified overlap with those specifically mentioned in DSM-5, including:

• Disturbed attention (97% of patients)

• Long-term memory impairment (89%)

• Short-term memory impairment (88%)

• Disorientation (76%)

• Reduced visuospatial ability (87%)

• Language disturbance (57%)

• Perceptual abnormalities (50%)

Because hallucinations might be the feature that is most likely to trigger a psychiatry consult, it is worth noting that at least half the patients denied having them.²

The results of this study suggest other pitfalls for how quickly expert management is recruited. A commonly observed shorthand for documenting mental status is “A&O × 3,” for alert and oriented to person, place, and time. Even if this reflects a thorough examination of orientation, which it may not, 25% of patients in this sample would not have shown abnormalities on that single-item screen. Meagher and colleagues also noted sleep-wake cycle disturbance (97%), motor agitation (62%), and retardation (62%) as common manifestations, although they were not explicitly mentioned in DSM-5 criteria. In addition to their prevalence, the finding that each of those 3 signs occurs early in the course of delirium reflects their clinical importance. The common signs and symptoms of delirium are listed in Table 1.

Subtypes and differential diagnosis

One of the more common disputes between clinicians following the same patient is simply whether the patient is delirious or cognitively well. The fluctuating nature of the disorder can cause a patient to present with baseline lucidity to one observer and then with marked disorganization and disorientation to another a few hours later. Rather than suggesting ineptitude of a colleague, these differing assessments should be taken as important diagnostic information.

In addition to fluctuating course, acute onset, impaired attention, and fragmented periods of sleep and wakefulness, several features may help differentiate delirium from dementia (Table 2). However, especially with more advanced dementia, the distinction can be more difficult than the textbooks suggest. Features of Lewy body dementia, including fluctuating awareness and visual hallucinations, make it particularly problematic. Even more difficult is determining whether there is a dementia underlying delirium, since signs of delirium tend to eclipse signs of dementia that might otherwise be more obvious.

Another factor that complicates the differentiation of delirium from other disorders is the hypoactive, hyperactive, and mixed (showing signs of both hypoactive and hyperactive) subtypes, which expand delirium’s potential for mimicry. The finding that delirium is often mistaken for depression reflects the overlapping features of the two disorders, including psychomotor poverty, amotivation, and sedation.³ On the other side of the spectrum, restlessness, psychomotor agitation, and hallucinations in hyperactive delirium may cause clinicians to consider anxiety, mania, or long-standing psychosis as possible causes.

Regardless of the subtype of delirium-hypoactive, hyperactive, or mixed-it is the temporal evolution (acute rather than insidious onset, fluctuating rather than constant) that provides the best clues to diagnosis. Another point worth noting about differentiating delirium from psychotic disorders such as schizophrenia is that hallucinations in delirium tend to be visual rather than auditory.

Rating scales

Rating scales can play a role in differentiating delirium from other disorders and also in monitoring response to treatment. Although not actually a delirium rating scale, the scale most commonly used in the context of delirium is the Mini-Mental State Examination (MMSE).⁴ It provides a coarse measure of performance on a number of cognitive domains, such as orientation, language, calculation, and memory. However, while areas of relative weakness might suggest particular lesions or deficits, the MMSE does not differentiate delirium from other causes of cognitive dysfunction.

A similar criticism can be leveled against the Montreal Cognitive Assessment (MoCA),⁵ although many clinicians have begun using it in place of the MMSE for brief cognitive screening. The MoCA has greater sensitivity in detecting mild cognitive impairment and provides better assessment of frontal lobe functions, including executive function, abstract thinking, and word generation. It is free and available for clinical use in several languages at www.mocatest.org.

Several rating scales have been developed specifically for delirium, each with its own strengths and weaknesses. The Confusion Assessment Method (CAM)⁶ is the most commonly used, likely because of its simplicity. It provides a screening algorithm with 4 items (acute onset and fluctuating course, inattention, and either disorganized thinking or altered level of consciousness) that can be used by nurses and others with less advanced psychiatric training. While the relative simplicity of CAM allows for large numbers of patients to be screened by nonpsychiatrists, its sensitivity can be significantly affected by the user’s experience.

Ely and colleagues^7,8 have extended the use of CAM to mechanically ventilated patients in the ICU with CAM-ICU. However, care should be taken when using CAM-ICU outside that specific setting because it is not sufficiently sensitive.⁹

With 13 severity items and 3 diagnostic items, the Delirium Rating Scale-Revised-98 (DRS-R-98) can be used to differentiate delirium from dementia, depression, or schizophrenia as well as to assess severity and record phenomenology for clinical or research purposes.¹⁰ It is generally used by clinicians with psychiatric training.

The Memorial Delirium Assessment Scale (MDAS) is similarly intended for use by clinicians with more advanced training. MDAS was initially validated in patients with advanced cancer or AIDS.¹¹ It is designed to be administered a number of times within the same day to allow observation of changes following clinical events or targeted interventions.

Although subtypes are often commented on in diagnosis, even more comprehensive ratings scales tend to include only 1 or 2 items to differentiate them (eg, Item 7: motor agitation; Item 8: motor retardation on the DRS-R-98; Item 9: decreased or increased psychomotor activity on the MDAS). While rating scales can be useful clinical tools and are especially valuable for research, thorough clinical evaluation supplemented by information from family and nursing staff is still the gold standard in eliciting information about fluctuating attention.

Distress to patients, family, and staff

Delirium is often a very frightening experience for patients and their friends and family. It can also make nursing care more difficult or even dangerous. Breitbart and colleagues¹² found significant delirium-related distress in hospitalized cancer patients as well as in their spouses, caregivers, and nurses. The presence of delusions was the strongest predictor of distress in patients with either hypoactive delirium or hyperactive delirium.

Jones and colleagues¹³ demonstrated an association between delusional memories and PTSD in patients who had been mechanically ventilated in the ICU. Overall, they found that in 9.2% of the previously ventilated ICU patients, PTSD related to the ICU admission developed 3 months after ICU discharge.

Long-term sequelae

Although causation is difficult to demonstrate definitively, there is mounting evidence that delirium is associated with more long-term cognitive decline. Bickel and colleagues¹⁴ examined cognitive performance 38 months after discharge in 200 hip surgery patients older than 60. Forty-one patients experienced postoperative delirium. At the time of follow-up, MMSE scores were below 24 for 54% of the patients with delirium and for 4% of those without. Logistic regression adjusted for age, sex, medical comorbidity, and preoperative cognitive performance still showed significant associations between delirium and cognitive impairment, subjective memory decline, and need for long-term care.

Findings from a meta-analysis indicate that in elderly patients, delirium is associated with increased risk of death (38% vs 28% in controls) at average follow-up of 23 months, increased risk of institutionalization (33% vs 11%) at average follow-up of 15 months, and increased risk of dementia (63% vs 8%) at average follow-up of 4 years.¹⁵ Confounding variables, such as age, sex, comorbid illness, illness severity, and baseline dementia, were controlled in the studies included in the meta-analysis.

More recently, Pandharipande and colleagues¹⁶ evaluated cognitive decline in patients with respiratory failure or shock that required ICU admission. They found that delirium developed in 74% of the 821 participants. At 12-month follow-up, 34% showed cognitive function similar to patients with moderate traumatic brain injury, and 24% performed at a level similar to what is observed in mild Alzheimer disease. Longer duration of delirium was correlated with worse cognitive function at follow-up.

Mortality

At least in some settings, delirium is associated with hastened death. Controlling for baseline cognitive function, physical function, and health status, Curyto and colleagues¹⁷ found that delirium in hospitalized elderly patients was associated with increased 3-year mortality (75% vs 51% in controls). An unfortunate association has also been seen between delirium and mor­tality in older patients.^18,19 Delirium in mechanically ventilated ICU patients appears to be an ominous sign.²⁰ In older ICU patients, it may be that not only the presence of delirium but also the duration of delirium is a risk factor.

Financial cost

Delirium presents a significant financial cost to the health care system. Milbrandt and colleagues²¹ calculated the influence of delirium on both ICU costs and overall hospitalization costs. They found that in patients who required mechanical ventilation in the ICU, delirium increased median ICU cost from $13,332 to $22,346 and median hospital costs from $27,106 to $41,836. They also found that these costs increased incrementally with severity of delirium. Even after controlling for possible confounding variables, such as age, comorbidity, severity of illness, degree of organ dysfunction, nosocomial infection, and hospital mortality, delirium was still associated with a 39% increase in ICU cost and a 31% increase in hospitalization cost.

Prevalence and incidence

Analysis of data from the East Baltimore Mental Health Survey showed that prevalence of delirium in the community increases significantly with advanced age: 0.4% in those older than 18 and 1.1% in those older than 55, but it climbs to 13.6% in those older than 85.²² Children are not immune to delirium. Pediatric delirium occurs in at least 30% of critically ill children.²³

In persons older than 75 in nursing homes, the prevalence of delirium can approach 60%.²⁴ There is also a high incidence of delirium in persons who undergo acute medical care. Postoperative periods are particularly high-risk times. Cardiac surgery is more likely to be followed by delirium than are other types of surgery. Findings from Rudolph and colleagues²⁵ suggest an incidence of 52% in postoperative cardiac surgery patients older than 60. Up to 70% of patients who require admission to an ICU during their hospitalization experience delirium at some point, and the incidence is as high as 88% in patients with terminal illness.^26-28

Risk factors

Knowledge of risk factors for delirium is useful for 2 main reasons. The first is that identification of risk factors may help predict risk of future delirium. For example, identification of multiple risk factors in a preoperative assessment might elicit a psychiatry consultation for postoperative monitoring. Because eliminating the medical condition causing delirium is the most definitive treatment, knowledge of risk factors also helps in trying to determine underlying causes that need to be addressed (Table 3).

A number of groups have attempted to identify premorbid risk factors that could be used to predict (and hopefully prevent) delirium by way of some kind of algorithm. While some risk factors are commonly identified as being important ones in such analyses, there are also many differences in results between studies. This is partly explained by studies that examined different populations (eg, postsurgical vs nursing home).

One of the most studied populations has been cardiac surgery patients. Giltay and colleagues²⁹ collected data on 8139 patients undergoing coronary artery bypass grafting and/or a valve procedure. They found that postoperative psychosis was associated with preoperative variables that included age, renal failure, dyspnea, heart failure, and left ventricular hypertrophy, as well as perioperative variables such as hypothermia, hypoxemia, low hematocrit value, renal failure, high sodium level, infection, and stroke. Unfortunately, despite the large sample size, the study did not identify a definitive list of key risk factors.

In a review of risk factors in cardiac surgery patients, Sockalingam and colleagues³⁰ identified a long list of risk factors ranging from the expected, such as opiate medications, to the less intuitive, such as marital problems. As an example of how risk factors differ between populations, Inouye andcolleagues³¹ found dementia, vision impairment, functional impairment, high comorbidity, and use of physical restraints to be the strongest risk factors for delirium in older patients.

Pathophysiology

Maldonado^32,33 has published thorough reviews of what is known about the pathophysiology of delirium. He groups current theories into the neuro­inflammatory, oxidative stress, neurotransmitter deficiency, neuroendocrine, diurnal dysregulation, network disconnectivity, and neuronal aging hypotheses.

The neuroinflammatory hypothesis suggests that systemic inflammatory processes from insults such as infection or surgery elicit inflammatory responses in the brain. Evidence includes a study by de Rooij and colleages,³⁴ who found increased cytokine levels in patients with delirium even after controlling for infection, age, and cognitive impairment. The oxidative stress hypothesis posits delirium to be a fundamental breakdown in cerebral metabolism with deficient oxygenation, which predisposes to delirium.³⁵

The neurotransmitter deficiency hypothesis is likely the best-known and the most basic version. It describes delirium as a disorder of acetylcholine deficiency and dopamine excess. It is also likely the theory most directly tied to clinical practice, since physicians who treat delirium are always on the lookout for anticholinergic medications that need to be discontinued. Dopamine-blocking antipsychotic medications are the standard pharmacological agents for management.

The neuroendocrine hypothesis focuses primarily on problematic effects of elevated glucocorticoid levels seen in times of physiological stress. At Memorial Sloan Kettering Cancer Center, we commonly see patients who become delirious as the result of exogenous glucocorticoids prescribed as part of chemotherapy regimens or to limit the adverse effects of cancer treatments.

The diurnal dysregulation theory points to the association between delirium and disrupted sleep and indicates that poor sleep generally predates the appearance of delirium. The network disconnectivity hypothesis applies more of a systems neuroscience approach to explaining the pathophysiology of delirium and includes evidence of abnormal coordination between brain regions from modern imaging techniques, including functional MRI.³⁶

The neuronal aging hypothesis integrates aspects of a number of the other hypotheses and provides a pathophysiological framework for why older patients are more susceptible to delirium. Maldonado^32,33 stresses the overlap in the different core hypotheses and suggests that they are primarily complementary rather than competing.

Nonpharmacological prevention and management

In a study of 852 elderly patients admitted to a general medical service, the incidence of delirium was reduced from 15% to 9% with a number of nonpharmacological interventions, including frequent reorientation, engagement in cognitively stimulating activities, promotion of sleep with sleep-inducing stimuli (eg, relaxation tapes, warm milk) and a sleep-promoting environment (eg, noise reduction), encouragement of physical activity, use of visual and auditory aids (eg, glasses, portable amplifying devices), and early treatment of dehydration.³⁷

Although pharmacological management of delirium in older patients should be a last resort, most medical and surgical wards do not emulate the therapeutic environment of Inouye and colleagues.³⁷ In an effort to reduce incidence and severity of delirium, some of the lowest hanging fruit may be environmental changes to hospital wards and behavioral changes for medical staff.

Pharmacological prophylaxis

To date, only a few studies have examined prophylactic use of antipsychotics in surgical patients. Among the studies that looked at prophylactic use of haloperidol, 2 found decreased incidence of delirium, while the third found only reduction in duration.^38-40 There is some evidence that the prophylactic use of risperidone and olanzapine has decreased the incidence of post­operative delirium, and a meta-analysis suggests prophylactic use of antipsychotics cuts the incidence in half.^41-43

Antipsychotic prophylaxis for ICU delirium has not been as successful. In a sample of ICU patients who required mechanical ventilation, there was no difference between haloperidol and placebo.⁴⁴ Using a completely different pharmacological strategy, Al-Aama and colleagues⁴⁵ found that prophylactic melatonin reduced the incidence of delirium in patients older than 65 who were admitted to an acute care hospital.

In summary, there is evidence for prophylaxis with antipsychotics in the postoperative setting but not the ICU setting. Further research is warranted on alternative strategies, such as melatonin.

Pharmacological management

The definitive intervention for delirium is to treat the underlying cause or causes, which often involves medications (eg, an antibiotic for a urinary tract infection). Aside from interventions to target etiologies, medications are also often used to target the signs and symptoms of delirium. Some argue that treating the signs and symptoms serves only to decrease distress and maintain safety for the patient, visitors, and staff. Others point to the long-term sequelae of delirium and theorize that treatment that decreases severity and/or duration decreases risk of cognitive decline.

Antipsychotics are used most often-haloperidol is the most commonly used. With potent dopamine antagonism and little anticholinergic effect, haloperidol is a logical choice for a disorder thought to be associated with a hyperdomaninergic/hypocholinergic state. Other advantages include the potential for intravenous administration and little autonomic effect. However, direct comparisons of effectiveness between antipsychotics tend not to reveal any differences.^46,47

• Chlorpromazine and risperidone were equally effective as haloperidol in randomized double-blind trials^48,49

• No significant difference was found between olanzapine and haloperidol or risperidone in randomized single-blind trials^50,51

• Quetiapine decreased the duration of delirium compared with placebo in a randomized double-blind trial⁵²

• No significant difference was found between aripiprazole and haloperidol in a nonrandomized open-label trial⁵³

The choice of medication is best guided by patient-specific factors. For example, quetiapine might be a good choice for a delirious patient with Parkinson disease.

It should be noted that an entirely different treatment strategy must be adopted for delirium due to alcohol withdrawal. The evolving best practices in treating alcohol withdrawal are beyond the scope of this review, but it is generally treated with benzodiazepines. Unfortunately, alcohol withdrawal delirium can be difficult to differentiate from other kinds of delirium. Factors that suggest alcohol withdrawal include a significant alcohol history, a history of alcohol withdrawal, laboratory tests that suggest alcohol abuse (eg, positive blood alcohol, elevated γ-glutamyl transferase level, elevated carbohydrate-deficient transferrin level, elevated aspartate aminotransferase/alanine aminotransferase ratio, elevated mean corpuscular volume), unstable vital signs, diaphoresis, and tremor.

Educating families

Unless there is clear conflict between a patient and a family member, it is invaluable to have a family member at the bedside of a patient with or at risk for delirium. Family members provide reorientation and reassurance, and they help patients get their needs met. Unfortunately, family members usually know little about delirium, which can result in defensive reactions when assessing or managing changes in mental status (eg, “You don’t understand. He’s not crazy. He doesn’t need a psychiatrist!”).

Gagnon and colleagues⁵⁴ found that providing education about delirium to family members increased their confidence in making treatment decisions. Similarly, Otani and colleagues⁵⁵ reported that 81% of family members found the receipt of an educational leaflet to be useful.

Although family members often do not know what delirium is, they are frequently the first to notice that something is “off” with the patient. Steis and colleagues⁵⁶ found that family members can be usefully integrated into more formal screening for delirium. They showed that family caregivers using the Family Confusion Assessment Method (FAM-CAM) demon­strated 88% sensitivity and 98% specificity for identifying delirium using CAM as a comparative standard.

There are a number of educational Web sites about delirium that can benefit both families and clinicians who are less familiar with the disorder. www.thisisnotmymom.ca is an example of a site that shows the important role family members play and also provides case examples that may help inform clinicians.

Future directions

Compared with disorders such as schizophrenia and depression, delirium has attracted relatively little clinical or research interest within psychiatry. Unfortunately, it has also traditionally been neglected by acute care, surgery, and other areas of medicine in which delirium is common. This historical neglect leaves enormous opportunity for progress in research and clinical practice that will ultimately lead to significant benefit to patients.

The complex pathophysiology of delirium and the broad spectrum of fluctuating clinical signs suggest opportunity for directing different medications at different physiological processes and tailoring management for individual patients. Rather than being an impediment to care, delirium’s span across several medical specialties should lead to collaboration between psychiatrists, neurologists, intensive care specialists, surgeons, geriatricians, and other specialists. Groups that draw on these different medical specialties and integrate work from fields such as genetics, clinical neurophysiology, psychopharmacology, and brain imaging will be the ones that lead us to a greater understanding of modulation of attention and awareness in both health and disease.

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Disclosures:

Dr Bates is a Staff Psychiatrist in the department of psychiatry at the University of British Columbia in Vancouver. Dr Alici is Assistant Attending Psychiatrist in the department of psychiatry and behavioral sciences at the Memorial Sloan Kettering Cancer Center in New York.

References:

1. Engel GL, Romano J. Delirium, a syndrome of cerebral insufficiency. J Chron Dis. 1959;9:260-277.

2. Meagher DJ, Moran M, Raju B, et al. Phenomenology of delirium: assessment of 100 adult cases using standardised measures. Br J Psychiatry. 2007;190:135-141.

3. Nicholas LM, Lindsey BA. Delirium presenting with symptoms of depression. Psychosomatics. 1995;36:471-479.

4. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-198.

5. Nasreddine ZS, Phillips NA, Bédirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53:695-699.

6. Inouye SK, van Dyck CH, Alessi CA, et al. Clarifying confusion: the confusion assessment method: a new method for detection of delirium. Ann Intern Med. 1990;113:941-948.

7. Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA. 2001;286:2703-2710.

8. Ely EW, Margolin R, Francis J, et al. Evaluation of delirium in critically ill patients: validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med. 2001;29:1370-1379.

9. Neufeld KJ, Hayat MJ, Coughlin JM, et al. Evaluation of two intensive care delirium screening tools for non-critically ill hospitalized patients. Psychosomatics. 2011;52:133-140.

10. Trzepacz PT, Mittal D, Torres R, et al. Validation of the Delirium Rating Scale-revised-98: comparison with the delirium rating scale and the cognitive test for delirium [published correction appears in J Neuropsychiatry Clin Neurosci. 2001;13:433]. J Neuropsychiatry Clin Neurosci. 2001;13:229-242.

11. Breitbart W, Rosenfeld B, Roth A, et al. The Memorial Delirium Assessment Scale. J Pain Symptom Manage. 1997;13:128-137.

12. Breitbart W, Gibson C, Tremblay A. The delirium experience: delirium recall and delirium-related distress in hospitalized patients with cancer, their spouses/caregivers, and their nurses. Psychosomatics. 2002;43:183-194.

13. Jones C, Bäckman C, Capuzzo M, et al. Precipitants of post-traumatic stress disorder following intensive care: a hypothesis generating study of diversity in care. Intensive Care Med. 2007;33:978-985.

14. Bickel H, Gradinger R, Kochs E, Förstl H. High risk of cognitive and functional decline after postoperative delirium: a three-year prospective study. Dement Geriatr Cogn Disord. 2008;26:26-31.

15. Witlox J, Eurelings LS, de Jonghe JF, et al. Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: a meta-analysis. JAMA. 2010;304:443-451.

16. Pandharipande PP, Girard TD, Jackson JC, et al; BRAIN-ICU Study Investigators. Long-term cognitive impairment after critical illness. N Engl J Med. 2013;369:1306-1316.

17. Curyto KJ, Johnson J, TenHave T, et al. Survival of hospitalized elderly patients with delirium: a prospective study. Am J Geriatr Psychiatry. 2001;9:141-147.

18. Leslie DL, Zhang Y, Holford TR, et al. Premature death associated with delirium at 1-year follow-up. Arch Intern Med. 2005;165:1657-1662.

19. McCusker J, Cole M, Abrahamowicz M, et al. Delirium predicts 12-month mortality. Arch Intern Med. 2002;162:457-463.

20. Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004;291:1753-1762.

21. Milbrandt EB, Deppen S, Harrison PL, et al. Costs associated with delirium in mechanically ventilated patients. Crit Care Med. 2004;32:955-962.

22. Folstein MF, Bassett SS, Romanoski AJ, Nestadt G. The epidemiology of delirium in the community: the Eastern Baltimore Mental Health Survey. Int Psychogeriatr. 1991;3:169-176.

23. Smith HA, Brink E, Fuchs DC, et al. Pediatric delirium: monitoring and management in the pediatric intensive care unit. Pediatr Clin North Am. 2013;60:741-760.

24. Sandberg O, Gustafson Y, Brännström B, Bucht G. Prevalence of dementia, delirium and psychiatric symptoms in various care settings for the elderly. Scand J Soc Med. 1998;26:56-62.

25. Rudolph JL, Jones RN, Levkoff SE, et al. Derivation and validation of a preoperative prediction rule for delirium after cardiac surgery. Circulation. 2009;119:229-236.

26. McNicoll L, Pisani MA, Zhang Y, et al. Delirium in the intensive care unit: occurrence and clinical course in older patients. J Am Geriatr Soc. 2003;51:591-598.

27. Massie MJ, Holland J, Glass E. Delirium in terminally ill cancer patients. Am J Psychiatry. 1983;140:1048-1050.

28. Lawlor PG, Gagnon B, Mancini IL, et al. Occurrence, causes, and outcome of delirium in patients with advanced cancer: a prospective study. Arch Intern Med. 2000;160:786-794.

29. Giltay EJ, Huijskes RV, Kho KH, et al. Psychotic symptoms in patients undergoing coronary artery bypass grafting and heart valve operation. Eur J Cardiothorac Surg. 2006;30:140-147.

30. Sockalingam S, Parekh N, Bogoch II, et al. Delirium in the postoperative cardiac patient: a review. J Card Surg. 2005;20:560-567.

31. Inouye SK, Zhang Y, Jones RN, et al. Risk factors for delirium at discharge: development and validation of a predictive model. Arch Intern Med. 2007;167:1406-1413.

32. Maldonado JR. Neuropathogenesis of delirium: review of current etiologic theories and common pathways. Am J Geriatr Psychiatry. 2013;21:1190-1222.

33. Maldonado JR. Pathoetiological model of delirium: a comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment. Crit Care Clin. 2008;24:789-856, ix.

34. de Rooij SE, van Munster BC, Korevaar JC, Levi M. Cytokines and acute phase response in delirium. J Psychosom Res. 2007;62:521-525.

35. Seaman JS, Schillerstrom J, Carroll D, Brown TM. Impaired oxidative metabolism precipitates delirium: a study of 101 ICU patients. Psychosomatics. 2006;47:56-61.

36. Choi SH, Lee H, Chung TS, et al. Neural network functional connectivity during and after an episode of delirium. Am J Psychiatry. 2012;169:498-507.

37. Inouye SK, Bogardus ST Jr, Charpentier PA, et al. A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med. 1999;340:669-676.

38. Kaneko T, Cai J, Ishikura T, et al. Prophylactic consecutive administration of haloperidol can reduce the occurrence of postoperative delirium in gastrointestinal surgery. Yonago Acta Med. 1999;42:179-184.

39. Wang W, Li HL, Wang DX, et al. Haloperidol prophylaxis decreases delirium incidence in elderly patients after noncardiac surgery: a randomized controlled trial*. Crit Care Med. 2012;40:731-739.

40. Kalisvaart KJ, de Jonghe JF, Bogaards MJ, et al. Haloperidol prophylaxis for elderly hip-surgery patients at risk for delirium: a randomized placebo-controlled study. J Am Geriatr Soc. 2005;53:1658-1666.

41. Prakanrattana U, Prapaitrakool S. Efficacy of risperidone for prevention of postoperative delirium in cardiac surgery. Anaesth Intensive Care. 2007;35:714-719.

42. Larsen KA, Kelly SE, Stern TA, et al. Administration of olanzapine to prevent postoperative delirium in elderly joint-replacement patients: a randomized, controlled trial. Psychosomatics. 2010;51:409-418.

43. Teslyar P, Stock VM, Wilk CM, et al. Prophylaxis with antipsychotic medication reduces the risk of post-operative delirium in elderly patients: a meta-analysis. Psychosomatics. 2013;54:124-131.

44. Page VJ, Ely EW, Gates S, et al. Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, double-blind, placebo-controlled trial [published correction appears in Lancet Respir Med. 2013;1:592]. Lancet Respir Med. 2013;1:515-523.

45. Al-Aama T, Brymer C, Gutmanis I, et al. Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial [published correction appears in Int J Geriatr Psychiatry. 2014;29:550]. Int J Geriatr Psychiatry. 2011;26:687-694.

46. Lonergan E, Britton AM, Luxenberg J, Wyller T. Antipsychotics for delirium. Cochrane Database Syst Rev. 2007(2):CD005594.

47. Friedman JI, Soleimani L, McGonigle DP, et al. Pharmacological treatments of non-substance-withdrawal delirium: a systematic review of prospective trials. Am J Psychiatry. 2014;171:151-159.

48. Breitbart W, Marotta R, Platt MM, et al. A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry. 1996;153:231-237.

49. Han CS, Kim YK. A double-blind trial of risperidone and haloperidol for the treatment of delirium. Psychosomatics. 2004;45:297-301.

50. Skrobik YK, Bergeron N, Dumont M, Gottfried SB. Olanzapine vs haloperidol: treating delirium in a critical care setting. Intensive Care Med. 2004;30:444-449.

51. Kim SW, Yoo JA, Lee SY, et al. Risperidone versus olanzapine for the treatment of delirium. Hum Psychopharmacol. 2010;25:298-302.

52. Devlin JW, Roberts RJ, Fong JJ, et al. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, double-blind, placebo-controlled pilot study. Crit Care Med. 2010;38:419-427.

53. Boettger S, Friedlander M, Breitbart W, Passik S. Aripiprazole and haloperidol in the treatment of delirium. Aust N Z J Psychiatry. 2011;45:477-482.

54. Gagnon P, Charbonneau C, Allard P, et al. Delirium in advanced cancer: a psychoeducational intervention for family caregivers. J Palliat Care. 2002;18:253-261.

55. Otani H, Morita T, Uno S, et al. Usefulness of the leaflet-based intervention for family members of terminally ill cancer patients with delirium. J Palliat Med. 2013;16:419-422.

56. Steis MR, Evans L, Hirschman KB, et al. Screening for delirium using family caregivers: convergent validity of the Family Confusion Assessment Method and interviewer-rated Confusion Assessment Method. J Am Geriatr Soc. 2012;60:2121-2126.