Delirium in Older Persons

The prevalence of delirium increases sharply with age, and about 20 percent of older patients have delirium at the time of hospital admission for any reason. This review summarizes the clinical manifestations of and risk factors for delirium and the evaluation of patients with this condition. It includes an update on the current understanding of the pathogenesis of delirium and provides guidance regarding practical measures to prevent this common complication.


Clinic a l Ch a r ac ter is tics
Because delirium remains a bedside diagnosis, understanding its clinical features (Table 1 and the Supplementary Appendix) is crucial to the diagnosis of delirium.Delirium has hypoactive and hyperactive forms (Table 1).The hypoactive form of delirium is more common among older persons and often goes unrecognized.

Etiologic and Risk Factors
The cause of delirium is typically multifactorial. 25n fact, the development of delirium involves the complex interrelationship between a vulnerable patient (one with predisposing factors) (Table 2) and exposure to precipitating factors or noxious insults (Table 3). 26,27Thus, in patients who are highly vulnerable to delirium, such as those with dementia and multiple coexisting conditions, it may develop as a result of relatively benign insults, such as one dose of a sleeping medication.Conversely, in patients who are not vulnerable to delirium, it develops only after exposure to multiple noxious insults, such as general anesthesia, major surgery, and psychoactive medications.Addressing just one contributing factor is unlikely to resolve delirium in an older person; they should all be addressed when possible.

Pathogenesis
The pathophysiology of delirium remains poorly understood.Electroencephalographic studies have demonstrated diffuse slowing of cortical background activity, which does not correlate with underlying causes. 28Neuropsychological and neuroimaging studies reveal generalized disruption in higher cortical function, with dysfunction in the prefrontal cortex, subcortical structures, thalamus, basal ganglia, frontal and temporoparietal cortex, fusiform cortex, and lingual gyri, particularly on the nondominant side. 29,30The leading hypotheses for the pathogenesis of delirium focus on the roles of neurotransmission, inflammation, and chronic stress.
Extensive evidence supports the role of cholinergic deficiency.Administration of anticholinergic drugs can induce delirium in humans and animals, and serum anticholinergic activity is increased in patients with delirium.Physostigmine reverses delirium associated with anticholinergic drugs, and cholinesterase inhibitors appear to have some benefit even in cases of delirium that are not induced by drugs. 15,29,31paminergic excess also appears to contribute to delirium, possibly owing to its regulatory influence on the release of acetylcholine. 29Dopaminergic drugs (e.g., levodopa and bupropion) are recognized precipitants of delirium, and dopamine antagonists (e.g., antipsychotic agents) effectively treat delirium symptoms.Perturbations of other neurotransmitters, such as norepinephrine, serotonin, γ-aminobutyric acid, glutamate, and melatonin, may also have a role in the pathophysiology of delirium, but the evidence is less well developed. 1,29,32These neurotransmitters may exert their influence through interactions with the cholinergic and dopaminergic pathways.
Cytokines, including interleukin-1, interleukin-2, interleukin-6, tumor necrosis factor α (TNF-α), and interferon, may contribute to delirium 1,29,33 by increasing the permeability of the bloodbrain barrier and altering neurotransmission.Finally, chronic stress brought on by illness or trauma activates the sympathetic nervous system and hypothalamic-pituitary-adrenocortical axis, resulting in increased cytokine levels and chronic hypercortisolism. 34Chronic hypercortisolism has deleterious effects on hippocampal serotonin (5-hydroxytryptamine [5-HT]) 5-HT 1A receptors, which may contribute to delirium. 29,35,36Given the clinical heterogeneity and multifactorial nature of delirium, it is likely that multiple pathogenic mechanisms contribute to the development of delirium.

Approach to Evaluation
A flowchart for the prevention and management of delirium from the time of admission of an older patient is shown in Figure 1.This approach, based on current clinical guidelines and expert opinion, 9,20 must be guided by the individual patient's medical history, findings on physical and neurologic examination, and clinical setting.Although the provision of detailed procedures is beyond the scope of this report, we will highlight common pitfalls to avoid.When a patient with confusion is admitted, determining the acuity of the change in mental status is the essential first step.Neglecting this step is the leading reason for missing the diagnosis of delirium.If no history can be obtained, then the patient should be assumed to be delirious until proved otherwise.Every older hospitalized patient should undergo brief but formal cognitive testing with the use of instruments such as the Mini-Mental State Examination and the Confusion Assessment Method, since subtle de-lirium is often missed.Older patients should be aroused during rounds and evaluated daily for the hypoactive form of delirium, which is often overlooked.
When clinicians search for the underlying cause of delirium, they need to be aware of the possibility of occult or atypical presentations of many diseases in the elderly, including myocardial infarction, infection, and respiratory failure, because delirium is often the sole manifestation of serious underlying disease.All preadmission and current medications should be reviewed; even long-standing medications can contribute to delirium and should be reevaluated.If changes in long-term medications are appropriate after the indications and risk-benefit ratios have been carefully weighed, the hospital represents the ideal venue for making these changes.A medical history must be meticulously obtained to detect occult alcohol or benzodiazepine use, which can contribute to delirium.Electroencephalography has a limited role in the diagnosis of delirium, because of its false negative rate of 17 percent and false positive rate of 22 percent 12 ; it is most useful for detecting occult seizures and differentiating delirium from psychiatric disorders.Neuroimaging studies have a low clinical yield (the number of positive results divided by the total number of studies performed) in the evaluation of delirium and should be reserved for patients with new focal neurologic signs, those with a history or signs of head trau-ma, those with fever and acute changes in mental status in whom encephalitis is suspected, or those with no other identifiable cause of the delirium. 12However, neuroimaging should be considered when the history cannot be obtained or the neurologic examination cannot be completed (e.g., when the patient is combative) so as not to miss uncommon conditions that are life-threatening but treatable, such as subarachnoid hemorrhage and encephalitis.

Pr e v ention a nd M a nagement
Preventing delirium is the most effective strategy for reducing its frequency and complications.Successful preventive strategies include multicomponent approaches to reduce risk factors.Because delirium has many causes, multicomponent approaches represent the most effective and clinically relevant ones.The Yale Delirium Prevention Trial 8 demonstrated the effectiveness of intervention protocols targeted toward six risk factors: orientation and therapeutic activities for cognitive impairment, early mobilization to avert immobilization, nonpharmacologic approaches to minimize the use of psychoactive drugs, interventions to prevent sleep deprivation, communication methods and adaptive equipment (particularly eyeglasses and hearing aids) for vision and hearing impairment, and early intervention for volume depletion.A randomized clinical trial involving patients who had had hip fractures demonstrated the effectiveness of a multicomponent strategy for geriatric consultation targeted toward 10 domains 38 : oxygen delivery to the brain, fluid and electrolyte balance, pain management, reduction in the use of psychoactive drugs, bowel and bladder function, nutrition, early mobilization, prevention of postoperative complications, appropriate environmental stimuli, and treatment of symptoms of delirium.
Once delirium occurs, the key steps in management are to address all evident causes, provide supportive care and prevent complications, and treat behavioral symptoms.Because delirium can be a medical emergency, the first aim of management is to address predisposing and precipitating factors promptly (Fig. 1).Supportive care should include protecting the patient's airway, maintaining hydration and nutrition, positioning and mobilizing the patient to prevent pressure sores and deep venous thrombosis, avoiding the  Infection with human immunodeficiency virus use of physical restraints, and supporting the patient's daily care needs.Nonpharmacologic approaches to managing symptoms of delirium should be instituted in every patient.These approaches include creating a calm, comfortable environment with the use of orienting influences, such as calendars, clocks, and familiar objects from home; regular reorienting communication with staff members; involving family members in supportive care; limiting room and staff changes; coordinating schedules for administering drugs, obtaining vital signs, and performing procedures to allow the patient an uninterrupted period for sleep at night with low levels of noise and lighting; and encouraging normal sleep-wake cycles by opening blinds and encouraging wakefulness and mobility during the daytime.Since may take weeks or months to resolve, patients must be cared for in supervised settings.Close clinical follow-up after discharge is needed, especially because of the poor long-term prognosis associated with delirium.
Pharmacologic management should be reserved for patients whose symptoms of delirium would threaten their own safety or the safety of other persons or would result in the interruption of essential therapy, such as mechanical ventilation or central venous catheters.Pharmacologic treatment strategies are outlined in Table 4.

R el ationship be t w een Delir ium a nd Dementi a
Delirium and dementia are highly interrelated, yet the nature of their interrelationship remains poorly examined.Although a cause-and-effect relation has not been established between delirium and dementia, investigation of their intersection may yield important insights that will advance our understanding of both conditions (see Table 3 in the Supplementary Appendix).Dementia is the leading risk factor for delirium, and fully two thirds of cases of delirium occur in patients with dementia. 1,39Thus, the underlying vulnerability of the brain in patients with dementia may predispose them to the development of delirium as a result of insults related to acute medical illnesses, medications, or environmental perturbations.Recent studies suggest that delirium persists much longer than previously believed, 4,40-44 with symptoms in many patients lasting months or years.The existence of the well-described enti-ties of persistent delirium 4,40-44 and reversible dementia 45 blurs the boundaries between these conditions.Moreover, studies have shown that delirium and dementia are both associated with decreased cerebral metabolism, cholinergic deficiency, and inflammation, 46 reflecting their overlapping clinical, metabolic, and cellular mechanisms.In fact, delirium and dementia may represent points along a continuum of cognitive disorders, rather than two entirely separate conditions. 39Does delirium contribute to dementia?Although it is not likely that the delirium itself causes the pathologic changes of dementia, there is no question that delirium contributes to worsening functional status, loss of independence, and poorer outcomes among patients with dementia.The long-standing traditional view is that delirium and dementia are two separate conditions; however, emerging evidence has highlighted their overlap.First, epidemiologic studies have documented long-term cognitive decline in patients with delirium, after controlling for relevant covariates. 47Second, several causes of delirium may not be completely reversible, particularly those resulting in neuronal injury and permanent cognitive sequelae, such as prolonged hypoxia or hypoglycemia. 39Third, neuroimaging studies demonstrate regions of hypoperfusion in patients with delirium. 48Thus, delirium may herald the onset of dementia in many instances.Fourth, dementia with Lewy bodies, which includes fluctuating cognition and visual hallucinations as core signs, illustrates the overlap of delirium and dementia.
Delirium can alter the course of an underlying dementia, with dramatic worsening of the trajectory of cognitive decline, resulting in more rapid progression of functional losses and worse long-term outcomes.This phenomenon has been well recognized clinically in elderly patients with dementia: clinicians and family members have noted that the patients "never returned to baseline" after an episode of delirium.][51][52] Delirium may serve as an important model for research by offering a unique approach to advance our general understanding of cognitive disorders and dementias (see Table 3 in the Supplementary Appendix).The development of delirium in certain persons may help to identify those who are vulnerable to cognitive decline through genetic predisposition or through the presence of early dementia or mild cognitive impairment that may otherwise remain unidentified.Moreover, a better understanding of the pathogenesis of delirium may help elucidate factors that lead directly to neuronal injury and, thus, to permanent cognitive sequelae.Studies investigating the pathogenesis of delirium with the use of neuropsychological testing, neuroimaging methods, electrophysiological methods, laboratory markers, genetic studies, and neuropathological approaches are greatly needed.Investigation of delirium provides an important opportunity to clarify the link between brain pathophysiology and behavioral manifestations, which might hold broader implications for other cognitive and psychiatric disorders.New prospects for therapy include strategies to increase acetylcholine activity in the brain (e.g., through the use of procholinergic agents and avoidance of highly anticholinergic drugs), the use of selective dopamine antagonists that affect D 1 , D 2 , D 3 , and D 4 receptors differently, and the use of drugs to enhance cerebrovascular flow (e.g., antiinflammatory or antiplatelet agents).Finally, targeting delirium with new therapeutic approaches may offer opportunities for early intervention, preservation of cognitive-reserve capacity, and prevention of permanent cognitive damage, which may potentially delay or abate the ultimate development of dementia.

Delirium as an Indicator of the Quality of Health Care
Delirium represents one of the most common preventable adverse events among older persons during hospitalization 53,54 and meets Williamson's criteria for an indicator of the quality of health care 55 : the condition is common, frequently iatrogenic, and integrally linked to processes of care.Although many cases of delirium may be unavoidable, clinical trials 8,38 provide compelling evidence that at least 30 to 40 percent of cases may be preventable.Many aspects of hospital care contribute to the development of delirium, including adverse effects of medications, complications of invasive procedures, immobilization, malnutrition, dehydration, the use of bladder catheters, and sleep deprivation. 9Delirium is currently included as a marker of the quality of care and patient safety by the National Quality Measures Clearinghouse of the Agency for Healthcare Research and Qual- ity (as explained at www.qualitymeasures.ahrq.gov/).After adjusting for case mix, higher delirium rates would be expected to correlate with lower quality of hospital care.The Assessing Care of Vulnerable Elders Project has ranked delirium among the top three conditions for which the quality of care needs to be improved. 56Total national costs related to preventable adverse events are estimated to be between $17 billion and $29 billion per year, 57 and delirium may account for at least a quarter of these costs. 53,54,57,58e changes required to reduce the incidence of delirium on a national scale would require shifts in local and national policies and system-wide changes to provide high-quality care for older persons. 9 Supported in part by grants (R21AG025193 and K24AG00949) from the National Institute on Aging.
No potential conflict of interest relevant to this article was reported.
This article is dedicated to the memory of Joshua Bryan Inouye Helfand.
I am indebted to Dr. Joseph Agostini for his helpful review of the manuscript and to Sarah Dowal and Patty Fugal for their assistance with the preparation of the manuscript.
Fluctuating course Symptoms tend to come and go or increase and decrease in severity over a 24-hour period Characteristic lucid intervals Inattention Difficulty focusing, sustaining, and shifting attention Difficulty maintaining conversation or following commands Disorganized thinking Manifested by disorganized or incoherent speech Rambling or irrelevant conversation or an unclear or illogical flow of ideas Altered level of consciousness Clouding of consciousness, with reduced clarity of awareness of the environment Cognitive deficits Typically global or multiple deficits in cognition, including disorientation, memory deficits, and language impairment Perceptual disturbances Illusions or hallucinations in about 30 percent of patients Psychomotor disturbances Psychomotor variants of delirium Hyperactive Marked by agitation and vigilance Hypoactive Marked by lethargy, with a markedly decreased level of motor activity Mixed Altered sleep-wake cycle Characteristic sleep-cycle disturbances Typically daytime drowsiness, nighttime insomnia, fragmented sleep, or complete sleep-cycle reversal Emotional disturbances Common Manifested by intermittent and labile symptoms of fear, paranoia, anxiety, depression, irritability, apathy, anger, or euphoria * Additional details are provided in

Table 1 . Clinical Features of Delirium.*
Table 2 in the Supplementary Appendix.
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Table 3 . Precipitating Factors or Insults That Can Contribute to Delirium.
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Figure 1 (facing page). Prevention and Management of Delirium in the Older Hospitalized Patient.
Thyroid-function tests include measurement of the thyroxine level, thyroid index, and thyrotropin level.More information about pharmacologic treatment can be found in Table4.
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Table 4 . Pharmacologic Treatment of Delirium.
* Intravenous use of lorazepam should be reserved for emergencies.