Chapter 7. Delirium
© American Psychiatric Publishing
Delirium, defined as an acute and sudden change in attention and overall cognitive function, is a serious medical problem for older persons—and one that is often fatal (Inouye et al. 2014b). Delirium is the most frequent complication affecting hospitalized patients ages 65 years and older. Despite its high prevalence and incidence, it often goes unrecognized. Hospitalized patients with delirium have a worse prognosis than patients without delirium and are at an increased risk of developing long-term cognitive and functional decline (Pandharipande et al. 2013; Rudolph et al. 2009; Saczynski et al. 2012), which leads to additional posthospitalization treatment costs, including institutionalization, rehabilitation services, and home health care (Inouye et al. 2014b). Because it is preventable in up to 40% of cases (Inouye et al. 1999; Marcantonio et al. 2001), delirium is increasingly the target for interventions to prevent its associated burden of downstream complications and costs and therefore is now included on the patient safety agenda (Wachter 2012) and as an indicator of health care quality for older patients (National Quality Measures 2003). Delirium is a costly condition, with total annual health care costs related to delirium and its complications estimated at over $164 billion (Leslie et al. 2008).
Epidemiology
Delirium is often the only sign of an acute and serious medical condition affecting a patient, and it most commonly occurs in frail older persons with multiple comorbidities. Table 7–1 presents the prevalence rates (present on admission) and incidence rates (new onset) of delirium in various patient populations. The highest incidence rates were observed in the intensive care unit (ICU) and postoperative and palliative care settings. Although high, these rates likely represent underestimates of true incidence rates, because many studies of delirium exclude patients with cognitive impairment or dementia at baseline. In general medical and geriatric wards, the rates of prevalence of delirium (present on admission) must be added to the incidence rates to yield the overall occurrence rates of delirium in these populations of 29%–64% (see Table 7–1). The prevalence of delirium in the community setting is relatively low (1%–2%), but its onset usually brings the patient to emergency care (Inouye et al. 2014b). On presentation to the emergency department, delirium is present in 8%–17% of all seniors and in 40% of nursing home residents (Inouye et al. 2014b).
Epidemiology Incidence, prevalence, and outcomes of delirium
Population | Prevalence (range),* incidence (range) | Outcomes (adjusted RR†) |
|---|---|---|
Surgical | ||
Cardiac
|
—
11%–46%
|
Cognitive dysfunction (RR = 1.7)
Functional decline (RR = 1.9)
|
Noncardiac
|
—
13%–50%
|
Functional decline (RR = 2.1)
Cognitive dysfunction (RR = 1.6)
|
Orthopedic
|
17%
12%–51%
|
Dementia/cognitive dysfunction (RR = 6.4–41.2)
Institutionalization (RR = 5.6)
|
Medical | ||
General medical
|
18%–35%
11%–14%
|
Mortality (RR = 1.5–1.6)
Functional decline (RR = 1.5)
|
Geriatric units
|
25%
20%–29%
|
Falls (RR = 1.3)
Mortality (RR = 1.9)
Institutionalization (RR = 2.5)
|
Intensive care
|
7%–50%
19%–82%
|
Mortality (RR = 1.4–13.0)
Longer LOS (RR = 1.4–2.1)
Extended mechanical ventilation (RR = 8.6)
|
Stroke
|
—
10%–27%
|
Mortality (RR = 2.0)
Any of 3 outcomes: increased LOS, functional impairment, or death (RR = 2.1)
|
Dementia
|
18%
56%
|
Cognitive decline (RR = 1.6–3.1)
Institutionalization (RR = 9.3)
Mortality (RR = 5.4)
|
Palliative care/cancer
|
—
47%
|
—
|
Nursing home/postacute care
|
14%
20%–22%
|
Mortality (RR = 4.9)
|
Emergency department
|
8%–17%
—
|
Mortality (RR = 1.7)
|
Note. LOS = length of stay; RR = relative risk.
*The sum of both prevalence (present on admission) and incidence (new onset) yields the overall occurrence rates of delirium in each setting.
†Adjusted relative risks were derived from studies that provided adjustment for at least one covariable.
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Source. Reprinted (with modifications) from Inouye SK, Westendorp RG, Saczynski JS, et al: “Delirium in Elderly People.” The Lancet 383(9920):911–922, 2014 with permission from Elsevier.
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Delirium is consistently associated with higher mortality rates across all nonsurgical populations, including general medical, geriatric, intensive care, stroke, dementia, nursing home, and emergency department (see Table 7–1). Delirium in the ICU is associated with a 2- to 4-fold increased risk of death both in and out of the hospital and with cognitive impairment for up to 12 months after discharge; patients who develop delirium while on general medical or geriatric wards are at 1.5-fold increased risk for death in the year following hospitalization; and delirium in the emergency department is associated with a 70% increased risk of death during the first 6 months after the visit (Inouye et al. 2014b; Pandharipande et al. 2013). Postoperative cognitive impairment is common among surgical patients who develop delirium, with impairments lasting up to 1 year postoperatively, and physical function is impaired for 30 days or more after discharge among surgical and nonsurgical patients who develop delirium (Rudolph et al. 2009; Saczynski et al. 2012). Prevalent delirium at admission to post-acute care is associated with a 5-fold increased risk of 6-month mortality (Marcantonio et al. 2005).
Diagnosis, Assessment, and Workup
The diagnostic criteria for delirium that appear in DSM-5 (American Psychiatric Association 2013) (Table 7–2) and the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10; World Health Organization 1993) (Table 7–3), are generally accepted as the current diagnostic standards. Expert consensus was used to develop the DSM-5 criteria, and sensitivity and specificity estimates of the criteria have not yet been reported.
Diagnosis, Assessment, and Workup DSM-5 diagnostic criteria for delirium
A. A disturbance in attention (i.e., reduced ability to direct, focus, sustain, and shift attention) and awareness (reduced orientation to the environment).
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B. The disturbance develops over a short period of time (usually hours to a few days), represents a change from baseline attention and awareness, and tends to fluctuate in severity during the course of a day.
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C. An additional disturbance in cognition (e.g., memory deficit, disorientation, language, visuospatial ability, or perception).
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D. The disturbances in Criteria A and C are not better explained by another preexisting, established, or evolving neurocognitive disorder and do not occur in the context of a severely reduced level of arousal, such as coma.
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E. There is evidence from the history, physical examination, or laboratory findings that the disturbance is a direct physiological consequence of another medical condition, substance intoxication or withdrawal (i.e., due to a drug of abuse or to a medication), or exposure to a toxin, or is due to multiple etiologies.
|
Specify whether:
Substance intoxication delirium
Substance withdrawal delirium
Medication-induced delirium
Delirium due to another medical condition
Delirium due to multiple etiologies
|
Specify if:
Acute
Persistent
|
Specify if:
Hyperactive
Hypoactive
Mixed level of activity
|
Note. Criteria set above contains only the diagnostic criteria and specifiers; refer to DSM-5 for the full criteria set, including specifier descriptions and coding and reporting procedures.
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Source. DSM-5 criteria for delirium reprinted from Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Washington, DC, American Psychiatric Association, 2013, pp. 596–598. Used with permission. Copyright © 2013 American Psychiatric Association.
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Diagnosis, Assessment, and Workup ICD-10 diagnostic criteria for delirium
For definite diagnosis, symptoms, mild or severe, should be present in each one of the following areas:
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1. Impairment of consciousness and attention (on a continuum from clouding to coma; reduced ability to direct, focus, sustain, and shift attention).
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2. Global disturbance of cognition (perceptual distortions, illusions, and hallucinations—most often visual; impairment of abstract thinking and comprehension, with or without transient delusions, but typically with some degree of incoherence; impairment of immediate recall and of recent memory but with relatively intact remote memory; disorientation for time as well as, in more severe cases, for place and person).
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3. Psychomotor disturbances (hypo- or hyperactivity and unpredictable shifts from one to the other; increased reaction time; increased or decreased flow of speech; enhanced startle reaction).
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4. Disturbance of the sleep-wake cycle (insomnia or, in severe cases, total sleep loss or reversal of the sleep-wake cycle; daytime drowsiness; nocturnal worsening of symptoms; disturbing dreams or nightmares, which may continue as hallucinations after awakening).
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5. Emotional disturbances, e.g., depression, anxiety or fear, irritability, euphoria, apathy, or wondering perplexity.
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Source. Reprinted from The ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research. Geneva, Switzerland, World Health Organization, 1993. Used with permission.
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Over 24 delirium instruments have been used in published studies (Adamis et al. 2010). The Confusion Assessment Method (CAM; Inouye et al. 1990) is the most widely used instrument for the identification of delirium and provides a simple diagnostic algorithm (Table 7–4) (Wei et al. 2008; Wong et al. 2010). The CAM algorithm has been validated in high-quality studies of over 1,000 patients and has a sensitivity of 94%, specificity of 89%, and high interrater reliability. The CAM has been translated into at least 12 languages; has been used in more than 4,000 published studies (Inouye et al. 2014b); has been adapted for use in the ICU (Ely et al. 2001), emergency departments (Han et al. 2009), and nursing homes; and is now included as part of the Minimum Data Set (Centers for Medicare and Medicaid Services 2010). Several behavioral checklists for symptoms of delirium that are used, particularly in nursing-based studies, include the Delirium Observation Screening Scale (Schuurmans et al. 2003), the Nursing Delirium Screening Checklist (Gaudreau et al. 2005), and the NEECHAM Confusion Scale (Neelon et al. 1996). Delirium severity is most widely measured using the Delirium Rating Scale (Trzepacz et al. 1988, 2001) and the Memorial Delirium Assessment Scale (Breitbart et al. 1997). A new severity instrument based on the CAM is now available (Inouye et al. 2014a). A chart method for retrospective identification of delirium has been validated (Inouye et al. 2005), but its sensitivity is limited compared with interview-based methods. A combined method (including both chart review and direct patient interview) captures the broadest number of patients with delirium (Saczynski et al. 2014). The Family Confusion Assessment Method has been developed and validated as a way to identify delirium from reports of informal caregivers (Steis et al. 2012).
Diagnosis, Assessment, and Workup Confusion Assessment Method (CAM) diagnostic algorithma
Feature 1. Acute onset and fluctuating course
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This feature is usually obtained from a reliable reporter, such as a family member, caregiver, or nurse, and is shown by a positive response to this question: Is there evidence of an acute change in mental status from the patient’s baseline?
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Feature 2. Inattention
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This feature is shown by a positive response to this question: Did the patient have difficulty focusing attention, for example, being easily distractible, or have difficulty keeping track of what was being said?
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Feature 3. Disorganized thinking
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This feature is shown by a positive response to this question: Was the patient’s thinking disorganized or incoherent, such as rambling or irrelevant conversation, unclear or illogical flow of ideas, or unpredictable switching from subject to subject?
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Feature 4. Altered level of consciousness
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This feature is shown by any answer other than “alert” to this question: Overall, how would you rate this patient’s level of consciousness? (alert [normal], vigilant [hyperalert], lethargic [drowsy, easily aroused], stupor [difficult to arouse], or coma [unarousable])
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aThe CAM ratings should be completed following brief cognitive assessment of the patient, such as with the Mini Mental State Exam (Folstein et al. 1975). The diagnosis of delirium by CAM requires the presence of features 1 and 2 and of either 3 or 4.
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Source. Adapted from Inouye SK, Vandyck CH, Alessi CA, et al.: “Clarifying Confusion: The Confusion Assessment Method—A New Method for Detection of Delirium.” Annals of Internal Medicine 113:941–948, 1990. Used with permission.
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Delirium goes unrecognized by clinicians in up to 70% of patients who develop this condition (Inouye et al. 2001); therefore, careful clinical assessment for this condition is imperative. Identification of delirium relies on insightful clinical judgment combined with a thorough medical evaluation. The clinician should assess for recent changes or updates in medication regimen, new infections, or recent development of medical illnesses that may contribute to delirium. Sudden and acute onset, fluctuating course, and alteration in attention are the central features of delirium. Therefore, it is important to establish a patient’s level of baseline cognitive functioning and the course of cognitive change when evaluating for the presence of delirium. A detailed and in-depth background interview with a proxy informant, such as a family member, caregiver, or medical professional who knows the patient, proves invaluable when documenting change in a patient’s mental status. To distinguish delirium from dementia, which can be very challenging, it is important to differentiate between 1) cognitive changes that increase and decrease in severity over a period of days, which is indicative of delirium, and 2) changes that are more chronic and progressive over a period of months to years, which is indicative of dementia.
The cognitive evaluation for delirium should encompass the following domains: global cognitive changes, impairment in attention, disorganized thought process, and altered level of consciousness. Global cognitive changes associated with delirium can be assessed through simple cognitive testing, combined with close clinical observations of behavior during test administration, such as the patient’s ease and fluidity and ability to complete tasks. Brief cognitive screening should be conducted with formal cognitive screening tests, such as the Short Portable Mental Status Questionnaire (Pfeiffer 1975), Mini-Cog (Borson et al. 2000), or Montreal Cognitive Assessment (Nasreddine et al. 2005). If time is extremely limited, then a basic screening can be done, which involves assessment of orientation along with an attention task, such as backward naming of the days of the week (allow 0 errors) or of the months of the year (allow 1 error), serial 7s (allow 1 error on five subtractions), or digit span backwards (normal: ≥ 3 digits backward).
It is important not to underestimate the waxing and waning periods of delirium, because periods of lucidity and reversal of symptoms can often be deceiving. Impairment in attention, a hallmark feature of delirium, is clinically manifested through the patient’s difficulty in focusing on the task at hand, maintaining or following a conversation, and/or shifting of attention, often leading to perseveration on a previous topic or task. Disorganized thought is present when the patient’s speech is incoherent or jumbled and when the patient lacks a clear or logical presentation of ideas; this problem can be similar to the “word salad” phenomenon seen in schizophrenia and other formal thought disorders. Alteration in consciousness is highly variable and can range from an agitated or aggressive state to one of lethargy or stupor. Other disturbances in cognition include deficits identified on cognitive assessment, such as memory deficit, disorientation, impairments in language or visuospatial ability, and perceptual disturbances such as hallucinations (visual, auditory, or tactile). Other clinical features commonly associated with delirium that are not included as key diagnostic criteria are psychomotor agitation, paranoid delusions, sleep-wake cycle disruption, and emotional lability.
Clinically, delirium typically presents in one of three major forms: hypoactive, hyperactive, or mixed. The hypoactive form, which is more common in older patients, is characterized by lethargy and reduced psychomotor functioning. It is important to note that the hypoactive form of delirium is associated with an overall poorer prognosis and often goes unrecognized by clinicians and caregivers (Inouye et al. 2001). The reduced level of patient activity associated with hypoactive delirium is often attributed to low mood or fatigue, which may contribute to its misdiagnosis or underrecognition. The hyperactive form of delirium is characterized by agitation, increased vigilance, and often concomitant hallucinations. The hyperactive form rarely goes unnoticed by caregivers or clinicians. In the mixed form of delirium, patients fluctuate between the hypoactive and the hyperactive forms. The mixed form creates a challenge in distinguishing symptoms of delirium from symptoms of other psychotic or mood disorders.
Table 7–5 summarizes the suggested workup for delirium. Several fundamental points in the evaluation of delirium are worthy of special emphasis. Often, delirium may be the initial and only sign of a serious and life-threatening underlying illness, such as sepsis, pneumonia, or myocardial infarction. Further complicating the evaluation of older patients is the occult or atypical presentation of disease in older persons. For instance, an octogenarian with myocardial infarction presents more often with delirium than with classic symptoms of chest pain or shortness of breath. Thus, a patient presenting with delirium should be screened for acute physiological disturbance such as hypoxemia, low blood glucose, and high arterial carbon dioxide. Another important principle is that the diagnostic evaluation (e.g., laboratory testing, neuroimaging) must be targeted based on the patient’s history and physical examination; an untargeted battery of testing is likely to result in low diagnostic yield (Hirano et al. 2006). For example, in patients with an identified medical etiology of delirium or with preexisting dementia, over 98% will have a normal brain scan (Hufschmidt and Shabarin 2008).
Diagnosis, Assessment, and Workup Evaluation of suspected delirium
History
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Baseline cognitive function and recent changes in mental status (e.g., family, staff)
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Recent changes in condition, new diagnoses, review of systems
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Review all current medications, including over-the-counter medications and herbal remedies
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Review any new medications and drug interactions
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Review alcohol and benzodiazepine use
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Assess for pain and discomfort (including, urinary retention, constipation, thirst)
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Vital signs
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Include temperature, oxygen saturation, fingerstick glucose
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Postural vital signs as needed
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Physical and neurological examination
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Search for signs of occult infection, dehydration, acute abdomen, deep vein thrombosis, other acute illness. Assess for sensory impairments.
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Search for focal neurological changes and meningeal signs
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Targeted laboratory evaluation (selected tests based on clues from history and physical)
|
Based on history and physical examination, consider:
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Laboratory tests: CBC, electrolytes, calcium, glucose, renal function, liver function, thyroid function, urinalysis, cultures of urine, blood, sputum, drug levels, toxicology screen, ammonia level, vitamin B12 level, cortisol level
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Arterial blood gas
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Electrocardiography
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Chest X-ray
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Lumbar puncture reserved for evaluation of fever with headache, and meningeal signs, or suspicion of encephalitis
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Targeted neuroimaging (selected patients)
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Assess focal neurological changes, since stroke can present as delirium
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Suspicion of encephalitis for temporal lobe changes
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History or signs of head trauma
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Electroencephalography (selected patients)
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Evaluate for occult seizures
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Differentiate psychiatric condition from delirium
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Note. CBC = complete blood count.
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Source. Reprinted from Inouye SK, Westendorp RG, Saczynski JS, et al: “Delirium in Elderly People.” The Lancet 383(9920):911–922, 2014, with permission from Elsevier.
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The clinician’s most important and difficult task is to differentiate delirium from dementia. Dementia is a strong risk factor for delirium, increasing the risk by two- to fivefold on hospital admission (see Table 7–7 below). Patients with dementia who develop a superimposed delirium experience a more rapid progression of cognitive dysfunction and worse long-term prognosis (Fick and Foreman 2000; Jackson et al. 2004). The key diagnostic feature that aids in distinguishing these two conditions is that delirium has an acute and rapid onset, whereas dementia is much more gradual in progression. Alterations in attention and changes in level of consciousness also point to a diagnosis of delirium. However, establishing the occurrence of those changes can be difficult if no baseline cognitive data are available or if preexisting cognitive deficits are reported by an informant. If the differentiation cannot be made with certainty, then given the life-threatening nature of delirium, the patient should be treated as delirious until proven otherwise.
Other important diagnoses that must be differentiated from delirium include psychiatric conditions such as depression, mania, and nonorganic psychotic disorders such as schizophrenia. In general, these conditions do not develop suddenly in the context of a medical illness. Although hallucinations and perceptual disturbances can occur within the context of delirium, alterations in attention and global cognitive impairment are the key features that help to differentiate delirium from other psychiatric conditions. Differentiating among diagnoses is critical because delirium carries a more serious prognosis without proper evaluation and management. For example, treatment for certain conditions such as depression or affective disorders may involve the use of drugs with anticholinergic activity, which in turn could exacerbate an unrecognized case of delirium. Establishing the diagnosis can be difficult when the clinician is faced with symptoms that are subtle, when a background history is unavailable, or when the clinician is faced with an uncooperative patient. Again, given the seriousness of delirium and the fact that certain medical treatments may actually worsen symptoms, it is best for the clinician to assume that delirium is present until further diagnostic information is available.
The electroencephalogram has limited sensitivity and specificity in the diagnosis of delirium. However, delirium does result in a characteristic pattern of diffuse slowing with increased theta and delta activity and poor organization of background rhythm that correlates with severity of delirium. Electroencephalography can be particularly useful to differentiate organic etiologies from functional or psychiatric disorders in patients who are difficult to assess, to evaluate deteriorating mental status in patients with dementia, and to identify occult seizures (e.g., nonconvulsive status epilepticus or atypical complex partial seizures) (Jacobson and Jerrier 2000; Jenssen 2005).
No specific laboratory tests currently exist that will aid in the definitive identification of delirium. The laboratory evaluation for delirium is intended to identify contributing factors that will need to be addressed, and the approach should be guided by astute clinical judgment and tailored to the individual situation. Laboratory tests that should be considered in the delirium evaluation include complete blood count, electrolytes, kidney and liver function, oxygen saturation, and glucose levels. Evaluation of occult infection can be obtained through blood cultures, urinalysis, and urine culture. Other laboratory tests, such as thyroid function, arterial blood gas, vitamin B12 level, cortisol level, drug levels, toxicology screen, and ammonia levels, may be helpful in identifying factors that contribute to delirium. An electrocardiogram and/or chest radiograph may prove useful in patients with cardiac or respiratory diseases.
In general, the routine use of neuroimaging in delirium is not recommended, because the overall diagnostic yield is low, and the findings from neuroimaging change the management of patients in less than 10% of cases (Hirao et al. 2006). Brain imaging techniques—computed tomography (CT), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI)—have low diagnostic yield in unselected patients but are recommended in cases of head trauma or injury, for evaluation of new focal neurological symptoms, for assessment for suspected encephalitis, or for evaluation of fever of unknown origin. Cerebrospinal fluid examination, accomplished through lumbar puncture, may be useful in cases where the suspicion of meningitis, encephalitis, or subarachnoid hemorrhage is high (Marcantonio 2011). It may also be indicated in cases where delirium is persistent or where no etiology of delirium can be identified.
Pathophysiology of Delirium
The fundamental pathophysiological mechanisms of delirium remain unclear, and because each episode of delirium has a unique set of contributors representing different causal mechanisms, it is unlikely that a single cause or pathophysiological mechanism for delirium will be identified. Increasing evidence suggests that several sets of biological factors interact and result in disruption of large-scale neuronal networks in the brain, leading to acute confusion, cognitive dysfunction, and delirium (Watt et al. 2013). Table 7–6 presents the mechanisms potentially contributing to delirium and their level of evidence.
Pathophysiology of Delirium Potential pathophysiological contributors to delirium
Biological factor | Type of data available | Review published |
|---|---|---|
Neurotransmitters
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Acetylcholine, dopamine, melatonin
|
E, O
|
Yes
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Gamma-aminobutyric-acid (GABA)
|
E, O
|
No
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Tryptophan, serotonin
|
O
|
Yes
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Glutamate, N-methyl-d-aspartate (NMDA)
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O
|
No
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Epinephrine/norepinephrine
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H
|
No
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Pro-inflammatory markers
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Interferon (IFN) α or β
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E
|
Yes
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Interleukin 6 (IL-6), 8 (IL-8)
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O
|
Yes
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Interleukin 10 (IL-10)
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O
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No
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Tumor necrosis factor (TNF-α), interleukin 1-β (IL 1-β), prostaglandin E (E2, EP1–4)
|
H
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Yes
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Physiological stressors
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Cortisol, S100B, neopterin, hypoxia
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O
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No
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Metabolic disorders
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Lactic acidosis
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E, O
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No
|
Hypo- or hyperglycemia
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O
|
No
|
Insulin-like growth factor 1 (IGF-1)
|
O
|
Yes
|
Hypercapnia
|
H
|
Yes
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Electrolyte disorders
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Sodium, calcium, magnesium
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E, O
|
No
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Genetic factors
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Apolipoprotein E (ApoE), dopamine transporter receptor
|
O
|
Yes
|
Glucocorticoid receptor
|
O
|
No
|
Toll-like receptor 4
|
H
|
No
|
Note. E = Experimental—Controlled data available in humans (e.g., clinical trials and/or inference from unintended side effects of medications); O = Observational—Only observational data available in humans; H = Hypothetical—Studies not yet available in humans to support the mechanism.
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Source. Reprinted from Inouye SK, Westendorp RG, Saczynski JS, et al: “Delirium in Elderly People.” The Lancet 383(9920):911–922, 2014, with permission from Elsevier.
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Although many neurotransmitters are implicated in delirium (Gaudreau and Gagnon 2005), the most frequently considered mechanism of delirium is dysfunction in the cholinergic system. Acetylcholine plays a key role in mediating consciousness and attentional processes. Given that delirium is manifested by an acute confusional state, often with alterations of consciousness, it is likely to have a cholinergic basis. Evidence for the cholinergic connection includes findings that anticholinergic drugs can induce delirium in humans and animals and that serum anticholinergic activity is increased in patients with delirium (Hshieh et al. 2008; Lauretani et al. 2010). Also, cholinesterase inhibitors have been found to reduce symptoms of delirium in some studies (Gleason 2003; Wengel et al. 1998).
Chronic stress induced by severe illness, trauma, or surgery involves sympathetic and immune system activation that may lead to delirium; this activation may include increased activity of the hypothalamic-pituitary-adrenal axis with hypercortisolism, release of cerebral cytokines that alter neurotransmitter systems, alterations in the thyroid axis, and modification of blood-brain barrier permeability (Hughes et al. 2012). Neuroimaging studies, using either CT or MRI, have demonstrated structural abnormalities in the brains of patients with delirium, especially in the splenium of the corpus callosum, thalamus, and right temporal lobe (Bogousslavsky et al. 1988; Doherty et al. 2005; Naughton et al. 1997; Ogasawara et al. 2005; Takanashi et al. 2006). Advanced neuroimaging techniques find overall and regional perfusion abnormalities in the brains of people with delirium (Fong et al. 2006; Pfister et al. 2008). Functional imaging may help to distinguish structural damage resulting from an episode of delirium from preexisting changes (Choi et al. 2012).
Risk Factors for Delirium
Although a single factor may lead to delirium, more commonly delirium is multifactorial in older persons (Inouye and Charpentier 1996). To facilitate immediate and effective diagnosis and treatment of delirium, it is important to identify all multifactorial contributors. The development of delirium involves the complex interrelationship between the multiple predisposing factors that make a patient vulnerable and exposure to noxious insults or precipitating factors (Figure 7–1). For example, a single dose of a sedative drug given to a patient who is cognitively impaired or severely ill may lead to delirium. However, a patient without severe illness or cognitive impairment has greater resistance to developing delirium unless he or she is repeatedly exposed to multiple insults such as surgery, anesthesia, and psychoactive medications (Gleason 2003). Addressing only a single noxious insult or factor may not aid in improving delirium. Rather, multicomponent approaches will be most effective for both prevention and treatment (O’Mahony et al. 2011).
Multifactorial model of delirium in older persons.
Note. The onset of delirium involves a complex interaction between the patient’s baseline vulnerability (predisposing factors) present on admission and precipitating factors or noxious insults occurring during hospitalization. See text for details.
Source. Reprinted from Inouye SK, Westendorp RG, Saczynski JS, et al: “Delirium in Elderly People.” The Lancet 383(9920):911–922, 2014, with permission from Elsevier.
Table 7–7 presents predisposing and precipitating factors identified in prospectively validated prediction models. The leading risk factors consistently identified at admission in both medical and noncardiac surgery populations were dementia or cognitive impairment, functional impairment, vision impairment, history of alcohol abuse, and advanced age (> 70 years). Comorbidity burden or presence of specific comorbidities (e.g., stroke, depression) was associated with an increased risk in all patient populations. In the ICU studies, younger individuals were included and baseline factors (e.g., dementia, functional impairment) were not significant independent predictors. Precipitating factors varied more across patient populations. In medical patients, polypharmacy, psychoactive medication use, and physical restraints were the leading factors, conferring up to a 4.5-fold increased risk. Abnormal laboratory values were risk factors in all populations, conferring an increased risk of between 40% and 500%.
Risk Factors for Delirium Risk factors for delirium from validated predictive models
Risk factors | General medicine | Surgery | Intensive care unit | |
|---|---|---|---|---|
Noncardiac | Cardiac | |||
Predisposing factors | ||||
Dementia
|
2.3–4.7
|
2.8
|
—
|
—
|
Cognitive impairment
|
2.1–2.8
|
3.5–4.2
|
1.3
|
—
|
History of delirium
|
—
|
3.0
|
—
|
—
|
Functional impairment
|
4.0
|
2.5–3.5
|
—
|
—
|
Vision impairment
|
2.1–3.5
|
1.1–3.0
|
—
|
—
|
Hearing impairment
|
—
|
1.3
|
—
|
—
|
Comorbidity/severity of illness
|
1.3–5.6
|
4.3
|
—
|
1.1
|
Depression
|
3.2
|
—
|
1.2
|
—
|
History of transient ischemia/stroke
|
—
|
—
|
1.6
|
—
|
Alcohol abuse
|
5.7
|
1.4–3.3
|
—
|
—
|
Older age (≥ 75 years)
|
4.0
|
3.3–6.6
|
—
|
1.1
|
Precipitating factors | ||||
Medications
| ||||
Multiple medications added
|
2.9
|
—
|
—
|
—
|
Psychoactive medication use
|
4.5
|
—
|
—
|
—
|
Sedative-hypnotics
|
—
|
—
|
—
|
4.5
|
Use of physical restraints
|
3.2–4.4
|
—
|
—
|
—
|
Use of bladder catheter
|
2.4
|
—
|
—
|
—
|
Physiological
| ||||
Elevated serum urea
|
5.1
|
—
|
—
|
1.1
|
Elevated BUN/creatinine ratio
|
2.0
|
2.9
|
—
|
—
|
Abnormal serum albumin
|
—
|
—
|
1.4
|
—
|
Abnormal sodium, glucose, or potassium
|
—
|
3.4
|
—
|
—
|
Metabolic acidosis
|
—
|
—
|
—
|
1.4
|
Infection
|
—
|
—
|
—
|
3.1
|
Any iatrogenic event
|
1.9
|
—
|
—
|
—
|
Surgery
| ||||
Aortic aneurysm
|
—
|
8.3
|
—
|
—
|
Noncardiac thoracic
|
—
|
3.5
|
—
|
—
|
Neurosurgery
|
—
|
—
|
—
|
4.5
|
Trauma admission
|
—
|
—
|
—
|
3.4
|
Urgent admission
|
—
|
—
|
—
|
1.5
|
Coma
|
—
|
—
|
—
|
1.8–21.3
|
Note. Data are relative risks. Some data are reported as ranges. BUN = blood urea nitrogen.
Source. Reprinted from Inouye SK, Westendorp RG, Saczynski JS, et al: “Delirium in Elderly People.” The Lancet 383(9920):911–922, 2014, with permission from Elsevier.
| ||||
Medications and Delirium
Medication use contributes to delirium in more than 40% of cases (Inouye 1994; Inouye and Charpentier 1996). A list of medications identified in the Beers Criteria by the American Geriatrics Society (2012) as causing or exacerbating delirium are listed in Table 7–8. The medications most frequently associated with delirium are those with psychoactive effects, such as sedative-hypnotics, anxiolytics, narcotics, and histamine type 2 (H2) blockers. Drugs with anticholinergic effects, including antipsychotics, antihistamines, antidepressants, antiparkinsonian agents, and anticonvulsants, are also commonly associated with delirium. Previous studies, including validated risk prediction models, have demonstrated that the use of psychoactive medication results in a fourfold increased risk of delirium, whereas the use of two or more psychoactive medications is associated with a fivefold increased risk (Inouye and Charpentier 1996). Sedative-hypnotic drugs are associated with a 3- to 12-fold increased risk of delirium, narcotics with a threefold risk, and anticholinergic drugs with a 5- to 12-fold risk (Agostini and Inouye 2003; Foy et al. 1995; Schor et al. 1992). A systematic review of prospective studies identified opioids, benzodiazepines, dihydropyridines, and antihistamines as increasing the risk of delirium (Clegg and Young 2011).
Medications and Delirium Drugs to avoid in delirium: Beers Criteria
All tricyclic antidepressants
|
Anticholinergics
|
Antihistamines
|
Antiparkinsonian agents
|
Muscle relaxants
|
Antidepressants
|
Antipsychotics
|
Antimuscarinics
|
Antispasmodics
|
Benzodiazepines (short-, intermediate-, and long-acting)
|
Nonbenzodiazepine hypnotics
|
Corticosteroids
|
Histamine type 2 (H2) receptor antagonists
|
Meperidine
|
Sedative-hypnotics
|
Thioridazine
|
Source. American Geriatrics Society 2012.
|
Polypharmacy leads to a proportionately greater risk for developing delirium. The increased risk is related to the direct toxicity of the medications themselves, as well as to the increased risk of drug-drug and drug-disease interactions. Some homeopathic or herbal therapies, especially those used for mood disorders (e.g., St. John’s wort, kava kava), may increase the risk of delirium, especially when used in combination with prescribed psychoactive medications. Given the role of medications in contributing to the development of delirium, it is essential to conduct a complete review of all prescription and over-the-counter medications a patient is taking. The majority of older patients take several prescribed medications during hospitalization, increasing the risk for drug-drug and disease-drug interactions. Medications with known psychoactive effects should be discontinued or minimized whenever possible. At the very least, steps should be taken to reduce dosage or to substitute medications with less toxic potential. In aging adults, medications may cause adverse effects even when given at the recommended dosages and with serum drug levels that are within the “therapeutic range.” Determining if the patient has a history of chronic sedative use or alcohol dependence is critical in assessing for withdrawal risk.
Prevention and Management of Delirium
Pharmacological Prevention and Management
Although clinical trials have used a variety of pharmacological approaches, at present there is no convincing, reproducible evidence that any of these treatments are clearly effective for either prevention or treatment of delirium. Many published pharmacological trials report no difference in delirium rates (Inouye et al. 2014b). In the majority of trials that showed a reduced rate of delirium following targeted pharmacological treatment, there was no corresponding impact on clinical outcomes, such as ICU or hospital length of stay, hospital complications, or mortality, or clinical outcomes were not measured. For instance, a randomized controlled trial of haloperidol versus placebo in 457 noncardiac surgery patients in the ICU showed reduced incidence of delirium (haloperidol 15.3% vs. placebo 23.2%, P = 0.03) but no difference in length of hospital stay, postoperative complications, or mortality (Wang et al. 2012). Similarly, several trials have reported that treatment resulted in potentially worse outcomes: olanzapine reduced incidence of delirium compared with placebo in 400 patients following hip replacement but resulted in greater duration and severity of delirium (Larsen et al. 2010), and rivastigmine resulted in higher delirium duration and mortality in 104 ICU patients (van Eijk et al. 2010). Notably, published trials use different approaches to the assessment of delirium and evaluate diverse patient populations; therefore, generalizing findings is difficult. Given the preponderance of evidence, however, pharmacological approaches to prevention and treatment are not recommended at this time (Barr et al. 2013; O’Mahony et al. 2011).
Primary prevention—that is, preventing delirium before it develops—is the most effective strategy to alleviate symptoms associated with delirium. The Hospital Elder Life Program (HELP; www.hospitalelderlifeprogram.org) utilizes a multicomponent targeted intervention approach to aid in preventing delirium and is the most widely disseminated approach to delirium prevention (Inouye et al. 1999, 2006). HELP is a hospital-wide program that was designed to implement delirium prevention strategies and to promote an overall increase in quality of medical care for older persons. The HELP interventions include the following: reorientation, therapeutic activities, reduction of psychoactive medications, early mobilization, promotion of sleep, maintaining of hydration and nutrition, and provision of vision and hearing adaptations. The program is implemented by a skilled interdisciplinary team, assisted by nursing staff and often trained volunteers.
In general, nonpharmacological approaches, such as those used in the HELP protocols, should be implemented as the first-line treatment of delirium (Table 7–9). Nonpharmacological treatment approaches include reorientation (e.g., using orientation boards, clocks, calendars), behavioral interventions, encouraging the presence of family members, and transferring a disruptive patient to a private room or closer to the nurse’s station for increased supervision. Consistent and compassionate staff are essential in facilitating contact and communication with the patient through frequent verbal reorienting strategies, clear instructions, frequent eye contact, and the inclusion of patients as much as possible in all decision making regarding their daily and medical care. Sensory deficits should be assessed and then corrected by ensuring that all assistive devices, such as eyeglasses and hearing aids, are readily available, functioning, and being used properly by the patient. The use of physical restraints should be minimized due to their role in prolonging delirium, worsening agitation, and increasing complications such as strangulation (Inouye et al. 2007). Strategies that increase the patient’s mobility, self-care, and independence should be promoted.
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