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The Delirium Dilemma - Advances in Thinking about

Diagnosis, Management, and Importance of ICU Delirium
Part I: Impact of Brain Dysfunction on Intensive Care

E. Wesley Ely, MD, MPH

Department of Medicine, Center for Health Services
Research and Division of Allergy/Pulmonary/Critical Care
Medicine, Vanderbilt University School of Medicine,
Nashville, TN; the Center for Health Services Research and
the VA Tennessee Valley Geriatric Research, Education and
Clinical Center (GRECC)

Photo: Dr. Wes Ely, MD

Correspondence: E. Wesley Ely, M.D., MPH, FACP, Division of Allergy/Pulmonary/Critical Care Medicine, Center for Health
Services Research, Vanderbilt University Medical Center, Nashville, TN 37232-8300, USA. (E-mail and other contact info can
be obtained from CWWJ’s Editor-in-Chief).

Key Words: Delirium, Cognitive Impairment, Neuropsychological Assessment, Intensive Care

Running title: Delirium in the ICU

Grant Support: Dr. Ely is the Associate Director of Research for the VA Tennessee Valley Geriatric Research and Education
Clinical Center (GRECC). He is a recipient of the Paul Beeson Faculty Scholar Award from the Alliance for Aging Research
and is a recipient of a K23 from the National Institute of Health (#AG01023-01A1).
No other financial support was provided

Clinical Window Web Journal: Outcome after Intensive Care Delirium, (#21, Vol. 6, January 2006)
[www.clinicalwindow.net]

Impact of brain dysfunction on intensive care

Patients in the intensive care unit (ICU) who experience delirium are exhibiting an under-
recognized form of “organ dysfunction.” Delirium is extremely common in ICU patients
due to factors such as co-morbidity, critical illness, and iatrogenesis. This neurologic
complication can be extremely hazardous in hospitalized older persons and is associated
with death, prolonged hospital stays, and institutionalization. Neurologic dysfunction
compromises patients’ ability to be removed from mechanical ventilation or achieve full
recovery and independence. Unfortunately, health care providers in the ICU are unaware
of delirium in many circumstances, especially those in which the patient’s delirium is
manifesting predominantly as the hypoactive (quiet) subtype as opposed to the
hyperactive (agitated) subtype. In the last few years, research on ICU delirium has

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revealed the importance of this problem in critically ill patients as well as methods for
routinely monitoring delirium at the bedside. The two parts of this article will review the
definition and salient features of delirium, its primary risk factors, validated methods for
bedside delirium assessment, pharmacological agents associated with the development
of delirium as well as both pharmacological and non-pharmacological strategies in
delirium management.

Historical terms, modern research, and our increasing knowledge

Historically, two words were used to describe confused patients. One was the Roman
word “delirium,” which referred to an agitated and confused person (think of hyperactive
delirium). The other was from the Greek word “lethargus,” which was used to describe a
quietly confused person (think of hypoactive delirium). ICU patients commonly
demonstrate both of these motoric subtypes as they progress through different stages of
their illness and therapy. In either case, the patient’s brain is not functioning normally. It
therefore makes sense that the original derivation of delirium comes from the Latin word
deliria, which literally means to “be out of your furrow.” For greater clarity and to avoid
misuse of terms such as dementia and delirium, we have included basic definitions of
some commonly referred to cognitive syndromes in Table 1.
In the ICU we aggressively monitor many organ systems for the development of
dysfunction or failure. For example, we use pulse oximetry and blood gases to monitor for
pulmonary dysfunction, blood pressure and electrocardiography to monitor for cardiac
dysfunction, and urine output and serum creatinine to monitor for renal dysfunction.
Health care professionals in the ICU have traditionally used inadequate monitoring
devices to detect dysfunction in arguably the most important organ of all – the brain.
Delirium, acute central nervous system (CNS) dysfunction resulting from any number of
common insults that ICU patients experience, has largely been overlooked in critical care
research until the past few years. Recent discussions of encephalopathy and organ
dysfunction secondary to sepsis fail to mention delirium as one of the clinical
manifestations of CNS dysfunction 1,2.
The ICU literature often refers to delirium as “ICU psychosis,” 3-8 which represents a
potentially dangerous misnomer. The development of delirium often goes unnoticed in the
ICU because we think of it as “part of the scenery,” or an expected and inconsequential
outcome of mechanical ventilation and other therapies necessary to save lives in the ICU.
A series of investigations has recently been conducted that provided validated means of
detecting delirium by non-psychiatrists (e.g., internists, nurses, or respiratory therapists).
The CNS monitoring instruments and observations from these investigations are leading
to a change of culture and practice in the ICU whereby we more closely follow patients for
the development of delirium and modify their care to help prevent this potentially
disastrous complication. Indeed, the most recent clinical practice guidelines of the Society
of Critical Care Medicine (SCCM) 9 have recommended routine (daily) monitoring of
delirium in all mechanically ventilated patients, which will be discussed later in this
chapter.

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Table 1: Highlights regarding cognitive syndromes

Expression What it means? Points to think

Confusion A characteristic occurring in delirium resulting in an Disturbed orientation with
altered state of consciousness, and characterized by respect to person, place, and
deficits in attention, memory, visuo-constructional ability, time.
and executive functions. (also defined as reduced mental
clarity, coherence, comprehension, and reasoning).
Delirium A disturbance of consciousness characterized by an Rapid onset, clouded
acute onset and fluctuating course of impaired cognitive consciousness
functioning, so that a patient’s ability to receive, process, (bewildered/confused).
store, and recall information is strikingly impaired. Often worse at night,
Delirium develops over a short period of time (hours to fluctuating.
days), is usually reversible, and is a direct consequence of
a medical condition, substance intoxication or
withdrawal, use of a medication, toxin exposure, or a
combination of these factors.

Dementia Development of a state of generalized cognitive deficits in Gradual onset, intellectual

which there is a deterioration of previously acquired impairment, memory
intellectual abilities usually developing over weeks and disturbance, personality/mood
months. The deficits include memory impairment and at change.
least one of the following: aphasia, apraxia, agnosia, or a No clouding of consciousness.
disturbance in executive functioning. The cognitive
deficits must be sufficiently severe to cause impairment
in occupational or social functioning, and they may be
progressive, static, or reversible depending on the
pathology and the availability of effective treatment.
Psychosis A major mental disorder characterized by hallucinations, Hallucinations/delusions,
delusions, or the inability to distinguish reality from impaired reality testing,
fantasy, which lead to an inability to maintain inappropriate mood and
interpersonal relations and to compromised daily impulse control.
functioning. No clouding of consciousness.

Pathophysiology and etiology of delirium

Delirium is thought to be related to imbalances in the synthesis, release, and inactivation
of neurotransmitters modulating the control of cognitive function, behavior, and mood 8,10.
Three of the neurotransmitter systems involved in the pathophysiology of delirium are
dopamine, gama-aminobutyric acid (GABA), and acetylcholine 11,12. While dopamine
increases excitability of neurons, GABA and acetylcholine decrease neuronal excitability11.
An imbalance of one or multiple of these neurotransmitters results in neuronal instability
and unpredictable neurotransmission. In general, an excess of dopamine and depletion of
acetylcholine are two major physiological problems felt to be central to delirium. In
addition to these neurotransmitter systems, others are thought to be involved in the

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development of delirium such as serotonin imbalance, endorphin hyperfunction, and

increased central noradrenergic activity 10,12.
A number of causal factors lead to neurotransmitter imbalance including reduction in
cerebral metabolism, primary intracranial disease, systemic diseases, secondary infection
of the brain, exogenous toxic agents, withdrawal from substances of abuse such as
alcohol or sedative-hypnotics agents, hypoxemia, metabolic disturbances, and the
administration of psychoactive medications such as benzodiazepines and narcotics 13.
Since the cerebral concentrations of these neurotransmitters are sensitive to many
organic and biochemical changes, many things can result in their imbalance 12,13.
Cognitive neuroscience and psychopharmacology are active areas of research, which will
hopefully yield advances in our understanding and treatment of delirium.

“Confusion” regarding delirium terminology

There are over 25 terms in the literature used to refer to delirium such as “subacute
befuddlement” and “toxic confusional state.” Others simply refer to delirium as confusion
or neurological impairment. The neurology literature tends to use the term “delirium”
exclusively to refer to the hyperactive subtype 14, while referring to hypoactive delirium as
encephalopathy. These subtypes are discussed in the next sections. As mentioned above,
“ICU psychosis” is a potentially dangerous misnomer, which refers to delirious patients
who are demonstrating increased psychomotor activity and hallucinations (i.e.,
hyperactive delirium) 3-8.

Prevalence and subtypes of ICU delirium

The prevalence of delirium in ICU cohort studies has been reported as 20% 15, 70% 16, or
80% 17, depending upon the characteristics of the patient population and the instrument
used. Its incidence is likely to increase in future years as older persons more frequently
receive ICU care. Two major developments that are frequently linked during older persons’
ICU course are the need for mechanical ventilation and the development of profound and
possibly persistent cognitive impairment 18. Almost every patient in the ICU receives either
narcotics or benzodiazepines at some point during their stay, yet physicians rarely modify
the quantity or dosing intervals of these drugs based on patient age. Patients on
mechanical ventilation are frequently sedated to the point of stupor or coma in order to
improve oxygenation, alleviate agitation, and to prevent them from removing support
devices. However, age is only rarely factored into complex decisions regarding how to
dose these potent medications, or when to remove sedatives and liberate patients from
mechanical ventilation. The result is that it is now commonplace in the ICU to find most
elderly patients receiving mechanical ventilation to be in a drug-induced state of
“suspended animation.” 19
The motoric subtypes of delirium are hypoactive, hyperactive, and mixed. Peterson et
al. 20 recently reported on delirium subtypes from a cohort of 613 ventilated and non-
ventilated ICU patients in whom delirium was monitored over 20,000 observations. These
investigators found that among patients who developed delirium, pure hyperactive

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delirium was rare (under 5%), while hypoactive and mixed types of delirium were the
predominant subtypes (~45% each). Interestingly, the hypoactive subtype was
significantly more common in older patients than in the young. The risk factors for and
clinical implications of these meteoric subtypes are the subject of ongoing investigations.
The period surrounding cessation of sedation represents a typical scenario in the ICU
setting in which delirium may either be easily recognized or completely missed by
clinicians. Patients emerging from the effects of sedation, they may do so peacefully or in
a combative manner. On one extreme are the “peaceful” patients, who are often
erroneously assumed to be thinking clearly. Delirium in this context is referred to as
“hypoactive delirium” and is characterized by decreased mental and physical activity and
inattention 6. Such mental status changes could lead to adverse outcomes such as
reintubation, which itself has been shown to increase ten-fold the risk of nosocomial
pneumonia and death. In addition, hypoactive delirium is associated with aspiration,
pulmonary embolism, decubitus ulcers, and other complications related to immobility.
On the other extreme are agitated or combative patients (i.e., hyperactive delirium),
who are at risk not only for self-extubation and subsequent reintubation, but also pulling
out central venous access and even falling out of bed. These patients are most often given
higher doses of sedatives that commit them to at least another day of mechanical
ventilation. This places patients at risk for being left in a cognitively impaired state and on
mechanical ventilation unnecessarily 21. Because of this difficult cycle, it is important for
health care professionals to avoid overuse of psychoactive medications and to develop
better methods of assessing cognitive function, especially during the transition from drug-
induced or metabolic coma to wakefulness.

Missing the diagnosis of delirium

The above-mentioned “quiet” or hypoactive delirium is frequently overlooked by
physicians and nurses 22-25. Delirium remains unrecognized by the clinician in as many as
66% to 84% of patients experiencing this complication 26,27, and it may be attributed
incorrectly to dementia, depression, or just an “expected” occurrence in the critically ill,
elderly patient 26. Many clinicians expect delirium to present with agitation or
hallucinations, features that are not required for the diagnosis. Other reasons for the lack
of recognition of delirium include infrequent cognitive assessments and the fluctuating
nature of delirium. It has been shown that the very development of delirium is associated
with fewer interactions and less time spent by nurses and physicians in direct patient
care28,29.

Geriatric ICU concerns and pre-existing cognitive impairment

It is estimated that over the next three decades the cost of care for those over 65 years
old will increase ten-fold 30. These data have been used to argue for limiting ICU care
provided to the elderly in order to conserve resources 31-33. However, a recent report from
Angus et al. documented that nearly 60% of all ICU days were incurred by patients older
than 65 years34. In fact, adults under 65 had 37 ICU days per year per 1,000 person-years

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vs. 240 for those over 75 years of age. The incidence of acute respiratory failure requiring
mechanical ventilation rises 10-fold from the age of 55 to 85 35, resulting in greater
numbers of elderly patients treated in our ICUs 36.
Because of these age-related demographics and the relationship between pre-existing
cognitive impairment and development of delirium, clinicians are likely to discover an
increased burden of delirium among hospitalized patients across the country 37,38. It has
been shown that advanced age and cognitive decline lead to reductions in the level of
interactions and potentially life-saving therapeutic interventions from clinicians and
caregivers 39,40. Despite this, we know that more and more elderly patients are being
admitted to the ICU than ever before 41, and certainly this will include older patients with
pre-existing cognitive impairment ranging from mild to overt dementia. A cohort
investigation by Pisani and others 42 studied the impact of pre-existing cognitive
impairment (mostly mild) on ICU outcomes, and found that those with and without
cognitive impairment had similar outcomes in terms of both ICU and hospital length of
stay and mortality. However, the persistence of delirium symptoms in such patients could
strongly effect discharge rates to nursing homes following hospitalization 24,26.

Prognostic significance of delirium

Reports indicate that central nervous system (CNS) organ dysfunction is associated with
complications of mechanical ventilation including aspiration, nosocomial pneumonia,
reintubation, and self-extubation 43-47. It has also been shown in mechanically ventilated
neurosurgical patients that the strongest predictor of failed extubation was an abnormal
Glasgow coma score48. In medical ICU patients, Salam et al. 49 showed that there were
important interactions between cognitive dysfunction and the likelihood of failed
extubation. CNS “failure” is an important predictor of outcome from sepsis 2.
In non-ICU populations, the development of delirium in the hospital is associated with
an in-hospital mortality of 25% to 33%, prolonged hospital stay, and three times the
likelihood of discharge to a nursing home 24,18,50. In a three-site study of medical non-ICU
patients, delirium was found to be an independent predictor of the combined outcome of
death or nursing home placement 51. Francis and Kapoor 52 found that two-year mortality
in patients having experienced delirium was 39% vs. 23% in controls, but multivariate
analysis showed that this was largely explained by baseline cognitive and functional
status. Perhaps the most convincing report of the independent association between
delirium and mortality among non-ICU patients was published by McCusker and
colleagues 53, showing an adjusted hazard of dying of 2.11 associated with the
development of delirium. This mortality increase has now been shown independent of
dementia status54.

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Among ICU patients, we now have evidence55 that delirium is a predictor of mortality
(Figure 1). In fact, the development of delirium is associated with a three-fold increase in
risk of death after controlling for pre-existing comorbidities, severity of illness, coma, and
the use of sedative and analgesic medications. These data also showed that delirium is
not simply a transition state from coma to normal, as delirium occurred just as often
among those who never developed coma as it did among those with coma, and persisted
in 11% of patients at the time of hospital discharge. Furthermore, three recent prospective
studies found that delirium was associated with an increased risk for dementia over 2 to 3
years 56-58. In light of these findings, future studies should determine whether or not
prevention or treatment of delirium changes clinical outcomes including mortality, length
of stay, cost of care, and long-term neuropsychological outcomes among survivors of
critical illness.

Figure 1. Relationship between delirium and six-month survival demonstrated as two

Kaplan-Meier plots.

Left: two survival groups. Two groups have been formed according to whether or not the patient ever developed
delirium in the ICU: Never Delirium had higher survival than the Ever Delirium 55.

Right - details of clinical severity. From the graph on the left the two groups have been subdivided to better
illustrate the phenomenology of delirium.
• Subgroups for Never Delirium: Patients were either Always Normal or Coma-Normal (e.g. first deeply sedated
but normal when sedative drugs stopped) and.
• Subgroups for Ever Delirium are Delirium Only and Delirium-Coma.

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Costs associated with delirium in the ICU patient

Delirium complicates the hospital stay of more than 2 to 3 million elderly patients per year
in the U.S., involving over 17.5 million in-patient days and accounting for over US$ 4 billion
in Medicare expenditures 59. In the only study to date reporting on costs associated with
delirium in the ICU, Milbrandt and colleagues 60 found that median ICU and hospital costs
were significantly higher for those with at least one episode of delirium vs. those with no
delirium (Figure 2). Even after controlling for important potentially confounding variables,
such as baseline comorbidities and severity of illness, delirium was associated with a 40%
relative increase in ICU and total hospital costs. In addition, the data demonstrated a
“dose-response” in which cumulative delirium severity was associated with incrementally
greater cost.

Figure 2. Delirium is significantly associated with increased ICU and hospital cost.

Median costs per patient according to clinical categorization of Ever delirium vs. Never Delirium (See fig 1
for grouping55).

The associated annual cost of ICU delirium could be enormous. In the study by
Milbrandt mentioned above 60, delirium occurred in 82% of mechanically patients and was
associated with an incremental increase in ICU cost of over $9000 per patient. In the
United States, there are approximately 880,000 to 2,760,000 ICU admissions annually for
respiratory failure requiring mechanical ventilation. Therefore, the estimated number of
cases of ICU delirium could range from 721,600 to 2,263,200 per year with an associated
increase in health care costs ranging between $6.5 and $20.4 billion. If we use the
incidence of delirium from a less severely ill ICU cohort in which delirium occurred in only

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19% of patients 61, the estimated annual costs would still be in the range of US$ 1.5 to US$
4.7 billion. Since some of the additional cost associated with delirium could be attributable
to unmeasured differences between patient groups, these estimates represent the upper
limit of the cost attributable to ICU delirium. However, even if only 20% of the difference in
costs between patients with and without delirium were in fact due to delirium, this would
still be a significant public health concern with US$ 300 million to US$ 4 billion in annual
attributable costs.

Note the readers

In this two-part article, there are a total of 111 scientific references. The second part:
Strategies for Optimal Management of ICU Delirium, appears in issue 21 of the Clinical
Window Web Journal - a combined list of references will be published in that article.

© 2005-2006 GE Healthcare Finland Oy – A General Electric Company –going to market as GE Healthcare. All rights
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Healthcare. ISSN 1795-6269.

Clinical Window Web Journal: Outcome after Intensive Care Delirium, (#21, Vol. 6, January 2006)
[www.clinicalwindow.net]

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