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Semin Respir Crit Care Med. Author manuscript; available in PMC 2022 February 01.
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Published in final edited form as:

Semin Respir Crit Care Med. 2021 February ; 42(1): 112–126. doi:10.1055/s-0040-1710572.
Prevention and Management of Delirium in the Intensive Care

Unit
Matthew F. Mart, MD1,2,*, Shawniqua Williams Roberson, MEng, MD2,3,4,*, Barbara Salas,
BA, MBBS5, Pratik P. Pandharipande, MD, MSCI2,6, E. Wesley Ely, MD, MPH1,2,7,8
1Divisionof Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center,
Nashville, Tennessee
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2Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Nashville, Tennessee
3Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee
4Department of Bioengineering, Vanderbilt University, Nashville, Tennessee
5The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United
Kingdom
6Divisionof Critical Care Medicine, Department of Anesthesiology, Vanderbilt University Medical
Center, Nashville, Tennessee
7Vanderbilt Center for Health Services Research, Vanderbilt University Medical Center, Nashville,
Tennessee
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8VATennessee Valley Healthcare System Geriatric Research Education and Clinical Center
(GRECC), Nashville, Tennessee
Abstract
Delirium is a debilitating form of brain dysfunction frequently encountered in the intensive care
unit (ICU). It is associated with increased morbidity and mortality, longer lengths of stay, higher
hospital costs, and cognitive impairment that persists long after hospital discharge. Predisposing
factors include smoking, hypertension, cardiac disease, sepsis, and premorbid dementia.
Precipitating factors include respiratory failure and shock, metabolic disturbances, prolonged
mechanical ventilation, pain, immobility, and sedatives and adverse environmental conditions
impairing vision, hearing, and sleep. Historically, antipsychotic medications were the mainstay of
delirium treatment in the critically ill. Based on more recent literature, the current Society of
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Critical Care Medicine (SCCM) guidelines suggest against routine use of antipsychotics for
delirium in critically ill adults. Other pharmacologic interventions (e.g., dexmedetomidine) are
under investigation and their impact is not yet clear. Nonpharmacologic interventions thus remain
the cornerstone of delirium management. This approach is summarized in the ABCDEF bundle
(Assess, prevent, and manage pain; Both SAT and SBT; Choice of analgesia and sedation;
Address for correspondence E. Wesley Ely, MD, MPH, Vanderbilt University, Medical Center Critical Illness, Brain Dysfunction,
and Survivorship (CIBS) Center, 2525 West End Ave, Suite 450, Nashville, TN 37203 (wes.ely@vumc.org).
*These authors acted as co-first authors.
Conflict of Interest
None declared.
Mart et al. Page 2
Delirium: assess, prevent, and manage; Early mobility and exercise; Family engagement and
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empowerment). The implementation of this bundle reduces the odds of developing delirium and
the chances of needing mechanical ventilation, yet there are challenges to its implementation.
There is an urgent need for ongoing studies to more effectively mitigate risk factors and to better
understand the pathobiology underlying ICU delirium so as to identify additional potential
treatments. Further refinements of therapeutic options, from drugs to rehabilitation, are current
areas ripe for study to improve the short- and long-term outcomes of critically ill patients with
delirium.
Keywords
delirium; ABCDEF bundle; cognitive impairment; critical illness; intensive care; early mobility;
antipsychotics; dementia
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Delirium is a common organ dysfunction encountered in critically ill adults and a significant
cause of morbidity and mortality. Delirium has been identified with critical illness as far
back as the ancient Roman empire, where the nobleman and encyclopedist Aulus Cornelius
Celsus described the manifestations of delirium in patients with wound infections and head
trauma in his seminal work, De Medicina.1 More than half of all patients in modern
intensive care units (ICUs) will go on to develop delirium at some point during their
admission.2–5 This is of particular importance, as delirium is independently associated with
an increased risk of death.6–8 Additionally, duration of delirium is the major risk factor for
cognitive impairment after critical illness, a form of ICU-acquired dementia that is
particularly debilitating.4,9–11 Lastly, the development of delirium is associated with
increased hospital length of stay and health care costs.12–15
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The mechanism of delirium is unclear and most likely a result of multiple pathways that are
affected during critical illness that alters normal cognition. Numerous pathological
mechanisms have been proposed, ranging from genetic defects to worsening brain
inflammation and poor cerebral blood flow, and to neurotransmitter imbalance.16–19
Multiple concurrent insults are likely responsible and vary depending on individual patients’
physiologic reserve and their severity of illness. Given the complex nature of the disease, a
multifaceted approach to delirium is warranted.
The management of ICU delirium has historically been challenging, as there have been very
few pharmacological options that have demonstrated efficacy in treating delirium once it
develops. For example, antipsychotics have consistently shown little benefit in treating the
disease.20,21 The prevailing approach to management is focused on prevention and early
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recognition. Prevention includes strategies to limit risk factors, such as catheter removal and
promoting a healthy sleep environment. It also includes targeted approach to analgosedation,
such as avoidance of benzodiazepine-based sedation and focusing on providing light
sedation in addition to encouraging patient mobilization. Early recognition of delirium
involves the use of well-validated instruments to screen for the disease, and when it is
identified, a focused search for potential etiologies such as occult infection should be
pursued. A bundle of care, incorporating these evidence-based care processes for delirium
management such as goal-directed light sedation and early mobilization, has demonstrated
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significant improvements in multiple important ICU outcomes, including delirium, days of

mechanical ventilation, and mortality.22,23 This synergistic bundle, called the ABCDEF
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bundle (Assess, prevent, and manage pain; Both SAT and SBT; Choice of analgesia and
sedation; Delirium: assess, prevent, and manage; Early mobility and exercise; Family
engagement and empowerment), represents the best management strategy for critically ill
patients with delirium. The future of delirium management will be focused on optimizing
these processes of care as well as identifying the basic, mechanistic underpinnings of the
disease to help develop novel treatment strategies to improve the care of the critically ill.
Manifestations and Outcomes of ICU Delirium

Manifestations
Delirium is a form of acute brain dysfunction that manifests as fluctuating attention and
impaired cognitive function. It can present with a variety of symptoms, including significant
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psychomotor agitation, depressed level of consciousness, or both. According to the

American Psychiatric Association’s Diagnostic and Statistical Manual—5th edition
(DSM-5) guidelines, delirium is an acute confusional state defined by acute disturbances in
attention, awareness, or cognition developing over hours to days due to disease or sedation
that is not better explained by an alternative diagnosis or a comatose state.24 Notably,
delirium can and often does coexist with underlying neurological disease such as dementia,
traumatic brain injury, and stroke and so is not precluded from developing in these patients.
25,26
The incidence of delirium varies among individual studies but is a frequent diagnosis in all
inpatient care settings. Vasilevskis and colleagues estimated that approximately one-third of
patients who were hospitalized ultimately developed delirium.27 Delirium is especially
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common in the ICU, with three-quarters of mechanically ventilated patients suffering with
disease and up to half of those not receiving mechanical ventilation developing delirium.
2,3,28,29
The symptomatology of delirium varies as well, particularly with respect to its psychomotor
manifestations. Delirium is classified into hyperactive, hypoactive, and mixed subtypes.
Hypoactive and mixed delirium are the most common presentations seen in the ICU,
accounting for over 90% of cases.30 Patients with hypoactive delirium are predominantly
lethargic with reduced motor activity, in contrast to patients with hyperactive delirium who
are often agitated and restless. Patients with mixed delirium have symptoms of both
hypoactive and hyperactive delirium that can change over the course of the disease.
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Outcomes
Advances in critical care medicine have substantially improved survival rates, yet delirium
remains a frequent and significant cause of morbidity and mortality with significant
downstream impairments in cognitive and physical functioning (Fig. 1). Patients with
delirium have increased mortality, both in the hospital and in the year following
hospitalization, as compared with nondelirious patients.31,32 The presence of delirium within
24 hours of a critical care admission is strongly associated with increased in-hospital
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mortality.33 Mechanically ventilated patients who develop delirium had greater 6-month
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mortality and a significantly longer length of stay in the hospital as compared with their
counterparts without delirium.7,12 Higher mortality has also been linked to delirium out to 1
year from admission among older critically ill adults.6,34,35 Notably, hypoactive delirium is
associated with higher mortality as compared with hyperactive delirium or mixed delirium.
36,37
In addition to higher mortality, delirious patients suffer from other physical complications.
Delirium has been consistently associated with both longer ICU and hospital length of stay.
7,34 Patients with delirium also spend a longer time on mechanical ventilation and have more
respiratory complications with increased difficulty weaning.34,38,39 Delirium has also been
associated with an increased likelihood of being discharged to a long-term care facility, and
patients with blood stream infections were also less likely to return to their baseline
functional status.34,40 Brummel and colleagues demonstrated that critically ill patients on
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mechanical ventilation who develop delirium had substantial impairments in their basic
activities of daily living as well as worse sensory-motor function at 3 and 12 month follow-
up.41 Prolonged mechanical ventilation and disability secondary to delirium prevents
patients from returning to their baseline and reduces their overall quality of life.
The neurocognitive impact of delirium extends beyond the acute illness. Older delirious
adults both with and without dementia demonstrated symptoms of delirium for months
following their initial episode, including symptoms of inattention and disorientation.42
Among the critically ill, delirious patients have greater cognitive impairment at hospital
discharge than those who were not delirious, with more severe delirium associated with
greater cognitive impairment.43 Girard and colleagues demonstrated that delirium was
independently associated with cognitive impairment in ICU survivors at 3 and 12 months
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after hospitalization with over 70% of ICU survivors experiencing cognitive impairment at
12 months.9 This finding was confirmed by Pandharipande and colleagues in the BRAIN-
ICU study.4 Cognitive impairment was seen across all age ranges in this cohort with similar
incidence to the Girard study. Of these, over one-third of patients had evidence of moderate
to severe cognitive impairment at 12 months. In a related study, delirium was associated with
significant cognitive impairment at 18-months post-ICU.44 Additionally, patients who
experience delirium also experience an increased risk of dementia and greater cognitive
decline. In older adults over the age 85 followed for 10 years, delirium was a strong
independent predictor of incident dementia.45 And in patients with pre-existing Alzheimer’s
dementia, delirium was associated with a significantly worse cognitive trajectory as
compared to those without delirium, adjusting for baseline disease severity and comorbidity.
46 In addition to the clinical manifestations, neuroimaging of delirium suggests important
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structural brain changes, such as atrophy and volume loss as well as white matter lesions.
47,48 Just as delirium worsens cognitive function in those with baseline dementia, pre-
existing neurologic disease also increases the risk of developing delirium.49,50 The persistent
cognitive dysfunction related to delirium has significant socioeconomic impact in that it is
also associated with reduced employment in ICU survivors.51 The link between delirium and
cognitive impairment represents an unfortunate reciprocal relationship that impacts the most
vulnerable critically ill patients.
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Along with cognitive impairment and increased incidence of dementia, there is increasing
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recognition of the psychological sequelae of delirium. Approximately three-quarters of

critically ill patients who were interviewed 2 weeks after surviving their initial illness
reported delusions, and those with limited factual recall of their hospitalizations had
significantly increased anxiety and symptoms of posttraumatic stress disorder (PTSD).52
Jackson and colleagues found that 37 and 33% of ICU survivors reported depressive
symptoms at 3 and 12 months after critical illness, respectively, with 7% of all survivors
having symptoms consistent with PTSD.53 Patel et al found that one in 10 patients following
critical illness had symptoms consistent with PTSD attributable to their ICU admission, and
that pre-existing psychiatric diagnoses such as anxiety, depression, or military-service-
related PTSD were associated with greater likelihood of ICU-related PTSD.54
The important downstream sequelae of delirium remain a significant challenge for the world
of critical care medicine. These complications of delirium range from higher in-hospital
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mortality and increased time of mechanical ventilation to long-term cognitive impairment,

disability, and psychiatric disease. Such problems mandate urgency in further elucidating
both the underlying pathophysiology and improving the clinical management of the disease.
What is clear is that focusing on the prevention of delirium in combination with aggressive
management of risk factors, as well as with other evidence-based practices to prevent
iatrogenesis, will be the mainstay of treatment and research going forward.
Risk Factors and Proposed Mechanisms

Delirium is triggered by an acute medical event.55,56 Despite its frequency and detrimental
outcomes, the condition is often underdiagnosed,55,57 and its pathophysiology is still poorly
understood.55 Identification of precipitating risk factors for delirium is important to
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implement, where possible, preventative strategies in patients who are most at risk. Multiple
factors appear to contribute to the acute syndrome, and over 100 of them have been studied
for a potential link with an increased risk for developing delirium in the ICU.27 These risks
can be grouped into two categories: risks that can predispose the patient to delirium
(modifiable and nonmodifiable) and risks related to the treatment received while in the ICU
or the environment (Fig. 2).58
Predisposing Factors
Patient Characteristics—Characteristics of the patient that have been consistently found
to increase the delirium risk include advanced age,59 pre-existing cognitive impairment,5,60
and history of hypertension.61 Some studies have found that cigarette smoking2,62 and
alcohol use60,61 increase the risk of delirium incidence, although the current evidence is
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insufficient to determine if they are independently associated with ICU delirium.59 Of these
predisposing factors, only uncontrolled hypertension, alcohol use, and cigarette smoking are
potentially modifiable.
A high number of comorbidities,63 cardiac disease,64 and frailty65,66 also appear to increase
the risk, although the evidence is still inconclusive.59 Patients with multiple comorbidities
and frailty have a lower physical and cognitive physiological reserve,67 which impairs the
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capacity to sustain normal brain functioning in response to the stress of critical illness and
may ultimately lead to delirium.68
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Pharmacological Treatment—There are other risks that are associated with the
treatment provided in the ICU. Studies have shown that the use of benzodiazepines
(especially lorazepam and midazolam) is independently associated with increased risk of
delirium.29,69–71 In addition, these studies have demonstrated a dose-dependent relationship,
whereby the risk is higher with higher benzodiazepine doses. This is particularly the case
when benzodiazepines are used as sedatives for mechanical ventilation.72–74
Opiates, especially morphine, have also been linked with delirium risk,2,29,69,75 and there
seems to be a correlation between administration of opiates with benzodiazepines and
increased delirium duration.69 The link between these medications and delirium may be
related to the duration of action of these agents, which increases the risk of drug
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accumulation in the setting of altered organ function. Furthermore, administration of

epidural analgesia2 and sedation with propofol76 also show some association, although the
evidence is still inconclusive.
Anticholinergic agents can also precipitate delirium,77 and systemic corticosteroids have
been shown to be significantly associated with transitioning to delirium from a nondelirious
or noncomatose state.78 The connection between delirium and psychopharmacological
agents is likely due to their effect on neurotransmitters that appear to be critical to the
emergence of delirium, in particular gamma-amino butyric acid (GABA), acetylcholine,
dopamine, and serotonin.79 An imbalance in the synthesis, release, and inactivation of these
neurotransmitters seems to be one of the mechanisms of delirium.80
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ICU Course
Critical illness constitutes a severe systemic insult, and patients admitted to intensive care
with a high severity of illness or high Acute Physiology and Chronic Health Evaluation II
(APACHE II) score,61,69 polytrauma,75,81,82 organ failure,81 and patients admitted to the
ICU after emergency surgery64,82,83 have a higher risk of delirium than patients with a less
severe systemic insult.27 Coma has also been shown to be a risk factor for delirium, in
particular iatrogenic coma induced pharmacologically.60,61
Moreover, studies have shown that prolonged mechanical ventilation,60,84 emergence from
delirium,59,85,86 requirement of blood transfusions,81,83,87 immobility,60,71,88–90 metabolic
acidosis,5,75 and pain29,61 are all independent risk factors for higher delirium risk. It has
been suggested that acute systemic inflammation, aging, and ischemic injury lead to the
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release of proinflammatory cytokines, which can threaten the integrity of the brain–blood
barrier (BBB).91,92 The disruption of the BBB in turns activates a series of events that can
lead to delirium. There is increasing evidence suggesting that hypoxia can lead to increased
brain dysfunction in critically ill patients, potentially contributing to long-term cognitive
impairment.93–95 Chronic intermittent hypoxia can induce neurodegenerative changes to
brain tissue that may predispose patients to delirium.96,97
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Finally, research has shown that the presence of plasma tryptophan,86,98 a precursor of the
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neurotransmitter serotonin, and inflammatory biomarkers (procalcitonin and C-reactive

protein)99–101 may be linked with the development of delirium. The mechanism behind C-
reactive protein and delirium appears to be associated with a disruption in the BBB due to
generation of reactive oxygen species.102 Research into biomarkers is a promising
development in the field of delirium, as their identification could constitute a useful
diagnostic tool which would enable early diagnosis and risk stratification.
Environment
Despite its importance for recovery, the quality of sleep in the ICU is known to be generally
poor.103 Factors that play a significant role include noise, frequent disruptions,
administration of medications that alter sleep architecture,104 and disturbance of the light–
dark cycle due to decreased exposure to natural light.80 Poor quality of sleep has been
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suggested as a potential modifiable risk factor for delirium105,106; although this association
has not yet been definitively established,107 sleep promotion is considered important and is
part of the strategy to prevent delirium proposed by the Society of Critical Care Medicine
(SCCM).
Overall, there seems to be a complex relationship between predisposing and precipitating

factors leading to delirium, involving structural characteristics, several neurotransmitters,
immunologic, physiologic and genetic factors, as well as iatrogenic and environmental
exposures. Thus, a highly fragile patient may develop delirium despite a lesser physiological
insult, and equally a patient with less comorbidities and good functional state may require a
more severe insult to develop delirium. A good understanding of these interrelated factors is
important to stratify patients in different risk categories, so that preventive strategies can be
developed leading to a reduction in the incidence of delirium.
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Historical Perspective on Management

The last few decades have seen a dramatic shift in the prevailing perspective on effective
management of delirium. For context, we provide a brief description of the historical
observations and practices that led to the current state of the field.
Early Perspectives and the Use of Antipsychotics

The early literature on delirium management focused primarily on alcohol-related
disturbances, in particular delirium tremens. For delirium in hospitalized psychiatric
patients, a combination of chloral hydrate and potassium bromide was recommended.108
During the mid-20th century, various treatments were proposed for “acute delirium” in
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association with hospitalization, systemic illness, or postoperative states. Such treatments

included paraldehyde and sodium chloride,109 physostigmine (particularly for delirium
related to surgery and anticholinergic administration),110 phenothiazine drugs,111 and even
electroconvulsive therapy.112 In 1978 the use of intravenous haloperidol was reported in a
series of 15 delirious patients during recovery from cardiac surgery113 and this became the
mainstay of treatment for delirium in the critically ill. The next several decades saw an
increasing reliance on antipsychotic medications for this purpose. In 2002 the SCCM
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guidelines for use of sedatives and analgesics in ICU recommended haloperidol as the
preferred agent for treatment of delirium.114
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Changing Perspectives on Antipsychotics

The appropriateness of first-generation antipsychotics as treatment for delirium was
challenged in the mid-2000s by reports that these medications increased mortality in the
elderly.115 Pursuant to this, second-generation (“atypical”) antipsychotics such as quetiapine
and risperidone began to gain popularity. The rationale was that these carry less risk of
adverse effects such as cardiac arrhythmias and neuroleptic malignant syndrome. A
systematic review of atypical antipsychotics versus haloperidol revealed that atypical
antipsychotics were at least as efficacious as haloperidol for the treatment of delirium.116 In
the past 10 years, however, it has become evident that antipsychotics do not diminish risk of
ICU delirium nor do they improve the negative outcomes associated with this state of acute
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brain failure. The Hope-ICU study randomized 142 mechanically ventilated patients to
receive intravenous haloperidol or normal saline until delirium-free or ICU discharge, but
found no difference in number of coma-free and delirium-free days, delirium duration, or
survival between the two groups.21 The HARPOON study randomized 245 acutely
hospitalized elderly patients to prophylactic haloperidol versus placebo and found no clear
differences in delirium incidence, duration, severity, or 3-month mortality.117 The MIND-
USA study compared haloperidol, ziprasidone, and placebo in a randomized, double-blind
trial and found no effect of either antipsychotic medication on the number of coma-free and
delirium-free days (Fig. 3). Thirty day and 90-day survivals were also similar among the
three groups.20 Another randomized, double-blind study of haloperidol, risperidone, and
placebo for delirium in inpatient hospice and palliative care patients found an increase in
delirium symptom severity among patients receiving haloperidol or risperidone compared
with placebo.118 A recent systematic review of antipsychotics for treating delirium in
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hospitalized adults found no difference among haloperidol, atypical antipsychotics, and

placebo in terms of delirium duration, hospital length of stay, or mortality.119 A second
review of antipsychotics for prevention of delirium found no evidence that haloperidol
lowers incidence or duration of delirium, hospital length of stay, or mortality compared with
placebo. The same review did, however, suggest a possibility that atypical antipsychotics
may decrease the incidence of delirium specifically in postoperative patients.120 The current
SCCM guidelines suggest against routine use of haloperidol or atypical antipsychotics for
prevention or treatment of delirium in critically ill adults.121
Current Knowledge of Management and Prevention

The surprising results of systematic studies of haloperidol and other antipsychotics, once
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thought to be the mainstay of delirium management, have led clinicians and researchers
alike to consider alternative therapies to prevent and treat delirium. However, the field is far
from identifying a “silver bullet.” This section describes the most promising pharmacologic
and nonpharmacologic therapies, the current state of investigation, and barriers or challenges
impeding widespread implementation.
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Pharmacological Management and Prevention

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Dexmedetomidine—Dexmedetomidine is a selective α−2 adrenoreceptor agonist that

may promote sleep–wake cycle regulation in addition to providing anxiolysis and sedation.
122 Use of dexmedetomidine for the prevention of delirium is controversial. In two double-
blind, randomized controlled trials, mechanically ventilated patients sedated with

dexmedetomidine had a 23% lower risk of delirium compared with those sedated with
midazolam,73 and more than twice as many coma-free and delirium-free days compared
with those sedated with lorazepam.72 An open-label, randomized controlled trial comparing
dexmedetomidine to usual care for first choice of sedation in mechanically ventilated
patients also found a slight increase in the number of coma-free and delirium-free days in
the dexmedetomidine group. There was, however, no difference in 90-day mortality between
the groups.123 This study was limited by the fact that a large percentage of the
dexmedetomidine group ultimately received other drugs such as propofol and fentanyl.
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There is a randomized controlled trial in progress that compares dexmedetomidine versus

propofol in mechanically ventilated patients with sepsis.124 Another randomized controlled
trial will compare the incidence of delirium in elderly cardiac surgery patients with or
without a single postoperative sleep-inducing dose of dexmedetomidine.125 The results of
these studies are eagerly awaited and will inform future potential uses of dexmedetomidine
in the prevention of delirium.
Regarding pharmacologic treatmentonce delirium develops, a recent Cochrane analysis

found evidence that dexmedetomidine may shorten duration of delirium, mechanical
ventilation, and ICU stay. That study found no evidence of difference in coma-free or
delirium-free days, long-term cognitive impairment, or mortality.126
Statins—As described previously, one of the postulated mechanisms of delirium

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pathogenesis involves inflammation within the central nervous system causing breakdown of
the BBB. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) have been
observed to exert an anti-inflammatory effect in humans and animals, and thus a protective
effect of statins in ICU delirium has been postulated.127 In support of this hypothesis,
preoperative statins are associated with decreased risk of postoperative delirium in elderly
patients undergoing cardiac surgery.128 Observational studies suggest a protective effect of
statins with respect to delirium development during critical illness129 and that this effect
may be mediated in part by the effect of statins on systemic inflammation as measured by
the C-reactive protein levels.130 However, an ancillary study of a prospective randomized
controlled trial comparing rosuvastatin and placebo in acute respiratory distress syndrome
found no effect on the incidence of delirium or on long-term cognitive impairment overall.
Patients in the rosuvastatin group had slightly worse delayed memory scores at 6-month
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follow-up (mean difference in scores: −1.2; 95% confidence interval [CI]: −2.2 to −0.2, p =
0.017).131
Ketamine—Ketamine is an intravenous N-methyl-D-aspartate (NMDA) receptor antagonist

with anesthetic, analgesic, antidepressant, and anti-inflammatory properties. Intraoperative
administration of ketamine significantly decreases postoperative inter-leukin-6
concentrations132 as well as postoperative opiate requirements.133 Hudetz et al found that
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ketamine administration during induction was also associated with an improvement in post-
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cardiac surgery cognitive dysfunction. The C-reactive protein concentration was also
significantly lower in the ketamine group (median: 7.9 vs. 11.6 mg/dL, p < 0.01).134 These
findings suggest that ketamine may hold promise as a prophylactic or therapeutic drug for
postoperative or critical illness delirium. Nevertheless, a randomized controlled trial
comparing a single intraoperative subanesthetic dose of ketamine to placebo did not find a
difference in incidence of postoperative delirium. The ketamine groups did, on the other
hand, suffer an increased rate of hallucinations and nightmares.135 Although this study used
similar doses of ketamine to the Hudetz study, the studies differed with respect to timing and
premedication protocols.
Thus far no pharmacologic agent has demonstrated efficacy in treating or preventing

delirium. The current SCCM guidelines suggest against routine use of dexmedetomidine,
statins, or ketamine for prevention of delirium in critically ill adults.121 One or more of these
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agents may turn out to be useful for delirium management, but given the heterogeneous
nature of the disorder, optimal treatment will likely depend on the prevailing risk factors, the
neurologic and systemic comorbidities, and the metabolic and physiologic profile of each
patient.
Nonpharmacologic Interventions
For decades, nonpharmacologic interventions have been the cornerstone of delirium
management and treatment.109 Interventions such as promoting regular sleep–wake cycles,
avoiding unnecessary invasive sensory stimulation, and regular reorientation have been
refined over the decades and have become standard of care in ICUs worldwide. These
interventions have largely been conceptualized in the continually evolving ABCDEF bundle.
136,137 Improvements in compliance with the ABCDEF bundle are associated with a
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reduction in mortality as well as a reduction in number of coma-free and delirium-free ICU

days (Fig. 4).22,23 The principal components of this approach can be summarized in the
ABCDEF bundle, described in the sections below.
Assess, Prevent, and Manage Pain—Critically ill patients experience pain at rest and
with routine procedures. Inadequately treated pain can result in delirium as well as several
other complications. Pain should be monitored routinely in all adult ICU patients. This can
be done by self-report in awake, communicative patients, or using validated behavioral pain
scales such as the Behavioral Pain Scale or the Critical Care Pain Observation Tool138 in
those who are unable to communicate pain.
Both SAT and SBT—Spontaneous awakening trials (SATs) are pauses of intravenous
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narcotics and sedatives. When appropriate, these medications are restarted at half the prior
dose. Spontaneous breathing trials (SBTs) are periods of minimal ventilator support. A
randomized, controlled trial comparing daily SBTs to standard of care in mechanically
ventilated patients revealed that those receiving SBTs had shorter time on the ventilator (4.5
vs. 6 days, p = 0.003). The intervention arm also had less ventilator-related complications
and lower costs of ICU care.139 A randomized controlled trial comparing a daily SAT and
SBT protocol with daily SBT plus routine sedation found that patients on the SAT plus SBT
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protocol spent more days breathing without assistance and less time in the ICU. Patients in
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the SAT arm were also less likely to die during the 12-month follow-up period. Reintubation
rates were similar in the two groups.28 The daily coordination of SATs and SBTs is a key
part of the timely cessation of mechanical ventilation and leads to improved ICU outcomes.
Choice of Analgesia and Sedation—Effective management of pain, anxiety, and

delirium is a primary objective in the ICU. This management needs to be based on agreed-
upon, patient-oriented goals and standardized assessment measures. There are several
validated scales published for assessment of sedation level in the ICU, for example the
Richmond Agitation–Sedation Scale (RASS) or the Riker Sedation–Agitation Scale.
The most effective medication and titration protocol for sedation and analgesia is not yet
clear, and likely depends on the clinical context and patient characteristics. The MENDS
randomized controlled trial compared lorazepam and dexmedetomidine for sustained
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sedation in mechanically ventilated patients and found that the dexmedetomidine groups
experienced more days alive without delirium or coma (median: 7.0 vs. 3.0 days, p = 0.01).
Costs of care were similar between the two groups.72 The MENDS2 study will compare
dexmedetomidine and propofol in septic patients on mechanical ventilation. Results from
that study are pending as of the writing of this review.
Delirium: Assess, Prevent, and Manage—A key component of delirium management

is monitoring for early identification and risk factor modification. The most widely used tool
for delirium assessment in the ICU is the Confusion Assessment Method for the ICU (CAM-
ICU).3 The CAM-ICU comprises four features: acute onset of mental status change or
fluctuating curse; inattention; disorganized thinking; and altered level of consciousness. Its
pooled values as a diagnostic test are 80% sensitivity and 95.9% specificity.140 Other tools
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include the Intensive Care Delirium Screening Checklist (ICDSC).141 The ICDSC comprises
eight items, including assessment of altered level of consciousness, inattention,
hallucination/delusions/psychosis, psychomotor agitation or retardation, inappropriate
speech or mood, sleep wake/cycle disturbance, and symptom fluctuation. Its pooled
sensitivity and specificity are 74 and 81.9%, respectively.140 It is important to assess patients
regularly to reduce the risk of overlooking hypoactive delirium, and the optimal time for this
assessment is during SATs.142
Once delirium is identified, management entails revisiting primary prevention measures,

including reorientation, an appropriate sleep environment, and adequate pain management.
Many of these nonpharmacological interventions are outlined in Table 1. Since the duration
of delirium predicts worse long-term outcomes,4 implementation of these nonpharmacologic
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measures can be expected to improve patient care.
Early Mobility and Exercise—Early mobility consists of a range of activities from

passive range of motion to ambulation with assistance. It is safe and feasible in critically ill
patients, and decreases days of delirium, duration of mechanical ventilation, ICU length of
stay, and overall hospital length of stay. Any member of the care team can perform early
mobility; the appropriate level of activity is determined based on the patient’s level of
sedation. Early mobilization during SATs was associated with improved odds of return to
Mart et al. Page 12
independent functional status by discharge (odds ratio: 2.7; 95% CI: 1.2–6.1) in a series of
critically ill adults on mechanical ventilation.143 Early combined cognitive and physical
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therapy has been shown to be feasible in a similar population, and outcomes are currently
under study.144
Family Engagement and Empowerment—Empowering family members to be equal

participants in patient care can improve ICU team performance and communication, reveal
key insights into the patient condition, and keep providers focused on the most salient goals
of care for each patient. This intervention may also lead to early identification of and
reduction in the burden of ICU-related psychological and emotional stress among family
members. Key elements of strategic communication with families include using simplified
speech, being concrete, and avoiding rapid communication. A recent systematic review and
meta-analysis of protocolized family support interventions found that such interventions
reduce ICU length of stay without impacting mortality.137 Additionally, specific programs
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have been developed to reproduce familiar environments for high-risk patients or to augment
the presence of family members in person or online to decrease the cognitive deficit of
critically ill patients at ICU discharge.145 The importance of family involvement in cognitive
rehabilitation has been recognized in other types of brain injury146 and may provide a
promising avenue for reducing the burden of brain injury due to delirium in ICU patients.
144,147 Other methods for creating comforting environments include music-based therapies,
which can improve physiologic measures associated with delirium148 and have been
recognized as potentially beneficial during critical illness and at the end of life.149 Such
interventions are the subject of ongoing study.150
Implementation Challenges and Difficulties

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Delirium is often underrecognized57,151; therefore the use of validated tools for its
identification is essential to improve patients’ outcomes.151,152 As previously mentioned, the
Pain, Agitation/Sedation, Delirium Immobility, and Sleep Disruption (PADIS) guidelines by
the SCCM recommend the use of either the CAM-ICU or the ICDSC to assess delirium in
critically ill adult patients.121 Despite the excellent reliability of these tools, systematic
screening for delirium is lacking in many ICUs151,153–155 due to several barriers.
Nurses often reported that delirium was difficult to evaluate in intubated patients,154,156–158
whereas others felt that sedated patients could not be assessed.154,157 However, the CAM-
ICU was specifically designed to assess nonverbal ICU patients receiving mechanical
ventilation, and the current CAM-ICU training manual159 indicates that the only condition
to be tested with the CAM-ICU is responsiveness to verbal stimulation irrespective of
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sedative use (RASS ≤ 3).
Other studies156,160 have noted that some clinicians believe that delirium can be identified
without an assessment tool. This is contrary to the evidence found by Spronk et al,57 which
suggests that delirium was very often missed without a validated screening tool such as the
CAM-ICU: nurses only recognized 35% of delirious days, while attending intensivists
performed even worse (only 28% of days with delirium were recognized). In another study
by van Eijk et al,161 almost three out of four patients of all ICU delirium were missed by
Mart et al. Page 13
doctors not using a validated assessment tool. Missed diagnosis may lead to lack of
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treatment, whereas false positives due to lack of objectivity may expose patients to
unnecessary pharmacological therapy despite its unproven efficacy56 and safety risks.162,163
In some units delirium screening is perceived as too complex154 or too time

consuming156,164 although assessment with the CAM-ICU or the ICDSC takes 2 to 5
minutes to complete.158,165 Some clinicians feel that CAM-ICU is unreliable,164,166 or
unnecessary, often choosing to use clinical observation instead of validated tools to monitor
agitation or to assess the ability to follow commands.154 This is especially the case in the
neurocritical care setting, where there is a perception that the CAM-ICU and ICDSC are
unsuitable. This in contrast to the findings by Mitasova et al,167 who have shown that the
CAM-ICU has a sensitivity of 76% and a specificity of 98% in patients who have suffered a
stroke. Moreover, Frenette et al168 found that both the CAM-ICU and the ICDSC had good
sensitivity and specificity in evaluating delirium in patients who had suffered a traumatic
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brain injury.167,168 Despite these findings, the assessment of neurocritically ill patients is
challenging especially in those with extreme depression, severe catatonia, and receptive
aphasia. Therefore, more research is needed to find suitable tools to diagnose and prevent
delirium in this population.
Other elements that have been reported as barriers for delirium assessment include lack of
knowledge about delirium or training to use the assessment,156,160,164 perception that it
cannot be prevented or that assessment is futile as there is no treatment for it157,158,164,166;
lack of confidence performing the CAM-ICU158; belief that the test is embarrassing for the
patient166; and low familiarity with the guidelines, lack of motivation to follow them, and
perception that following guidelines regarding delirium screening would not impact
positively on patient’s care.164
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More broadly, the implementation of the ABCDEF bundle as a whole has been shown to
substantially improve outcomes, including reducing the odds of developing delirium and
reducing the chances of needing mechanical ventilation.23,136 Barriers for implementing the
ABCDEF as a bundle are similar to the ones encountered when using a delirium assessment
tool. Some are related to the patient, including safety concerns in terms of hemodynamical
instability or lack of cooperation.169 The majority are related to the clinician implementing
the bundle, in particular lack of knowledge about its benefits, reluctance to follow
guidelines, preference for autonomy, perceived increased workload,170 and lack of
confidence in the bundle’s efficacy.169–171 Finally, there are barriers related to the structure
of the ICU, including culture and organization, teamwork, physical environment, lack of
resources, and inadequate management/leadership.169,171,172
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Practical Considerations for the Treatment of Delirium

At the individual level, for the clinician at the bedside, the management of delirium can be
difficult. The physician must understand delirium as a form of acute organ failure, in this
instance, a form of acute brain failure. One must be familiar with and look for the various
manifestations of delirium, from hypoactive to hyperactive disease. Additionally, similar to
other organ failures, a search for the cause is warranted. Whether in the ICU or on the
Mart et al. Page 14
medical/surgical wards, acute deliriogenic insults due to disease or treatment should be

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evaluated when evaluating a patient. There are several mnemonics that have been developed
to remind the clinician of potential etiologies. One commonly used mnemonic is “Dr. DRE,”
where “DRE” refers to categories of causes of delirium including diseases, drugs that need
to be removed, and environmental risk factors (Table 2). This particular tool is useful for any
patient that is hospitalized, not just the critically ill patient in the ICU. One should look for
diseases, such as sepsis or heart failure, as potential etiologies, as well as sequelae of acute
and chronic diseases, such as metabolic abnormalities. The clinician should also look for
potentially harmful drugs, such as benzodiazepines or antihistamines, that could be
contributing. In addition to evaluating for new or worsening disease processes and removing
offending drugs, evaluation of the patient’s environment is paramount to addressing
delirium. For example, is the patient restrained or immobile in bed with limited day time
stimulus that orients the patient to place and time? Simple interventions, such as providing
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the patient’s eyeglasses and hearing aids and encouraging mobility during the day, are
effective at reducing delirium and represent good clinical care. The clinician could also
assess and make changes to night time vital checks or other bedside interventions in an effort
to promote restful and restorative sleep.
Implementing the above assessments and interventions is the front-line of bedside

management of delirium. While the majority of the scientific literature does not demonstrate
any benefit to the use of medications such as antipsychotics to treat or reduce the duration of
delirium, there may be uncommon indications for their use. For example, for the patient with
significant hyperactive delirium who is a danger to themselves due to removing medical
devices or for falls at the bedside, discrete, limited use of antipsychotics may be indicated to
prevent harm. The clinician should understand that such use is not to treat or improve
delirium but is instead to reduce agitation that may result in harm. If such an intervention is
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needed, one should also continue to look for reversible etiologies and nonpharmacological
interventions to manage and reduce delirium. Using this judicious approach, in addition to
systemic implementation of evidence-based bundles such as the ABCDEF bundle, will
provide the best care for patients.
Conclusion and Future Directions

Delirium is a devastating condition in critically ill patients with wide-ranging impacts, from
cognitive impairment to psychological distress to short-term, and perhaps long-term,
mortality. It is common, with studies indicating that the majority of patients receiving
routine critical care interventions such as mechanical ventilation develop the disease at some
point in their hospitalization. The downstream consequences of delirium go beyond the ICU
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to impact patients for months to years after critical illness.
These facts have increased the urgency to better understand the disease and its pathobiology
as well as identify potential treatments and mitigate risk factors. There has been substantial
interest in pharmacological treatments for delirium, with widespread use of antipsychotics. It
has been estimated that 1 in 10 critically ill patients are given antipsychotics in the setting of
delirium,173 with up to 30% of all adult, nonpsychiatric admissions to the hospital receiving
antipsychotics.174 Yet multiple, prospective studies of antipsychotics have shown that they
Mart et al. Page 15
are ineffective, and they are no longer recommended in care guidelines.20,21,121 The most
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effective treatment, and the standard of care for critically ill patients, is the ABCDEF
bundle. It has demonstrated a significant reduction in delirium in a dose-responsive manner,
in addition to improving other important outcomes such as days of mechanical ventilation
and readmission rates.22,23 The future picture of the critically ill patient is no longer one of a
deeply sedated, immobile patient on mechanical ventilation, but instead one of a patient up
and out of bed, walking, interacting with family and the care team, even with invasive
interventions such as mechanical ventilation or continuous renal replacement therapy. Going
forward, all ICU patients should be managed utilizing the guidelines and framework as
outlined in the ABCDEF bundle to reduce delirium, limit iatrogenesis, and optimize patient-
centered outcomes.
There remain numerous areas of investigation to tackle the scourge of delirium in the most
critically ill patients. Ongoing mechanistic studies are needed to further understand the
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complex and inter-related pathways that are at work in the development of delirium. Such
studies will provide other potential targets for therapeutic interventions and also help
elucidate other risk factors that could be mitigated in the critical care environment. For
example, future medications that can selectively modify the neuroinflammation and
neurotransmitter disturbances may be developed from ongoing basic science studies of
delirium, and care practices that impact delirium such as optimizing the sleep environment
and limiting noxious stimuli will be increasingly understood at the molecular level. There
also remain questions regarding our optimal practices in the ICU to prevent or reduce
delirium—what is the best sedation choice for patients requiring mechanical ventilation?
How, and to what extent, should we mobilize and exercise our critically ill patients? The
data surrounding the ABCDEF bundle are convincing and represent a significant advance in
delirium care and for ICU care as a whole. Further investigation into the best practices to
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implement the bundle widely, in both large and small ICUs, will be needed to optimize care
universally. Following critical illness, questions regarding care abound—for example, how
can primary care physicians and post-ICU recovery clinics work together to reduce the
untoward sequelae of critical illness? Each of these ongoing areas of investigation is
important and necessary to address in the future to improve patient care and outcomes.
As the care of the critically ill patient improves, so does our understanding of delirium and
its consequences. As knowledge advances, the importance of unraveling both the pathways
of disease and improving its prevention and treatment increases exponentially. While no
single agent has been identified yet that prevents and/or treats delirium, significant advances
have been made. Increasingly, the standard of care in the ICU for managing delirium centers
upon integrated, symbiotic care processes such as those outlined in the ABCDEF bundle,
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which both prevents delirium and limits its duration. Further refinements of therapeutic
options, from drugs to rehabilitation, are needed and are current areas ripe for study to
improve the lives of critically ill, delirious patients.
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Fig. 1.
Risk factors for and outcomes after ICU delirium. Pre-existing conditions, such as frailty or
comorbid diseases, contribute to critical illness, and in combination with modifiable risks,
such as immobility and drug use, lead to the development of delirium and its long-term
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complications. ICU, intensive care unit.
Mart et al. Page 26
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Fig. 2.
Predisposing and precipitating factors for developing ICU delirium. Delirium is a result of
both baseline, or predisposing, risk factors (top) and acquired, or precipitating, risk factors
(bottom). These may be modifiable (left) or nonmodifiable (right). ICU, intensive care unit.
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Mart et al. Page 27
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Fig. 3.
Effects of haloperidol, ziprasidone, and placebo on ICU delirium or coma. In a randomized
clinical trial of 566 ICU patients receiving haloperidol, ziprasidone, or placebo for treatment
of hypoactive or hyperactive delirium, there were no significant differences among groups in
days with delirium, days with coma, or days alive without delirium or coma. These analyses
were adjusted for age, pre-existing cognitive impairment, Clinical Frailty Score and
Charlson Comorbidity Index score at baseline, and modified Sequential Organ Failure
Assessment score and Richmond Agitation–Sedation Scale score at randomization. ICU,
intensive care unit. Reproduced with permission from Girard et al.20
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Mart et al. Page 28
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Fig. 4.
Association between proportional performance of the ABCDEF bundle and patient
outcomes. Adjusted hazard ratio and 95% confidence interval for ICU discharge, hospital
discharge, and death, comparing patients with a given proportion of eligible ABCDEF
bundle elements performed on a given day with patients with none of the bundle elements
performed that day. Hazard ratios are adjusted for baseline, ICU admission characteristics,
and daily covariates, measured the same day as bundle performance. ICU, intensive care
unit. Reproduced with permission from Pun et al.22
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Mart et al. Page 29
Table 1
Primary delirium prevention principles

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Primary delirium prevention principles
• Repeated reorientation
• Provisions of cognitively stimulating activities multiple times a day
• A sleep protocol
• Early mobilization
• Timely removal of catheters and physical restraints
• Use of eye glasses, magnifying lenses, hearing aids, and earwax disimpaction
• Correction of dehydration
• Use of a scheduled pain management protocol
• Minimization of unnecessary noise and tactile stimuli
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Mart et al. Page 30
Table 2
“Dr. DRE” mnemonic for clinicians to address delirium at the bedside

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Mnemonic Clinical causes and interventions

Diseases Evaluate the patient for new or worsening disease, such as congestive heart failure or sepsis, as well as other disease findings
such as metabolic abnormalities
Drug Removal Look for and stop deliriogenic medications including benzodiazepines, antihistamines, and inappropriate opioids
Environment Encourage daytime mobilization and remove restraints, provide frequent reorientation as well as cues such as clocks and
windows to the outside, reduce night-time interventions to promote restful sleep
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Prevention and Management of Delirium in the Intensive Care

significant improvements in multiple important ICU outcomes, including delirium, days of

Manifestations and Outcomes of ICU Delirium

psychomotor agitation, depressed level of consciousness, or both. According to the

recognition of the psychological sequelae of delirium. Approximately three-quarters of

mortality and increased time of mechanical ventilation to long-term cognitive impairment,

Risk Factors and Proposed Mechanisms

accumulation in the setting of altered organ function. Furthermore, administration of

neurotransmitter serotonin, and inflammatory biomarkers (procalcitonin and C-reactive

Overall, there seems to be a complex relationship between predisposing and precipitating

Historical Perspective on Management

Early Perspectives and the Use of Antipsychotics

association with hospitalization, systemic illness, or postoperative states. Such treatments

Changing Perspectives on Antipsychotics

hospitalized adults found no difference among haloperidol, atypical antipsychotics, and

Current Knowledge of Management and Prevention

Pharmacological Management and Prevention

Dexmedetomidine—Dexmedetomidine is a selective α−2 adrenoreceptor agonist that

blind, randomized controlled trials, mechanically ventilated patients sedated with

There is a randomized controlled trial in progress that compares dexmedetomidine versus

Regarding pharmacologic treatmentonce delirium develops, a recent Cochrane analysis

Statins—As described previously, one of the postulated mechanisms of delirium

Ketamine—Ketamine is an intravenous N-methyl-D-aspartate (NMDA) receptor antagonist

Thus far no pharmacologic agent has demonstrated efficacy in treating or preventing

reduction in mortality as well as a reduction in number of coma-free and delirium-free ICU

Choice of Analgesia and Sedation—Effective management of pain, anxiety, and

Delirium: Assess, Prevent, and Manage—A key component of delirium management

Once delirium is identified, management entails revisiting primary prevention measures,

measures can be expected to improve patient care.

Early Mobility and Exercise—Early mobility consists of a range of activities from

Family Engagement and Empowerment—Empowering family members to be equal

Implementation Challenges and Difficulties

sedative use (RASS ≤ 3).

In some units delirium screening is perceived as too complex154 or too time

Practical Considerations for the Treatment of Delirium

medical/surgical wards, acute deliriogenic insults due to disease or treatment should be

Implementing the above assessments and interventions is the front-line of bedside

Conclusion and Future Directions

to impact patients for months to years after critical illness.

is an independent predictor of longer hospital stay: a prospective analysis of 261 non-ventilated

ITC6–ITC3, ITC6–ITC4, ITC6–ITC5, ITC6–ITC6, ITC6–ITC7, ITC6–ITC8, ITC6–ITC9, ITC6–

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complications. ICU, intensive care unit.

Primary delirium prevention principles

Primary delirium prevention principles

“Dr. DRE” mnemonic for clinicians to address delirium at the bedside

Mnemonic Clinical causes and interventions

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