REVIEW

C URRENT
OPINION Acute encephalopathy in the ICU: a
practical approach
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Pedro Kurtz a,b,
, Mark van den Boogaard c,
, Timothy D. Girard d,y
and Bertrand Hermann e,f,y
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Purpose of review
Acute encephalopathy (AE) -- which frequently develops in critically ill patients with and without primary
brain injury -- is defined as an acute process that evolves rapidly and leads to changes in baseline
cognitive status, ranging from delirium to coma. The diagnosis, monitoring, and management of AE is
challenging. Here, we discuss advances in definitions, diagnostic approaches, therapeutic options, and
implications to outcomes of the clinical spectrum of AE in ICU patients without primary brain injury.
Recent findings
Understanding and definitions of delirium and coma have evolved. Delirium is a neurocognitive disorder
involving impairment of attention and cognition, usually fluctuating, and developing over hours to days.
Coma is a state of unresponsiveness, with absence of command following, intelligible speech, or visual
pursuit, with no imaging or neurophysiological evidence of cognitive motor dissociation. The CAM-ICU(7)
and the ICDSC are validated, guideline-recommended tools for clinical delirium assessment, with
identification of clinical subtypes and stratification of severity. In comatose patients, the roles of continuous
EEG monitoring and neuroimaging have grown for the early detection of secondary brain injury and
treatment of reversible causes.
Summary
Evidence-based pharmacologic treatments for delirium are limited. Dexmedetomidine is effective for
mechanically ventilated patients with delirium, while haloperidol has minimal effect of delirium but may
have other benefits. Specific treatments for coma in nonprimary brain injury are still lacking.
Keywords
coma, delirium, encephalopathy, intensive care, outcomes

INTRODUCTION: BRIDGING THE LINK

BETWEEN DELIRIUM AND COMA

Definitions and terminology a

For decades, literature on encephalopathy was highly
heterogeneous, with segregation between disciplines
and terms lacking clear definitions, such as acute
brain dysfunction, acute brain failure, confusional
&& &
state or altered mental status [1 ,2 ,3]. An interna-
tional consensus of experts, endorsed by 10 Societies
including the American and European societies of
Neurology and Intensive Care Medicine, agreed on
the definition of acute encephalopathy (AE): a rap-
idly developing (usually in <4 weeks) pathobiologi-
cal brain process leading to changes in baseline
cognitive status. AE is thus a substrate, of which
the clinical expression ranges from subsyndromal
delirium to delirium and to coma, with potential
additional features such as dysautonomia, move-
&&
ment disorders, seizure, or even focal signs [1 ].
D’Or Institute of Research and Education, bInstituto Estadual do
C
erebro Paulo Niemeyer, Rio de Janeiro, Brazil, cRadboud University
Medical Center, Department of Intensive Care, Nijmegen, The Nether-
lands, dCenter for Research, Investigation, and Systems Modeling of
Acute Illness (CRISMA) in the Department of Critical Care Medicine,
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania,
USA, eMedical Intensive Care Unit, H^ opital Europ
een Georges Pompi-
dou, Assistance Publique des H^ opitaux de Paris – Centre (APHP-
Centre) and fINSERM UMR 1266, Institut de Psychiatrie et Neuro-
sciences de Paris (IPNP), Universit

e Paris Cit
e, Paris, France
Correspondence to Pedro Kurtz, MD, PhD, FNCS, IDOR, Instituto D’Or
de Pesquisa e Ensino. Rua Diniz Cordeiro 30. Postal code 22281-100.
Rio de Janeiro, Brazil. E-mail: kurtzpedro@mac.com


These authors contributed equally for this manuscript and are joint first
authors.
y
These authors contributed equally for this manuscript and are joint
senior authors.
Curr Opin Crit Care 2024, 30:106–120
DOI:10.1097/MCC.0000000000001144

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 Acute encephalopathy in the ICU: a practical approach Kurtz et al.
KEY POINTS
 Acute encephalopathy is an acute process that
develops rapidly (<4 weeks) and leads to changes in
baseline cognitive status, ranging from delirium
to coma.
 Delirium is a neurocognitive disorder involving
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impairment of attention and cognition, usually
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fluctuating, and developing over a short period of time
(hours to days).
 Coma is a state of unresponsiveness, with absence of
command following, intelligible speech, or visual
pursuit. No imaging or neurophysiological evidence of
cognitive motor dissociation is allowed.
 Both coma and delirium are associated, in nonprimary
brain injured patients, with increased mortality and
long-term cognitive decline.
 Management of medical coma involve EEG monitoring
and neuroimaging for early detection of secondary
brain injury and treatment of reversible causes. Other
specific treatments are lacking in nonprimary
brain injury.
 The CAM-ICU(7) and the ICDSC are valid and
reliable tools for delirium assessment. Identification of
clinical subtypes and stratification of severity have been
associated with cognitive outcomes.
 Pharmacologic evidence of effective treatments for
delirium is limited. Dexmedetomidine is effective for
mechanically ventilated patients with delirium.
Haloperidol seems to have survival benefits in ICU
patients with delirium, determined in two secondary
analyses of recent randomized trials showed.
Delirium is defined as a neurocognitive disorder
involving disturbances of both attention and cog-
nition that develop over a short period of time, tend
to fluctuate, and cannot better explained by another
preexisting, established, or evolving neurocognitive
disorder [4]. Subsyndromal delirium refers to less
severe changes in cognition that do not fulfill all
delirium criteria [5]. Coma is classically defined as a
state of ‘unarousable unresponsiveness’ [6]. Yet
brain imaging evidence challenges this conception,
and a new definition was proposed by an interna-
tional consensus of the Curing Coma Campaign
initiative (CCI) from the Neurocritical Care Society
&
[7 ] (Table 1).
Long restricted to brain dysfunction caused by
nonstructural injuries, acute encephalopathy (AE) is
independent of the underlying etiology and can
either be due to primary brain injury or to systemic
injuries such as toxic, metabolic, or infectious dis-
eases. In this review, we will discuss the patho-
physiology of AE, the clinical presentation and
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management of coma and delirium, and the future
of AE research. Given that most of the existing liter-
ature exclude primary brain injury, we will focus on
AE due to systemic causes. Nevertheless, those with
primary brain injury remain particularly sensitive to
systemic triggers and exhibit a high rate of AE [8,9].
Prevalence and burden on outcome
AE occurs in up to 50% of septic ICU patients and in
up to 70% of mechanically ventilated elderly
patients. Delirium prevalence is also high in other
critical care populations. The pooled prevalence of
ICU delirium in North and South America, Europe
&&
and Asia countries is 31.8% [10 ,11]. The wide
range of prevalence found across settings reflects
the interaction between the types of patients con-
cerned, who vary in age, frailty, and the number and
severity of precipitating factors.
In the most recent cohorts including sepsis
associated encephalopathy (SAE) patients with a
glasgow coma scale (GCS) <15 or delirium features,
reported incidences were 53% in a French multi-
center study [12] and up to 68% in a cohort of sepsis
&&
from US databases MIMIC-IV and eICU [13 ]. The
median delirium duration among SAE was 3 (inter-
quartile range, IQR 2–6) days [14]. However, SAE
remains a broad syndrome with severity ranging
from mild delirium to deep coma, impacting patient
prognosis accordingly [12,14]. Less common (and
often underappreciated) causes of encephalopathy
and delirium are alcohol related. Severe alcohol
withdrawal syndrome can lead to delirium tremens
and/or seizures, while Wernicke encephalopathy
can present with confusion, ataxia, and/or ophthal-
moplegia [15–17].
Both delirium and coma are associated with short-
term mortality and long-term cognitive outcomes,
with over 3 times likelihood to die for SAE patients
[18,19]. Its impact depends on the severity, duration,
and clinical phenotype [20–22] (Fig. 1). Different
clinical phenotypes of SAE have been described.
The mixed phenotype of SAE (42%), including
patients with shock/hypoxemia and metabolic
derangements, have higher mortality compared to
ischemic/hypoxic (29%), metabolic (20%) and unspe-
cified (14%) ones. The presence and duration of sed-
ative-associated, hypoxic, or septic delirium, which
co-occurred in two-thirds of patients, were independ-
ently associated with cognitive scores 12 months after
admission [14]. A meta-analysis also reported signifi-
cant associations between delirium and long-term
cognitive decline [odds ratio (OR) 2.30, 95% confi-
dence interval (CI) 1.85–2.86] [23]. Though not yet
clear, if causality is demonstrated, delirium might be a
modifiable risk factor for dementia.
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 Acute neurological problems

Table 1. Coma and delirium definitions

Coma definitiona
1. No command-following
2. No intelligible speech or recognizable gesture
3. No volitional movement (reflexive movement may occur)
4. No visual pursuit, fixation, saccade to stimuli or eye opening or closing to command.
5. The above criteria are not due to use of paralytic agents, active use of sedatives, or another neurologic or psychiatric disorder
(catatonia, conversion disorder, locked-in syndrome, or neuromuscular disorder for instance)
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6. No electrophysiological or functional imaging evidence of cognitive motor dissociation.

All 6 criteria (1-6) are required to define coma
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Delirium diagnostic criteriab

A. A disturbance in attention (i.e., reduced ability to direct, focus, sustain, and shift attention) and awareness (reduced orientation to the
environment).
B. The disturbance develops over a short period of time (usually hours to a few days), rep-resents a change from baseline attention and
awareness, and tends to fluctuate in severity during the course of a day.
C. An additional disturbance in cognition (e.g., memory deficit, disorientation, language, visuospatial ability, or perception).
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.
E. There is evidence from the history, physical examination, or laboratory findings that the disturbance is a direct physiological
consequence of another medical condition, sub-stance 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.
All five criteria (A-E) are required to diagnose delirium.
Subsyndromal delirium
Acute change in cognition that does not fulfill all the above DSM-5 diagnostic criteria for delirium.

a &
According to an international expert consensus of the Curing Coma Campaign initiative from the Neurocritical Care Society [7 ].
b
From the DSM-5-TR (American Psychiatric Association, 2013).

A common pathophysiology of acute metabolites, especially in case of increased produc-

encephalopathy
AE pathophysiology is complex and incompletely
understood. Animal models are challenging to
develop [24], and it is hard to infer causation from
human studies. Yet, although studies on coma mainly
come from patients with structural injury, anesthesia-
induced loss of consciousness and sleep science
[25,26], and studies on delirium mainly come from
&&
nonstructural causes [10 ], impairment of both con-
tent (awareness) and level (arousal) of consciousness
are core features of both disorders [27]. Additionally,
most of the systemic causes of delirium can cause
coma and vice versa [14]. Indeed, proposed frame-
works to explain global cognition disturbance share
two key features: (i) altered neurotransmission with
excitatory/inhibitory imbalance ultimately leading to
disintegration/dysfacilitation, that is, the disruption
of whole-brain dynamics with reduced functional
connectivity between key neural networks subserving
attention and consciousness [28–36] (meso-circuit
[37–39]) and (ii) dorsal brainstem arousal network
[40–42] with an important modulatory role of the
autonomic and limbic systems [43].
Aside from direct lesions of these structures, many
precipitating factors can, in isolation or in combina-
tion, lead to this disintegration. The main proposed
factors are neuroinflammation [44–47], cerebral bio-
energetic insufficiency [12,48], macro- [49–51] and
micro-vascular changes with endothelial dysfunction
&&
[52,53 ], accumulation of neurotoxic drugs or
tion and/or reduced clearance, increased inhibitory
tone [54], and impaired excitatory signaling with
cholinergic deficiency [55,56] (see supplementary
material for a more detailed description, http://
links.lww.com/COCC/A52) (Fig. 2 and Table 2). All
of these can be favored by an underlying predisposi-
tion, the most common being aging and dementia
[57]. These pathways are also closely related and often
combined, such as in septic associated encephalop-
athy [58–60] or hepatic encephalopathy [61]. Never-
theless, specific etiologies and clinical presentations
may involve them differentially. In summary, AE is
likely due to the breakdown of complex homeostasis
[62], reflecting the inability of the (vulnerable) brain
&
to show resilience in response to acute stressors [63 ].
COMA
Clinical assessment
The clinical evaluation of AE is challenging in the
ICU, and the neurologic examination of critically ill
patients without primary brain injury is often
neglected. Several factors of critical illness, e.g.,
metabolic derangements and analgo-sedation,
may further hinder the diagnosis of AE. Hypoactive
delirium or coma, far more common than the hyper-
active presentation (i.e., agitated delirium), may
prove especially difficult to detect and monitor in
the absence of validated screening tools [60]. An

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 Acute encephalopathy in the ICU: a practical approach Kurtz et al.
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FIGURE 1. Pathophysiology of acute encephalopathy. Acute encephalopathy results from the failure of a vulnerable brain
(predisposing factors) to show resilience to an acute stressor (precipitating factors). Depending on the precipitating factors,
several pathophysiological pathways will be involved (often in combination) and result in a disruption of whole-brain dynamics
resulting in the acute change in cognition meeting criteria of either coma or delirium (clinical phenotypes). Acute stressors in
bold are susceptible to leading to both coma and delirium, whereas the other are mainly responsible for delirium. The figure
was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0
unported license.

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 Acute neurological problems
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FIGURE 2. Acute encephalopathy trajectory and burden on outcome. 4AT, 4AT rapid clinical test for delirium; ADL, activities
of daily living; CAM-ICU, Confusion Assessment Method in the ICU; CRS-r, Coma Recovery Scale -- revised; FOUR, Full
Outline Of Unresponsiveness; GCS, Glasgow Coma Scale; HADS, Hamilton Anxiety and Depression Scale; ICDSC, Intensive
Care Delirium Screening Checklist; ICU, intensive care unit; MMSE, Mini Mental State Examination; MoCA, Montreal
Cognitive Assessment; IADL, Instrumental Activities of Daily Living; PCL-5, Posttraumatic Stress Disorder Checklist for DSM-5;
RASS, Richmond Assessment Sedation Scale; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status;
SAS, Riker Sedation-Agitation Scale; SF, Short-Form general health survey

international survey examining the variability of
assessed coma features and current practices for
management and prognosis was published recently
&
by the CCI [7 ]. It showed that 28% of respondents
disagreed with the expert definition of coma
described. Moreover, GCS was used as a diagnostic
tool, irrespective of coma etiology, in 94% of cases,
followed by complete neurological examination in
74%, NIHSS in 49%, CAM-ICU in 29%, and FOUR
score in 22%. In addition to the assessment of the
level and content of consciousness, the evaluation
of brainstem reflexes showed relevance in nonpri-
marily brain-injured patients [64]. In a prospective
study, brainstem reflexes were impaired in half of
sedated mechanically ventilated patients, which
was associated with 28-day mortality [65]. Recently,
digital pupillometry was tested in septic patients,
but no prognostic association was found [66]. Larger
prospective studies are needed to evaluate the role of
structured clinical approaches, including screening
scales, brainstem assessments and pupillometry, in
critically ill patients with acute encephalopathy.
Neuroimaging
Neuroimaging is pivotal in the investigation of
coma and in some cases of delirium, especially when
focal deficits, brainstem impairment, or unex-
plained altered mental status are present. Computed
tomography (CT) and magnetic resonance imaging
(MRI) may identify patients with a higher risk of
developing long-term sequelae. CT is the first
option, although with low yield. In a meta-analysis,
100% of ICU patients with altered mental status
underwent a CT scan, with positive findings in only
12% of studies [67]. MRI can add further diagnostic

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 Acute encephalopathy in the ICU: a practical approach Kurtz et al.

Table 2. Common etiologies of delirium and/or coma and associated diagnostic work up
Traumatic
- Hemorrhagic lesions (ICH, extradural/subdural hematoma, SAH, - CT with angiography
intraventricular hemorrhage) - Transcranial Doppler/optic nerve sheath diameter
- Parenchymal contusions
- Hydrocephalus
- Diffuse axonal lesions
Vascular
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- Hemorrhagic lesions (ICH, extradural/subdural hematoma, SAH, - CT with angiography

intraventricular hemorrhage) - MRI
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- Acute ischemic stroke and cerebral vasculitis

- Cerebral venous thrombosis
- Posterior reversible encephalopathy syndrome (PRES)
- Cerebral gas or fat embolism
Infectious (bacterial, viral, fungal, parasitic, mycobacterial)
- Meningitis - LP/CSF biochemical and microbiologic analysis
- Encephalitis - Blood, urine, respiratory specimen cultures
- Abcess, empyema - CT with angiography/MRI
- Ventriculitis - Immunodeficiency screening
- Vasculitis - EEG
- Sepsis-associated encephalopathy - Serological status
Metabolic
- Glucose and electrolyte disturbance (hypoglycemia, dysnatremia, - Capillary and blood glucose
dyscalcemia), dehydration - Sodium, calcium
- Organ failure : hepatic encephalopathy, uremic encephalopathy, - Serum creatinine, urea
hypercapnia, hypoxemia, hypotension - Liver enzymes, PT
- Severe hypothermia or malignant hyperthermia - Arterial blood gases
- Vitamin deficiency / malnutrition (Gayet-Wernicke, Marchiafava-Bignami, - Ammonia
. . .) - Thiamin and other vitamins dosage
- Osmotic demyelination syndrome - EEG
- Neurometabolic diseases (mitochondrial diseases, inborn errors of - Metabolic/Enzymatic/Genetic tests
metabolism,. . .)
Tumor
- Primary and secondary brain tumors - CT with angiography
- Carcinomatous meningitis - MRI
- Paraneoplastic encephalitis - LP/CSF with antibody testing
- Biopsies/histology
Epilepsy
- Generalized or complex partial status epilepticus - EEG
- Non convulsive status epilepticus
Endocrine
- Hypothyroidism - TSH, T3, T4
- Adrenal insufficiency, panhypopituitarism - Cortisol and ACTH stimulation tests
Inflammatory and dysimmune disorders
- Antibody-mediated encephalitis - Serum and CSF antibodies (extracellular and intracellular, AQP4, MOG)
- Systemic vasculitis and connective tissue disease (SLE, SjS, Bechet, ANCA - Blood immunological workup
vasculitis, Scleroderma. . .) - WBC, Hb, platelets, coagulation tests, CK, LDH
- Sarcoidosis - Urine analyses (proteinuria, hematuria)
- Acute disseminated encephalomyelitis (ADEM) and other demyelinating - Biopsies/histology
diseases
Toxic (intoxication or withdrawal)
- Sedatives: benzodiazepines, opioids, other sedatives - Alcohol
- Psychotropic drugs: antipsychotics, antidepressants, lithium, antiepileptic - Therapeutic drug monitoring (antibiotics, lithium, valproate, . . .)
- Other drugs: anticholinergics, antihistaminics, antibiotics, chemotherapies, - HbCO
... - Rapid urine drug test
- Narcotics: opioids, cocaine, amphetamines, . . . - Arterial blood gases
- Ethanol and other alcohols (ethylene glycol, methanol),
- Environmental: carbon monoxyde, lead, pesticides. . .
Other
- Constipation, fecal impaction, digestive occlusion, urinary retention - Bladder ultrasound
- Physical restraints, pain, immobility
- Sleep deprivation, environmental factors
- Surgery
- Catatatonia

This table does not include anamnestic and clinical examination work up which are the first and often most important steps. In bold, a suggested standard first-line
work up in the absence of any obvious etiology of AE. Other tests will be performed either guided by patient’s history and examination or as a second-line work-
up.
CSF, cerebrospinal fluid; CT, cerebral computed tomography; EEG, electroencephalogram; Hb, hemoglobin; ICH, intracranial hemorrhage; LP, lumbar punction;
MRI, cerebral magnetic resonance imaging; SAH, subarachnoid hemorrhage; SjS, Sj€ ogren syndrome, SLE, systemic lupus erythematous; WBC, white blood cells.

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 Acute neurological problems
and prognostic information. Seminal studies have
shown that changes in white matter integrity are
associated with the severity/duration of delirium
and encephalopathy [68–70]. In a SAE cohort, 62
out of 156 showed acute brain lesions in MRI, from
which 14 were compatible with posterior reversible
encephalopathy syndrome (PRES), 26 with cerebro-
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vascular infarcts, and 22 with white matter lesions
[71]. Interestingly, PRES patterns were related to
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seizures and abdominal sepsis. Other recent small
prospective cohorts have shown associations of
brain volume reductions (i.e., neuronal loss, brain
atrophy) with biomarkers of secondary brain injury
(e.g., p-tau, complement breakdown products), use
of mechanical ventilation, and clinical outcomes.
Changes in the hippocampus, amygdala, and white
matter regions were more common in SAE nonsur-
vivors, while cognitive decline post hospital dis-
charge was associated with heterogeneous MRI
&&
alterations in SAE and delirium [10 ,71–75].
Neurophysiology
The increased availability of continuous electroen-
cephalography (cEEG) in the ICU has transformed
this method into a cornerstone in the diagnosis and
monitoring of AE of nonprimary brain injury
[76,77]. Seminal investigations had shown that,
though electrographic seizures and nonconvulsive
status are rare, periodic discharges occur in up to 1/4
of severe sepsis patients, with these and malignant
patterns associated with short- and long-term out-
comes [78,79]. EEG obtained after sedation interrup-
tion in 121 unresponsive mechanically ventilated
patients demonstrated that background frequency
>4 Hz and reactivity to external stimuli were asso-
ciated with a reduced risk of death (hazard ratio,
0.38; CI 95%, 0.16–0.9). Surprisingly, no correlation
was found between EEG patterns and command
following [80]. Another sepsis cohort with 92
patients who underwent EEG found that the pres-
ence and burden of rhythmic and periodic dis-
charges was associated with unfavorable outcomes,
including mortality, even after correction for
severity. The impact of the duration of interictal
activity highlights the potential effects of treatment
on outcomes, although no randomized data are
available [81]. Currently, experts agree that in the
context of encephalopathy and coma, nonconvul-
sive electrographic seizures should be treated with
anticonvulsants and/or sedatives, while controversy
remains as to which therapeutic approach interictal
findings deserve. Usually, continuous EEG monitor-
ing is advised when high-risk epileptiform activity is
detected [76,82]. Another important research topic is
the yield of continuous versus routine EEG. A
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randomized trial failed to show differences in out-
comes between those undergoing either method but
demonstrated an increased seizure detection and
more frequent modification of antiseizure treatment
in the cEEG group [83]. Randomized studies testing
cEEG-based treatment strategies are warranted, espe-
cially in nonprimary brain injury.
EEG applications in the ICU include the assess-
ment of acute disorders of consciousness (DoC) and
prediction of recovery of comatose patients. The bulk
of this literature includes patients with severe primary
brain injury, such as cerebral hemorrhages and car-
diac arrest, but its relevance extends to all comatose
states. Major progress has been made in the develop-
ment of EEG biomarkers using resting and stimulus-
based approaches. An example of resting EEG assess-
ment of the severity of coma is the cortical functional
connectivity, with potential applications in early AE
states. Stimulus- and task-based approaches have also
been critical in better understanding acute, subacute,
and chronic DoC. Studies have shown that quanti-
tative EEG measures detect command-following in
otherwise unresponsive (i.e., comatose) ICU patients,
a state currently defined as cognitive-motor dissoci-
ation (CMD). Knowledge about CMD has grown and
multimodal approaches (including functional MRI)
are able to refine its detection and association with
outcomes. Future studies may integrate CMD with
resting state neuroimaging metrics and measures of
functional connectivity to further support predic-
&&
tions of recovery [25,84,85 ].
Management
The mainstays of coma management are the treat-
ment of its underlying cause, the prevention of
secondary insults with supportive care, and early
and intensive rehabilitation encompassing physical
and neurophysiological therapy.
Urgent identification of reversible causes of coma
is mandatory [86] as several etiologies require timely
treatment initiation, e.g., status epilepticus (convul-
sive and nonconvulsive) [82,87], sepsis [88,89], and
meningitis/encephalitis [90–92]. Even hypoglyce-
mia, if prolonged, can lead to irreversible brains
lesions [93,94]. Thus, prompt initiation of antibiotic
or antiepileptics, correction of a metabolic disturb-
ance, withholding of neurotoxic drugs, and reversal
of intoxication with antidotes should be considered.
Other less common toxic-metabolic etiologies also
require specific management approaches such as ure-
mic, hepatic, and Wernicke encephalopathy, as well
as severe alcohol withdrawal syndromes [15–17].
All comatose patients should be carefully moni-
tored in order to prevent secondary systemic and
neurological insults. Clinicians should prevent both
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 Acute encephalopathy in the ICU: a practical approach Kurtz et al.
hypoxia and hyperoxia [95], target normal pH and
PaCO2, and control blood glucose aiming within
140–180 mg/dL (8–11 mmol/L) without episodes of
hypoglycemia [12,96,97]. Despite no clear demon-
stration of benefit [98,99], prevention of fever with
antipyretic drugs is a common practice. Hypother-
mia is controversial [100,101] and could even be
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harmful [102]. These general measures should be
associated with the avoidance of neurotoxic drugs
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and the minimization of sedation exposure, through
the avoidance of deep sedation and daily interrup-
tion of sedation and/or nurse-driven goal-directed
protocols based on nonbenzodiazepine sedatives
[103]. Data to support invasive and/or multimodal
brain monitoring of medical coma are lacking. Intra-
cranial pressure monitoring can be indicated in spe-
cific etiologies [104,105], and noninvasive screening
with transcranial Doppler [106,107] may select
patients that undergo further monitoring.
Specific treatments of coma aimed at restoring
network connectivity and neurotransmitter balance
have been studied in primary brain injury [25,108].
Evidence shows that pharmacological stimulation
with amantadine, a dopaminergic agonist-antago-
nist, elicited consciousness improvement after a 4-
week regimen in patients with TBI in a placebo-
controlled randomized trial [109], but with uncer-
tain long-term effects [110]. Other stimulants lack
evidence, especially in medical coma. Cholinergic
drugs are theoretically appealing, but rivastigmine
led to increased mortality in delirium [111]. Other
promising avenues are noninvasive electromagnetic
stimulation with transcranial direct current and
vagus nerve stimulation [112–114]. The latter could
act both by activating arousal networks [115] and by
modulating immune response [116,117]. In a recent
trial in traumatic coma, sensory stimulation of the
right median nerve improved awakening and 6-
&
month functional outcome [118 ]. Whether these
impressive results will be replicated or apply to a
population of medical coma is still unknown. Never-
theless, multimodal interventions with sensory stim-
ulation are likely beneficial. Intensive rehabilitation
encompassing physical and neurophysiological ther-
apy improved short- and long-term functional out-
come and reduced long-term cognitive impairment
in ICU mechanically ventilated patients [119,120],
although with no change in coma duration and with
uncertain underlying mechanisms.
DELIRIUM
Clinical presentation
Delirium involves disturbances of both attention
and cognition that develop over a short period of
time, tend to fluctuate, and are not better explained
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Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.
by another preexisting, established, or evolving neu-
rocognitive disorder (Table 1) [121]. Though some-
times obvious in a delirious ICU patient, inattention
may be subtle in others and only detected using an
attention test [122].
The cognitive disturbance includes memory
and perception, sometimes leading to delusional
thoughts. Reversal (or disappearance) of the sleep–
wake cycle is common, especially in the ICU, where
environmental cues are often lacking. Psychomotor
activity can be increased, manifesting as agitation
and/or semi-purposeful activity, or decreased, man-
ifesting as lethargy.
Assessment
Although delirium is common in the ICU, it often
goes unrecognized [123]. Failure to detect delirium
in this setting, however, may have adverse conse-
quences. One ICU study found that being screened
for delirium was associated with less time on the
ventilator and in the ICU, as well as reduced in-
hospital mortality [124].
The Confusion Assessment Method for the ICU
(CAM-ICU; Fig. 3) [125,126] and the Intensive Care
Delirium Screening Checklist (ICDSC; Table 3) [127]
have been proven valid and reliable ICU delirium
screening tools, including in mechanically venti-
lated patients receiving sedation. Both tools are
guideline-recommended for use in ICU adults [128].
Assessment for delirium is a two-step process,
with level of consciousness assessed first. The Riker
Sedation-Agitation Scale (SAS) [129] and Richmond
Agitation-Sedation Scale (RASS) [130,131] are well
validated tools, often used in this population, and
can be incorporated into a delirium assessment.
After confirming that a patient has some response
to verbal stimuli (i.e., is SAS 3 or RASS 3 or more
alert), the CAM-ICU or the ICDSC can be used to
evaluate for delirium.
The CAM-ICU evaluates for four key features of
delirium: change from baseline or fluctuating course
of mental status, inattention, altered level of con-
sciousness, and disorganized thinking (Fig. 1). The
ICDSC consists of eight items (either present or
absent) resulting in a score from 0 to 8 using infor-
mation obtained throughout the course of a nursing
shift or over the course of a 24-h period (Table 3)
[127]. In the first validation study, a score of 4 or
more identified patients with delirium with a sensi-
tivity of 99% and specificity of 64%. In general ICU
populations, both tools have an excellent pooled
sensitivity of 0.85 (95% CI: 0.77–0.91) and 0.87
(95% CI: 0.70–0.95) and specificity of 0.95 (95%
CI: 0.90–0.97) and 0.91 (95% CI: 0.85–0.95) for the
CAM-ICU and the ICDSC, respectively [132].
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 Acute neurological problems
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FIGURE 3. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) Flowsheet. A patient screens positive for
delirium if features 1 and 2 and either feature 3 or feature 4 are present. From www.icudelirium.org

Detecting delirium in brain-injured patients diagnostic performances of the CAM-ICU and

is challenging, as consciousness disorders and ICDSC remain good but are notably lower than in
other features of acute encephalopathy might be the nonbrain-injured population [133]. Nonverbal
falsely attributed to the primary brain-lesion. The features, such as those of the ICDSC [134] and

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 Acute encephalopathy in the ICU: a practical approach Kurtz et al.

Table 3. Application of the Intensive Care Delirium Screening Checklist

1. Altered level of consciousness -- choose ONE from A to E.
A. Exaggerated response to normal stimulation SAS ¼ 5, 6, 7 or RASS ¼ þ1 to þ4 (1 point)
B. Normal wakefulness SAS ¼ 4 or RASS ¼ 0 (0 points)
C. Response to mild or moderate stimulation SAS ¼ 3 or RASS 1 to 3 (1 point)
(follows commands)
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D. Response only to intense and repeated SAS ¼ 2 or RASS 4
Stop assessment

stimulation (e.g. loud voice and pain)
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E. No response SAS ¼ 1 or RASS 5
Stop assessment

2. Inattention (1 point if any present)
A. Difficulty in following commands OR
B. Easily distracted by external stimuli OR
C. Difficulty in shifting focus.
Does the patient follow you with their eyes?
3. Disorientation (1 point for any abnormality)
A. Mistake in either time, place or person
Does the patient recognize ICU caregivers who have cared for him/her and not recognize those that have not? What kind of place are you in?
(list examples)

4. Hallucinations or Delusions (1 point for either)

A. Equivocal evidence of hallucinations or a behavior due to hallucinations
(Hallucination ¼ perception of something that is not there with NO stimulus) OR
B. Delusions or gross impairment of reality testing
(Delusion ¼ false belief that is fixed/unchanging)
Any hallucinations now or over past 24 h? Are you afraid of the people or things around you? [fear that is inappropriate to the clinical situation]
5. Psychomotor Agitation or Retardation (1 point for either)
A. Hyperactivity requiring the use of additional sedative drugs or restraints in
order to control potential danger (e.g. pulling IV lines out or hitting staff) OR
B. Hypoactive or clinically noticeable psychomotor slowing or retardation
Based on documentation and observation over shift by primary caregiver
6. Inappropriate Speech or Mood (1 point for either)
A. Inappropriate, disorganized, or incoherent speech OR
B. Inappropriate mood related to events or situation.
Is the patient apathetic to current clinical situation (i.e. lack of emotion)?
Any gross abnormalities in speech or mood? Is patient inappropriately demanding?
7. Sleep/Wake Cycle Disturbance (1 point for any abnormality)
A. Sleeping less than four hours at night OR
B. Waking frequently at night (do not include wakefulness initiated by medical
staff or loud environment) OR
C. Sleep 4 h during day
Based on primary caregiver assessment
8. Symptom Fluctuation (1 point for any)
Fluctuation of any of the above items (i.e., 1 -- 7) over 24 h (e.g. from one shift to another)
Based on primary caregiver assessment
TOTAL ICSDC SCORE (Add 1 -- 8) ____________

ICDSC, Intensive Care Delirium Screening Checklist; SAS, Sedation Agitation Scale; RASS, Richmond Agitation Sedation Scale. Modified from Devlin et al.,
combined didactic and scenario-based education improves the ability of intensive care unit staff to recognize delirium at the bedside. Crit Care 2008;12(1):R19.

fluctuations in mental status (in either wakefulness,
consciousness, attention, orientation, or motor
activity) [135] might constitute more reliable indi-
cators of delirium in this population, notably in
patients with aphasia.
Subtypes
Delirium subtypes have been traditionally classified
based on psychomotor activity or presumed
etiology. Motoric subtypes encompass hyperactive
delirium (increased activity, restlessness, irritability,
and/or combativeness), hypoactive delirium
(reduced activity, decreased alertness, withdrawal,
and/or somnolence), and mixed delirium with signs
and symptoms that fluctuate between hyperactivity
and hypoactivity. Though hyperactive delirium typ-
ically draws more attention (and pharmacologic
treatment), hypoactive delirium is more common
and more linked to adverse long-term outcomes
[136]. The biological underpinnings of these
motoric subtypes remain largely unknown.

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Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.

 Acute neurological problems
Clinical subtypes, based on presumed etiology,
are challenging due to numerous risk factors in ICU
patients. A study applying clinical criteria found that
two-thirds of all delirium days met criteria for two or
more clinical subtypes, with three subtypes
(hypoxic, septic, and sedative-associated) being asso-
ciated with long-term cognitive impairment [14].
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Complexities in delirium subtypes during crit-
ical illness and limited understanding of patho-
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physiology suggest unrecognized subtypes may
exist. One recent study using latent class analysis
identified four subtypes in ICU patients, each with
distinct characteristics, delirium durations, and in-
hospital mortality. Reproducibility in other ICU
populations and predictive value for treatment
response require further investigation [137].
Severity
Delirium severity in critical illness can be measured
through various approaches. The CAM-ICU-7 rates
symptoms from absent to severe (the overall score
ranges from 0 to 7) correlating with in-hospital
mortality [138]. The ICDSC measures severity by
the total observed symptoms; with scores from 1
to 3 indicating subsyndromal delirium and a higher
&&
score indicating more severe delirium [139 ,140].
Duration of delirium, with a median [IQR] typically
around 2 [1–7] days in a general ICU population
[141] and 4 [2–7] days in patients with respiratory/
circulatory failure, also reflect severity of brain dys-
function and predicts long-term cognitive out-
comes, with prolonged durations associated with
more severe cognitive impairment up to a year later
[22]. Specifically, prolonged delirium (>14 days) is
associated with older and sicker patients [142] and
deleterious short- and long-term outcome [143] but
also strongly with the use of physical restraint,
indicating that ICU care could be improved.
Though recently identified delirium subtypes
differed in their duration [137,142], delirium dura-
tion does not necessarily point to a single etiology
and several causes coexist, a prolonged or worsening
acute encephalopathy (i.e.one involving transition
from delirium to coma) should prompt a renewed
etiological work-up.
Management
Comprehensive delirium management should con-
nect all aspects of delirium, including monitoring,
risk stratification, prevention, and treatment.
Prevention
Prevention of delirium is important due to its dele-
terious short- and long-term sequalae. Dexmedeto-
midine, which is indicated only in specific ICU
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populations, is the only pharmacologic agent that
effectively prevents ICU delirium (OR 0.43; 95% CI
&&
0.21–0.85) with a moderate certainty [144 ]. Delir-
ium is multifactorial and therefore multicompo-
nent interventions are key [145]. Though these
approaches are ideally applied in all ICU patients,
they may be targeted towards those with the highest
delirium risk, determined using one of the 12 ICU
delirium prediction models [146], in resource-
constrained settings.
Nonpharmacologic multicomponent interven-
tions, like early mobilization, reorientation, cogni-
tive stimulation, and family participation, reduce
delirium (OR 0.43; 95% 0.22–0.84) [145]. The ABC-
DEF bundle (Box 1), a special form of a multicom-
ponent intervention, is associated with reduced
delirium. Importantly, the higher the compliance
to the bundle, the better the outcomes [147]. This
relationship highlights the importance of high-
quality implementation efforts, e.g., data literacy
training, organizational support, value proposition,
and interprofessional teamwork activities [148].
Role of sedation in ICU delirium
management
Tailoring sedation to achieve light sedation (using
e.g., RASS or SAS) rather than deep sedation, pro-
motes better patient outcomes, including less
delirium. Utilizing sedation protocols and daily
interruptions allows for the titration of sedative
agents. Importantly, short-acting sedatives, like dex-
medetomidine and propofol, are recommended
[103] whereby dexmedetomidine, is preferred over
benzodiazepines for sedation due to its unique pro-
file. It provides sedation while allowing patients to
remain interactive, potentially reducing the inci-
dence of delirium. Since benzodiazepines have been
associated with an increased risk of delirium, their
avoidance is recommended.
Monitoring for ICU delirium
Delirium monitoring is an important part of delir-
ium management and as previously mentioned this
Box 1. A2F bundle
A Assess, prevent, and manage pain
B Both spontaneous awakening and breathing trials
C Choice of analgesia and sedation
D Delirium assessment, prevention, and management
E Early Mobility and exercise
F Family engagement/empowerment
Volume 30  Number 2  April 2024
 Acute encephalopathy in the ICU: a practical approach Kurtz et al.
should be done with recommended delirium assess-
ment tools by well trained nurses. Due to the fluc-
tuating course of delirium, patients should be
assessed at least once a shift or, if patients mental
status changes, more often. This frequent assess-
ment enhances early intervention and treatment
of the underlying cause of delirium.
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Delirium treatment in ICU settings
Due to its multifactorial origin, it is unlikely that
there is one golden bullet that targets multiple
involved pathways. So, also delirium treatment
should be multifactorial, starting with treating the
underlying cause, for example, infection, pain,
hypoxia, electrolyte disturbances, but also reducing
delirogenic drugs, for example, benzodiazepines,
anticholinergics, and antihistamines. There are no
delirium treatment studies performed using non-
pharmacological interventions only for prevention.
However, those preventions were mostly continued
when delirium occurred. The recent network meta-
analyses also showed that there was a trend towards
a reduction in delirium duration when using multi-
component interventions (-0.76 days; 95% CI
2.08–0.56) and seems therefore promising [145].
Pharmacologic treatment of ICU delirium with
antipsychotics lacks effectiveness in resolving ICU
&& &
delirium promptly [149,150,151 ,152 ]. One large
RCT suggested haloperidol may reduce mortality in
& &&
delirious patients [153 ,154 ], though other trials
found no effect on delirium or mortality, and anti-
psychotics for symptoms management remains
inconclusive. However, the burden of suffering
from delirium can be very serious for which anti-
psychotics are still optional, but the use of this
should be balanced against potential side effects.
Dexmedetomidine is recommended for agitation
or sedation in delirious, mechanically ventilated
patients [103].
CONCLUSION
The understanding of AE in the ICU has evolved
significantly in recent years, with current consensus
definitions recently published, its spectrum ranging
from subsyndrome delirium to deep coma, and
etiology varying from primary brain injury to acute
systemic disease. Delirium and coma share complex
and incompletely understood pathophysiology, and
both clearly lead to increased mortality and cogni-
tive impairment. Coma diagnosis/detection and
management remain challenging, especially in crit-
ically ill patients under sedation for other acute
problems, but neuroimaging and cEEG have proved
useful in identifying cerebral complications and
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Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.
treatable pathological patterns. Moreover, multimo-
dal approaches, especially through noninvasive
methods, show promise for monitoring of comatose
patients with nonprimary brain injury and for pre-
diction of recovery in severe disorders of conscious-
ness. Data on specific treatments for medical coma
states are lacking, with limited evidence deriving
from primary brain injury literature, especially trau-
matic brain injury and stroke.
Managing ICU delirium requires a multifaceted
approach encompassing prevention, sedation strat-
egies, vigilant monitoring, and targeted treatment.
Employing evidence-based practices, including mul-
timodal analgesia, light, and noise control, and
awakening and breathing coordination, can signifi-
cantly reduce delirium. Additionally, judicious seda-
tion with agents like dexmedetomidine, routine
delirium screening, and the integration of nonphar-
macological interventions form the cornerstone of
effective delirium management in the ICU. Person-
alized care, tailored to the unique needs of each
patient, remains paramount in optimizing out-
comes in this vulnerable population.
FUTURE OF ACUTE ENCEPHALOPATHY
RESEARCH
Future research on AE should focus on three main
areas. First, a better understanding of its individu-
alized pathophysiology and notably the relation-
ship between the acute phase and long-term
sequalae. This will require the identification of dif-
ferent endotypes based on multimodality (patient’s
predisposition, underlying etiology, clinical, bio-
markers and electrophysiological phenotypes, out-
come trajectories). Second, the development of early
AE detection tools, notably in delirium, to allow
prevention and rapid therapeutic interventions.
These will most probably be based on (quantitative)
neurophysiological tools. Third, on developing spe-
cific treatments, not only on coma awakening and
delirium recovery, but also targeting the reduction
of long-term cognitive impairment. The first two
points will be key to foster personalized timely
therapeutic interventions aimed at reducing the
burden of AE in critically ill patients.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
www.co-criticalcare.com 117
 Acute neurological problems
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Volume 30  Number 2  April 2024