REGULAR RESEARCH ARTICLES

Refining Delirium: A Transtheoretical

Model of Delirium Disorder with
Preliminary Neurophysiologic Subtypes
Mark A. Oldham, M.D., Joseph H. Flaherty, M.D., Jose R. Maldonado, M.D.

The development of delirium indicates neurophysiologic disruption and predicts un-

favorable outcomes.This relationship between delirium and its outcomes has inspired
a generation of studies aimed at identifying, predicting, and preventing both de-
lirium and its associated sequelae. Despite this, evidence on delirium prevention and
management remains limited. No medication is approved for the prevention or treat-
ment of delirium or for its associated psychiatric symptoms.This unmet need for effective
delirium treatment calls for a refined approach. First, we explain why a one-size-fits-
all approach based on a unitary biological model of delirium has contributed to variance
in delirium studies and prevents further advance in the field. Next, in parallel with
the shift from dementia to “major neurocognitive disorder,” we propose a transtheoretical
model of “delirium disorder” composed of interactive elements—precipitant, neuro-
physiology, delirium phenotype, and associated psychiatric symptoms.We explore how
these relate both to the biopsychosocial factors that promote healthy cognition
(“procognitive factors”) and to consequent neuropathologic sequelae. Finally, we outline
a preliminary delirium typology of specific neurophysiologic disturbances. Our model
of delirium disorder offers several avenues for novel insights and clinical advance: it
univocally differentiates delirium disorder from the phenotype of delirium, high-
lights delirium neurophysiology as a treatment target, separates the core features of
delirium from associated psychiatric symptoms, suggests how procognitive factors in-
fluence the core elements of delirium disorder, and makes intuitive predictions about
how delirium disorder leads to neuropathologic sequelae and cognitive impair-
ment. Ultimately, this model opens several avenues for modern neuroscience to unravel
this disease of antiquity. (Am J Geriatr Psychiatry 2018; 26:913–924)
Key Words: Delirium model, neurophysiology, subtypes, encephalopathy, neurocognitive
disorder, cognitive decline

Received November 17, 2017; revised March 21, 2018; accepted April 4, 2018. From the Department of Psychiatry (MAO), University of
Rochester Medical Center, Rochester, NY; Envision-Questcare Physician Services (JHF), Geriatrics, Dallas, TX; and the Department of Psychiatry
(JRM), Stanford University School of Medicine, Stanford, CA. Send correspondence and reprint requests to Dr. Mark A. Oldham, Department
of Psychiatry, University of Rochester Medical Center, 300 Crittenden Blvd., Box PSYCH, Rochester, NY, 14642. e-mail: mark_oldham@
URMC.rochester.edu
© 2018 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jagp.2018.04.002

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Refining Delirium

Highlights
• The immense clinical and neurophysiologic diversity in delirium suggests that the current
one-size-fits-all approach may be misguided.
• We propose a refined model of delirium disorder composed of interactive elements
that elucidates key relationships and clarifies delirium nomenclature.
• Our transtheoretical model highlights delirium neurophysiology as a novel treatment
target.
• We introduce a preliminary list of delirium disorder subtypes based on underlying neu-
rophysiologic disturbance(s).

reflects our limited knowledge of the condition.17

INTRODUCTION Thus, we need to refine our understanding of de-
lirium in order to enhance the clinical utility of
The development of delirium alerts clinicians to neu-
diagnosis, elucidate how delirium associates with poor
rophysiologic compromise and often foreshadows long-
outcomes, and advance our understanding of its
term cognitive and functional decline.1,2 That delirium
neurophysiology.17–19 We have three aims: 1) to explain
is associated with poor outcomes has been known for
our rationale for refining delirium; 2) to introduce a
decades,3 and this knowledge has generated fervent
transtheoretical model of delirium disorder that divides
interest in identifying delirium predictors with the goal
it into its component parts, thereby offering novel clin-
of enhancing risk stratification4 and ultimately pre-
ical and research inroads; and 3) to propose a delirium
venting delirium.5 However, as important as prevention
typology based on discrete neurophysiologic distur-
is, current delirium prevention protocols fail to prevent
bances. In so doing, we hope to inspire a disruptive
delirium in over 60% of cases.6,7 Furthermore, there is
shift in the field of delirium that holds promise for clin-
no consensus on the best strategy to manage de-
ical advance.
lirium after onset, and there is no conclusive evidence
that by ameliorating the symptoms of delirium we
prevent the poor physical and cognitive outcomes cur-
Why We Need to Refine Delirium
rently attributed to it.
Despite definitive advances in recognition and un- Our goal is to create a more accurate and precise
derstanding of its sequelae, little progress has been made model of delirium with clear research and treatment
in understanding the neurophysiology of delirium implications. In the traditions of Engel and Romano20
beyond Lipowski’s authoritative work over a quarter and Lipowski,8 delirium is commonly, though not
century ago.8,9 Current delirium management proto- unanimously,21 viewed as a unitary condition that
cols advocate for proactive screening, with the represents a shared “final common pathway.”22 A
assumption that case finding improves care and leads convergent phenotype, though, does not imply that all
to effective treatment.10 Once delirium occurs, though, deliria are created equal.23 For instance, not all cases
interventions may have limited effect on managing its of heart failure have the same etiology.24 Although many
symptoms or hastening its resolution.11,12 Further, heart failure patients express similar physical find-
whereas delirium commonly resolves in a few days as ings (i.e., phenotype), heart failure itself is caused by
its underlying cause improves,13 it may persist for weeks discrete pathophysiologic entities (e.g., ischemia, au-
even after the initial precipitants have resolved.14,15 Cur- toimmunity). Further, these specific causes require
rently, no medication is approved by the U.S. Food and disease-specific management with some commonali-
Drug Administration to prevent or treat delirium, and ties in the management of the convergent phenotype
nonpharmacologic interventions have failed to dem- (e.g., diuresis for fluid overload). Similarly, we suggest
onstrate clear efficacy in managing delirium.11 that subsumed under the clinical entity of delirium are
The lack of concrete delirium treatment options rep- discrete neurophysiologic conditions that cause con-
resents an urgent, unmet need,16 and we believe this vergent clinical features.

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Box 1. Clinical Factors that Contribute to Substantial Variance in Delirium Studies

• Delirium phenotypes are heterogeneous and may fluctuate widely, both within patients and in a relative-
ly short period. This variability challenges our understanding of the neural circuits involved in each case.
• Although a telltale sign of underlying neurophysiologic disruption, delirium is an insensitive clinical sign.
Therefore, it cannot be used as a reliable screening tool for medical illness (i.e., not every patient exposed
to diphenhydramine25 or experiencing sepsis26 develops delirium).
• Delirium is nonspecific for cause. Like fever, delirium may be due equally to anticholinergic toxidrome
or sepsis. Similarly, both alcohol intoxication and withdrawal can present with delirium.
• The development of delirium is not necessary for the development of long-term cognitive impairment
after acute medical illness. Even subsyndromal delirium may be associated with significant neuropatho-
logic insults.27
• The development of delirium alone is insufficient to cause negative long-term sequelae.1

Several additional factors conspire against devel- is problematic because “delirium” indiscriminately de-
oping a one-size-fits-all approach to delirium (Box 1). scribes both the clinical syndrome and a diagnosable
In particular, investigations into delirium biomarkers disorder, which makes clear discussion about the con-
have yielded inconsistent findings,28,29 and studies of dition difficult. Hereafter, we will restrict the term
neuroleptics for delirium prevention and treatment delirium to the clinical phenotype, and we introduce
have produced heterogeneous results.30 These find- the term delirium disorder for the diagnosable condi-
ings may suggest a plurality of neurophysiologically tion as an analog to other Diagnostic and Statistical
distinct conditions under our current umbrella term. Manual (DSM) diagnoses (e.g., dementia has been re-
Attempts to collate these validating factors31 into a labeled major neurocognitive disorder).
unitary biological model called delirium may be This model illustrates that delirium disorder (i.e.,
holding us back from refining our understanding and shaded, dashed box at Figure 1 center) occurs when
approach to this multiplex syndrome. one or more delirium precipitants lead to neurophysi-
Although a patient with delirium is at risk of per- ologic disruption, in turn causing delirium (again, the
manent, irreversible brain damage, the nature of this clinical phenotype). Patients with delirium disorder typ-
predictive association remains poorly understood. ically, but not always, exhibit additional associated
Similar to how outcomes after surgery are suscepti- psychiatric symptoms that extend beyond the core
ble to confounding by indication,32,33 delirium outcome features of delirium. Delirium and its associated psy-
studies are susceptible to confounding by comorbidity, chiatric symptoms are shaded differently in Figure 1
illness severity, and underlying neurophysiologic re- to emphasize this distinction and encourage clinical
silience or its converse vulnerability (sometimes called differentiation between these associated psychiatric
allostasis).34,35 We predict that the relationship between symptoms and the core features of the delirium phe-
delirium and many of its associated poor outcomes may notype. The arrows in Figure 1 represent causal
prove epiphenomenal.36 This is because current models contingencies. That is, although there are circum-
of comorbidity, such as the Charlson Comorbidity stances under which each may occur, causal pathways
Index, are incomplete, our measures of illness sever- are not implied. For instance, a neurophysiologic
ity are similarly limited, and we have no reliable way disturbance that may cause delirium in certain cir-
to assess neurophysiologic resilience or vulnerability. cumstances may lead to subsyndromal delirium
in others. As this model implies, identifying discrete
neurophysiologic processes would invite novel op-
Delirium Disorder: The Model
portunities for managing delirium and for preventing
We propose a transtheoretical model of delirium dis- long-term cognitive impairment due to neuropatho-
order (Figure 1) that divides the condition into its logic sequelae. Below we define the interactive elements
interactive elements. Current delirium nomenclature of our model.

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Refining Delirium

FIGURE 1. Trans-theoretical model of delirium disorder. This model divides delirium disorder into its interactive elements to
reveal key relationships.

Delirium Disorder. DSM-5 and International Classifi- tions, such as neuroleptics, used to “treat delirium”
cation of Diseases, Tenth Revision, delirium are aimed principally at these symptoms. These may
diagnoses each require the presence of delirium and include both positive symptoms (i.e., aggression, im-
at least one precipitant presumed to lead to a neu- pulsivity, affective dysregulation, social disinhibition,
rophysiologic disturbance that mediates the perceptual disturbances, and delusions) and
relationship between precipitant and phenotype. De- negative symptoms (i.e., avolition, withdrawal, and
lirium disorder, then, encompasses precipitant, anhedonia).
neurophysiologic disturbance, and delirium. This Delirium Precipitants. These entail the biological insults
proposal is further intended to parallel the recent or “causes” that lead to delirium by way of neuro-
transition in DSM-5 from dementia to major physiologic disruption. They may include medical
neurocognitive disorder. and surgical conditions as well as psychoactive sub-
Delirium. We use this specifically to describe the core stances. Often, more than one delirium precipitant
clinical features that define delirium—that is, the de- will be identified.38
lirium phenotype. Though delirium typically implies Delirium Neurophysiology. Neurophysiologic disrup-
neurophysiologic compromise and a biological pre- tion in delirium is complex, but emerging data
cipitant, it is agnostic to these. It includes a change suggest that there are discrete neurophysiologic
in cognition, impaired awareness, inattention, dis- routes from a given delirium precipitant to the con-
organized thinking, and fluctuations in arousal. vergent phenotype of delirium. As we explore in
Delirium has a severity37 and duration,1 each of section 3 below, a model of delirium disorder that
which is associated with outcomes. Curiously absent includes discrete neurophysiologic subtypes stands
from the definition of delirium is its functional to elucidate key relationships between neurophysi-
impact. Delirium nearly universally causes func- ology and both its upstream precipitants and its
tional impairment (e.g., inattention that impedes resultant phenotype.
rehabilitation efforts), much the same way that the Procognitive Factors. These baseline biopsychosocial
convergent clinical features of heart failure (e.g., ex- factors are integral to promoting healthy cognitive
ertion intolerance and edema) do. function (Table 1) and explain how each person is
Psychiatric Symptoms. Although clinicians may use variably resilient or vulnerable to delirium. Disrup-
the word delirium casually to refer to the psychi- tion in procognitive factors 1) may modify the
atric symptoms occurring with delirium (e.g., neurophysiologic impact of delirium precipitants;
speaking of a patient as “floridly delirious” or having 2) may influence neurophysiologic disturbances,
an “agitated delirium”), the core features of de- thereby potentiating, propagating, or mitigating de-
lirium should be differentiated from its associated lirium; or 3) if severe enough may serve as an
psychiatric symptoms. Notably, most interven- independent delirium precipitant. Defining

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TABLE 1. Procognitive Factors

How disruption may compromise

Procognitive factor Relationship with cognition cognition
Baseline neural Key neural networks are involved in generating consciousness and Insults to neural integrity may lead to reduced
integrity cognition,39 and the correlation between neural integrity and resilience in response to acute
mental capacity is exemplified in clinicopathologic studies. neurophysiologic stress,41 with certain
Developmental and acquired neurocognitive disorders predispose networks such as the default mode network
to delirium.40 The most common application is in older playing more important roles.42
adults—especially those with cognitive impairment at
baseline—who have accrued neural insults (“neuronal
aging hypothesis”).22
Resting brain Chronic hypoperfusion, as in cerebrovascular disease or heart failure, Metabolic disruption and energy deficiency
perfusion represents vulnerability to delirium. Acute hypoperfusion leading to oxidative stress and
(or isolated hypoxia) compromises brain function and leads to neurotransmitter dysfunction.
delirium.43 Chronic hypoperfusion has also been implicated in not
only vascular cognitive impairment44 but Alzheimer45 dementia.
Nutritional status Adequate nutrition is required for all levels of health. Acute deficiency Metabolic disruption and energy deficiency may
in several B vitamins (B1, B3, B6) may cause delirium,46 and both lead to oxidative stress and neurotransmitter
folate and B12 deficiencies are associated with cognitive decline. dysfunction.
Studies of specific diets and dietary health find an association
between undernutrition and cognitive decline.47 Interestingly,
several nutrients are involved in DNA methylation and other
epigenetic changes.48
Hydration status Dehydration itself is a common cause of hospital admission among Metabolic disruption may lead to oxidative
older adults.49 Loss of as little as 1%–2% of body water can stress and neurotransmitter dysfunction.
impair cognition.50
Sleep and circadian Sleep deprivation or restriction influences arousal, attention, memory, Dyssynchrony among brain regions along with
rhythm integrity and state stability.51,52 Interventions to restore circadian rhythms multi-system organ dysfunction
have shown promise in preventing delirium.53 Circadian rhythms (cardiovascular, immune, endocrine, et al.).
extend to all organ systems, including, for instance, general
metabolism,54 immune function,55 and endocrine system.56
Adequate sensory The neuropsychological effects of sensory deprivation have been Unclear. Sensory deprivation may lead to release
stimulation studied for more than half a century.57 In a classic report, delirium phenomena akin to Charles Bonnet
was attributed to bilateral eye patching.58 Sensory overload, on the syndrome. Perhaps nociceptive stimuli
other hand, remains poorly understood.59 Current contribute to sensory overload.
nonpharmacologic approaches to delirium emphasize adequate
sensory stimulation, though the independent effect sensory
deprivation or overload has on causing or potentiating delirium
remains unclear.
Physical activity Early physical and occupational therapy of mechanically ventilated Unclear. Daytime inactivity may blunt circadian
level ICU patients reduces delirium duration and increases ventilator-free rhythms, lead to muscle and bone
days.60 In general, physical activity and exercise play a critical role deterioration, and contribute to poor
in maintaining cognitive health61 and are of particular interest in engagement in care and recovery.
older people.62 Conversely, advancing frailty, which commonly
includes measures of physical activity, vigor, and speed, confers
vulnerability to delirium.
Cognitive activation Cognitive stimulation therapy, a type of group therapy, enhances Unclear. Conscious activity turns off the default
functioning and quality of life in patients with cognitive mode network and activates task-positive
impairment.63 Nevertheless, it remains to be proven if cognitive networks. Investigations on network activity
training enhances fluid intelligence in healthy adults64 or whether and connectivity may offer insights into the
mental exercise prevents cognitive decline.65 value of cognitive activation.
Degree of Socialization requires higher order executive function and Unclear. As with cognitive activation above,
socialization interpersonal acumen that is often more than the sum of its parts. socialization requires activation and
Socialization is critical for overall well-being and quality of life, coordination of complex neural networks.
though evidence of its effects on cognition remains preliminary.66

procognitive factors as such provides a biological Neuropathologic Sequelae. A delirium precipitant or

rationale for the benefits of multicomponent, the neurophysiologic disruption it causes may lead
nonpharmacologic interventions in preventing and to persisting neuropathologic changes—either neu-
managing delirium. ronal or extraneuronal—leading to the development

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Refining Delirium

of long-term cognitive and functional impairment.67 hypoactivity), whereas hypoactive delirium may com-
Neuronal pathology may include necrosis, apoptosis, promise other procognitive factors (e.g., nutrition and
atrophy, edema, axonal injury, or cytoarchitectural hydration). The relationship between procognitive
change (i.e., intraneuronal deposition, inclusion factors and delirium disorder is especially relevant for
bodies, or mineralization). Extraneuronal patholo- those with dementia because such patients have high
gy may involve gliosis, microglial activation, or baseline vulnerability to delirium precipitants71 and
demyelination. may be uniquely vulnerable to neurophysiologic
insults70 and exhibit uniquely discordant clinical fea-
By characterizing our model as transtheoretical, we tures when evaluated using a phenomenology-based
mean to differentiate it from previous theory-specific approach.72
models (e.g., the cholinergic deficiency hypothesis) The severity and duration of delirium are associ-
because it provides a heuristic framework of interac- ated with neuropathologic sequelae and development
tive elements rather than advocates for the primacy of of long-term cognitive impairment.1,37 However, it is
one unifying neurophysiologic model.22 It draws upon not yet clear which precipitants are more offensive
previous hypotheses and, as detailed below, attempts than others, which neurophysiologic abnormalities are
to make their valuable insights actionable. Certain up- more likely to cause these negative outcomes, or how
stream neurophysiologic disturbances (e.g., electrolyte they do so.70 It stands to reason that different precipi-
disturbances) will lie closer to the proximal delirium tants, along with their attendant neurophysiologic
precipitant, whereas downstream effects (e.g., network disturbances, will lead to different neuropathologic
dysconnectivity) may begin to merge as they near sequelae. Thus, this model offers some guidance for
common final pathway(s).68 It is possible that the best targeted research in these areas.
substantiated models to date have the most robust ev- Whereas all aspects of delirium are clinically mean-
idence because these findings (again, e.g., cholinergic ingful, their meaning varies with clinical situation.
deficiency) are found in the most common types of de- Consider the three clinical examples in Table 2. As il-
lirium disorder (e.g., among medically ill older adults) lustrated in the second of these examples, the core
but may not apply to other types (e.g., alcohol with- features of delirium and its associated psychiatric symp-
drawal delirium in middle age). We emphasize that this toms are not benign; they can cause personal distress,
transtheoretical model is enhanced by ongoing at- compromise recovery from illness, disrupt care, and
tempts to develop further candidate models of delirium lead to mechanical or other medical interventions that
neurophysiology.41 subsequently cause adverse outcomes. However, these
It is not well understood how procognitive factors effects should be differentiated from the neuropatho-
or their deficiency share a relationship with each of logic sequelae due to specific delirium precipitants
the elements of delirium disorder depicted in our and/or delirium neurophysiology. We underscore that
model, despite clear evidence in the literature that any relationship between neuropathologic sequelae and
such relationships exist.69,70 We posit that each of these either delirium precipitant or neurophysiology is caus-
relationships is likely bidirectional. Deficits in ally contingent: not all precipitants or neurophysiologic
procognitive factors (e.g., poor nutrition) can rise to states that cause delirium cause neuropathology. We
the level of a delirium precipitant (e.g., thiamine should be careful not to implicate delirium, the syn-
deficiency); conversely, delirium precipitants (e.g., drome, as directly neuropathogenic. That is, any
surgery) can negatively affect procognitive factors relationship between delirium and adverse outcomes
(e.g., via postoperative physical inactivity). Next, defi- should have a biologically plausible explanation.75
cits in procognitive factors (e.g., resting brain Studies of how delirium is associated with nega-
hypoperfusion) can generate delirium neurophysiol- tive outcomes are beginning to emerge,70,74 but it
ogy (i.e., oxidative stress and perhaps epigenetic remains unclear which neurophysiologic types of
changes48); conversely, delirium neurophysiology delirium disorder contribute to these untoward out-
(e.g., neuroinflammation) can disrupt procognitive comes. Provocatively, recent findings in a murine
factors (e.g., sleep and circadian rhythms). Finally, a model of delirium suggest that the physiologic pre-
deficiency in certain procognitive factors (e.g., social cipitant for certain types of delirium may even be
withdrawal) may cause features of delirium (e.g., mechanistically dissociable from the physiologic causes

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TABLE 2. How Delirium and Its Psychiatric Symptoms May Be Associated With Outcome

Case 1 Case 2 Case 3

Clinical scenario Midazolam use for procedural A patient who develops delirium with A critically ill patient with delirium due to
sedation in an adult. No psychiatric symptoms and injures sepsis who develops irreversible
postprocedural cognitive himself due to agitation. cognitive impairment (i.e., fails to return
impairment occurs. to premorbid cognitive baseline).
Description of Delirium is due to a Delirium may present with behavioral or Delirium reflects an underlying pathogenic
relationship nonpathogenic, reversible psychological symptoms such as brain state, which in turn causes
neurophysiologic change.32 agitation or persecutory delusions. cognitive decline and accelerates brain
Here, no lasting cognitive Here, the negative outcome is mediated aging.73 Here, cognitive decline is due to
impairment occurs. by a behavioral disturbance. a pathogenic brain insult, not delirium
itself.
Clinical relevance Not all delirium may presage Psychiatric symptoms of delirium may Delirium may herald an underlying
negative outcomes. Delirium cause injury and lead to neuropathologic process which leads to
indicates a neurophysiologic interventions (e.g., restraints) that then long-term cognitive impairment. The
disturbance, and defining the compromise outcomes.74 Persistent relationship between delirium and
disturbance and any inanition may lead to deconditioning, outcome, again, is epiphenomenal.
upstream precipitants is key. pressure ulcers, contractures, et al.
Delirium may also alert to
reduced cognitive resilience.

of brain injury manifesting as irreversible cognitive the delirium field ought to consider adopting a similar
impairment.76 A transtheoretical model of delirium approach. The five current DSM-5 delirium subtypes
disorder that identifies interactive relationships, as (i.e., substance intoxication delirium, substance
described above, offers a mechanistic approach to withdrawal delirium, medication-induced delirium,
identifying targets for basic science research and delirium due to another medical condition, and de-
informs clinical trials aimed at improving outcomes. lirium due to multiple etiologies) are inadequate for
this purpose. In Table 3 we provide common types of
delirium disorder based on precipitants, describe as-
Subtyping Delirium Disorder by
sociated neurophysiology, and outline precipitant-
Neurophysiology
specific interventions.
The limitations of the current delirium subtypes have Based on review of common delirium precipitants
been debated for decades.9,24 Psychomotor activity is in Table 3, we outline a preliminary typology of de-
the most common means of delirium subtyping; lirium neurophysiology in Table 4, which builds on
however, motoric subtypes may be unstable over time,77 previous efforts to organize the complex underpin-
and though they can provide clues to neurophysiol- nings of delirium.21,90 Our goal is to make recent work
ogy (i.e., increased activity of gamma-aminobutyric acid on models of delirium actionable to improve clinical
in hepatic encephalopathy may contribute to de- care. For each neurophysiologic type, an illustrative
lirium), they principally acknowledge arousal level. prototype is suggested along with theorized avenues
Geographic delirium (e.g., postoperative delirium, ICU for translational interventions based on discrete neu-
delirium, delirium superimposed on dementia) is rophysiology. We should not expect one type of
another common method of delirium subtyping. In- neurophysiology-guided intervention to be effective
voking clinical context is pragmatic because it for all types of delirium disorder despite indistin-
aggregates shared vulnerabilities, risk factors, clini- guishable phenotypes (e.g., dexmedetomidine may
cal features, and similar clinical interventions along effectively combat postoperative noradrenergic
with their attendant physiologic effects. Such ap- overactivity but would be unlikely to address cumu-
proaches do limit some variance across deliria, but this lative effects of brain aging).
is liable to create a mirage of biological coherence. A case of delirium disorder with multiple precipi-
Just as the field of neurocognitive disorders has em- tants may exhibit features of more than one kind of
phasized the need to specify etiology (DSM-5 lists 13 delirium neurophysiology. Consider, for instance, a
etiologic subtypes of major neurocognitive disorder),78 patient with urinary tract infection and hyponatremia

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Refining Delirium

TABLE 3. Common Delirium Precipitants With Associated Neurophysiology and Current Interventions

Delirium precipitant Candidate neurophysiology Precipitant-specific interventions

Peripheral infection (e.g., urinary Neuroinflammation Antibiotics
tract infection)79
Sepsis-associated encephalopathy Oxidative stress Antibiotics and circulatory support
Neuroinflammation
Neuropathologic sequelae include microvascular
ischemia and hemorrhage
Cerebral hypoperfusion (heart attack Oxidative stress Restore circulation to hypoperfused, ischemic,
or heart failure) or hypoxia or hypoxic tissues
(COPD or pulmonary embolism)
Electrolyte disturbances Neurotransmitter dysfunction Careful correction of disturbances
(e.g., hyponatremic
encephalopathy)
Postoperative statea Neuroinflammation Nonpharmacologic interventions alone
Paraictal encephalopathy Network dysconnectivity Antiepileptics for seizures, though their use for
encephalopathy per se is untested
Traumatic brain injury80 Glutamatergic overactivity Nonpharmacologic interventions81: amantadine
Oxidative stress has been studied later in recovery,82 and
Associated structural damage (DAI, focal ischemia, neuroleptics in particular may hinder
BBB breakdown) cognitive recovery81
Uremic encephalopathy83 Neuroinflammation Renal replacement
Oxidative stress
Glutamatergic overactivity (due to uremic toxins,
especially nitric oxidase-inhibiting guanidine
compounds)
Cystocerebral syndrome Dysautonomia (afferent β3-adrenergic activation due Bladder decompression
(i.e., encephalopathy due to to bladder distention)
urinary retention)84
Hepatic encephalopathy Glutamatergic overactivity (due to high ammonia)85 Lactulose ± rifaximin
Cerebral edema related to elevated glutamine Early evidence: probiotics, branched-chain
Neuroinflammation amino acids, L-ornithine L-aspartate,
flumazenil (benzodiazepine antagonist)
Valproic acid (VPA)-associated Glutamatergic overactivity86 (VPA-induced carnitine Levocarnitine and discontinue valproic acid
hyperammonemic deficiency → high ammonia → glutamate excess)
encephalopathy Cerebral edema related to elevated glutamine87,88
Anticholinergic toxidrome Cholinergic deficiency Physostigmine (optional/potentially diagnostic)
Corticosteroid intoxication Neuroendocrine (HPA axis) Limit corticosteroids as feasible
Benzodiazepine intoxication GABA-ergic overactivity Flumazenil (optional/potentially diagnostic)
Alcohol withdrawal delirium Glutamatergic overactivity Benzodiazepine
Dysautonomia (excess noradrenergic tone) Early evidence: valproic acid, carbamazepine
Malignant catatonia GABA-ergic deficit Benzodiazepines and electroconvulsive therapy
Glutamatergic overactivity Early evidence: NMDA receptor antagonists,
Dysautonomia (excess noradrenergic tone) valproic acid, carbamazepine, thyroid (T3)
supplementation
Anti-NMDA receptor encephalitis Glutamatergic overactivity 1st line: corticosteroids ± IVIG/plasmapheresis
Neuroinflammation 2nd line: rituximab, cyclophosphamide, and less
commonly the antimetabolites azathioprine,
mycophenolate, methotrexate

Notes: BBB: blood-brain barrier; COPD: chronic obstructive pulmonary disease; DAI: diffuse axonal injury; GABA: gamma-
aminobutyric acid; HPA: hypothalamic-pituitary-adrenal; IVIG: intravenous immunoglobulin; VPA: valproic acid.
a
Neurophysiology may differ based on surgery and type of anesthesia. Use of cardiopulmonary bypass may also influence outcomes and,
as such, research in postoperative delirium not uncommonly divides major operations into cardiac and noncardiac surgery.

who is on several anticholinergic medications. delirium neurophysiology are present, patients may
Similarly, even in certain delirium disorders with a benefit from multipharmacologic interventions that
common precipitant, a patient may have multiple target each physiologic disturbance—analogous to
concurrent neurophysiologic types present (see hepatic using multicomponent nonpharmacologic interven-
encephalopathy and sepsis-associated encephalopa- tions to target several procognitive factor deficiencies
thy in Table 3). Therefore, where multiple types of simultaneously. Of course, such an approach would

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TABLE 4. Delirium Disorder Subtypes Based on Neurophysiology

Delirium neurophysiology Prototype Theorized translational intervention

a
Neuroinflammation Postoperative delirium Anti-inflammatory interventions (e.g., minocycline, NSAIDs), therapeutic
Pneumonia-associated delirium hypothermia, intravenous immunoglobulin
Paraneoplastic encephalitis
Oxidative stress Cardiac arrest Antioxidant compounds (e.g., N-acetyl cysteine, high-dose vitamins),
therapeutic hypothermia, supraphysiologic melatonin
Cerebral edema89
• Vasogenic Mechanical brain injury Glucocorticoids, aquaporin 4 inhibitor (e.g., piroxicam), VEGF inhibitors
• Cytotoxic Hyponatremic encephalopathy Sulfonylurea inhibitors (e.g., glibenclamide), NKCCl inhibitors (e.g.,
bumetanide)
• Increased intracranial Acute hydrocephalus Mannitol, hyperventilation
pressure
Neuroendocrine (HPA axis) Corticosteroid psychosis Antiglucocorticoids (e.g., ketoconazole or mifepristone)
Circadian arrhythmia Sleep restriction/deprivation as Light therapy, melatonin agonist therapy, use of nondeliriogenic
in hyperthyroidism or perhaps hypnotics, regulating circadian rhythm of sleep-wake cycle, physical
mania activity, feeding, et al.
Brain aging Sundowning (“nocturnal delirium”) Emphasize nonpharmacologic interventions, limit/avoid psychoactive
medications
Neurotransmitter dysfunctionb
• Cholinergic deficiency Anticholinergic toxidrome Cholinesterase inhibitors (e.g., physostigmine)
• Glutamatergic overactivity Anti-NMDA receptor encephalitis NMDA receptor antagonist, gabapentin/pregabalin, calcium channel
modulators (lamotrigine, VPA)
• GABA-ergic overactivity Benzodiazepine intoxication Benzodiazepine receptor modulators
• Dopaminergic overactivity L-DOPA intoxication Dopamine receptor modulators
• Serotoninergic overactivity Serotonin syndrome Cyproheptadine or mirtazapine
• Noradrenergic overactivity Alcohol withdrawal delirium α1-antagonist, α2-agonist, β-blocker
Network dysconnectivity Multifactorial delirium Postoperative early ambulation or other nonpharmacologic interventions
incorporating procognitive factors, which may have multisystem
benefits

Notes: GABA: gamma-aminobutyric acid; HPA: hypothalamic-pituitary-adrenal; NMDA: N-methyl-D-aspartate; NSAIDs: nonsteroidal
anti-inflammatory drugs; VEGF: vascular endothelial growth factor; VPA: valproic acid.
a
Neuroinflammation likely involves several overlapping subtypes, including cytokine-predominant responses (e.g., postoperatively), cel-
lular immunity with macrophage/microglia activation (brain abscess), antibodies to neuron cell-surface epitopes (antibody-associated encephalitis),
and cytotoxic T-cell injury (paraneoplastic encephalitis). Effects on hemostasis due to regional vasodilation or vasoconstriction (as in sepsis)
commonly lead to hypoperfusion and, subsequently, oxidative stress.
b
These neurophysiologic disruptions accompany many types of delirium and may involve certain “final common pathways.” It is unclear
whether there are precipitant-specific subtypes that uniquely represent these pathophysiologic states.

need to be balanced with the understandable risk of A delirium disorder typology based on neuro-
polypharmacy and potential for adverse effects. physiology would complement current approaches
Current management of delirium involves “treat- by offering the opportunity to target specific de-
ing the underlying cause” (i.e., addressing delirium lirium neurophysiology as well. It also may allow
precipitants), managing delirium with an emphasis on clinicians to manage delirium where a precipitant is
its associated psychiatric symptoms, and promoting not immediately identified (e.g., treating associated
procognitive factors with nonpharmacologic interven- noradrenergic overactivity), when no clear precipi-
tions (see Figure 1). It bears repeating that most agents, tant is identified despite thorough evaluation,91 or
such as neuroleptics, used to “treat delirium” are in- when persisting neurophysiologic disruption propa-
tended to “manage” its psychiatric symptoms. In gates delirium even after the index insult has passed
most instances, there is only indirect evidence that (e.g., postoperative inflammation which presents
these agents correct underlying neurophysiologic after index tissue injury92). Further, it may prevent
alterations, and their effect on specific types of neu- neurophysiologic insults from leading to permanent
rophysiology and procognitive factors is theoretical neuropathologic sequelae (e.g., persistent hypoxia
at best. leading to demyelination93).

Am J Geriatr Psychiatry 26:9, September 2018 921

Refining Delirium

A pathophysiologically informed approach to de- peripheral cholinesterase activity, are routinely as-
lirium disorder may also elucidate how delirium sessed in delirium and meaningfully inform care.
contributes to neuropathology and associated long-
term impairment. We cannot overemphasize that
delirium itself should not be implicated as the cause CONCLUSION
of long-term sequelae and that we ought not to
presume that by preventing delirium we have ipso facto There is an urgent need for a clearer understand-
prevented a neurophysiologic process that leads to ing of delirium disorder as well as effective treatments
neuropathology. We should also be vigilant for the po- for this all too common, disabling condition. Several
tential paradox where we have prevented delirium but factors have served as formidable barriers to devel-
worsened outcomes (e.g., interventions might blunt oping effective delirium treatments and making
phenotypic manifestations, rather than alter underly- definitive clinical advance; among these include de-
ing neurophysiologic changes). Merely preventing lirium’s diverse clinical features, the broad scope of
delirium may lead us to overlook otherwise quies- delirium precipitants, the potential for confounded out-
cent biological insults or miss subtle neurophysiologic comes in medically ill and medically complex cohorts,
disruption causing indolent, accumulating neuropa- and even the varied meanings of the word delirium
thology. That is, we might save the canary while itself.
poisoning the coalminers.76 Our proposed model of delirium disorder, itself com-
Our transtheoretical model with proposed neuro- posed of interactive elements, does several things:
physiologic subtypes offers several directions for 1) it allows for univocal differentiation between de-
future research. Principally, though, our typology is lirium disorder and the clinical phenotype of delirium;
provisional and requires validation. Homogeneous 2) it proposes and highlights delirium neurophysiol-
cohorts (e.g., postcardiotomy delirium, hepatic en- ogy as a largely unexplored treatment target; 3) it
cephalopathy) are likely to limit statistical variance differentiates the core features of delirium from asso-
and allow for more targeted validation studies. For ciated psychiatric symptoms; 4) it suggests “how”
instance, are there biomarkers or functional imaging procognitive factors influence the elements of de-
findings that reliably define specific neurophysi- lirium disorder, thereby providing biological rationale
ologic subtypes? The provisional nature of our typology for their effect; and 5) it allows for mechanistic pre-
is also invitation for further refinement. As neuro- dictions about the relationship between the elements
physiologic subtypes are validated, a generation of of delirium disorder and subsequent cognitive im-
studies ought to evaluate the efficacy of theorized pairment. We pair this model with a preliminary
translational interventions. In fact, future delirium delirium disorder typology based on candidate neu-
intervention studies would do well to assess biologi- rophysiologic disturbances, which may provide a much
cally plausible biomarkers to define the delirium needed roadmap for progress and allow us to apply
disorder subtypes that respond to such interven- modern neuroscience to this disease of antiquity.
tions. It is not unreasonable to envision a future This manuscript received no formal funding, there are
where bioassays, such as specific cytokine levels no disclosures to report, and the authors report no con-
or patterns, a dexamethasone suppression test, or flicts of interest.

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