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R E V I E W Open Access
Long-term cognitive impairment after
acute respiratory distress syndrome: a
review of clinical impact and
pathophysiological mechanisms
Cina Sasannejad
1
, E. Wesley Ely
2
and Shouri Lahiri
3,4,5*
Abstract
Acute respiratory distress syndrome (ARDS) survivors experience a high prevalence of cognitive impairment with
concomitantly impaired functional status and quality of life, often persisting months after hospital discharge. In this
review, we explore the pathophysiological mechanisms underlying cognitive impairment following ARDS, the
interrelations between mechanisms and risk factors, and interventions that may mitigate the risk of cognitive
impairment. Risk factors for cognitive decline following ARDS include pre-existing cognitive impairment, neurological
injury, delirium, mechanical ventilation, prolonged exposure to sedating medications, sepsis, systemic inflammation,
and environmental factors in the intensive care unit, which can co-occur synergistically in various combinations.
Detection and characterization of pre-existing cognitive impairment imparts challenges in clinical management and
longitudinal outcome study enrollment. Patients with brain injury who experience ARDS constitute a distinct
population with a particular combination of risk factors and pathophysiological mechanisms: considerations raised by
brain injury include neurogenic pulmonary edema, differences in sympathetic activation and cholinergic transmission,
effects of positive end-expiratory pressure on cerebral microcirculation and intracranial pressure, and sensitivity to
vasopressor use and volume status. The blood-brain barrier represents a physiological interface at which multiple
mechanisms of cognitive impairment interact, as acute blood-brain barrier weakening from mechanical ventilation and
systemic inflammation can compound existing chronic blood-brain barrier dysfunction from Alzheimer’s-type
pathophysiology, rendering the brain vulnerable to both amyloid-beta accumulation and cytokine-mediated
hippocampal damage. Although some contributory elements, such as the presenting brain injury or pre-
existing cognitive impairment, may be irreversible, interventions such as minimizing mechanical ventilation
tidal volume, minimizing duration of exposure to sedating medications, maintaining hemodynamic stability,
optimizing fluid balance, and implementing bundles to enhance patient care help dramatically to reduce
duration of delirium and may help prevent acquisition of long-term cognitive impairment.
Keywords: ARDS, Cognitive impairment, Outcomes, ICU delirium, Blood-brain barrier, Inflammation, Mechanical
ventilation, Pathophysiological mechanisms
© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
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(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
* Correspondence: shouri.lahiri@csmc.edu
3
Division of Neurocritical Care, Department of Neurology, Cedars-Sinai
Medical Center, 127 S. San Vicente Blvd, AHSP Building, Suite A6600, A8103,
Los Angeles, CA 90048, USA
4
Division of Neurocritical Care, Department of Neurosurgery, Cedars-Sinai
Medical Center, 127 S. San Vicente Blvd, AHSP Building, Suite A6600, A8103,
Los Angeles, CA 90048, USA
Full list of author information is available at the end of the article
Sasannejad et al. Critical Care (2019) 23:352
https://doi.org/10.1186/s13054-019-2626-z
Introduction
Cognitive decline following acute respiratory distress syn-
drome (ARDS) complicates recovery from critical illness,
particularly among elderly patients with pre-existing cogni-
tive impairment. Although the exact pathophysiological
mechanisms are unknown, it is widely believed that neuro-
logical injury due to acute systemic inflammatory dysregu-
lation or impairments in cerebrovascular hemodynamics
contribute to cognitive decline after ARDS. In this article,
we review epidemiology, risk factors, putative pathophysio-
logical mechanisms, and possible therapeutic approaches to
minimize cognitive decline after ARDS.
Background and epidemiology
Cognitive impairment in survivors of acute respiratory
distress syndrome: clinical burden and long-term
sequelae
Acute respiratory distress syndrome (ARDS) affects
200,000 patients per year in the USA, accounting for
10.4% of ICU admissions and 25–40% mortality risk [1,
2]. ARDS survivors experience a high prevalence of
cognitive impairment: 70–100% at hospital discharge,
46–80% at 1 year, and 20% at 5 years [3,4]. ARDS sur-
vivors score significantly lower on standardized quality
of life assessments compared to severity-matched con-
trols at 6- and 12-month follow-up [5,6]. ARDS survi-
vors also experience higher overall healthcare costs,
exercise limitations, and persistent psychological and
physical disability despite lung function recovery at 5-
year follow-up [7]. Upon 1-year follow-up, survivors
demonstrate impaired executive function and short-
term memory and increased rates of anxiety and de-
pression [1,8], in addition to post-traumatic stress dis-
order [9]. Neurocognitive testing of ARDS survivors at
2-year follow-up reveals residual emotional and cogni-
tive sequelae in nearly half of patients [10]. In addition
to depression and anxiety, testing shows impairments
in executive function, learning, and memory, with 50%
of those affected performing below the 6th percentile
on multiple instruments [10]. Selected clinical studies
relevant to the understanding of post-ARDS cognitive
impairment are summarized in Table 1.
Ascertaining the true cognitive impact of ARDS requires
distinction between patients with pre-ARDS cognitive im-
pairment and patients who develop new cognitive symptoms
after ARDS. Although established instruments, such as the
Mini-Mental State Examination (MMSE), identify general
memory impairment at a single point in time, two limitations
arise in ICU populations: incomplete patient participation
and the inability to distinguish between delirium, dementia,
or the simultaneous presence of both [11]. These limitations
led to the development of instruments more sensitive in
discerning between different types and timescales of cogni-
tive impairment. The Confusion Assessment Method for
Intensive Care Unit patients (CAM-ICU) shows high sensi-
tivity and specificity in detecting delirium in mechanically
ventilated patients, incorporating questions addressing the
onset of mental status change, inattention, disorganized
thinking, and changes in the patient’s level of consciousness
[12]. Other instruments have been developed to evaluate for
pre-existing cognitive deficits: the Modified Blessed Demen-
tia Rating Scale (mBDRS) and the Informant Questionnaire
on Cognitive Decline in the Elderly (IQCODE) [13]. These
instruments more sensitively detect pre-existing cognitive
impairment by incorporating questions about activities of
daily living and practical examples of learning or memory in
the patient’s pre-morbid daily life experiences, thereby redu-
cing the burden of direct participation expected from the pa-
tient or allowing completion by proxy [11,14]. The mBDRS
assesses for dementia across 11 items encompassing mem-
ory, money management, navigation, activities of daily living,
and personality changes, while the IQCODE measures longi-
tudinal cognitive decline across 16 items encompassing
memory, tool utilization, learning, decision-making, and
problem solving [11,13]. While these instruments show high
overall agreement, the IQCODE demonstrates greater sensi-
tivity, while the mBDRS is less dependent on access to a
proxy [11,13]. In the long-term follow-up of survivors of
ARDS, the MMSE shows poor sensitivity in detecting cogni-
tive impairment and weak-to-moderate correlation with
neuropsychological testing [15]. Implementation and devel-
opment of specialized cognitive assessment tools may help
better guide decisions regarding capacity and medications, in
addition to improving our understanding of the significant
impact of cognitive decline after ARDS.
ARDS in brain injury
ARDS in the context of acute brain injury constitutes a
distinct clinical scenario from other types of ARDS, char-
acterized by earlier sympathetic activation and potential
interactions between positive pressure ventilation, cerebral
autoregulatory, and microcirculatory function [16]. ARDS
independently predicts mortality and poor neurological
outcome in patients with acute brain injury, particularly in
traumatic brain injury or intracerebral hemorrhage [17].
Stevens and Puybasset posited a “brain-lung-brain axis”by
which severe neurological injury from traumatic brain in-
jury, subarachnoid hemorrhage, or status epilepticus can
provoke concurrent pulmonary injury, in turn worsening
overall neurocognitive outcomes [18]. Up to 25% of pa-
tients with severe brain injury develop ARDS and up to
50% develop pulmonary edema, the former increasing the
likelihood of death or vegetative state threefold [19,20].
Patients with brain injury incur the greatest risk for devel-
oping ARDS in the initial 2–3 days after injury and ap-
proximately 1 week after injury [21,22]. Sympathetic
activation, systemic inflammation, pulmonary insuffi-
ciency, and shock contribute to the risk of ARDS early in
Sasannejad et al. Critical Care (2019) 23:352 Page 2 of 12
hospitalization [21,22]. The second peak of ARDS risk re-
flects ventilator-associated pneumonia and sepsis [21,22]:
comatose patients experience an increased frequency of
pneumonia between hospital days 4–7andareatriskfor
aspiration of oropharyngeal secretions during and after in-
tubation [23]. An observational study of patients with
severe traumatic brain injury identified cerebral midline
shift exceeding 5 mm and prior drug abuse as risk factors
for ARDS [19]. Furthermore, patients with concurrent
ARDS and brain injury who experienced worse long-term
cognitive outcome tended to demonstrate lower systemic
blood pressure, higher intracranial pressure, and lower
Table 1 Selected clinical studies investigating post-ARDS cognitive impairment
Author(s) Year Methodology Results/conclusions
Davidson et al. 1999 Prospective cohort (n= 146) Patients who survived ARDS experience significantly reduced quality of life following
discharge compared to critically ill patients without ARDS
Hopkins et al. 1999 Prospective cohort (n= 62) Survivors of ARDS demonstrate cognitive impairments in memory, attention,
concentration, and processing speed: 100% at discharge and 78% at 1 year after
discharge
Contant et al. 2001 Observational (n= 161) ARDS following severe head injury results in severe intracranial hypertension. Targeting
intracranial pressure rather than cerebral blood flow improves outcomes
Georgiadis
et al.
2001 Prospective interventional (n= 20) In patients with acute stroke receiving mechanical ventilation, changes in cerebral
perfusion pressure are mediated by mean arterial pressure rather than by positive end-
expiratory pressure. Positive end-expiratory pressure does not increase intracranial pres-
sure as long as hemodynamic stability is maintained
Holland et al. 2003 Prospective cohort (n= 137) In patients with traumatic brain injury, ARDS independently predicts mortality and is
associated with worse long-term neurological outcome
Ely et al. 2004 Prospective cohort (n= 275) Delirium independently predicts higher mortality and longer hospital stay among
patients treated with mechanical ventilation
Mascia et al. 2005 Prospective interventional (n= 12) Positive end-expiratory pressure does not affect intracranial pressure when inducing al-
veolar recruitment, but does lead to significant increases in PaCO
2
and intracranial pres-
sure when inducing alveolar hyperinflation
Muench et al. 2005 Prospective interventional (n= 10) In hemodynamically unstable patients with severe subarachnoid hemorrhage, increases
in positive end-expiratory pressure disturb cerebrovascular autoregulation, resulting in
significant decreases in mean arterial pressure and regional cerebral blood flow
Mascia et al. 2007 Observational (n= 82) High-tidal-volume mechanical ventilation is associated with the development of ARDS
after severe brain injury
Fong et al. 2009 Secondary analysis of prospective
cohort (n= 408)
Delirium accelerates cognitive decline in patients with probable or possible Alzheimer’s
disease
Taccone et al. 2009 Observational (n= 21) Septic shock impairs cerebral autoregulation in patients with septic shock, particularly
with concurrent hypercapnia
Janz et al. 2010 Retrospective cohort (n= 7 from
database of 379)
Brain autopsy of patients with ICU delirium shows hypoxic ischemic damage in the
hippocampus, suggesting a link between ICU delirium and long-term cognitive
impairment
van den
Boogard et al.
2011 Exploratory observational (n=
100)
The underlying mechanism of delirium may differ in patients with systemic inflammation
versus patients without systemic inflammation and is mediated by different cytokines for
each mechanism
Mikkelsen et al. 2012 Prospective cohort (n= 102) Survivors of ARDS 1 year following discharge demonstrate a confluence of cognitive
impairment, psychiatric sequelae, and diminished quality of life. Hypoxemia and
conservative fluid management are associated with these long-term impairments
Elmer et al. 2013 Retrospective cohort (n= 697) High-tidal-volume mechanical ventilation in patients with intracerebral hemorrhage is
associated with the development of ARDS and increased mortality
Pandharipande
et al.
2013 Prospective cohort (n= 821) At 12-month follow-up after discharge, 1/4 of patients who had been critically ill demon-
strate cognitive impairment similar in severity to that seen in mild Alzheimer’s disease,
and 1/3 similar in severity to that seen in traumatic brain injury
Needham et al. 2014 Prospective cohort (n= 203) At 6- and 12-month follow-up, ARDS survivors demonstrated impairments in 6-min walk
distance and physical function outcomes. Minimizing the duration of intensive care and
corticosteroid use may reflect modifiable risk factors
Girard et al. 2018 Prospective cohort (n= 1040
enrolled, n= 586 follow-up)
Patients with ARDS, septic shock, or both experience multiple subtypes of delirium
associated with long-term cognitive impairment at 3- and 12-month follow-up, including
hypoxic, septic, unclassified, and sedative-associated delirium. The durations of these de-
lirium subtypes predict worse cognitive function at 12-month follow-up, particularly
sedative-associated delirium
Sasannejad et al. Critical Care (2019) 23:352 Page 3 of 12
cerebral perfusion pressure [19]. Among patients with in-
tracerebral hemorrhage, 27% develop ARDS, with high-
tidal-volume mechanical ventilation constituting the
greatest risk factor, followed by positive fluid balance and
blood transfusion [24]. Despite this, existing prognostic
models for acute brain injury largely do not include ARDS
as a variable that may independently limit the extent of
neurocognitive recovery.
Risk factors for cognitive decline
Risk factors for long-term cognitive impairment com-
prise a combination of irreversible clinical factors, po-
tentially modifiable clinical complications of provider
interventions, and pathophysiological events that may
occur in the natural history of ARDS in brain injury. Fig-
ure 1illustrates the confluence of these factors and how
they may culminate in an adverse long-term cognitive
outcome. The heterogeneity of ARDS etiology and sever-
ity can expose patients to varying balances of these fac-
tors: for instance, ARDS of a pulmonary etiology may
expose patients to more severe hypoxemia, whereas
ARDS related to sepsis may expose patients to more se-
vere inflammatory activation, while overall disease sever-
ity can impact length of stay.
Pre-existing cognitive impairment and the interface of
delirium and dementia
Pre-existing cognitive impairment is a risk factor for
cognitive decline after critical illness [25,26], though
data are limited by under-recognition of pre-existing
cognitive impairment [14] or exclusion of patients with
pre-existing cognitive impairment from longitudinal
follow-up studies [1,6]. Alzheimer’s disease, character-
ized by cerebral accumulation and deposition of the
amyloid-βpeptide, is the most common type of cogni-
tive impairment [27,28]. Although one third of elderly
patients admitted to the intensive care unit have pre-
existing cognitive impairment, this history is often un-
known to their medical teams [14], in turn precluding
comparisons of pre-morbid versus longitudinal cognitive
performance. Among patients confirmed not to have
pre-existing dementia, one study found hospitalization
itself significantly associated with a greater likelihood of
developing dementia, along a temporal pattern of abrupt,
rather than gradual, cognitive decline [29].
Delirium during critical illness predicts long-term
cognitive decline after ARDS [1,4,26], and longer
durations of delirium in critically ill patients predict
more severe cognitive impairment at 1-year follow-up
[30]. The closely intertwined relationship between de-
lirium and pre-existing cognitive impairment raises a
physiological question: does long-term cognitive im-
pairment following ARDS reflect a reduction in the
threshold for developing delirium due to underlying
Alzheimer’spathology,ordoesdeliriumcontributein-
dependently to this end? It is known that pre-existing
cognitive impairment is a key underlying risk factor
for delirium, which affects as many as 70–87% of crit-
ically ill patients [31,32]. Particularly among the eld-
erly, ICU delirium can persist during hospitalization
following transfer from the ICU in 40–50% of pa-
tients, commonly with incomplete resolution by dis-
charge [33]. A meta-analysis of long-term sequelae of
delirium in elderly patients found increased risk of
developing dementia within 3–5 years of discharge,
with an odds ratio of 12.52 (95% CI 1.86–84.21) [34].
Patients with Alzheimer’s disease, when hospitalized,
arethreetimesaslikelyasadultswithoutdementia
to experience delirium; cognitive deficits can persist
up to 5 years after discharge [25]. Clinically, patients
with Alzheimer’s disease who experience delirium suf-
fer accelerated cognitive decline beyond the natural
course of dementia alone, with twofold increases in
the slope of decline [35]. Recent pathology-based
studies corroborate delirium-associated acceleration of
cognitive decline independent of pre-existing demen-
tia pathology [36].
Delirium subtypes and pathways
Studies of the pathophysiology of short- and long-term
cognitive impairment reflect similarities and differences
between delirium and dementia pathways, in which pre-
existing pathophysiology diminishes the reserve with
which to face acute insults. Shared mechanistic features
of dementia and delirium include synaptic disconnection
resulting from the loss of presynaptic terminals, dimin-
ished cholinergic activity leading to impaired arousal
and inattention, and microglial activation perpetuating
systemic inflammation [37]. Girard et al. classify the
phenotypes of delirium in the intensive care unit into
five subtypes: sedative-associated, hypoxic, septic/inflam-
matory, metabolic, and unclassified [30]. Among these,
the duration of metabolic delirium is not associated with
long-term adverse cognitive outcomes [30]. Pathophysio-
logically, MacLullich et al. classify the etiologies of delir-
ium into two categories: direct brain insults—primary
insults such as hemorrhage, hypoxia, hypoperfusion, or
drugs—versus aberrant stress responses—the dysfunc-
tion of ordinarily adaptive responses to acute systemic
stressors such as infection or trauma [38]. Differences in
serum markers between patients with inflammatory ver-
sus non-inflammatory delirium suggest activation of
multiple possible pathways: a systemic inflammation
pathway associated with IL-8 elevation among patients
with inflammation, and an alternative pathway charac-
terized by elevation of amyloid-βand IL-10 in patients
without inflammation, suggesting activation of existing
pathways of underlying cognitive impairment [39].
Sasannejad et al. Critical Care (2019) 23:352 Page 4 of 12
Individual pathophysiological mechanisms may be asso-
ciated with multiple delirium subtypes in which a single
phenotype dominates, and these relationships remain an
active area of investigation.
ARDS and hypoxemia: short-term and long-term effects
Profound hypoxemia is one of the cardinal features of
ARDS. While, in the short-term, this can predispose pa-
tients to hypoxic delirium phenotypes [30], lower PaO
2
levels are associated with long-term cognitive impair-
ment at 12-month follow-up, particularly in the domains
of executive function and psychomotor tasks [1,40].
Inflammation and septic delirium
The production of cytokines TNF-α, IL-6, IL-1α, and IL-
1βcan produce a constellation of behaviors termed
“sickness behavior,”comprising impaired concentration,
malaise, diminished motivation, psychomotor retard-
ation, and depression [41], corresponding with septic de-
lirium. In one study, this state was found to be
associated with recruitment of additional brain struc-
tures in order to maintain the same level of cognitive
performance during systemic inflammation [42]. Existing
brain injury enhances vulnerability to inflammation: in
mouse models of neurodegenerative disease, lipopolysac-
charide in brain-injured versus control mice induces
Fig. 1 Confluence of clinical risk factors and pathophysiological events culminating in cognitive impairment following ARDS and brain injury.
Combinations of irreversible clinical risk factors, pathophysiological events, and modifiable clinical risk factors, each occurring to varying extents,
produce an aggregate sum of risk for long-term cognitive impairment. Cognitive outcomes reflect a continuum up to a threshold beyond which
a patient is likely to experience an adverse outcome, defined as long-term cognitive impairment. The aggregate sum of these factors can bring
the patient’s risk for long-term impairment closer toward this threshold (the upward trajectory indicated by the red arrow); however, minimization
of modifiable clinical factors can bring the aggregate sum further away from the threshold, promoting a less adverse cognitive outcome (the
downward trajectory indicated by the green arrow)
Sasannejad et al. Critical Care (2019) 23:352 Page 5 of 12
compounded cognitive deficits on maze-learning tasks
greater than exaggerated sickness behavior alone [43].
Mechanical ventilation and inflammatory and sedative-
associated delirium
Mechanical ventilation is independently associated with
persistent cognitive impairment, diminished quality of
life, and depression [44]. One third of mechanically
ventilated patients perform abnormally on neurocogni-
tive testing at 6 months, comprising deficits in visuo-
construction, visual memory, psychomotor speed, and
verbal fluency [44]. Accelerated Alzheimer’s disease-type
pathophysiology can follow short-term high-tidal-
volume mechanical ventilation in mice, including im-
paired β-amyloid clearance, increased inflammation me-
diated by TNF-αand IL-6, and altered blood-brain
barrier permeability [45]. Prolonged courses of mechan-
ical ventilation in ARDS also expose patients to sedating
medications and anesthesia. Among delirium subtypes,
sedative-associated delirium is the most common and,
with prolonged duration, associated with the greatest de-
gree of long-term cognitive impairment at 12 months
following discharge [30]. Among sedative types, benzodi-
azepines impart the greatest risk for delirium, while dex-
medetomidine has been associated with lower risk for
delirium [46]; however, data and practice choices are
limited, as most intensive care unit patients are treated
with multiple sedatives [30]. The effect of paralytic ex-
posure on long-term cognitive outcomes is unknown
[3]. Continuous exposure to sedative medications over
several days results in impaired sedative clearance, in
turn exacerbating delirium [30]. In addition to inducing
acute-on-chronic cholinergic transmission dysfunction
in elderly patients, transient axonal damage may repre-
sent another mechanism by which sedatives can contrib-
ute to long-term cognitive decline [47].
Table 2 Selected animal studies investigating post-ARDS cognitive impairment
Author(s) Year Animal
model
Results/conclusions
De la Torre
et al.
1992 Rat Chronic cerebrovascular insufficiency following ligation of the common carotid and left subclavian arteries in aged
rats induces behavioral and cognitive impairments consistent with dementia
Pappas et al. 1996 Rat Rats exposed to chronic reduction of cerebral blood flow following carotid artery ligation develop memory
dysfunction and cell loss in the CA1 region of the hippocampus
Feldman
et al.
1997 Rabbit Positive end-expiratory pressure reduces intracranial compliance in rabbits
Wilson et al. 2003 Mouse High-tidal-volume mechanical ventilation upregulates cytokines in mouse lungs
Altmeier
et al.
2005 Mouse Systemic inflammation simulated by lipopolysaccharide in mechanically ventilated mice induces cytokine-mediated
lung injury in mechanically ventilated wild-type mice
Fries et al. 2005 Pig Mechanically ventilated pigs exposed to hypoxemia with lung injury develop histopathologic changes in the CA1
region of the hippocampus not when exposed to the same degree of hypoxemia alone, suggesting lung injury as
a mechanism of damage independent from hypoxemia
Semmler
et al.
2005 Rat Systemic inflammation induces apoptosis in the rat brain, particularly in the hippocampus
Wilson et al. 2005 Mouse Pulmonary inflammation following high-tidal-volume mechanical ventilation in mice without underlying lung injury
is mediated by TNF-α
Bickenbach
et al.
2009 Pig Low- versus high-tidal-volume mechanical ventilation improves cerebral tissue oxygenation in pigs
Wolthuis
et al.
2009 Mouse Mechanical ventilation even at lower tidal volumes causes lung injury in wild-type mice without history of lung
disease
Bickenbach
et al.
2011 Pig Mechanically ventilated pigs exposed to hypoxemia with lung injury demonstrate trends toward elevated cytokines
IL-6 and TNF-αin the CA1 region of the hippocampus versus mechanically ventilated pigs exposed to hypoxemia
alone
Heuer et al. 2011 Pig In mechanically ventilated pigs, ARDS results in elevations in TNF-α, IL-6, and IL-1β, which further increase in pigs
with acute intracranial hypertension. The combination of ARDS and acute intracranial hypertension results in hippo-
campal damage. Acute intracranial hypertension induces lung injury and extravascular lung water
Imamura
et al.
2011 Mouse In a mouse model of septic encephalopathy, an IL-1βcytokine-mediated process disrupts the synaptic processing
of long-term potentiation in the hippocampus
Davis et al. 2015 Mouse Baseline neurodegeneration in mice increases the risk, duration, and severity of delirium
Shohami
et al.
2016 Rat TNF-αand IL-6 are detected in the contused hemisphere of rats soon after closed head injury, but not in healthy
rats. TNF-αis detected as early as 1 h after injury and peaks at 4h, whereas IL-6 is detected at 3–5 h and peaks at 8
h after injury
Lahiri et al. 2019 Mouse High-tidal-volume mechanical ventilation simulates Alzheimer’s disease pathophysiology in transgenic Alzheimer’s
disease and wild-type mice
Sasannejad et al. Critical Care (2019) 23:352 Page 6 of 12
Putative biological mechanisms
Inflammation and hypoxemia
Animal studies of ARDS reflect a wide range of ap-
proaches, including murine and porcine models, chem-
ical lung injury, ventilator-induced lung injury following
mechanical ventilation, and combinations of lung injury
with systemic inflammatory states, such as sepsis [48].
Selected animal studies relevant to the understanding of
the mechanisms of post-ARDS cognitive impairment are
summarized in Table 2. While ARDS models typically
invoke a high-tidal-volume strategy, it is important to
note that mechanical ventilation itself, even at low tidal
volumes, can still cause lung injury [49].
Various mechanisms of ARDS-mediated neurological
damage have been theorized, including hypoxemia and
cytokine-mediated damage [50]. A porcine model of
ARDS identified cytokine-mediated brain damage from
lung injury, rather than hypoxemia, as the major patho-
physiological contributor to hippocampal damage, spe-
cifically in CA1 and CA2 [50]. A subsequent study on
pigs randomized to mechanical ventilation-induced
ARDS versus hypoxia-only groups found greater cogni-
tive impairment and trends toward increased hippocam-
pal inflammation and systemic IL-6 and TNF-α
expression among ARDS subjects, further corroborating
the distinct pathophysiological roles of mechanical venti-
lation and concomitant cytokine release [51]. Among
mechanical ventilation groups, low-tidal-volume ventila-
tion is associated with improved brain tissue oxygen-
ation and reduced cytokine release compared to high-
tidal-volume groups [52].
Animal models also demonstrate that ARDS associated
with acute brain injury differs in physiology, time course,
and treatment from traditional ARDS: it occurs later and
features sympathetic nervous system activation, which,
in turn, can trigger neurogenic pulmonary edema sec-
ondary to increased alpha-adrenergic activity [53,54].
ARDS is frequently triggered by sepsis, a proinflamma-
tory condition characterized by elevated peripheral cyto-
kines and cerebral hypoperfusion, culminating in
multifactorial encephalopathy and end-organ damage
[55]. Peripheral cytokine elevation alters blood-brain
barrier metabolism by activating endothelial cells, while
simultaneously impairing systemic and cerebral blood
flow, altering glucose metabolism in the brain, and ex-
posing patients to deleterious environmental factors in
the course of treatment [55]. Cerebral autoregulation
disruption in early septic shock further compounds sys-
temic hypotension, as endotoxin-triggered inducible ni-
tric oxide synthase production excessively vasodilates
blood vessels, precluding appropriate modulation of vas-
cular resistance [56]. Patients with concurrent sepsis and
ARDS incur further risk for impaired cerebral autoregu-
lation, as sepsis renders the cerebral autoregulatory
mechanism more sensitive to P
a
CO
2
: in one study, 50%
of septic patients with low P
a
CO
2
lost autoregulation,
rising to 100% with normal or high P
a
CO
2
[56].
Blood-brain barrier damage and amyloid-βclearance
The blood-brain barrier is a key neurobiological struc-
ture underlying cognitive function. Under normal
physiological conditions, the blood-brain barrier trans-
ports amyloid-βprotein from within neurons to the
extracellular space, where it can be cleared by the glym-
phatic system [57–59]. Accumulated amyloid-βworsens
blood-brain barrier dysfunction by increasing permeabil-
ity, impairing transporter function, and modulating
endothelial cell expression patterns, in turn perpetuating
impairment in the clearance of amyloid-βand inflamma-
tory cytokines [60]. Amyloid-βtoxicity induces apoptosis
in blood-brain barrier endothelial cells and downregu-
lates tight junction proteins Zo-1, occludin, and claudin
[61]. Hippocampal blood-brain barrier breakdown has
been identified early in the disease course in transgenic
Alzheimer’s disease mouse models, with breakdown pre-
ceding the detection of amyloid-βdeposits, cerebral
amyloid angiopathy, or behavioral changes [58]. Animal
studies demonstrate a relationship between amyloid-β
deposits and hippocampal damage, as intrahippocampal
injection of amyloid-βin rats specifically induced apop-
tosis in the CA1 region of the hippocampus [62].
Amyloid-βimpairs the memory-consolidation process of
long-term potentiation in the rat hippocampus in a
time- and concentration-dependent fashion [63], mech-
anistically comprising impairments in intracellular cal-
cium homeostasis and NMDA receptor function [27].
Pathophysiological similarities between Alzheimer’s
disease and the acute sequelae of high-tidal-volume
mechanical ventilation in mice suggest a link between
the mechanisms underlying cognitive damage in ARDS,
Alzheimer’s disease, and delirium through a combination
of inflammation and amyloid-βaccumulation [45].
Mechanical ventilation increases cerebral TNF-αinde-
pendently of serum TNF-α, suggesting that cerebral
amyloid-βdeposition in this setting may reflect a direct
response to mechanical ventilation or pulmonary injury
rather than sequelae of systemic inflammation [45].
Neuroimaging comparisons of ARDS survivors within
a year of hospital discharge, versus healthy matched con-
trol patients, demonstrate accelerated cerebral and hip-
pocampal atrophy [64]. This is consistent with autopsy
findings from deceased intensive care unit patients who
had experienced delirium, in which hippocampal hyp-
oxic ischemic lesions were not only the most commonly
identified abnormality, but were also found only in pa-
tients who had experienced ARDS [65]. Magnetic
resonance imaging studies have identified hippocampal
blood-brain barrier dysfunction preceding structural or
Sasannejad et al. Critical Care (2019) 23:352 Page 7 of 12
functional phenotypes [66]. Post-mortem studies reflect
consistency with these results, with evidence of micro-
vascular damage and leukocyte infiltration at the sites of
blood-brain barrier damage [66].
Acute and chronic blood-brain barrier insults:
linking risk factors and mechanisms
Acute weakening, diminished reserve, cytokine
circulation, and apoptosis
ARDS and concomitant systemic inflammation reflect a
multifactorial array of simultaneous insults, comprising
cytokine release, metabolic dysregulation, impaired cere-
bral perfusion, medication side-effects, and environmen-
tal stimuli including physical restraints and noise [55].
Peripheral cytokine release generates positive feedback,
inciting further cytokine production through vagal tone
increase, blood-brain barrier endothelial activation, and
humoral system activation [55]. These processes collect-
ively culminate in microglial activation, releasing add-
itional cytokines, nitric oxide, and reactive oxidative
species within the central nervous system [55]. Micro-
glial activation occurs not only in systemic inflammation,
but also in aging, as older rodents injected with periph-
eral E. coli lipopolysaccharide produced cytokines, pri-
marily IL-1β, selectively in the hippocampus [67,68]. A
study investigating anatomic patterns of apoptosis in a
mouse model of systemic inflammation identified the
hippocampus as the most vulnerable region to Bax-
mediated apoptotic cascade activation following nitric
oxide synthase production downstream of microglial ac-
tivation [69].
Anatomical studies of humans and rodents confirm
the selective vulnerability of the CA1 hippocampal layer
to ischemic injury in a mechanism thought to reflect
glutamate excitotoxicity [70]. Mouse models of septic
encephalopathy confirm the role of IL-1βin damaging
learning and memory centers of the hippocampus, as
hippocampal neurons expressing IL-1βdemonstrated
electrophysiological evidence of inhibition of long-term
potentiation [71], thereby acting in a similar mechanism
as amyloid-β-mediated impairment of learning and
memory [72]. Existing blood-brain barrier damage sec-
ondary to amyloid-βaccumulation is associated with di-
minished cerebral blood flow and impaired blood flow
regulation in the elderly, secondary to impaired neuro-
vascular coupling [73]. This, in turn, can render patients
with Alzheimer’s disease susceptible to worsening cogni-
tive dysfunction in the setting of systemic hypoperfusion
and hypoxemia, which are common in ARDS [73].
The mechanistic relationships of brain and lung injur-
ies reflect synergy rather than direct causality, as brain
injury itself triggers cytokine production, including
TNF-αand IL-6 [74]. Indeed, lungs harvested from rab-
bits that had undergone brain herniation were less
resilient in tolerating high-pressure mechanical ventila-
tion compared to sham craniostomy animals, suggesting
potentiation of ARDS by systemic inflammation, in turn
due to brain injury [75]. Baseline blood-brain barrier
weakening, from chronic amyloid-βaccumulation, ren-
ders patients with mild cognitive impairment and Alz-
heimer’s disease susceptible to increased hippocampal
exposure to cytokines. Systemic inflammation, from
ARDS and sepsis, in turn, perpetuates cytokine-mediated
hippocampal damage by imparting acute-on-chronic
blood-brain-barrier damage while simultaneously in-
creasing systemic cytokine circulation.
Organ crosstalk in the setting of injurious mechanical
ventilation is not limited to brain-lung interactions. Ani-
mal studies demonstrate lung-kidney and lung-gut inter-
actions yielding insight into the pathogenesis of multi-
organ dysfunction syndrome, as rabbits exposed to high-
tidal-volume mechanical ventilation developed epithelial
cell apoptosis in the kidney and small intestine [76]. In
addition to cytokine-mediated damage and apoptosis,
additional mechanisms of acute kidney injury associated
with high-tidal-volume mechanical ventilation include
renal blood flow redistribution, hypoperfusion from sys-
temic hemodynamic changes, and metabolic disruption
from blood gas changes [77]. Human studies corroborate
this relationship, with a threefold increase in the risk of
acute kidney injury among critically ill patients exposed
to invasive mechanical ventilation (OR 3.58, 95% CI
1.85–6.92) [78].
Positive pressure ventilation and amyloid-βaccumulation
Despite benefits of positive end-expiratory pressure
(PEEP) in improving oxygenation and alveolar recruit-
ment, its application also introduces physiological risk:
increased intrathoracic pressure from PEEP can impair
both cerebral venous outflow and systemic venous re-
turn, resulting in simultaneously increased intracranial
pressure and reduced cerebral perfusion pressure, re-
spectively [16]. Animal studies have found increased
intracranial pressure and decreased mean arterial pres-
sure with increases in PEEP, in addition to reduced
intracranial compliance [79]. In another study on a
mouse model of stroke, increased PEEP reduced cerebral
perfusion pressure by reducing mean arterial pressure,
but had minimal effect on intracranial pressure when
mean arterial pressure remained stable, reinforcing the
importance of hemodynamic stability [79]. Human stud-
ies confirm the effects of PEEP in hemodynamically un-
stable patients, as PEEP up to 20 cm H
2
O was shown in
one study to significantly decrease mean arterial pres-
sure and cerebral blood flow [80]. Consequences of
PEEP on cerebral microcirculation therefore may com-
pound effects from other potential mechanisms of cogni-
tive impairment in critically ill patients with both ARDS
Sasannejad et al. Critical Care (2019) 23:352 Page 8 of 12
and brain injury, exacerbating both the cerebral hypo-
perfusion of sepsis and the impairment in amyloid-β
clearance following impaired cerebral outflow in vulner-
able patients. In another study in acutely brain-injured
patients, PEEP leading to alveolar hyperinflation in-
creased dead space and P
a
CO
2
, in turn resulting in arter-
ial vasodilation and concomitantly increased intracranial
pressure, with further worsening in the setting of dimin-
ished intracranial compliance [81]. The effects of PEEP
on cerebrovascular hemodynamics, neurological injury,
and cognitive outcomes remain largely unknown and
represent an active area of research.
Therapies
Ventilation
Ventilation of neurologically injured patients entails a
balance between preventing intracranial pressure ele-
vation secondary to hypercarbia while minimizing ex-
posure to an injurious factor. The association between
high-tidal-volume ventilation and ARDS in patients
with intracerebral hemorrhage highlights the import-
ance of incorporating tidal volume minimization in
ventilation setting strategies [24]. Animal studies com-
paring low- versus high-tidal-volume ventilation in
porcine ARDS models find improved oxygenation and
lower lactate levels in brain tissue when using low-
tidal-volume ventilation, which is supported by clin-
ical outcomes in human patients [52,82]. Patients
ventilated at lower tidal volumes (≤8mL/kg) follow-
ing cardiac arrest had a significantly higher chance of
being classified as cerebral performance category 1 at
follow-up [82]. Avoidance of benzodiazepines and se-
lection of dexmedetomidine as a sedative agent may
reduce the risk of delirium in patients with ARDS re-
gardless of neurological injury status [46].
Given the systemic inflammatory effects of ARDS, in
addition to murine studies implicating TNF-αin mediat-
ing neutrophil recruitment in the early phases of high-
tidal-volume-associated stretch lung injury, immunomo-
dulating therapies such as monoclonal antibodies against
TNF-αmay represent a future area of pharmacotherapy
[83]. As the receptor for advanced glycation end prod-
ucts (RAGE) has been found to mediate amyloid-βinflux
and microglial activation at the blood-brain barrier, this
may also represent a future pharmacological target in
humans, with data from mouse models of Alzheimer’s
disease showing effective control of amyloid-βaccumu-
lation and amyloid-β-mediated cellular stress using
RAGE inhibitors [84].
Fluid management
Fluid management reflects another vital juncture of con-
sideration, particularly among neurologically injured pa-
tients with concurrent sepsis. The Fluid and Catheter
Treatment Trial found that despite similar 60-day mor-
tality, patients with ARDS treated with conservative
rather than liberal fluid management (central venous
pressure < 4 versus 10–14, respectively) experience
shorter intensive care unit stays and fewer days requiring
a ventilator [85]. However, follow-up of this trial found
an association between conservative fluid management
and worse cognitive function [1]. The choice of whether
to target treatment toward cerebral perfusion pressure
or intracranial pressure goals in the management of
brain injury invites further consideration of fluid man-
agement strategy in this patient population. A study
comparing treatment strategies in patients with severe
traumatic brain injury found a significantly elevated risk
of developing ARDS among patients receiving cerebral
perfusion pressure-targeted treatment compared to
those receiving intracranial pressure-targeted treatment,
with an odds ratio of 5.1 [19]. Patients with brain injur-
ies appear uniquely susceptible to deleterious effects of
vasopressors: when vasopressors were used in order to
meet cerebral perfusion pressure goals, the risk of devel-
oping ARDS further rose, with odds ratios of 5.7 with
epinephrine (95% CI 1.0375–34.3323) and 10.8 with
dopamine (95% CI 1.4–488.3) [19]. The widespread use
of high PEEP in ARDS raises questions of whether inter-
actions between PEEP and intracranial pressure or cere-
bral perfusion pressure require changes in practice when
treating neurologically injured patients who do go on to
develop ARDS. Studies investigating the relationship be-
tween PEEP and cerebral microcirculation identify
hemodynamic stability as an important factor mitigating
against adverse effects of PEEP [79,80]. Specifically, des-
pite adverse microcirculatory effects of PEEP, Muench
et al. found that it was only in the scenario of existing
hemodynamic instability that PEEP adversely decreased
cerebral perfusion pressure [80], and Georgiadis et al.
similarly found that PEEP did not affect intracranial
pressure as long as mean arterial pressure remained
stable [79]. Therefore, while fluid minimization may be
beneficial in a general population of critically ill patients
[85], aggressive application of a conservative fluid man-
agement approach in neurologically injured patients—es-
pecially if vasopressors become required to maintain
hemodynamic stability—may contribute to not only the
risk of ARDS, but also that of cerebral hypoperfusion
after initiating treatment with high-PEEP ventilation. Fu-
ture studies are needed to determine an optimal, per-
haps individualized PEEP threshold, that maximizes
pulmonary and neurological function.
Other interventions
The interdisciplinary, collaborative environment of the
intensive care unit allows for coordinated patient care
optimization approaches to mitigate contributors to
Sasannejad et al. Critical Care (2019) 23:352 Page 9 of 12
patient discomfort and long-term adverse effects. These
interventions not only are relevant for neurologically in-
jured cohorts of patients with ARDS, but may also im-
prove outcomes in the general population of intensive
care unit patients. A recent example of such an ap-
proach is the ABCDEF bundle, comprising the following
elements: assess, prevent, and manage pain; both spon-
taneous awakening trials and spontaneous breathing tri-
als; choice of analgesia and sedation; delirium: assess,
prevent, and manage; early mobility and exercise; and
family engagement and empowerment [86]. Implementa-
tion of the ABCDEF bundle for 15,000 patients as part
of the ICU Liberation Collaborative found that patients
treated with this bundle experienced significant differ-
ences in outcomes compared to those who did not, in-
cluding higher likelihoods of discharge home and
survival within the first 7 days of hospitalization, and
lower likelihoods of coma, delirium, physical restraint
use, ventilator-dependence, and readmission [86]. Im-
provements in each of these outcomes showed a signifi-
cant dose-response corresponding with compliance with
the bundle, in which 10% increases in bundle compli-
ance produced 15% improvement in survival and days
without coma and delirium [86]. Minimizing corticoster-
oid use and length of stay may also reduce the risk of
adverse long-term cognitive and physical outcomes
among ARDS survivors [6].
Conclusion
Reducing the practical burden of cognitive recovery fol-
lowing critical illness depends crucially on understand-
ing the links between brain injury and lung injury. New
deficits in learning and memory, and new development
of psychiatric illness, inherently limit the maximum ex-
tent of recovery by restricting the extent to which pa-
tients can meaningfully participate in rehabilitation. The
influence of pre-existing cognitive impairment on sus-
ceptibility and recovery highlights the importance of ac-
curate detection and definition of cognitive impairment.
Evidence for distinct patterns of inflammatory damage,
the predilection of cytokines for the hippocampus, and
activation of systemic inflammatory pathways in high-
tidal-volume mechanical ventilation collectively support
minimizing tidal volume as much as possible to avoid
ARDS, in turn helping prevent further endothelial and
microglial activation of the inflammatory cascade. The
ability to control and monitor parameters such as PEEP
and fluid balance in the intensive care unit setting pro-
vides an opportunity to optimize treatment on an indi-
vidual basis to minimize the risk of long-term cognitive
impairment.
As new data continue to reveal increasing layers of
complexity with which these parameters influence the
brain-lung axis and one another, further studies will
hope to elucidate management strategies that entail not
just minimization or maximization of individual vari-
ables, but a balanced and nuanced approach to achieve
both physical and cognitive recovery from ARDS. Mind-
ful implementation of multidisciplinary approaches to
providing more humanistic patient care may improve
long-term cognitive outcomes.
Abbreviations
ARDS: Acute respiratory distress syndrome; CAM-ICU: Confusion Assessment
Method for Intensive Care Unit Patients; PEEP: Positive end-expiratory pres-
sure; RAGE: Receptor for advanced glycation end products; ABCDEF: Assess,
prevent, and manage pain; both spontaneous awakening trials and
spontaneous breathing trials; choice of analgesia and sedation; delirium:
assess, prevent, and manage; early mobility and exercise; and family
engagement and empowerment
Acknowledgements
Not applicable
Authors’contributions
CS, EWE, and SL drafted the manuscript. All authors read and approved the
final manuscript.
Funding
NIH/NIA R03AG064106, American Academy of Neurology Institute (SL).
Availability of data and materials
Not applicable
Ethics approval and consent to participate
Not applicable
Consent for publication
Not applicable
Competing interests
EWE: Pfizer and Orion honoraria for CME events. NIH and VA Funding. CS
and SL declare that they have no competing interests.
Author details
1
Division of Neurocritical Care and Emergency Neurology, Department of
Neurology, Yale School of Medicine, New Haven, CT, USA.
2
Critical Illness,
Brain Dysfunction, Survivorship (CIBS) Center, Department of Pulmonary and
Critical Care Medicine, Veteran’s Affairs Tennessee Valley Geriatric Research
Education and Clinical Center (GRECC), Vanderbilt University School of
Medicine, Nashville, TN, USA.
3
Division of Neurocritical Care, Department of
Neurology, Cedars-Sinai Medical Center, 127 S. San Vicente Blvd, AHSP
Building, Suite A6600, A8103, Los Angeles, CA 90048, USA.
4
Division of
Neurocritical Care, Department of Neurosurgery, Cedars-Sinai Medical Center,
127 S. San Vicente Blvd, AHSP Building, Suite A6600, A8103, Los Angeles, CA
90048, USA.
5
Division of Neurocritical Care, Department of Biomedical
Sciences, Cedars-Sinai Medical Center, 127 S. San Vicente Blvd, AHSP
Building, Suite A6600, A8103, Los Angeles, CA 90048, USA.
Received: 18 July 2019 Accepted: 27 September 2019
References
1. Mikkelsen ME, Christie JD, Lanken PN, Biester RC, Taylor Thompson B,
Bellamy SL, et al. The adult respiratory distress syndrome cognitive
outcomes study: long-term neuropsychological function in survivors of
acute lung injury. Am Thoracic Soc. 2012;185(12):1307–15.
2. Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, et al.
Epidemiology, patterns of care, and mortality for patients with acute
respiratory distress syndrome in intensive care units in 50 countries. JAMA.
2016;315(8):788–13.
3. Herridge MS, Moss M, Hough CL, Hopkins RO, Rice TW, Bienvenu OJ, et al.
Recovery and outcomes after the acute respiratory distress syndrome
Sasannejad et al. Critical Care (2019) 23:352 Page 10 of 12
(ARDS) in patients and their family caregivers. Intensive Care Med. 2016;
42(5):725–38.
4. Wilcox ME, Brummel NE, Archer K, Ely EW, Jackson JC, Hopkins RO.
Cognitive dysfunction in ICU patients: risk factors, predictors, and
rehabilitation interventions. Crit Care Med. 2013;41:S81–98.
5. Davidson TA, Caldwell ES, Curtis JR, Hudson LD, Steinberg KP. Reduced
quality of life in survivors of acute respiratory distress syndrome compared
with critically ill control patients. JAMA. 1999;281(4):354–60.
6. Needham DM, Wozniak AW, Hough CL, Morris PE, Dinglas VD, Jackson JC, et al.
Risk factors for physical impairment after acute lung injury in a national,
multicenter study. Am J Respir Crit Care Med. 2014;189(10):1214–24.
7. Herridge MS, Tansey CM, Matté A, Tomlinson G, Diaz-Granados N, Cooper A,
et al. Functional disability 5 years after acute respiratory distress syndrome.
N Engl J Med. 2011;364(14):1293–304.
8. Mikkelsen ME, Shull WH, Biester RC, Taichman DB, Lynch S, Demissie E, et al.
Cognitive, mood and quality of life impairments in a select population of
ARDS survivors. Respirology. 2009;14(1):76–82.
9. Kapfhammer HP, Rothenhäusler HB, Krauseneck T, Stoll C, Schelling G. Posttraumatic
stress disorder and health-related quality of life in long-term survivors of acute
respiratory distress syndrome. Am J Psychiatr. 2004;161(1):45–52.
10. Hopkins RO, Weaver LK, Collingridge D, Parkinson RB, Chan KJ, Orme JF.
Two-year cognitive, emotional, and quality-of-life outcomes in acute
respiratory distress syndrome. Am J Respir Crit Care Med. 2005;171(4):340–7.
11. Lee HB, DeLoatch CJ, Cho S, Rosenberg P, Mears SC, Sieber FE. Detection
and management of pre-existing cognitive impairment and associated
behavioral symptoms in the intensive care unit. Crit Care Clin. 2008;24(4):
723–36- viii.
12. Ely EW, Inouye SK, Bernard GR, Gordon SM, Francis J, May L, et al. Delirium
in mechanically ventilated patients. JAMA. 2001;286(21):2703–10.
13. Pisani MA, Inouye SK, McNicoll L, Redlich CA. Screening for preexisting
cognitive impairment in older intensive care unit patients: use of proxy
assessment. J Am Geriatr Soc. 2003;51(5):689–93.
14. Pisani MA, Redlich C, McNicoll L, Ely EW, Inouye SK. Underrecognition of
preexisting cognitive impairment by physicians in older ICU patients. CHEST
J. 2003;124(6):2267–74.
15. Pfoh ER, Chan KS, Dinglas VD, Girard TD, Jackson JC, Morris PE, et al.
Cognitive screening among acute respiratory failure survivors: a cross-
sectional evaluation of the Mini-Mental State Examination. Crit Care. 2015;
19:220.
16. Oddo M, Citerio G. ARDS in the brain-injured patient: what’s different?
Intensive Care Med. 2016;42(5):790–3.
17. Holland MC, Mackersie RC, Morabito D, Campbell AR, Kivett VA, Patel R,
et al. The development of acute lung injury is associated with worse
neurologic outcome in patients with severe traumatic brain injury. J
Trauma. 2003;55(1):106–11.
18. Stevens RD, Puybasset L. The brain-lung-brain axis. Intensive Care Med.
2011;37:1054–6.
19. Contant CF, Valadka AB, Gopinath SP, Hannay HJ, Robertson CS. Adult
respiratory distress syndrome: a complication of induced hypertension after
severe head injury. J Neurosurg. 2001;95(4):560–8.
20. Mascia L, Andrews PJ. Acute lung injury in head trauma patients. Intensive
Care Med. 1998;24(10):1115–6.
21. Mascia L, Zavala E, Bosma K, Pasero D, Decaroli D, Andrews P, et al. High
tidal volume is associated with the development of acute lung injury after
severe brain injury: an international observational study. Crit Care Med.
2007;35(8):1815–20.
22. Piek J, Chesnut RM, Marshall LF, van Berkum-Clark M, Klauber MR, Blunt BA,
et al. Extracranial complications of severe head injury. J Neurosurg. 1992;
77(6):901–7.
23. Bronchard R, Albaladejo P, Brezac G, Geffroy A, Seince P-F, Morris W, et al.
Early onset pneumonia: risk factors and consequences in head trauma
patients. Anesthesiology. 2004;100:234–9.
24. Elmer J, Hou P, Wilcox SR, Chang Y, Schreiber H, Okechukwu I, et al. Acute
respiratory distress syndrome after spontaneous intracerebral hemorrhage*.
Crit Care Med. 2013;41(8):1992–2001.
25. Gross AL, Jones RN, Habtemariam DA, Fong TG, Tommet D, Quach L, et al.
Delirium and long-term cognitive trajectory among persons with dementia.
Arch Intern Med. 2012;172(17):1324–8.
26. Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT,
et al. Long-term cognitive impairment after critical illness. N Engl J Med.
2013;369(14):1306–16.
27. Danysz W, Parsons CG. Alzheimer’s disease, β-amyloid, glutamate, NMDA
receptors and memantine - searching for the connections. Br J Pharmacol.
2012;167(2):324–52.
28. Takahashi RH, Nagao T, Gouras GK. Plaque formation and the intraneuronal
accumulation of β-amyloid in Alzheimer’s disease. Pathol Int. 2017;67(4):
185–93.
29. Ehlenbach WJ, Hough CL, Crane PK, Haneuse SJPA, Carson SS, Curtis JR,
et al. Association between acute care and critical illness hospitalization and
cognitive function in older adults. JAMA. 2010;303(8):763–70.
30. Girard TD, Thompson JL, Pandharipande PP, Brummel NE, Jackson JC, Patel
MB, et al. Clinical phenotypes of delirium during critical illness and severity
of subsequent long-term cognitive impairment: a prospective cohort study.
Lancet Respir Med. 2018;6(3):213–22.
31. McNicoll L, Pisani MA, Zhang Y, Ely EW, Siegel MD, Inouye SK. Delirium in
the intensive care unit: occurrence and clinical course in older patients. J
Am Geriatr Soc. 2003;51(5):591–8.
32. Pisani MA, Murphy TE, Van Ness PH, Araujo KLB, Inouye SK. Characteristics
associated with delirium in older patients in a medical intensive care unit.
Arch Intern Med. 2007;167(15):1629–34.
33. Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE, et al.
Delirium as a predictor of mortality in mechanically ventilated patients in
the intensive care unit. JAMA. 2004;291(14):1753–62.
34. Witlox J, Eurelings LSM, de Jonghe JFM, Kalisvaart KJ, Eikelenboom P, van
Gool WA. Delirium in elderly patients and the risk of postdischarge
mortality, institutionalization, and dementia: a meta-analysis. JAMA. 2010;
304(4):443–51.
35. Fong TG, Jones RN, Shi P, Marcantonio ER, Yap L, Rudolph JL, et al. Delirium
accelerates cognitive decline in Alzheimer disease. Neurology. 2009;72(18):
1570–5.
36. Davis DHJ, Muniz-Terrera G, Keage HAD, Stephan BCM, Fleming J, Ince PG,
et al. Association of delirium with cognitive decline in late life: a
neuropathologic study of 3 population-based cohort studies. JAMA
Psychiatry. 2017;74(3):244–51.
37. Davis DHJ, Skelly DT, Murray C, Hennessy E, Bowen J, Norton S, et al.
Worsening cognitive impairment and neurodegenerative pathology
progressively increase risk for delirium. Am J Geriatr Psychiatr. 2015;23(4):
403–15.
38. MacLullich AMJ, Ferguson KJ, Miller T, de Rooij SEJA, Cunningham C.
Unravelling the pathophysiology of delirium: a focus on the role of aberrant
stress responses. J Psychosom Res. 2008;65(3):229–38.
39. van den Boogaard M, Kox M, Quinn KL, van Achterberg T, van der Hoeven
JG, Schoonhoven L, et al. Biomarkers associated with delirium in critically ill
patients and their relation with long-term subjective cognitive dysfunction;
indications for different pathways governing delirium in inflamed and
noninflamed patients. Crit Care. 2011;15(6):R297.
40. Hopkins RO, Weaver LK, Pope D, Orme JF, Bigler ED, Larson-LOHR V.
Neuropsychological sequelae and impaired health status in survivors of
severe acute respiratory distress syndrome. Am J Respir Crit Care Med. 1999;
160(1):50–6.
41. Dantzer R. Cytokine-induced sickness behavior: mechanisms and
implications. Ann N Y Acad Sci. 2001;933:222–34.
42. Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Dolan RJ, et al. Neural
origins of human sickness in interoceptive responses to inflammation. Biol
Psychiatry. 2009;66(5):415–22.
43. Cunningham C, MacLullich AMJ. At the extreme end of the
psychoneuroimmunological spectrum: delirium as a maladaptive sickness
behaviour response. Brain Behav Immun. 2013;28(C):1–13.
44. Jackson JC, Hart RP, Gordon SM, Shintani A, Truman B, May L, et al. Six-
month neuropsychological outcome of medical intensive care unit patients.
Crit Care Med. 2003;31(4):1226–34.
45. Lahiri S, Regis GC, Koronyo Y, Fuchs DT, Sheyn J, Kim EH, et al. Acute
neuropathological consequences of short-term mechanical ventilation in
wild-type and Alzheimer’s disease mice. Crit Care. 2019;23(1):63.
46. Shah FA, Girard TD, Yende S. Limiting sedation for patients with acute
respiratory distress syndrome - time to wake up. Curr Opin Crit Care. 2017;
23(1):45–51.
47. Evered L, Silbert B, Scott DA, Zetterberg H, Blennow K. Association of
changes in plasma neurofilament light and tau levels with anesthesia and
surgery. JAMA Neurol. 2018;75(5):542–6.
48. Matute-Bello G, Frevert CW, Martin TR. Animal models of acute lung injury.
Am J Phys Lung Cell Mol Phys. 2008;295(3):L379–L99.
Sasannejad et al. Critical Care (2019) 23:352 Page 11 of 12
49. Wolthuis EK, Vlaar APJ, Choi G, Roelofs JJTH, Juffermans NP, Schultz MJ.
Mechanical ventilation using non-injurious ventilation settings causes lung
injury in the absence of pre-existing lung injury in healthy mice. Crit Care.
2009;13(1):R1.
50. Fries M, Bickenbach J, Henzler D, Beckers S, Dembinski R, Sellhaus B, et al. S-
100 protein and neurohistopathologic changes in a porcine model of acute
lung injury. Anesthesiology. 2005;102(4):761–7.
51. Bickenbach J, Biener I, Czaplik M, Nolte K, Dembinski R, Marx G, et al.
Neurological outcome after experimental lung injury. Respir Physiol
Neurobiol. 2011;179(2–3):174–80.
52. Bickenbach J, Zoremba N, Fries M, Dembinski R, Doering R, Ogawa E, et al.
Low tidal volume ventilation in a porcine model of acute lung injury
improves cerebral tissue oxygenation. Anesth Analg. 2009;109(3):847–55.
53. Dai S-S, Wang H, Yang N, An J-H, Li W, Ning Y-L, et al. Plasma glutamate–
modulated interaction of A2AR and mGluR5 on BMDCs aggravates traumatic brain
injury–induced acute lung injury. J Exp Med. 2013;210(4):839–51.
54. Winklewski PJ, Radkowski M, Demkow U. Cross-talk between the
inflammatory response, sympathetic activation and pulmonary infection in
the ischemic stroke. J Neuroinflammation. 2014;11(1):415–8.
55. Sonneville R, Verdonk F, Rauturier C, Klein IF, Wolff M, Annane D, et al.
Understanding brain dysfunction in sepsis. Ann Intensive Care. 2013;3(1):15.
56. Taccone FS, Castanares-Zapatero D, Peres-Bota D, Vincent J-L, Berre J, Melot
C. Cerebral autoregulation is influenced by carbon dioxide levels in patients
with septic shock. Neurocrit Care. 2009;12(1):35–42.
57. Wang J, Gu BJ, Masters CL, Wang Y-J. A systemic view of Alzheimer disease
- insights from amyloid-βmetabolism beyond the brain. Nat Rev Neurol.
2017;13(10):612–23.
58. Montagne A, Zhao Z, Zlokovic BV. Alzheimer’s disease: a matter of blood-
brain barrier dysfunction? J Exp Med. 2017;214(11):3151–69.
59. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. A
paravascular pathway facilitates CSF flow through the brain parenchyma
and the clearance of interstitial solutes, including amyloid beta. Sci Transl
Med. 2012;4(147):1–11.
60. Erickson MA, Banks WA. Blood–brain barrier dysfunction as a cause and
consequence of Alzheimer’s disease. J Cerebral Blood Flow Metab. 2013;
33(10):1500–13.
61. Song J, Choi S-M, Whitcomb DJ, Kim BC. Adiponectin controls the apoptosis and
the expression of tight junction proteins in brain endothelial cells through AdipoR1
under beta amyloid toxicity. Cell Death Dis. 2017;8(10):e3102.
62. Miguel-Hidalgo JJ, Cacabelos R. Beta-amyloid(1-40)-induced
neurodegeneration in the rat hippocampal neurons of the CA1 subfield.
Acta Neuropathol. 1998;95(5):455–65.
63. Freir DB, Holscher C, Herron CE. Blockade of long-term potentiation by
beta-amyloid peptides in the CA1 region of the rat hippocampus in vivo. J
Neurophysiol. 2001;85(2):708–13.
64. Hopkins RO, Gale SD, Weaver LK. Brain atrophy and cognitive impairment in
survivors of acute respiratory distress syndrome. Brain Inj. 2006;20(3):263–71.
65. Janz DR, Abel TW, Jackson JC, Gunther ML, Heckers S, Ely EW. Brain autopsy
findings in intensive care unit patients previously suffering from delirium: a
pilot study. J Crit Care. 2010;25(3):538.e7–12.
66. Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, et al.
Blood-brain barrier breakdown in the aging human hippocampus. Neuron.
2015;85(2):296–302.
67. Barrientos RM, Higgins EA, Biedenkapp JC, Sprunger DB, Wright-Hardesty KJ,
Watkins LR, et al. Peripheral infection and aging interact to impair
hippocampal memory consolidation. Neurobiol Aging. 2006;27(5):723–32.
68. Chen J, Buchanan JB, Sparkman NL, Godbout JP, Freund GG, Johnson RW.
Neuroinflammation and disruption in working memory in aged mice after
acute stimulation of the peripheral innate immune system. Brain Behav
Immun. 2008;22(3):301–11.
69. Semmler A, Okulla T, Sastre M, Dumitrescu-Ozimek L, Heneka MT. Systemic
inflammation induces apoptosis with variable vulnerability of different brain
regions. J Chem Neuroanat. 2005;30(2–3):144–57.
70. Harry GJ, Lefebvre d’Hellencourt C. Dentate gyrus: alterations that occur
with hippocampal injury. NeuroToxicology. 2003;24(3):343–56.
71. Imamura Y, Wang H, Matsumoto N, Muroya T, Shimazaki J, Ogura H, et al.
Interleukin-1βcauses long-term potentiation deficiency in a mouse model
of septic encephalopathy. Neuroscience. 2011;187:63–9.
72. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, et al.
Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair
synaptic plasticity and memory. Nat Med. 2008;14(8):837–42.
73. Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer’s
disease and other disorders. Nat Rev Neurosci. 2011;12(12):723–38.
74. Shohami E, Novikov M, Bass R, Yamin A, Gallily R. Closed head injury triggers
early production of TNFαand IL-6 by brain tissue. J Cerebral Blood Flow
Metab. 2016;14(4):615–9.
75. López-Aguilar J, Villagrá A, Bernabé F, Murias G, Piacentini E, Real J, et al.
Massive brain injury enhances lung damage in an isolated lung model of
ventilator-induced lung injury. Crit Care Med. 2005;33(5):1077–83.
76. Imai Y, Parodo J, Kajikawa O, de Perrot M, Fischer S, Edwards V, et al.
Injurious mechanical ventilation and end-organ epithelial cell apoptosis and
organ dysfunction in an experimental model of acute respiratory distress
syndrome. JAMA. 2003;289(16):2104–12.
77. Ko GJ, Rabb H, Hassoun HT. Kidney-lung crosstalk in the critically ill patient.
Blood Purif. 2009;28(2):75–83.
78. van den Akker JP, Egal M, Groeneveld JA. Invasive mechanical ventilation as
a risk factor for acute kidney injury in the critically ill: a systematic review
and meta-analysis. Crit Care. 2013;17(3):R98.
79. Georgiadis D, Schwarz S, Baumgartner RW, Veltkamp R, Schwab S. Influence
of positive end-expiratory pressure on intracranial pressure and cerebral
perfusion pressure in patients with acute stroke. Stroke. 2001;32(9):2088–92.
80. Muench E, Bauhuf C, Roth H, Horn P, Phillips M, Marquetant N, et al. Effects
of positive end-expiratory pressure on regional cerebral blood flow,
intracranial pressure, and brain tissue oxygenation*. Crit Care Med. 2005;
33(10):2367–72.
81. Mascia L, Grasso S, Fiore T, Bruno F, Berardino M, Ducati A. Cerebro-
pulmonary interactions during the application of low levels of positive end-
expiratory pressure. Intensive Care Med. 2005;31(3):373–9.
82. Beitler JR, Ghafouri TB, Jinadasa SP, Mueller A, Hsu L, Anderson RJ, et al.
Favorable neurocognitive outcome with low tidal volume ventilation after
cardiac arrest. Am J Respir Crit Care Med. 2017;195(9):1198–206.
83. Wilson MR, Choudhury S, Takata M. Pulmonary inflammation induced by
high-stretch ventilation is mediated by tumor necrosis factor signaling in
mice. Am J Phys Lung Cell Mol Phys. 2005;288(4):L599–607.
84. Deane R, Singh I, Sagare AP, Bell RD, Ross NT, LaRue B, et al. A multimodal
RAGE-specific inhibitor reduces amyloid beta-mediated brain disorder in a
mouse model of Alzheimer disease. J Clin Invest. 2012;122(4):1377–92.
85. National Heart L, and Blood Institute Acute Respiratory Distress Syndrome
(ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, Bernard GR,
Thompson BT, Hayden D, et al. Comparison of two fluid-management
strategies in acute lung injury. N Engl J Med 2006;354(24):2564–2575.
86. Pun BT, Balas MC, Barnes-Daly MA, Thompson JL, Aldrich JM, Barr J, et al.
Caring for critically ill patients with the ABCDEF bundle: results of the ICU
liberation collaborative in over 15,000 adults. Crit Care Med. 2019;47(1):3–14.
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