Systematic review of cognitive impairment and brain insult after mechanical ventilation

Abstract

We conducted a systematic review following the PRISMA protocol primarily to identify publications that assessed any links between mechanical ventilation (MV) and either cognitive impairment or brain insult, independent of underlying medical conditions. Secondary objectives were to identify possible gaps in the literature that can be used to inform future studies and move toward a better understanding of this complex problem. The preclinical literature suggests that MV is associated with neuroinflammation, cognitive impairment, and brain insult, reporting higher neuroinflammatory markers, greater evidence of brain injury markers, and lower cognitive scores in subjects that were ventilated longer, compared to those ventilated less, and to never-ventilated subjects. The clinical literature suggests an association between MV and delirium, and that delirium in mechanically ventilated patients may be associated with greater likelihood of long-term cognitive impairment; our systematic review found no clinical study that demonstrated a causal link between MV, cognitive dysfunction, and brain insult. More studies should be designed to investigate ventilation-induced brain injury pathways as well as any causative linkage between MV, cognitive impairment , and brain insult.

Full text

Bassietal. Crit Care (2021) 25:99
https://doi.org/10.1186/s13054-021-03521-9
REVIEW
Systematic review ofcognitive impairment
andbrain insult aftermechanical ventilation
Thiago G. Bassi1,2 , Elizabeth C. Rohrs1,3 and Steven C. Reynolds1,3*
Abstract
We conducted a systematic review following the PRISMA protocol primarily to identify publications that assessed any
links between mechanical ventilation (MV) and either cognitive impairment or brain insult, independent of underly-
ing medical conditions. Secondary objectives were to identify possible gaps in the literature that can be used to
inform future studies and move toward a better understanding of this complex problem. The preclinical literature
suggests that MV is associated with neuroinflammation, cognitive impairment, and brain insult, reporting higher
neuroinflammatory markers, greater evidence of brain injury markers, and lower cognitive scores in subjects that were
ventilated longer, compared to those ventilated less, and to never-ventilated subjects. The clinical literature suggests
an association between MV and delirium, and that delirium in mechanically ventilated patients may be associated
with greater likelihood of long-term cognitive impairment; our systematic review found no clinical study that dem-
onstrated a causal link between MV, cognitive dysfunction, and brain insult. More studies should be designed to
investigate ventilation-induced brain injury pathways as well as any causative linkage between MV, cognitive impair-
ment, and brain insult.
Keywords: Ventilators, Mechanical, Brain injuries, Delirium, Apoptosis, Cognitive impairment
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Introduction
Mechanical ventilation (MV) is considered essential in
the Intensive Care Unit (ICU) [1]. While it is undeniable
that MV is a crucial life-support tool, it may also cause
injury to distal organs, such as the lungs, diaphragm,
and brain [2, 3]. Ventilation-induced brain injury (VIBI)
is well known in neonatology, as a consequence of either
hyperoxia or the use of intermittent positive pressure
ventilation [4]; in adult patients, the existence of VIBI
is still unknown. Preclinical experiments have, how-
ever, shown lower cognitive scores in subjects ventilated
longer, and that these subjects had greater levels of brain
insult, neuroinflammation, and neuronal apoptosis than
subjects either mechanically ventilated less, or sponta-
neously breathing [5, 6]. Currently, direct links between
MV, delirium, cognitive impairment, and neuroinflam-
mation have not been established in the literature.
Delirium is a complex disturbance of consciousness,
characterized by acute changes in cognition, a direct
consequence of a medical condition, medical treat-
ment, or intoxicating substance [7]. Pathophysiologically,
some authors have classified the mechanism that trig-
gers delirium into two distinct categories, direct brain
insult (such as hemorrhagic stroke), and aberrant stress
response (such as systemic stress induced by MV, sepsis,
septic shock, systemic inflammation post-surgery, etc.)
[8]. Regardless of the mechanism that triggers delirium,
it is postulated that delirium is a result of an imbal-
ance in neurotransmitters, specifically acetylcholine
and dopamine, impairing the connection among several
brain areas [8–11]. Taking as an example a case–control
post-mortem study of deceased ICU patients without
direct brain injury, higher levels of inflammatory cells
were reported in the hippocampi of deceased patients
with delirium than in patients without delirium [5]. is
Open Access
*Correspondence: sreynolds.md@gmail.com
1 Simon Fraser University, Burnaby, Canada
Full list of author information is available at the end of the article

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Bassietal. Crit Care (2021) 25:99
indicates that when neuroinflammation is triggered, by
direct brain insult, aberrant systemic stress response, or
some other mechanism, it may be associated with cogni-
tive dysfunction [5, 12, 13]. However, it is likely that there
are many factors beyond neuroinflammation that can
contribute to cognitive impairment in the ICU, such as
medications, immobility, overload of sensory input and
lack of adequate sleep [7–10].
We sought to explore the current knowledge in the lit-
erature regarding MV, delirium, cognitive impairment,
and neuroinflammation, through a systematic review.
e primary objective of this systematic review was to
identify published papers that assess any link between
MV and either cognitive impairment or brain insult,
independent of underlying medical conditions. Our sec-
ondary objective was to identify possible gaps in the lit-
erature that can inform the design of future studies for a
better understanding of this complex problem.
Methodology
is study was conducted following the Preferred
Reporting Items for Systematic Review and Meta-Anal-
ysis (PRISMA) protocol. Searches were performed by a
librarian at the Health Sciences Library at Fraser Health
Authority, Royal Columbian Hospital (New Westmin-
ster, Canada). Searches were conducted using the fol-
lowing sources: Medline (1946-present), EMBASE
(1974-present), Cochrane Database of Systematic
Reviews, Cochrane Central Register of Controlled Trials,
Cochrane Methodology Register, and the Database of
Abstracts of Reviews and Effects (DARE).
Search strategies were developed based on the search
interface, to ensure an appropriate balance between
search sensitivity and specificity. e searches were also
stratified into two separate concepts, with one search
conducted in each database focused on ‘preclinical’ arti-
cles concerning any link between MV and brain insult
(Fig.1a), and a second search focused on ‘clinical’ arti-
cles concerning any link between MV and either cogni-
tive impairment or delirium during the hospital stay and
after hospital discharge (Fig.1b). e preclinical papers
were used for consideration of putative mechanisms for
brain insult after MV and to identify gaps in the preclini-
cal literature. Articles were limited to prospective and
retrospective studies published in English. Keyword,
adjacency, wildcard, and subject heading searching were
employed in all search strategies to maximize the sensi-
tivity of the search, while publication limits, specific clin-
ical terms, and variants of these were used to increase the
specificity of the search results.
Formal searches for articles were run using pre-estab-
lished keywords (see Additional file 1: Table A), all of
which were conducted on January 28, 2020. Subse-
quently, a screening review of all the articles identified in
the formal searches was performed. During the screen-
ing review, the abstract of each article was reviewed by
the lead author (TGB) to identify articles that clearly met
the predetermined exclusion criteria of our study pro-
tocol (see Additional file1: TableB). Duplicate articles
Identification
Screening
Eligibility
Included
Clinical papers excluded
n=2537
Duplicate clinical papers removed
n=44
Clinical eligibility review
Clinical papers after exclusion criteria applied n=70
Clinical papers after duplicates removed n=26
Clinical formal search
Clinical papers identified n=2607
Clinical papers included n=26
In-depth clinical review
Clinical papers fully evaluated n=26
Results
Preclinical formal search
Preclinical papers identified n=1686
Preclinical papers excluded
n=1665
Duplicate preclinical papers removed
n=12
Preclinical eligibility review
Preclinical papers after exclusion criteria applied n=21
Preclinical papers after duplicates removed n=9
In-depth preclinical review
Preclinical papers fully evaluated n=9
Preclinical papers included n=9
Results
ab
Fig. 1 Systematic review process and results. a Review process for the preclinical papers. b Review process for the clinical papers

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Bassietal. Crit Care (2021) 25:99
were eliminated as part of the screening review. Articles
not eliminated during the screening review then under-
went an in-depth review. e full manuscripts selected
were evaluated independently by two investigators (TGB
and ECR) to reduce the risk of individual bias. e two
reviewers (TGB and ECR) used the Downs and Black
checklist to assess the quality of each included full man-
uscript, to compare and reconcile independent evalu-
ations. In the event of significant score discrepancies, a
third reviewer (SCR) independently evaluated the paper
and served as the adjudicator.
e clinical articles were grouped into three sub-
groups: papers that reported MV as an independent vari-
able increasing the likelihood for delirium; papers that
reported delirium as an independent variable increasing
the likelihood for prolonged MV; papers that reported
delirium in mechanically ventilated patients increasing
the likelihood for long-term cognitive impairment. Odds
ratios (OR) were used to calculate the weight and hetero-
geneity of the manuscripts, using inverse covariance with
a random-effects model. Where it was not provided, OR
was calculated utilizing data in the papers. P v alue < 0.1
for the chi-square test was considered significant. Het-
erogeneity was evaluated using Higgins metric (I2), where
I2 > 75% was considered significant heterogeneity, I2 of
40–74% was considered moderate heterogeneity, and
I2 < 39% was considered no heterogeneity. All statistical
analyses were performed using Review Manager software
(RevMan, Version 5.4.1, e Cochrane Collaboration,
2020).
Results
Results from our preclinical and clinical systematic
reviews are available in Tables1 and 2, respectively. Nine
preclinical publications and 26 clinical publications were
identified. e papers reviewed were produced in five
continents: North America 9 (9 clinical, 0 preclinical),
South America 3 (3 clinical, 0preclinical), Europe 12 (5
clinical, 7 preclinical), Asia 9 (7 clinical, 2 preclinical),
and Oceania 2 (2 clinical, 0 preclinical).
Papers were scored according to the Downs and Black
checklist. Of the 35 papers selected, 0 scored ‘excellent,’
15 (43%) scored ‘good’ (9 clinical, 6 preclinical), 18 (51%)
scored ‘fair’ (clinical 15, preclinical 3), and 2 (6%) scored
‘poor’ (both clinical).
All nine preclinical papers measured neuroinflamma-
tion, and seven also used brain cellular apoptosis after
MV as an outcome (see Table 1). Neuroinflammation
was indicated by the elevated presence of microglia, ele-
vated presence of reactive astrocytes, or elevated pres-
ence of inflammatory markers. Brain cellular apoptosis
was demonstrated by terminal deoxynucleotidyl trans-
ferase dUTP nick end labeling (TUNEL) positive cells,
by phosphorylation of glycogen synthetase kinase 3b
(GSK3b), or by cleavage of poly-adenosine-diphosphate-
ribose polymerase-1 (PARP-1). One paper used S100
serum concentration to demonstrate brain insult. ree
preclinical papers evaluated cognition after MV, all show-
ing lower cognitive scores in subjects after mechanical
ventilation. ese three papers used as a measurement
of cognitive function either a fear-conditioning test to
quantify freezing time, or a validated porcine neurologi-
cal deficit score.
All 26 clinical papers evaluated delirium during hos-
pitalization as either a primary or secondary variable of
interest (Table2). e most common population studied
was ICU patients (24 publications), followed by cardio-
vascular surgical patients (one publication) and trauma
patients (one publication) (Table 2). irteen papers
included exclusively mechanically ventilated ICU patients
in their studies (Table2). Duration of MV, greater admin-
istration of sedative drugs, age > 65, physical immobility,
physical restraint, low APACHE II score, sepsis, hyper-
tension, low level of hemoglobin at hospital admission,
smoking, alcohol consumption (> 2 drinks daily), and
low albumin concentration at ICU admission were risk
factors identified either for delirium during hospitaliza-
tion or for long-term cognitive impairment after hospital
discharge.
Twelve clinical papers found that duration of MV is
an independent variable associated with a greater likeli-
hood of patients developing delirium during hospitali-
zation. Ten of these twelve papers reported odds ratios
ranging from 2.23 to 10.50, with a pooled odds ratio of
3.42 (Fig.2). No heterogeneity between the papers was
observed with p = 0.55 for Chi-square, and an I2 of 0%.
One paper that included only mechanically ventilated
patients reported that delirium was diagnosed in 68%
of the patients studied; in those patients diagnosed with
delirium, median duration of delirium was 1 day (IQR
1–2), and median day of occurrence of delirium was day 5
of MV (IQR 3–7); the authors concluded that prolonged
MV is associated with greater likelihood of delirium dur-
ing hospitalization [43] . Another paper reported that in
cancer patients, time of MV increased the likelihood for
delirium with an OR of 1.06. is paper reported an aver-
age of 8days of MV for patients with delirium and 2days
of MV for patients without delirium.
Nine clinical papers found that delirium during hos-
pitalization is an independent variable associated with
a greater likelihood for a longer duration of MV in ICU
patients. Seven of these nine papers reported odds
ratios ranging from 1.15 to 10.14 with a pooled odds
ratio of 2.06 (Fig.3). ree of these seven papers did
not originally report odds ratio; odds ratios were calcu-
lated from data in these three papers. e heterogeneity

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Bassietal. Crit Care (2021) 25:99
between the papers was considered substantial with
p < 0.0001 for Chi-square and an I2 of 99%. Of the nine
papers, one reported that patients with severe delirium
were mechanically ventilated for a median of 222 h
(IQR 106–384), patients with moderate delirium were
mechanically ventilated for a median of 24 h (IQR
12–124), and patients with no delirium were mechani-
cally ventilated for a median of 18h (IQR 12–41), with
statistically significant differences between the groups,
p = 0.001 [22]. One of the nine papers reported that
patients with delirium during hospitalization were
mechanically ventilated longer than patients without
delirium during hospitalization (19.5days, SD 15.8 vs.
9.3days, SD 8.8, respectively, p = 0.003) [17].
Five clinical papers found delirium as a predictor of
a greater likelihood for chronic cognitive impairment.
All five papers included exclusively mechanically ven-
tilated patients. ese five papers reported odds ratios
ranging from 3.30 to 7.86 with a pooled odds ratio of
3.76 (Fig. 4). One of these five papers did not origi-
nally report odds ratio; the odds ratio was calculated
from data in that paper. No heterogeneity between the
papers was observed, with p = 0.83 for Chi-square and
an I2 of 0%.
Table 1 Summary of preclinical publications reviewed
Publication Population Mechanical ventilation/
experimental model Neuro-inflammation/
cellular apoptosis
observed after
mechanical ventilation
Low cognitive scores
measured after
mechanical ventilation
Brain area(s) studied
2005, Fries et al. [14] Pigs
(n = 14) Yes/tidal volume 10 ml/
kg, lung injury (by
reduced inspired oxy-
gen and by bronchoal-
veolar lavage)
Yes – Hippocampus
2011, Quilez et al. [15] Mice
(n = 24) Yes/low tidal volume
(8 ml/kg), high tidal
volume (30 ml/kg),
and spontaneously
breathing
Yes – Hippocampus, retrosplenial
cortex, thalamus, central
amygdala, paraventricular
nuclei, and supraoptic
nuclei
2011, Bickenbach et al.
[16]Pigs
(n = 10) Yes/tidal volume 10 ml/
kg, lung injury (by oleic
acid and by bronchoal-
veolar lavage)
Yes Yes Hippocampus
2013, Gonzalez-Lopez
et al. [4]Mice
(n = 127) Yes/low peak inspiratory
pressure (12 cmH2O)
and high peak
inspiratory pressure
(20 cmH2O)
Yes – Hippocampus
2015, Chen et al. [5] Mice
(n = 86) Yes/peak inspiratory pres-
sure (15 cmH2O) (1 h,
3 h and 6 h), and spon-
taneously breathing
Yes Yes Hippocampus
2016, Chen et al. [6] Mice
(n = 72) Yes/peak inspiratory pres-
sure (15 cmH2O) (1 h,
3 h and 6 h), and spon-
taneously breathing
Yes Yes Hippocampus
2018, Kamuf et al. [13] Pigs
(n = 20) Yes/tidal volume 7 ml/
kg, lung injury (by oleic
acid and by bronchoal-
veolar lavage)
Yes – Hippocampus
2019, Lopez-Aguilar et al.
[17]Pigs
(n = 17) Yes/tidal volume 10 ml/
kg, three different head
positions (+ 30°, + 5°,
− 30°)
Yes – Hippocampus
2019, Gonzalez-Lopez
et al. [18]Mice
(n = 32) Yes/high tidal volume
(20–30 ml/kg) and
spontaneously breath-
ing
Yes – Hippocampus

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Bassietal. Crit Care (2021) 25:99
Another paper reported that more than 8days of MV
increased the likelihood for long-term cognitive impair-
ment two years after hospitalization, with a risk ratio of
1.48 [24].
Discussion
Our preclinical search found evidence that MV is a
contributing factor that can induce brain insult, either
by inducing systemic inflammation or by changing the
vagal signal, associated with neuroinflammation and
neuronal death [3, 5, 6, 13–18]. Moreover, all preclini-
cal studies reported in our systematic review found
brain insult after MV [3, 5, 6, 13–18]; three preclinical
studies found an association between the brain insult
and worse cognitive scores in prolonged mechanically
ventilated subjects in comparison with either never-
ventilated subjects or short-term mechanically venti-
lated subjects [3, 5, 6]. Although these studies were not
Table 2 Summary of clinical publications reviewed
Publication Study type Number of patients Summary of participants Outcomes analyzed
Delirium Long-term
cognitive
impairment
2002, Granberg et al. [19] Prospective cohort study 19 Mechanically ventilated ICU
patients Yes –
2004, Ely et al. [20] Prospective cohort study 275 Mechanically ventilated ICU
patients Yes Yes
2006, Peterson et al. [21] Prospective cohort study 375 ICU patients Yes –
2007, Balas et al. [22] Prospective cohort study 114 ICU patients Yes –
2008, Lin et al. [23] Prospective cohort study 143 Mechanically ventilated ICU
patients Yes –
2009, Rompaey et al. [24] Prospective cohort study 523 ICU patients Yes –
2010, Girard et al. [25] Prospective cohort study 126 Mechanically ventilated ICU
patients Yes Yes
2010, Tsuruta et al. [26] Prospective cohort study 172 ICU patients Yes –
2010, Shehabi et al. [27] Prospective cohort study 354 Mechanically ventilated ICU
patients Yes –
2012, Sharma et al. [28] Prospective cohort study 140 ICU patients Yes –
2013, Haas et al. [29] Prospective cohort study 1216 ICU patients Yes Yes
2013, Norkiene et al. [30] Prospective cohort study 87 Cardiovascular surgery patients Yes –
2014, Brummel et al. [31] Prospective cohort study 126 Mechanically ventilated ICU
patients Yes Yes
2014, Tsuruta et al. [32] Prospective cohort study 180 Mechanically ventilated ICU
patients Yes Yes
2014, Connor et al. [33] Prospective cohort study 80 Mechanically ventilated ICU
patients Yes –
2015, Mehta et al. [34] Prospective cohort study 430 Mechanically ventilated ICU
patients Yes Yes
2015, Hsieh et al. [35] Prospective cohort study 564 Mechanically ventilated ICU
patients Yes –
2016, Almeida et al. [36] Prospective cohort study 113 ICU patients Yes –
2017, Chen et al. [37] Prospective cohort study 620 ICU patients Yes –
2017, Mesa et al. [38] Prospective cohort study 230 Mechanically ventilated ICU
patients Yes –
2017, Rueden et al. [39] Prospective cohort study 215 Trauma patients Yes –
2018, Shehabi et al. [40] Prospective cohort multicenter
study 710 Mechanically ventilated ICU
patients Yes –
2018, Singh et al. [41] Retrospective cohort study 67,333 ICU patients Yes –
2018, Sanchez-Hurtado et al. [42] Prospective cohort study 109 ICU/cancer patients Yes –
2018, Mitchell et al. [43] Prospective cohort study 148 Mechanically ventilated ICU
patients Yes Yes
2019, Torres-Contreras et al. [44] Prospective cohort study 134 ICU patients Yes –

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Bassietal. Crit Care (2021) 25:99
able to entirely control for factors that co-varied with
MV, such as sedation or immobility, there is a consist-
ent signal across all studies showing an association
between MV and brain insult. High levels of pro-apop-
totic proteins and elevated levels of inflammatory cells
in the brain after MV were reported in nine preclinical
Fig. 2 Forest plot showing the odds ratios for duration of MV as an independent variable associated with increased likelihood of delirium. The size
of each black dot corresponds to the weight effect of the study in the meta-analysis. Red diamond represents the pooled odds ratio
Fig. 3 Forest plot showing the odds ratios for delirium as an independent variable associated with increased likelihood of prolonged MV. The size
of each black dot corresponds to the weight effect of the study in the meta-analysis. Red diamond represents the pooled odds ratio

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Bassietal. Crit Care (2021) 25:99
papers identified in our systematic review (see Table1)
[3, 5, 6, 13–18].
Preclinical considerations regardingputative mechanisms
forcognitive impairment afterMV
According to our preclinical search, the mechanism of
action for brain insult after MV has two postulated path-
ways, inflammation and neural signaling [3, 5, 6, 13–18].
Inammatory pathway
Six preclinical papers investigated the inflammatory
pathway for brain insult after MV [5, 6, 13–15]. In the
postulated inflammatory pathway for VIBI, MV creates
a pro-inflammatory systemic state that triggers neuro-
inflammation in the brain [5, 6, 15]. ree preclinical
papers found that subjects mechanically ventilated for
a longer duration (6 h) had greater serum inflamma-
tory markers and greater neuroinflammation either than
subjects ventilated for a shorter duration (1h) or than
subjects that were never ventilated [5, 6, 15]. One study
demonstrated that the activation of pulmonary toll-
like receptor-4 was responsible for the initiation of the
inflammatory cascade since toll-like receptor-4 knock-
out subjects did not demonstrate the neuroinflammatory
effects after MV, even when ventilated longer (6h) [6].
is same study showed that toll-like receptor-4 knock-
out subjects after six hours of MV had cognitive scores
(freezing time and locomotor activity) similar to the
never-ventilated group [6]. e inflammatory hypothesis
was challenged by one study that investigated the levels
of inflammatory and apoptotic markers in the hippocam-
pus after inducing lung injury [13]. is study showed
that mechanically ventilated pigs without lung injury and
mechanically ventilated pigs with lung injury showed
similar levels of inflammatory and apoptotic brain mark-
ers, thereby concluding that the inflammatory process
induced by lung injury was not the factor responsible for
the hippocampus insult, but rather MV itself [13].
Neural signaling pathway
Two preclinical papers investigated the neural pathway
for brain insult after MV [3, 18]. It has been proposed
that the neural signal coming from the vagus nerve trig-
gers neuroinflammation and brain injury during MV [3].
In the postulated neural pathway for VIBI, the vagal affer-
ent signal changes as a result of cyclical alveolar stretch
due to positive-pressure MV, leading to activation of
pulmonary transient receptor potential vanilloid chan-
nel type 4 (TRPV4), and consequently to a reduction in
gene expression of pulmonary TRPV4 and purinergic
type 2X receptors [18]. According to the authors, the
pulmonary TRPV4 activation would lead to a hippocam-
pal overexpression of type 2 dopamine receptors, which
would deactivate the B/glycogen synthetase kinase 3β
(Akt/GSK3β), initiating the apoptotic cascade [18]. In
order to demonstrate the hypothesized neural signaling
pathway for VIBI, researchers compared hippocampal
Fig. 4 Forest plot showing the odds ratios for delirium during MV as an independent variable associated with increased likelihood of long-term
cognitive impairment. The size of each black dot corresponds to the weight effect of the study in the meta-analysis. Red diamond represents the
pooled odds ratio

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Bassietal. Crit Care (2021) 25:99
apoptosis in mechanically ventilated subjects with chemi-
cal vagotomy, with surgical vagotomy, and without vagot-
omy, and in never-ventilated subjects [3, 18]. It was found
that vagotomy, either chemical or surgical, mitigated ven-
tilation-induced brain injury [3]. e vagotomised groups
had levels of hippocampal apoptosis similar to the never-
ventilated group, resulting in the conclusion that the
vagal signal triggered the brain injury after the initiation
of MV [3, 18]. Moreover, to demonstrate that dopamine
overexpression was part of the mechanism that triggered
cellular apoptosis, the authors showed that the adminis-
tration of a dopamine blocker mitigated the brain insult
after MV in a group of subjects without vagotomy, under
the same conditions that led to brain insult in mechani-
cally ventilated subjects [3].
Cognitive impairment andMV (preclinical)
Cognition after MV was evaluated in three preclinical
studies identified in our search [5, 6, 14]. Two papers
demonstrated that experimental mice undergoing six
hours of MV had lower cognitive scores at three days
post-extubation than either one-hour-MV mice or never-
ventilated mice [5, 6]. One paper showed that a possible
mechanism for cognitive impairment was the overex-
pression of TLR4 receptors in the lungs and in the brain,
triggering inflammation and promoting the proliferation
of pro-inflammatory microglia and reactive astrocytes,
impairing brain function [6]. To demonstrate the role of
neuroinflammation in cognitive impairment, the authors
showed that TLR4-knockout subjects undergoing pro-
longed MV had similar microglia, reactive astrocytes,
systemic inflammatory markers, and cognitive scores to
control subjects [6]. Moreover, in prolonged mechani-
cally ventilated subjects, neuroinflammation resulted in
synapse degeneration, cytochrome c release, cleaved cas-
pase-3, and cleaved PARP-1 activation, which may have
consequently led to the worse cognitive scores observed
in this group compared to the control group [5]. e
effects of inflammation on cognition were assessed in
one paper [14]; mechanically ventilated pigs with hypox-
emia caused by lung injury due to surfactant depletion
had worse cognitive performance 5days after extubation
than mechanically ventilated pigs with hypoxemia caused
by reduction in inspired oxygen concentration [14]. e
authors concluded that the inflammatory process may be
a key factor for cognitive impairment in pigs [14].
The connection betweentidal volume andbrain activity
e connection between hippocampal activity and the
breathing cycle was demonstrated by one preclinical
study [18]. is study used functional MRI to analyze
hippocampus activity, comparing higher-tidal-volume
subjects with lower-tidal-volume subjects [18]. e
authors demonstrated that higher-tidal-volume MV
resulted in more hippocampus activity, and that higher
activation of the hippocampus during high-tidal-volume
MV was correlated with more tissue injury [18]. In addi-
tion to the hippocampus, other brain areas were also
studied during MV. Greater numbers of c-Fos-positive
cells were observed in the retrosplenial cortex and in the
thalamus of high-tidal-volume subjects when compared
to low-tidal-volume subjects [16]. C-Fos is a neuronal
activity marker expressed after neuronal depolarization
[40]. Neurons express c-Fos protein proportionally to
the stimulus applied, either chemical or electrical [40].
In low-tidal-volume subjects, c-Fos was expressed at low
levels, while in high-tidal-volume subjects, this neuronal
activity marker was expressed at high levels [16]. e
authors stated that the tidal volume used during MV may
have led to pathological neuronal activity in the retros-
plenial cortex and in the thalamus, since the high-tidal-
volume group expressed greater c-Fos protein in these
brain areas than the low-tidal-volume group [16]; also,
the brain insult observed was proportional to the tidal
volume delivered, suggesting a potential iatrogenic effect
of MV on the brain [16].
Current clinical literature perspective oncognitive
impairment andMV
Mechanically ventilated patients are frequently sedated
and typically have worse health conditions than patients
who are never ventilated [19, 21, 22, 35, 37, 45]. It is
extremely challenging to show any causative linkage
between MV, delirium and cognitive impairment. is is
in part because the MV “package” has multiple insepa-
rable variables, such as sedation and physical immobil-
ity. For instance, mechanically ventilated patients receive
more drugs and are more physically inactive than spon-
taneously breathing patients [19, 21, 22, 35, 37, 45]. e
greater use of drugs and greater prevalence of physical
inactivity in mechanically ventilated patients might be
factors that also affect the health of the patient, wors-
ening the cognitive functions [19, 21, 22, 35, 37, 45].
Additionally, widespread use of MV in a heterogene-
ous patient population makes the isolation of causal
relationships difficult. Although multiple risk factors
have been identified for delirium and long-term cogni-
tive impairment in our systematic review, papers that
utilized multivariate analysis have consistently shown
either duration of MV as an independent variable associ-
ated with delirium, or delirium as an independent vari-
able associated with prolonged duration of MV [16, 17,
20–29, 45]. Moreover, delirium in mechanically venti-
lated patients was correlated with a greater likelihood
for long-term cognitive impairment than mechanically
ventilated patients without delirium [20, 24, 26, 30, 38,

Page 9 of 12
Bassietal. Crit Care (2021) 25:99
42]. e papers analyzed in this systematic review did
not establish a direct causal link between duration of MV,
delirium, and long-term cognitive impairment; however,
our review identified important gaps in the literature that
can be used in designing future studies.
Duration ofMV asanindependent variable fordeveloping
delirium duringhospitalization
Our systematic review identified twelve papers that
showed an association between longer duration of MV
and a greater likelihood of a patient developing delir-
ium during hospitalization, when compared either with
patients mechanically ventilated fewer days, or with
spontaneously breathing patients [19–21, 24, 30, 32, 35,
36, 43–45]. For instance, ten papers found odds ratios
between 1.06 and 10.50 for a greater likelihood that a
patient develops delirium during hospitalization when
the duration of MV is longer than one day (Fig.2) [19–21,
24, 32, 35, 36, 43, 44]. Ten of these twelve papers showed
a dose-dependent aspect, as, regardless of comorbidities,
the longer the duration of MV, the greater the likelihood
of delirium with a pooled odds ratio of 3.42 [19–21, 24,
30, 32, 35, 36, 43, 44]. No heterogeneity was observed
after analysis of these ten papers. e homogeneity of
these papers may be interpreted as a strong and con-
sistent signal indicating that increased duration of MV
increases the likelihood for delirium [19–21, 24, 30, 32,
35, 36, 43, 44].
Delirium duringhospitalization asanindependent
variable forprolonged duration ofMV
Although multiple risk factors may prolong the days on
MV in critically ill patients, delirium has been commonly
identified as one of those risk factors for prolonged dura-
tion of MV [22, 25–27, 29, 31, 35, 36, 41]. Nine clinical
papers found an association between delirium and pro-
longed MV, of which seven calculated the odds ratio and
two calculated how much longer, either in days or hours,
delirium prolonged MV [22, 25–27, 29, 31, 35, 36, 41].
Seven of nine papers identified by our systematic review
showed that patients with delirium during hospitaliza-
tion have greater likelihood to be mechanically ventilated
longer than patients without delirium during hospitaliza-
tion with a pooled odds ratio of 2.06 (Fig.3) [22, 25, 27,
29, 31, 35, 36]. Patients who were diagnosed with delir-
ium during hospitalization underwent between seven
and ten more days on MV, compared with patients who
were not diagnosed with delirium [35, 41]. Although a
positive correlation between delirium and MV has been
shown in our systematic review, the clinical literature has
not reported any causative linkage between them [22,
25, 27, 29, 31, 35, 36]. Our systematic review indicates a
high heterogeneity for the seven papers selected in this
subgroup analysis. is may be a consequence of a small
standard error for each of the studies included in the
analysis. Another reason may be the high degree of heter-
ogeneity typically observed in the ICU patient population
studied resulting in a wide range of results reported. Dif-
ferent methods to measure the outcomes, different study
designs and different types of interventions may also have
affected heterogeneity. However, all studies included in
this part of our analysis investigated delirium as an inde-
pendent factor for prolonged MV, showing ORs higher
than 1. Regardless of the heterogeneity of the papers ana-
lyzed, it seems that when an ICU patient develops delir-
ium it increases the likelihood for prolonged MV.
Delirium inmechanically ventilated patients associated
withincreased likelihood oflong‑term cognitive
impairment
Delirium in mechanically ventilated patients was also
found to be one risk factor associated with long-term
cognitive impairment [20, 26, 38, 42]. Four papers
included only mechanically ventilated patients, reported
that patients who developed delirium during hospitaliza-
tion had a greater likelihood of showing long-term cog-
nitive dysfunction than patients who did not develop
delirium during hospitalization, reporting odds ratios
ranging from 3.20 to 7.86 with a pooled odds ratio of
3.76 (Fig.4) [20, 26, 38, 42]. Moreover, in mechanically
ventilated patients with delirium during hospitalization,
long-term cognitive deficits were subsequently identified
up to seven times as often, compared to mechanically
ventilated patients without delirium during hospitaliza-
tion, although this may be due to underlying predispo-
sition rather than MV itself [20, 26, 38, 42]. ese four
papers reported that more than 2days of MV is associ-
ated with up to four times greater likelihood of develop-
ing acute cognitive impairment, and that those patients
who develop acute cognitive impairment have up to
twice the risk of persistent chronic cognitive impair-
ment [20, 26, 30, 38, 42]. e residual impact of delirium
in mechanically ventilated patients was detected up to
6years after hospital discharge [20, 42]. e lack of het-
erogeneity observed may be an indicator that when a
mechanically ventilated patient develops delirium it con-
siderably increases the likelihood for long-term cognitive
impairment.
Gaps inthecurrent literature andtheneed forfuture
studies
Our systematic review identified some notable gaps in
the scientific literature. Firstly, we note that none of the
identified preclinical or clinical papers investigated ven-
tilatory strategies, focusing, for example, either on venti-
lation power or on driving pressure, and their effects on

Page 10 of 12
Bassietal. Crit Care (2021) 25:99
cognitive outcomes. ree preclinical papers investigated
alternative methods, either pharmacological or surgical,
to prevent VIBI [3, 6, 18]. Dopamine receptors, TLR-4
receptorsand TRPV4 receptorsare pharmacological tar-
gets that, when blocked, were reported to prevent VIBI.
In addition, either chemical or surgical vagotomy also
showed reduced hippocampal apoptosis and inflamma-
tion, even during high-tidal-volume MV; however, vagot-
omy is not a viable solution in clinical practice [3, 6, 18].
Secondly, only nine preclinical publications were identi-
fied in our search; this suggests that more work is needed
in this area in order to better understand the effects of
MV on the brain [3, 5, 6, 13–18]. Notably, all nine pre-
clinical studies used injurious (high-tidal-volume or high
peak-inspiratory-pressure) ventilation; this observation
raises the question as to whether the effects of lung-pro-
tective MV on the brain should also be studied preclini-
cally [3, 5, 6, 13–18]. irdly, of the preclinical studies
identified, three observed greater neuronal activity dur-
ing MV; this finding should be more thoroughly inves-
tigated in future studies to better understand whether
the changes in the neurophysiology during MV result in
harmful effects on the brain [16]. Fourthly, it is important
to recognize that many other factors are linked to delir-
ium and cognitive impairment in critically ill patients;
our systematic review found that MV may be associated
with delirium, but no study showed any causative link-
age between MV and delirium. Considering these obser-
vations, more preclinical studies should be designed
focusing on the investigation of potential causal links
between MV, brain insult, and cognitive impairment, and
more clinical studies should be designed to investigate
the possibility of causal links between MV, brain insult,
and delirium and cognitive impairment, controlling for
potentially confounding factors that co-vary with dura-
tion of MV, such as sedation and immobility.
Conclusion
is systematic review showed an association between
MV and acute cognitive impairment.
In our search, preclinical papers showed acute cogni-
tive impairment after MV, describing greater neuroin-
flammation and lower cognitive scores in subjects with
longer duration of MV.
Clinically, increased duration of MV may be associated
with a greater risk for delirium during hospitalization.
Moreover, delirium in mechanically ventilated patients
may be associated with long-term cognitive impairment,
and residual cognitive impairment can be observed up to
6years after hospital discharge.
Preclinical and clinical studies that investigate the rela-
tionship between different ventilation strategies and cog-
nitive impairment have not been reported. Conducting
such studies may be worthwhile in order to better under-
stand cognitive impairment after MV.
While our systematic review identified gaps in the lit-
erature that can be considered when designing future
studies to further evaluate the relationships between
MV, brain insult, and cognitive impairment, our findings
confirm that future work is needed to identify any causal
links between them.
Supplementary Information
The online version contains supplementary material available at https ://doi.
org/10.1186/s1305 4-021-03521 -9.
Additional le1. Additional information about the systematic review,
such as keywords used for the search and exclusion criteria used.
Acknowledgements
The authors would like to acknowledge and thank the following people
for their efforts and assistance in completing this body of work: Matt Gani,
Dawn Bitz, Doug Evans, Viral Thakkar, Suzette Williams, Samar Hejazi, Teresa
Nelson and Brooke Ballantyne Scott.
Authors’ contributions
TGB was responsible for hypothesis generation. TGB and SCR were respon-
sible for the conception of this study. TGB, SCR, and ECR contributed to
study design and data interpretation. TGB, SCR, and ECR were responsible for
writing the article. TGB and ECR performed data acquisition. TGB, ECR, and
SCR conducted data analysis. All authors have agreed with the final version
of the manuscript before submission. All authors read and approved the final
manuscript.
Funding
This study was supported by grants from Lungpacer Medical, Inc., The Royal
Columbian Hospital Foundation, TB Vets and MITACS.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from
the corresponding author on reasonable request.
Declarations
Ethical approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
ECR and SCR have received consulting fees from Lungpacer Medical, Inc.
TGB is an employee of Lungpacer Medical, Inc. SCR is listed on a patent for
Lungpacer Medical, Inc.
Author details
1 Simon Fraser University, Burnaby, Canada. 2 Lungpacer Medical Inc,
Vancouver, Canada. 3 Royal Columbian Hospital, Fraser Health Authority, 260
Sherbrooke Street, New Westminster, BC V3L 3M2, Canada.
Received: 14 November 2020 Accepted: 1 March 2021
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