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Systematic review of cognitive impairment and brain insult after mechanical ventilation

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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.
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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 [811]. 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 [710].
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, 1318]. Moreover, all preclini-
cal studies reported in our systematic review found
brain insult after MV [3, 5, 6, 1318]; 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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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
Page 7 of 12
Bassietal. Crit Care (2021) 25:99
papers identified in our systematic review (see Table1)
[3, 5, 6, 1318].
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, 1318].
Inammatory pathway
Six preclinical papers investigated the inflammatory
pathway for brain insult after MV [5, 6, 1315]. 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
Page 8 of 12
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,
2029, 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 [1921, 24, 30, 32, 35,
36, 4345]. 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) [1921,
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 [1921, 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 [1921, 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, 2527, 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, 2527, 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, 1318]. 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, 1318]. 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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... Mechanical ventilation is often a crucial life-support tool in the resuscitation of patients with acute lung injury and ARDS [68,69]. However, mechanical ventilation per se can induce brain damage either by inducing an excessive release of pro-inflammatory cytokines (e.g., Il-1b, IL-6 and TNF-a) or by changing the vagal signal leading to neuroinflammation and neuronal death [37,50,68,[70][71][72][73][74]. ...
... Mechanical ventilation is often a crucial life-support tool in the resuscitation of patients with acute lung injury and ARDS [68,69]. However, mechanical ventilation per se can induce brain damage either by inducing an excessive release of pro-inflammatory cytokines (e.g., Il-1b, IL-6 and TNF-a) or by changing the vagal signal leading to neuroinflammation and neuronal death [37,50,68,[70][71][72][73][74]. Interestingly, an increased amount of evidence suggests that even a short period of mechanical ventilation may dramatically increase hippocampal and plasma levels of IL-1b, IL-6 and TNF-a [71]. ...
... The authors reported that mechanical ventilation with tidal volume of 5-8 ml/kg and moderate levels of PEEP led to PaCO2 levels of 50-60 mmHg without negatively affecting intracerebral pressure [117]. Moreover, clinical and experimental studies have shown that ventilation with high tidal volumes induces higher hippocampal activation associated with more tissue injury and a pathological neuronal activity, suggesting an iatrogenic effect of high tidal volume ventilation on the brain [68]. ...
Article
Full-text available
A complex interrelation between lung and brain in patients with acute lung injury (ALI) has been established by experimental and clinical studies during the last decades. Although, acute brain injury represents one of the most common insufficiencies in patients with ALI and acute respiratory distress syndrome (ARDS), the underlying pathophysiology of the observed crosstalk remains poorly understood due to its complexity. Specifically, it involves numerous pathophysiological parameters such as hypoxemia, neurological adverse events of lung protective ventilation, hypotension, disruption of the BBB, and neuroinflammation in such a manner that the brain of ARDS patients—especially hippocampus—becomes very vulnerable to develop secondary lung-mediated acute brain injury. A protective ventilator strategy could reduce or even minimize further systemic release of inflammatory mediators and thus maintain brain homeostasis. On the other hand, mechanical ventilation with low tidal volumes may lead to self-inflicted lung injury, hypercapnia and subsequent cerebral vasodilatation, increased cerebral blood flow, and intracranial hypertension. Therefore, by describing the pathophysiology of ARDS-associated acute brain injury we aim to highlight and discuss the possible influence of mechanical ventilation on ALI-associated acute brain injury.
... 14,22,23 In contrast, endotracheal intubation and mechanical ventilation (MV) are other factors that can alter brain function. 25,26 Comatose patients are unable to breathe spontaneously for ventilation and therefore should receive MV, usually via an endotracheal tube. 27 Although intubation and MV are lifesaving procedures that compensate for breathing impairment resulting from coma, they are not without complications. ...
... 31,32 Importantly, after recovery, long-term intubation of mechanically ventilated patients in critical care units is linked with neurological impairment, such as memory and cognitive decline. 26 To date, several explanations have been introduced to understand the relationship between cognitive problems and MV. 26,33 However, part of this cognitive decline may result from changes in the neural activities of related networks, 26 probably because of eliminated nasal airflow and the lack of olfactory receptor stimulation induced by endotracheal intubation. ...
... 26 To date, several explanations have been introduced to understand the relationship between cognitive problems and MV. 26,33 However, part of this cognitive decline may result from changes in the neural activities of related networks, 26 probably because of eliminated nasal airflow and the lack of olfactory receptor stimulation induced by endotracheal intubation. 34 Growing evidence shows that nasal breathing in mammals, including humans, generates oscillations extending to distant brain areas, such as the cortical and subcortical regions, [35][36][37] and diminishes when breathing deviates from the nasal pathway. ...
Article
Objectives Coma state and loss of consciousness are associated with impaired brain activity, particularly gamma oscillations, that integrate functional connectivity in neural networks, including the default mode network (DMN). Mechanical ventilation (MV) in comatose patients can aggravate brain activity, which has decreased in coma, presumably because of diminished nasal airflow. Nasal airflow, known to drive functional neural oscillations, synchronizing distant brain networks activity, is eliminated by tracheal intubation and MV. Hence, we proposed that rhythmic nasal air puffing in mechanically ventilated comatose patients may promote brain activity and improve network connectivity. Materials and Methods We recorded electroencephalography (EEG) from 15 comatose patients (seven women) admitted to the intensive care unit because of opium poisoning and assessed the activity, complexity, and connectivity of the DMN before and during the nasal air-puff stimulation. Nasal cavity air puffing was done through a nasal cannula controlled by an electrical valve (open duration of 630 ms) with a frequency of 0.2 Hz (ie, 12 puff/min). Results Our analyses demonstrated that nasal air puffing enhanced the power of gamma oscillations (30–100 Hz) in the DMN. In addition, we found that the coherence and synchrony between DMN regions were increased during nasal air puffing. Recurrence quantification and fractal dimension analyses revealed that EEG global complexity and irregularity, typically seen in wakefulness and conscious state, increased during rhythmic nasal air puffing. Conclusions Rhythmic nasal air puffing, as a noninvasive brain stimulation method, opens a new window to modifying the brain connectivity integration in comatose patients. This approach may potentially influence comatose patients’ outcomes by increasing brain reactivity and network connectivity.
... Patients with cirrhosis and hepatic encephalopathy are particularly susceptible to the complications of mechanical ventilation because of possible underlying circulatory, neurologic, and immunologic dysfunction [11]. Because mechanical ventilation itself may be associated with further impairment in cardiovascular and cognitive function and immune defense, patients with cirrhosis may be at a greater risk for developing shock, progressive delirium, and infection, among other complications [22][23][24]. ...
Article
Background: Unresponsive patients with toxic-metabolic encephalopathies often undergo endotracheal intubation for the primary purpose of preventing aspiration events. However, among patients with pre-existing systemic comorbidities, mechanical ventilation itself may be associated with numerous risks such as hypotension, aspiration, delirium, and infection. Our primary aim was to determine whether early mechanical ventilation for airway protection was associated with increased mortality in patients with cirrhosis and grade IV hepatic encephalopathy. Methods: The National Inpatient Sample was queried for hospital stays due to grade IV hepatic encephalopathy among patients with cirrhosis between 2016 and 2019. After applying our exclusion criteria, including cardiopulmonary failure, data from 1,975 inpatient stays were analyzed. Patients who received mechanical ventilation within 2 days of admission were compared to those who did not. Univariable and multivariable logistic regression analyses were performed to identify clinical factors associated with in-hospital mortality. Results: Of 162 patients who received endotracheal intubation during the first 2 hospital days, 64 (40%) died during their hospitalization, in comparison to 336 (19%) of 1,813 patients in the comparator group. In multivariable logistic regression analysis, mechanical ventilation was the strongest predictor of in-hospital mortality in our primary analysis (adjusted odds ratio, 3.00; 95% confidence interval, 2.14-4.20; P<0.001) and in all sensitivity analyses. Conclusion: Mechanical ventilation for the sole purpose of airway protection among patients with cirrhosis and grade IV hepatic encephalopathy may be associated with increased in-hospital mortality. Future studies are necessary to confirm and further characterize our findings.
... In non-COVID-19 patients, a causal association between IMV and long-lasting cognitive dysfunction has not been demonstrated [88]; anyhow, prolonged IMV exposing individuals to higher cumulative doses of sedatives and opioids increases the risk for delirium known factor associated with long-term cognitive impairment [89,90 & ]. Depending on the hospital setting (ICU or general ward), delirium incidence among SARS-CoV-2 infected patients ranges from 11% to 80% [66,91,92]. ...
Article
Purpose of review: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), can trigger a myriad of neuropsychiatric manifestations. As a 2-year-old disease (at the writing of this manuscript), its long-term cognitive and neuropsychiatric implications, known as post-COVID-19 conditions, are incompletely recognized and mechanistically obscure. Recent findings: Fatigue, anxiety, depression, posttraumatic stress disorder, and cognitive dysfunction are reported more frequently in COVID-19 survivors than in matching, non-COVID-19 population. Risk factors are unclear, including comorbidities, age at COVID-19 onset, or disease severity; women, however, have been reported to be at increased risk than men. Although the frequency of these symptoms decreases over time, at least one in five will have persistent cognitive and neuropsychiatric manifestations one year after recovering from COVID-19. Summary: Neurocognitive and psychiatric post-COVID-19 long-term conditions are frequent and complex multifactorial sequelae. Several acute and chronic factors such as hypoxemia, cerebral thrombotic and inflammatory endothelial damage, and disruption of the blood-brain barrier (leading to parenchymal translocation of pro-inflammatory molecules, cytokines, and cytotoxic T lymphocytes) are involved, leading to microglial activation and astrogliosis. As an evolving topic, evidence derived from prospective studies will expand our understanding of post-COVID-19 these long-term outcomes.
... Mechanisms for the deterioration of neurologic function after lung injury remain unclear and may include hypoxia and the effects of MV and its consequential inflammatory response [44]. A systematic review in 2021 showed an association between MV and acute cognitive impairment, and preclinical papers showed acute cognitive impairment after MV, describing greater neuroinflammation and lower cognitive scores in subjects with a longer MV duration [45]. On the other hand, patients with ARDS may experience long periods of hypoxia, leading to the hypothesis that they might develop brain lesions and atrophy similar to those observed in other disorders with concomitant hypoxia [46]. ...
Article
The brain-lung interaction can seriously affect patients with traumatic brain injury, triggering a vicious cycle that worsens patient prognosis. Although the mechanisms of the interaction are not fully elucidated, several hypotheses, notably the "blast injury" theory or "double hit" model, have been proposed and constitute the basis of its development and progression. The brain and lungs strongly interact via complex pathways from the brain to the lungs but also from the lungs to the brain. The main pulmonary disorders that occur after brain injuries are neurogenic pulmonary edema, acute respiratory distress syndrome, and ventilator-associated pneumonia, and the principal brain disorders after lung injuries include brain hypoxia and intracranial hypertension. All of these conditions are key considerations for management therapies after traumatic brain injury and need exceptional case-by-case monitoring to avoid neurological or pulmonary complications. This review aims to describe the history, pathophysiology, risk factors, characteristics, and complications of brain-lung and lung-brain interactions and the impact of different old and recent modalities of treatment in the context of traumatic brain injury.
... However, preclinical studies investigating VABI in fully grown subjects have shown that mechanically ventilated subjects have greater numbers of microglia, greater numbers of reactive astrocytes, and a higher incidence of cellular apoptosis compared with never-ventilated subjects (3,5,6,8). Two recently published systematic reviews on MV associated with brain injury reported 13 preclinical papers that describe hippocampal apoptosis and neuroinflammation as experimental findings linked to VABI (9,10). In a porcine model, our group showed that even lung-protective MV settings were associated with brain injury after 50 hours of MV (5); moreover, in the same study, our group showed that serum concentrations of GFAP (glial fibrillary acid protein) and UCHL1 (ubiquitin carboxy-terminal hydrolase L1) were greater in the MV subjects than in the never-ventilated subjects, revealing an opportunity for the use of these markers for VABI (5,6). ...
Article
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Rationale: Mechanical ventilation (MV) is associated with hippocampal apoptosis and inflammation, and it is important to study strategies to mitigate them. Objectives: Explore whether temporary transvenous diaphragm neurostimulation (TTDN) in association with MV mitigates hippocampal apoptosis and inflammation after 50 hours of MV. Methods: Normal-lung porcine study comparing apoptotic index, inflammatory markers, and neurological-damage serum markers between never-ventilated subjects, subjects undergoing 50 hours of MV plus either TTDN every other breath or every breath, and subjects undergoing 50 hours of MV (MV group). MV settings in volume control were tidal volume of 8 ml/kg, and positive end-expiratory pressure of 5 cmH2O. Measurements and Main Results: Apoptotic indices, microglia percentages, and reactive astrocyte percentages were greater in the MV group in comparison to the other groups (p<0.05). Transpulmonary pressure at baseline and at study end were both lower in the group receiving TTDN every breath, but lung injury scores and systemic inflammatory markers were not different between the groups. Serum concentrations of four neurological-damage markers were lower in the group receiving TTDN every breath than in the MV group (p<0.05). Heart rate variability declined significantly in the MV group and increased significantly in both TTDN groups over the course of the experiments. Conclusion: Our study found that mechanical ventilation is associated with hippocampal apoptosis and inflammation, independent of lung injury and systemic inflammation. Also, in a porcine model, TTDN results in neuroprotection after 50 hours, and the degree of neuroprotection increases with greater exposure to TTDN.
... Also, included studies did not report some important factors such as stroke risk factors that may have confounded the reported ABIs. A recent systematic review demonstrated that delirium and cognitive impairment were associated with mechanical ventilation, and therefore, it is possible that poor neurological outcome may be attributed to mechanical ventilation alone [69]. However, that study was not focused on subjects with ARDS and our study only included animals and patients with ARDS and provides a comprehensive review of ABI after ARDS. ...
Article
Acute respiratory distress syndrome (ARDS) has been associated with secondary acute brain injury (ABI). However, there is sparse literature on the mechanism of lung-mediated brain injury and prevalence of ARDS-associated secondary ABI. We aimed to review and elucidate potential mechanisms of ARDS-mediated ABI from preclinical models and assess the prevalence of ABI and neurological outcome in ARDS with clinical studies. We conducted a systematic search of PubMed and five other databases reporting ABI and ARDS through July 6, 2020 and included studies with ABI and neurological outcome occurring after ARDS. We found 38 studies (10 preclinical studies with 143 animals; 28 clinical studies with 1175 patients) encompassing 9 animal studies (n = 143), 1 in vitro study, 12 studies on neurocognitive outcomes (n = 797), 2 clinical observational studies (n = 126), 1 neuroimaging study (n = 15), and 13 clinical case series/reports (n = 15). Six ARDS animal studies demonstrated evidence of neuroinflammation and neuronal damage within the hippocampus. Five animal studies demonstrated altered cerebral blood flow and increased intracranial pressure with the use of lung-protective mechanical ventilation. High frequency of ARDS-associated secondary ABI or poor neurological outcome was observed ranging 82–86% in clinical observational studies. Of the clinically reported ABIs (median age 49 years, 46% men), the most common injury was hemorrhagic stroke (25%), followed by hypoxic ischemic brain injury (22%), diffuse cerebral edema (11%), and ischemic stroke (8%). Cognitive impairment in patients with ARDS (n = 797) was observed in 87% (range 73–100%) at discharge, 36% (range 32–37%) at 6 months, and 30% (range 25–45%) at 1 year. Mechanisms of ARDS-associated secondary ABI include primary hypoxic ischemic injury from hypoxic respiratory failure, secondary injury, such as lung injury induced neuroinflammation, and increased intracranial pressure from ARDS lung-protective mechanical ventilation strategy. In summary, paucity of clinical data exists on the prevalence of ABI in patients with ARDS. Hemorrhagic stroke and hypoxic ischemic brain injury were commonly observed. Persistent cognitive impairment was highly prevalent in patients with ARDS.
Article
Cardiac surgery is associated with a higher incidence of postoperative delirium(POD)than other surgeries and presents special features such as the use of the heart-lung machine and postoperative intensive care unit(ICU)management. Neuroinflammation has been suggested to be associated with the development of POD, but treatment methods have not yet been established. Pain control is the first POD prophylactic management that anesthesiologists should implement. However, it is important to take continuous measures throughout the perioperative period including preoperative identification/sharing of data of patients at high risk of delirium, intraoperative embolism control, anesthesia depth monitoring to prevent cerebral infarction, and postoperative sedation/analgesia management. As cardiac surgery becomes less invasive, cardiac anesthesia will be performed more frequently in elderly and high-risk patients, making POD more prevalent. POD is a severe postoperative complication that impacts the cognition and life prognosis of patients and requires multidisciplinary collaboration in which the anesthesiologist plays a key role.
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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.
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Objectives: Mechanical ventilation can cause ventilator-induced brain injury via afferent vagal signaling and hippocampal neurotransmitter imbalances. The triggering mechanisms for vagal signaling during mechanical ventilation are unknown. The objective of this study was to assess whether pulmonary transient receptor potential vanilloid type-4 (TRPV4) mechanoreceptors and vagal afferent purinergic receptors (P2X) act as triggers of ventilator-induced brain injury. Design: Controlled, human in vitro and ex vivo studies, as well as murine in vivo laboratory studies. Setting: Research laboratory. Subjects: Wild-type, TRPV4-deficient C57BL/6J mice, 8-10 weeks old. Human postmortem lung tissue and human lung epithelial cell line BEAS-2B. Intervention: Mice subjected to mechanical ventilation were studied using functional MRI to assess hippocampal activity. The effects of lidocaine (a nonselective ion-channel inhibitor), P2X-purinoceptor antagonist (iso-PPADS), or genetic TRPV4 deficiency on hippocampal dopamine-dependent pro-apoptotic signaling were studied in mechanically ventilated mice. Human lung epithelial cells (BEAS-2B) were used to study the effects of mechanical stretch on TRPV4 and P2X expression and activation. TRPV4 levels were measured in postmortem lung tissue from ventilated and nonventilated patients. Measurements and main results: Hippocampus functional MRI analysis revealed considerable changes in response to the increase in tidal volume during mechanical ventilation. Intratracheal lidocaine, iso-PPADS, and TRPV4 genetic deficiency protected mice against ventilationinduced hippocampal pro-apoptotic signaling. Mechanical stretch in both, BEAS-2B cells and ventilated wild-type mice, resulted in TRPV4 activation and reduced Trpv4 and P2x expression. Intratracheal replenishment of adenosine triphosphate in Trpv4 mice abrogated the protective effect of TRPV4 deficiency. Autopsy lung tissue from ventilated patients showed decreased lung TRPV4 levels compared with nonventilated patients. Conclusions: TRPV4 mechanosensors and purinergic receptors are involved in the mechanisms of ventilator-induced brain injury. Inhibition of this neural signaling, either using nonspecific or specific inhibitors targeting the TRPV4/adenosine triphosphate/P2X signaling axis, may represent a novel strategy to prevent or treat ventilator-induced brain injury.
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Introduction: The acute respiratory distress syndrome is not only associated with a high mortality, but also goes along with cognitive impairment in survivors. The cause for this cognitive impairment is still not clear. One possible mechanism could be cerebral inflammation as result of a "lung-brain-crosstalk". Even mechanical ventilation itself can induce cerebral inflammation. We hypothesized, that an acute lung injury aggravates the cerebral inflammation induced by mechanical ventilation itself and leads to neuronal damage. Methods: After approval of the institutional and state animal care committee 20 pigs were randomized to one of three groups: lung injury by central venous injection of oleic acid (n = 8), lung injury by bronchoalveolar lavage in combination with one hour of injurious ventilation (n = 8) or control (n = 6). Brain tissue of four native animals from a different study served as native group. For six hours all animals were ventilated with a tidal volume of 7 ml kg-1 and a scheme for positive end-expiratory pressure and inspired oxygen fraction, which was adapted from the ARDS network tables. Afterwards the animals were killed and the brains were harvested for histological (number of neurons and microglia) and molecular biologic (TNFalpha, IL-1beta, and IL-6) examinations. Results: There was no difference in the number of neurons or microglia cells between the groups. TNFalpha was significantly higher in all groups compared to native (p < 0.05), IL-6 was only increased in the lavage group compared to native (p < 0.05), IL-1beta showed no difference between the groups. Discussion: With our data we can confirm earlier results, that mechanical ventilation itself seems to trigger cerebral inflammation. This is not aggravated by acute lung injury, at least not within the first 6 hours after onset. Nevertheless, it seems too early to dismiss the idea of lung-injury induced cerebral inflammation, as 6 hours might be just not enough time to see any profound effect.
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Objective The aim of this study was to estimate the incidence of delirium and its risk factors among critically ill cancer patients in an intensive care unit (ICU). Materials and Methods This is a prospective cohort study. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) was measured daily at morning to diagnose delirium by a physician. Delirium was diagnosed when the daily was positive during a patient's ICU stay. All patients were followed until they were discharged from the ICU. Using logistic regression, we estimated potential risk factors for developing delirium. The primary outcome was the development of ICU delirium. Results There were 109 patients included in the study. Patients had a mean age of 48.6 ± 18.07 years, and the main reason for admission to the ICU was septic shock (40.4%). The incidence of delirium was 22.9%. The mortality among all subjects was 15.6%; the mortality rate in patients who developed delirium was 12%. The only variable that had an association with the development of delirium in the ICU was the days of use of mechanical ventilation (OR: 1.06; CI 95%: 0.99–1.13;p=0.07). Conclusion Delirium is a frequent condition in critically ill cancer patients admitted to the ICU. The duration in days of mechanical ventilation is potential risk factors for developing delirium during an ICU stay. Delirium was not associated with a higher rate of mortality in this group of patients.
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Objective To establish the prevalence of delirium in a general intensive care unit and to identify associated factors, clinical expression and the influence on outcomes. Methods This was a prospective cohort study in a medical surgical intensive care unit. The Richmond Agitation-Sedation Scale and Confusion Assessment Method for the Intensive Care Unit were used daily to identify delirium in mechanically ventilated patients. Results In this series, delirium prevalence was 80% (N = 184 delirious patients out of 230 patients). The number of patients according to delirium psychomotor subtypes was as follows: 11 hyperactive patients (6%), 9 hypoactive patients (5%) and 160 mixed patients (89%). Multiple logistic regression modeling using delirium as the dependent outcome variable (to study the risk factors for delirium) revealed that age > 65 years, history of alcohol consumption, and number of mechanical ventilation days were independent variables associated with the development of delirium. The multiple logistic regression model using hospital mortality as the dependent outcome variable (to study the risk factors for death) showed that severity of illness, according to the Acute Physiology and Chronic Health Evaluation II, mechanical ventilation for more than 7 days, and sedation days were all independent predictors for excess hospital mortality. Conclusion This Latin American prospective cohort investigation confirmed specific factors important for the development of delirium and the outcome of death among general intensive care unit patients. In both analyses, we found that the duration of mechanical ventilation was a predictor of untoward outcomes.
Article
Objective To determine the incidence and the factors associated with delirium in intensive care unit patients. Methods A cohort study conducted on 134 patients in the intensive care unit at a clinic in Bucaramanga, Colombia, who were recruited in the first 24 h following admission and on whom the Richmond Agitation-Sedation Scale (RASS), PRE-DELIRIC version in Spanish, and Confusion Assessment method for Intensive Care Unit (CAM-ICU) were applied; the outcome was evaluated through daily monitoring with CAM-ICU. Results The incidence of delirium was 20.2%, the predominating type was hypoactive at 66.7%, followed by the hyperactive type at 7.4% and mixed at 25.9%. Fifty-two percent of the patients with delirium died. In the bivariate analysis, the use of sedatives (Relative Risk (RR) 2.4, 95% confidence interval (95% CI) = 1.2–4.5), infection (RR = 2.8, 95% CI = 1.3–5.9), metabolic acidosis (RR = 4.3, 95% CI = 2.3–8.0), mechanical ventilation (RR = 4.6, 95% CI = 2.0–10.6), aged over 60 years (RR = 2.3, 95% CI = 1.09–5.3) and APACHE score greater than 14 (RR = 3.0) (95% CI = 1.1–8.2) were identified as risk factors for delirium. The multivariate analysis only found a relationship with infection (RR = 3.8, 95% CI = 1.6–9.1) and being aged over 60 years (RR = 3.2, 95% CI 1.2–8.3). Conclusions delirium is frequent in patients in the intensive care unit, especially the hypoactive type. Half of the patients with delirium died. The main risk factors for delirium are infection and being over 60 years age, therefore, delirium prevention activities should focus on these critical patients.
Article
We previously corroborated benefits of the Trendelenburg position in the prevention of ventilator-associated pneumonia (VAP). We now investigate its potential effects on the brain versus the semirecumbent position. We studied seventeen anesthetized pigs and randomized to be ventilated and positioned as follows: duty cycle (TI/TTOT) of 0.33, without positive end-expiratory pressure (PEEP), placed with the bed oriented 30° in anti-Trendelenburg (control group); positioned as in the control group, with TI/TTOT adjusted to achieve an expiratory flow bias, PEEP of 5 cm H2O (IRV-PEEP); positioned in 5° TP and ventilated as in the control group (TP). Animals were challenged into the oropharynx with Pseudomonas aeruginosa. We assessed hemodynamic parameters and systemic inflammation throughout the study. After 72 hours, we evaluated incidence of microbiological/histological VAP and brain injury. Petechial haemorrhages score was greater in the TP group (p = 0.013). Analysis of the dentate gyrus showed higher cell apoptosis and deteriorating neurons in TP animals (p < 0.05 vs. the other groups). No differences in systemic inflammation were found among groups. Cerebral perfusion pressure was higher in TP animals (p < 0.001), mainly driven by higher mean arterial pressure. Microbiological/histological VAP developed in 0, 67 and 86% of the animals in the TP, control and IRV-PEEP groups, respectively (p = 0.003). In conclusion, the TP prevents VAP; yet, we found deleterious neural effects in the dentate gyrus, likely associated to cerebrovascular modification in such position. Further laboratory and clinical studies are mandatory to appraise potential neurological risks associated with long-term TP.
Article
Objective: To determine the incidence and the factors associated with delirium in intensive care unit patients. Methods: A cohort study conducted on 134 patients in the intensive care unit at a clinic in Bucaramanga, Colombia., who were recruited in the first 24hours following admission and on whom the Richmond Agitation-Sedation Scale (RASS), PRE-DELIRIC version in Spanish, and Confusion Assessment method for Intensive Care Unit (CAM-ICU) were applied; the outcome was evaluated through daily monitoring with CAM-ICU. Results: The incidence of delirium was 20.2%, the predominating type was hypoactive at 66.7%, followed by the hyperactive type at 7.4% and mixed at 25.9%. Fifty-two percent of the patients with delirium died. In the bivariate analysis, the use of sedatives (Relative Risk(RR) 2.4, 95% confidence interval (95% CI) = 1.2-4.5), infection (RR = 2. 8, 95% CI=1.3-5.9), metabolic acidosis (RR = 4 3, 95% CI=2.3-8.0), mechanical ventilation (RR = 4 6, 95% CI=2.0-10.6), aged over 60 years (RR = 2 3, 95% CI=1.09-5.3) and APACHE score greater than 14 (RR = 3. 0) (95% CI=1.1-8.2) were identified as risk factors for delirium. The multivariate analysis only found a relationship with infection (RR = 3 8, 95% CI=1.6-9.1) and being aged over 60 years (RR = 3 2, 95% CI 1.2-8.3). Conclusions: delirium is frequent in patients in the intensive care unit, especially the hypoactive type. Half of the patients with delirium died. The main risk factors for delirium are infection and being over 60 years age, therefore, delirium prevention activities should focus on these critical patients.
Article
Objectives: In the absence of a universal definition of light or deep sedation, the level of sedation that conveys favorable outcomes is unknown. We quantified the relationship between escalating intensity of sedation in the first 48 hours of mechanical ventilation and 180-day survival, time to extubation, and delirium. Design: Harmonized data from prospective multicenter international longitudinal cohort studies SETTING:: Diverse mix of ICUs. Patients: Critically ill patients expected to be ventilated for longer than 24 hours. Interventions: Richmond Agitation Sedation Scale and pain were assessed every 4 hours. Delirium and mobilization were assessed daily using the Confusion Assessment Method of ICU and a standardized mobility assessment, respectively. Measurements and main results: Sedation intensity was assessed using a Sedation Index, calculated as the sum of negative Richmond Agitation Sedation Scale measurements divided by the total number of assessments. We used multivariable Cox proportional hazard models to adjust for relevant covariates. We performed subgroup and sensitivity analysis accounting for immortal time bias using the same variables within 120 and 168 hours. The main outcome was 180-day survival. We assessed 703 patients in 42 ICUs with a mean (SD) Acute Physiology and Chronic Health Evaluation II score of 22.2 (8.5) with 180-day mortality of 32.3% (227). The median (interquartile range) ventilation time was 4.54 days (2.47-8.43 d). Delirium occurred in 273 (38.8%) of patients. Sedation intensity, in an escalating dose-dependent relationship, independently predicted increased risk of death (hazard ratio [95% CI], 1.29 [1.15-1.46]; p < 0.001, delirium hazard ratio [95% CI], 1.25 [1.10-1.43]), p value equals to 0.001 and reduced chance of early extubation hazard ratio (95% CI) 0.80 (0.73-0.87), p value of less than 0.001. Agitation level independently predicted subsequent delirium hazard ratio [95% CI], of 1.25 (1.04-1.49), p value equals to 0.02. Delirium or mobilization episodes within 168 hours, adjusted for sedation intensity, were not associated with survival. Conclusions: Sedation intensity independently, in an ascending relationship, predicted increased risk of death, delirium, and delayed time to extubation. These observations suggest that keeping sedation level equivalent to a Richmond Agitation Sedation Scale 0 is a clinically desirable goal.
Article
Purpose We aimed to determine the frequency of RET mosaicism in Hirschsprung disease (HSCR), test whether it has been underestimated, and to assess its contribution to HSCR risk. Methods Targeted exome sequencing (n = 83) and RET single-gene screening (n = 69) were performed. Amplicon-based deep sequencing was applied on multiple tissue samples. TA cloning and sequencing were conducted for validation. Results We identified eight de novo mutations in 152 patients (5.2%), of which six were pathogenic mosaic mutations. Two of these patients were somatic mosaics, with mutations detected in blood, colon, and saliva (mutant allele frequency: 35–44%). In addition, germ-line mosaicism was identified in four clinically unaffected subjects, each with an affected child, in multiple tissues (mutant allele frequency: 1–28%). Conclusion Somatic mutations of the RET gene are underrecognized in HSCR. Molecular investigation of the parents of patients with seemingly sporadic mutations is essential to determine recurrence risk in these families.