Intensive Care Med
https://doi.org/10.1007/s00134-023-07079-8
RECENT ADVANCES IN ICU
Invasive mechanical ventilation
Irene M. J. Wong1, Niall D. Ferguson1,2,3,6,7,8*  and Martin Urner1,4,5
© 2023 Springer-Verlag GmbH Germany, part of Springer Nature
Mechanical ventilation is provided to up to 20 million
patients annually in intensive care units (ICUs) world-
wide. Despite lung-protective mechanical ventilation
strategies, the mortality of mechanically ventilated
patients remains high, especially in patients with acute
respiratory distress syndrome (ARDS). Current lung-
protective mechanical ventilation strategies include
lower tidal volume (TV) ventilation of 4–6 ml/kg pre-
dicted body weight (PBW), the potential use of higher
positive end-expiratory pressure (PEEP) without routine
stepwise recruitment maneuvers for moderate-to-severe
ARDS, early prone positioning, the use of extracorpor-
eal life support (ECLS), and the practice of spontaneous
breathing trials [1]. This article outlines recent advances
in mechanical ventilation and discusses innovative con-
cepts that after further investigation have the potential to
change future practice.
Acute respiratory distress syndrome
Most evidence surrounding ventilation strategies is based
on studies in ARDS patients. ARDS is a syndrome char-
acterized by an acute onset of hypoxemic respiratory
failure in the context of bilateral opacities on the chest
x-ray that are not explained by cardiogenic pulmonary
edema. Notably, survival mainly depends on the extent of
lung injury rather than whether criteria for ARDS were
reached [2]. Furthermore, considerable heterogeneity in
risk factors, physiological characteristics, and biology
of the syndrome might not be captured by the current
ARDS definition, making it difficult to identify effective
treatment strategies [3]. The PRoVENT-COVID study
*Correspondence: niall.ferguson@uhn.ca
8
Toronto General Hospital, 585 University Avenue, MaRS‑9012, Toronto,
ON M5G 2N2, Canada
Full author information is available at the end of the article
group has brought to the forefront the different pheno-
types that can occur from a single cause of lung injury [4].
Advances in precision medicine might allow us to better
identify subsets of patients that share a distinct clinical
and molecular phenotype associated with response to
specific therapies [5].
Lung protective mechanical ventilation
To further mitigate the risk of ventilator-induced lung
injury, the REST trial measured the effect of lowering
tidal volumes below 6 mL/kg PBW in patients with mod-
erate-to-severe hypoxemic respiratory failure, facilitated
by extracorporeal carbon dioxide removal ­ (ECCO2R)
[6]. The study was stopped early for futility and feasibil-
ity. The intervention group had two fewer ventilator-free
days and more frequent serious adverse events, including
intracranial hemorrhage and bleeding. However, many
questions remain as a low-efficiency ­ECCO2R device was
used, experience with ­ECCO2R or extra corporeal mem-
brane oxygenation (ECMO) varied across centers, a het-
erogeneous group of patients was investigated, and the
achieved between group differences in tidal volumes and
driving pressures were relatively small. Prior to applica-
tion in daily clinical routine, further research is needed
to determine the impact of ultra-low tidal volume ven-
tilation, potentially targeting a subgroup of patients at a
higher risk of overdistention injury and using ­ECCO2R
devices with higher efficiency. Moreover, in a re-analysis
of pooled data from five randomized trials, dominated by
the ARDS Network ARMA trial, Goligher and colleagues
demonstrated that the impact of tidal volume limitation
on mortality varied considerably according to baseline
elastance with no effect seen when elastance was low [7].
Therefore, driving pressure—a measure that combines
both tidal volume and elastance—may represent a more
promising target variable for lung-protective ventilation,
because tidal volume is measured in relation to the ability
of the lungs to stretch and expand.
Optimal PEEP titration during mechanical ventilation
can also influence regional transpulmonary pressures,
thereby mitigating the risk of ventilator-associated lung
injury. However, it still needs to be fully understood how
to select the best PEEP regarding patient-relevant out-
comes. The recruitment-to-inflation (R/I) ratio compares
the ratio of lung compliances when PEEP is released
from a higher to a lower level, thereby allowing one to
detect phenotypes that might be responsive to alveolar
recruitment [8]. The ratio is easily measured, but some
imprecision exists between measurements across dif-
ferent ventilators [9]. PEEP titration to end-expiratory
transpulmonary pressures, as guided by esophageal
pressure (Pes) measurements, has previously been inves-
tigated in the EPVent-2 trial. No differences in mortal-
ity or days free from mechanical ventilation were found
compared to empirically setting PEEP and F ­ iO2 levels. A
post-hoc analysis of the EPVent-2 trial showed differing
treatment effects based on multiorgan dysfunction sever-
ity and potential mortality benefits in patients with lower
APACHE-II scores. Adjusted for multiorgan dysfunction,
Fig. 1  Innovative concepts under investigation that might change the future practice of mechanical ventilation. ECCO2R extracorporeal carbon
dioxide removal, PEEP positive end-expiratory pressure
Pes-guided PEEP titration to achieve transpulmonary
pressure closer to 0 ­cmH2O was associated with greater
survival [10]. Although concepts such as ultra-lung-pro-
tective ventilation, R/I ratio to detect responsiveness to
recruitment, or PEEP titration to esophageal pressures
are promising and based on sound physiological reason-
ing, their efficacy needs to be further tested in studies
with large cohorts of patients.
Most ventilation strategies aim to protect the lungs
from additional injury, while the effects of mechanical
ventilation on the cardiovascular system have often been
overlooked. About 21% of ARDS patients have signs of
right ventricular dysfunction and this is associated with
increased mortality [11]. Hence, prospective studies are
needed to investigate how heart–lung interactions and
altered right heart function modify the effectiveness of
ventilation strategies in patients with respiratory failure,
and if the presence of right heart dysfunction should be
considered during the decision-making process of initiat-
ing venovenous ECMO support [12].
Supportive care during mechanical ventilation
Supportive care plays a pivotal role during mechanical
ventilation. Ventilated patients frequently suffer from
pain, agitation, and delirium, which might lead to venti-
lator dyssynchrony and high respiratory drive and effort,
thereby contributing to patient-self-inflicted lung injury.
A proposal has been made to update the sedation bun-
dle to ABCDEF-R for ARDS patients, where “R” stands
for respiratory drive control [13]. The proposed approach
first attempts to modulate respiratory drive and effort
with PEEP titration or different ventilation modes with
light sedation before increasing sedation and using neu-
romuscular blockade in a tiered approach [13]. Such a
strategy might reduce the use of deep sedation but has
not yet been investigated in terms of patient-relevant
outcomes. Also, there is a poor correlation between seda-
tion depth and respiratory drive and effort, as measured
with airway occlusion pressures (P0.1), and expiratory
occlusion pressures (Pocc) [14]. Dianti and colleagues
tested the feasibility of a strategy to limit both lung and
diaphragm injury in patients with moderate-to-severe
ARDS. They observed wide variations in respiratory
efforts ranging from apnea to excessive efforts depending
on the level of sedation [15]. Notably, the suggested lung
and diaphragm-protective targets were rarely achieved
without partial neuromuscular blockade or veno-venous
ECMO support.
Further developments have been made to investigate
how diaphragm dysfunction during mechanical ventila-
tion can be influenced. Temporary transvenous phrenic
nerve stimulation did not increase the proportion of
successful weaning in a small study of patients who
failed two weaning attempts. However, the investigators
observed an increase in the patient’s maximal inspira-
tory pressure and diaphragm thickening fraction [16],
suggesting a potential future role of this intervention in
treating more challenging cases of weaning failure.
Take‑home message
As summarized in Fig.  1, recent advances in invasive
mechanical ventilation are characterized by the grow-
ing awareness that ARDS is a highly heterogeneous syn-
drome, and interventions to improve clinical outcomes
need to be tailored to specific patient subgroups that
share distinct clinical and possibly molecular phenotypes.
Many of the concepts described above are very innova-
tive and have a solid physiological rationale but have yet
to be tested in large clinical studies. Ongoing research
efforts, therefore, continue to investigate treatment strat-
egies that optimally support the patient during recovery
from the underlying illness, while mitigating the risk of
additional harm associated with mechanical ventilation.
Author details
1
 Interdepartmental Division of Critical Care Medicine, University of Toronto,
Toronto, Canada. 2 Departments of Medicine and Physiology, University
of Toronto, Toronto, Canada. 3 Division of Respirology and Critical Care Medi-
cine, Department of Medicine, University Health Network, Toronto, Canada.
4
 Department of Anesthesiology and Pain Medicine, University of Toronto,
Toronto, Canada. 5 Department of Anesthesia and Pain Management,
University Health Network, Toronto, Canada. 6 Institute of Health Policy, Man-
agement, and Evaluation, University of Toronto, Toronto, Canada. 7 Toronto
General Research Institute, Toronto, Canada. 8 Toronto General Hospital, 585
University Avenue, MaRS‑9012, Toronto, ON M5G 2N2, Canada.
Data availability
There is no original data associated with this paper - so not relevant.
Declarations
Conflicts of interest
The authors declare no conflicts of interest related to this article.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations.
Received: 11 March 2023 Accepted: 13 April 2023
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