EXPERT REVIEW OF MEDICAL DEVICES

https://doi.org/10.1080/17434440.2023.2255521

REVIEW

Mechanical ventilation in patients with acute respiratory distress syndrome: current

status and future perspectives
Denise Battaglinia*, Ida Giorgia Iavaronea,b*, Chiara Robbaa,b, Lorenzo Ball a,b
, Pedro Leme Silvac
and Patricia R. M. Rocco c
a
Anesthesia and Intensive Care, IRCCS Ospedale Policlinico San Martino, Genoa, Italy; bDepartment of Surgical Sciences and Integrated Diagnostics
(DISC), University of Genoa, Genoa, Italy; cLaboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of
Rio de Janeiro, Rio de Janeiro, Brazil

ABSTRACT ARTICLE HISTORY

Introduction: Although there has been extensive research on mechanical ventilation for acute respira­ Received 3 July 2023
tory distress syndrome (ARDS), treatment remains mainly supportive. Recent studies and new ventila­ Accepted 1 September 2023
tory modes have been proposed to manage patients with ARDS; however, the clinical impact of these KEYWORDS
strategies remains uncertain and not clearly supported by guidelines. The aim of this narrative review is Acute respiratory distress
to provide an overview and update on ventilatory management for patients with ARDS. syndrome; mechanical
Areas covered: This article reviews the literature regarding mechanical ventilation in ARDS. ventilation; ventilator-
A comprehensive overview of the principal settings for the ventilator parameters involved is provided induced lung injury;
as well as a report on the differences between controlled and assisted ventilation. Additionally, new personalized mechanical
modes of assisted ventilation are presented and discussed. The evidence concerning rescue strategies, ventilation; rescue therapy
including recruitment maneuvers and extracorporeal membrane oxygenation support, is analyzed.
PubMed, EBSCO, and the Cochrane Library were searched up until June 2023, for relevant literature.
Expert opinion: Available evidence for mechanical ventilation in cases of ARDS suggests the use of
a personalized mechanical ventilation strategy. Although promising, new modes of assisted mechanical
ventilation are still under investigation and guidelines do not recommend rescue strategies as the
standard of care. Further research on this topic is required.

1. Introduction /FiO2 ≤315 with SpO2 ≤97%), with an end-expiratory pressure

of 5 cmH2O or HFNO ≥30 L/min [8].
Since the most recent definition of acute respiratory distress
Although several supportive and pharmacologic treatments
syndrome (ARDS) was adopted in 2012 [1], several changes in
have evolved over the last decades, to date, ARDS management
ARDS management have occurred, with implications relevant
remains mainly supportive; mechanical ventilation (MV) is the
to the definition of ARDS. After more than 10 years of clinical cornerstone of supportive therapy for patients with ARDS [9]. The
application of the Berlin definition, its advantages and pitfalls current aims of MV include minimizing ventilator-induced lung
have been fully discussed, and will probably result in an injury (VILI) while maintaining an adequate gas exchange. In its
updated definition of ARDS in the near future [2]. The most contemporary interpretation, lung protective ventilation
controversial aspects of the Berlin definition include the aim of includes the use of low tidal volumes (VT), limiting plateau pres­
including all causes of hypoxemic respiratory failure in a single sure (PPLAT), driving pressure (ΔP), mechanical power (MP), indi­
syndrome [3], the low level of correspondence with postmor­ vidualized levels of positive end-expiratory pressure (PEEP), early
tem findings of diffuse alveolar damage [4], the limitations of prone positioning in moderate-to-severe cases and, in cases of
chest radiography in terms of low reliability and limited avail­ refractory hypoxemia, the use of rescue strategies such as recruit­
ability in resource-limited settings [5], the lack of criteria for ment maneuvers (RMs) and extracorporeal membrane oxygena­
patients receiving high flow nasal oxygen (HFNO) [6], and the tion (ECMO) [9]. Recent research is also focusing on new
risk of both over- and underdiagnosis of ARDS in real-world therapeutic strategies, such as the adoption of spontaneous
settings [7]. breathing during the early phases of the disease [10], and the
In 2023, a panel of experts issued a proposal for a new identification of sub-phenotypes that may benefit from specific
definition of ARDS as an acute diffuse lung injury character­ treatments [11]. New ventilatory modes have been proposed,
ized by inflammation, bilateral opacities (even if identified on but the impact of these strategies is still uncertain and not clearly
lung ultrasonography by an expert operator), hypoxemia supported by guidelines.
(arterial partial pressure of oxygen [PaO2]/fraction of inspired This narrative review provides an overview and update on
oxygen [FiO2] ≤300 or peripheral saturation of oxygen [SpO2] ventilatory management for patients with ARDS.

CONTACT Patricia R. M. Rocco [email protected] Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University
of Rio de Janeiro, Centro de Ciências da Saúde, Avenida Carlos Chagas Filho, 373, Bloco G1-014, Ilha do Fundão, Rio de Janeiro 21941-902, Brazil
*
These authors contributed equally.
© 2023 Informa UK Limited, trading as Taylor & Francis Group
2 D. BATTAGLINI ET AL.

soon as possible, even in the emergency department, to max­

Article highlights imize the probability of using low VT in the ICU [21].
● Mechanical ventilation for patients with ARDS should focus on
Recent knowledge and guidelines recommend
a personalized strategy, with individualized parameters. a personalized MV strategy [22], tailor-made on the character­
● Current targets of mechanical ventilation include adequate oxygena­ istics of each patient, aiming for a VT of 4–8 mL/kg PBW to
tion, lung protective parameters, and limited patient-ventilator asyn­
chronies, thus mitigating ventilator-induced lung injury.
prevent alveolar overdistention and lung damage [2,9,23–26].
● Novel modes of mechanical ventilation are currently under investiga­
tion, and preliminary findings have highlighted their potential bene­
fits for patients with ARDS. 2.2. Positive end-expiratory pressure
● Rescue strategies are considered for patients with ARDS who are
unable to achieve safe oxygenation thresholds, thus optimizing Atelectasis caused by the collapse of alveoli is common in
patients’ clinical response.
cases of ARDS and could benefit from the application of
PEEP [27]. PEEP has a relevant role in cyclic recruitment/dere­
cruitment in animal models of surfactant depletion, but this
does not always occur in a clinical setting [28,29]. PEEP is
2. Lung protective ventilation strategies a fundamental parameter in an MV strategy in patients with
ARDS [1]; however, it is well known that PEEP can have both
2.1. Tidal volume positive and negative effects. The application of PEEP is ben­
Decades ago, the conventional approach to MV for ARDS eficial for alveolar recruitment, reduction of intrapulmonary
included the use of high tidal volumes (VT) (10–15 mL/kg of shunt, and arterial oxygenation [30]. Similarly, by avoiding
predicted body weight [PBW]). In 2000, the results of the atelectasis and increasing the end-expiratory lung volume,
ARMA trial led to an important modification in the manage­ PEEP seems to prevent VILI through a reduction of dynamic
ment of MV in ARDS, showing that mortality was reduced with strain. However, PEEP could have unfavorable effects by
low VT (<6 mL/kg PBW) compared with conventional larger increasing the risk of volutrauma and consequently pulmonary
tidal volumes [12]. Nowadays, it is well known that an MV stress and static strain [31]. From a hemodynamic point of
strategy using higher VT can lead to volutrauma and bio­ view, PEEP can contribute to reducing cardiac output. The
trauma [13,14]; a lung protective ventilation strategy using cardiac function curve may shift to the right as a result of
low VT (4–6 mL/kg PBW) is the actual standard of care for MV increased intrathoracic pressure caused by PEEP. Cardiac out­
in ARDS [15], although these targets are often disregarded in put and venous return would decrease if the venous return
clinical practice [7]. curve remained unchanged (Figure 1). On the other hand,
The ARDSNet trial revealed that the use of VT of 6 mL/kg venous return and cardiac output are kept steady
PBW to minimize alveolar overdistension can decrease mortal­ in situations of increased heart rate or mean systemic pres­
ity by 22% compared with an MV strategy using high VT (10– sure. PEEP has no effect on the left ventricle’s transmural
15 mL/kg PBW) [12]. Recent guidelines tolerate the use of VT pressure gradient during the diastolic phase, but it does
>6 mL/kg PBW in cases of obstinate hypercapnia to optimize cause a decrease in afterload and transmural pressure during
gas exchange [16]. the systolic phase. A cross-over trial on obese patients showed
A recent study comparing MV approaches with VT ≤6.5 mL/ increased atelectasis and hypoxemia as a result of the signifi­
kg PBW and ≥6.5 mL/kg PBW showed an increased risk of cant abdomen and chest wall loads on the diaphragm, thus
death of 23% for each increase in VT of 1 mL/kg PBW [17]. needing higher pleural pressure and airway pressure to
Conversely, the LUNG SAFE study showed that a median value
of VT ≥7.1 mL/kg compared with VT ≤7.1 mL/kg was not
related to increased mortality [18].
Despite the strong recommendation to use low VT in
patients with ARDS [19,20] it seems that less than 60% of
the patients with ARDS receive VT ≤8 mL/kg PBW [18], possibly
due to frequent underdiagnosis of ARDS [7].
Furthermore, the early application of lung protective stra­
tegies with low VT on admission to the intensive care unit
(ICU) played a significant role in patients with ARDS.
A ventilation strategy with low VT (6 mL/kg PBW) applied
from primary admission to the ICU seems to decrease mortal­
ity more than a delayed lung protective ventilation approach
[17]. On the other hand, the ARDSNet trial comparing lower
and traditional VT [12] has not reported differences in mortal­
ity among patients ventilated with higher VT (8–10 mL/kg
PBW) at the beginning of ARDS and during the first 48 h [12].
In addition, the Lung-Protective Ventilation Initiated in the Figure 1. The main detrimental effects of positive end-expiratory pressure
Emergency Department (LOV-ED) study reported that (PEEP) on hemodynamics. LV, left ventricle; RAP, right atrial pressure; RV, right
a ventilation approach with low VT should be applied as ventricle.
 EXPERT REVIEW OF MEDICAL DEVICES 3

maintain appropriate oxygen saturation. Perfusion may Generally, PEEP value should not be set >15 cmH2O [25], and
decrease at these greater pressures. Increased oxygen deliv­ lower PEEP values are recommended to guarantee optimal oxy­
ery, which is ultimately the parameter that counts for tissues, genation (SpO2, 88–92% or PaO2, 55–70 mmHg) [50], and PPLAT,
may not be altered, limiting the advantage of increased ΔP, and hemodynamics should be monitored and maintained
saturation [32]. within safe ranges. New ARDS guidelines from the European
In critically ill patients, cardiac output can increase, low­ Society of Intensive Care Medicine (ESICM) were unable to
ering myocardial oxygen demand. This improvement in ejec­ make a recommendation for/against routine use of a higher
tion from the left ventricle reduces cardiac work. Similarly, PEEP/FiO2 strategy versus low PEEP/FiO2 strategy [2]. In addition,
according to lung and chest wall elastance, another reason guidelines were unable to recommend PEEP titration using the
for cardiac output modifications is related to the changes in respiratory mechanics technique or PEEP/FiO2 strategy.
pleural pressure caused by PEEP. In addition, an increase in
PEEP may result in an increase or decrease in pulmonary
2.3. Plateau pressure and driving pressure
vascular resistance [33].
On the one hand, PEEP increases pleural and right atrial Plateau pressure (PPLAT) is an important parameter to monitor
pressure and decreases venous return [34]; on the other hand, and titrate lung protective ventilation [51,52]. PPLAT is the
by increasing pulmonary vascular resistance, PEEP increases elastic component that the ventilator exerts on the alveoli
right ventricular afterload [34,35]. and is measured on occluding airways at end-inspiration [53].
In a recent study, De Santis Santiago et al. [36] investigated Static compliance of the respiratory system (Crs = VT/(PPLAT
the hemodynamic consequences of high PEEP in obese − PEEP)) [54] is decreased in patients with ARDS [55] even
patients with ARDS. This study showed that higher levels of though its real prognostic value is unclear [56]. The difference
PEEP (19 cmH2O versus 7 cmH2O) in this specific population between PPLAT and PEEP is defined as ΔP, which can also be
could result in a reduction in harmful heart–lung interactions. calculated as the ratio of VT/Crs [57], and it represents the
Thus, in this case, PEEP improves respiratory system compli­ inflating pressure in the aerated lungs [24,57,58]. In short, ΔP
ance, allowing the use of a lower driving pressure without is roughly related to the dynamic lung strain [24,58].
compromising return venous function [32]. Therefore, in ARDS, which presents reduced Crs, VT may
Two meta-analyses found improvement in survival when lead to higher ΔP and consequently higher lung stress [59].
a lung protective ventilation strategy using low VT (4–5 mL/kg In this scenario, lower VT may ventilate mainly the baby lung
PBW) with high PEEP strategy (open lung strategy) was and avoid lung hyperinflation [58].
adopted [20,37]. Application of high PEEP resulted in a lower The use of a ΔP threshold as a strategy to set VT and PEEP
risk of death and better oxygenation [38]. and maintain low stress remains controversial. The titration of
High PEEP (15 cmH2O) was not related to increased survival PEEP based on ΔP is suggested in patients with brain injuries
in three large randomized controlled trials (RCTs) [39–41]. Only and ARDS [60,61], but, in general, it is debated whether this
the ART study described higher mortality in individuals with strategy could be adopted to set PEEP to reduce the ΔP value
hemodynamic instability in the case of an MV strategy using in ARDS [22,42].
high PEEP (>15 cmH2O) and aggressive RMs [42]. Furthermore, The association between increased mortality and increased
in the PHARLAP study, RMs seemed to be associated with PPLAT and ΔP is well known. The LUNG SAFE trial demonstrated
cardiac arrhythmias [43]. that PPLAT, PEEP, and ∆P are related to ARDS prognosis, and
Moreover, another meta-analysis of moderate-to-severe low ∆P (<14 cmH2O) seems to be associated with a decreased
ARDS indicated that high PEEP with lung RMs may increase risk of mortality in patients with ARDS [18]. However, there is
mortality [44]. A recent systematic review with network meta- no evidence that titrating PEEP based on ∆P improves clinical
analysis confirmed increased mortality associated with the MV outcomes.
strategy when higher PEEP was combined with RMs, and In a previous study, PPLAT was considered a more significant
a possible advantage in mortality of a higher PEEP approach determinant of mortality and outcome than ΔP [23]. On the
not including the use of RMs compared with low PEEP strate­ other hand, a meta-analysis suggested ΔP as the most likely
gies [45]. variable to predict mortality in patients with ARDS ventilated
Current research is focused on personalizing PEEP strate­ with a lung protective ventilation strategy. Accordingly,
gies according to the heterogeneity of patients and the pat­ although increased ΔP (>15 cmH2O) seems to be associated
tern of disease [25]. For example, the use of a low PEEP/PaO2, with an increased risk of mortality [62], low ∆P might be
FiO2 table, appears one of the simplest methods to individua­ related to decreased mortality when protective PPLAT and VT
lize PEEP at the bedside [46] and, overall, RCTs have failed to values are preserved [63].
demonstrate advantages in mortality when different PEEP A recent study suggests that the positive effects of low ∆P
setting strategies were compared with this standard approach. might be sustained by the application of lower VT (<6 mL/kg
Higher PEEP seems to be valuable in a selected population PBW) more than by using higher PEEP (>12 cmH2O), especially
[47], suggesting that the distinction between high and low if resulting in increased PPLAT [24].
PEEP might be eliminated [25]. The use of the best ΔP value to regulate MV in patients
Nevertheless, the best PEEP level remains under debate and with ARDS [25] is discouraged, and it is highly recommended
further studies are required [9,42,48]. Excessively high or low to take the global settings of ventilation (PEEP, VT, lung
PEEP can promote lung damage, even in ultraprotective MV, mechanics) into account and not consider ΔP as an isolated
despite no clinically relevant differences in MP or ΔP [49]. variable [64].
4 D. BATTAGLINI ET AL.

Current knowledge recommends adopting an individua­ is still controversy on which component of MP is most impor­
lized MV strategy [65] aiming at a target PPLAT of ≤30 cmH2 tant for causing VILI [75]. Different elements of MP have dis­
O [22,66] and ΔP <13–15 cmH2O, associated with low VT and tinct effects on its value: doubling RR increases MP by 1.4-fold,
the lowest PEEP that can maintain a reasonable level of oxy­ doubling PEEP increases MP by twofold, and doubling VT
genation (at least SpO2, 88–92% or PaO2, 55–70 mmHg) [67]. increases MP by fourfold [76]. This is an interesting point. If
we only double the PEEP level, the expected decrease in ΔP is
rarely half. In other words, when MP considers [PEEP × VT] +
2.4. Mechanical power
elastic work + resistive work, it will increase; however, ΔP is
MP is the amount of energy transferred to the respiratory decreasing and is therefore protective. MP and ΔP go in
system by the ventilator per unit of time, which considers different directions. If the MP formula considers only the
several variables of lung protective ventilation, including elastic component, the decrease in ΔP will follow the decrease
respiratory rate, flow, and inflation pressure. MP has the in MP [76]. Another important contradiction is that the appli­
advantage of converging many respiratory parameters in cation of zero PEEP decreased MP and increased ΔP in com­
a unique formula, and thus is probably more accurate than parison with the use of PEEP in children, suggesting that
a single parameter for lung protective ventilation [68]. MP is despite lowering MP, it is difficult to believe that this MV
usually calculated using complex and poorly applicable for­ approach at zero PEEP is more protective than PEEP for
mulas; therefore, simplified formulas have been developed for ARDS [77].
easy application at the bedside: pressure control MV: Future directions on the use of MP include its normalization
MP = 0.098 × VT × RR × (∆P + PEEP); volume control MV: to the size of the lung. Many attempts have been made by
MP = 0.098 × VT × RR × (Ppeak − ∆P/2), where RR is the respira­ normalizing to body weight, compliance or functional residual
tory rate. In a recent large animal study, MP as low as 3 J/min capacity, or the MP ratio between the measured MP and the
worsened lung injury, which was also confirmed for MP MP applied to eliminate carbon dioxide [78]. However, to date,
between 7 and 12 J/min, thus suggesting that MP per se can the variable required to normalize MP remains controversial.
promote lung injury, which may even worsen by increasing
the intensity of MV [69].
2.5. Controlled versus assisted mechanical ventilation
Observational data suggest that a value of MP > 17 J/min is
associated with adverse outcomes [70]. Another observational For decades, patients with ARDS have been mainly ventilated
study found an association between MP and mortality only in controlled MV modes, with assisted modalities used only
when MP was normalized to the compliance or the amount of when reaching the weaning phase, defined as the process of
aerated lung tissue [71]. In patients with ARDS, MP > 22 J/min gradually withdrawing the patient from ventilatory support.
was associated with increased mortality at 28 days and 3 Increased VILI has been noted after changes in the transpul­
years [72]. monary pressure [79], which can be higher in patients with
In the ARDS Network trial [12], the low VT group (6 mL/kg spontaneous breathing efforts compared with those without
PBW) showed hyperventilation with RR (about 29–30 bpm) spontaneous breathing efforts [80]. VILI can be characterized
higher than in the high VT group (12 mL/kg PBW). On the by excessively high inspiratory transpulmonary pressure and
first day of data collection, MP in the low VT group was volume (lung stress and strain, respectively), which can pro­
lower (30.6 J/min) than in the high VT group (33.1 J/min). No duce excessive alveolar wall distention and potentially harmful
difference in PaCO2 was observed between the groups over stretching or overdistention of the lung parenchyma. In addi­
time. With a reduction in VT toward the protective range, an tion, it can result from insufficient PEEP levels, when the air­
increase in RR was expected to guarantee minute ventilation way pressure and expiratory volume are too low, because this
at safe levels, avoiding acidosis. With regard to MP, although may result in cyclic alveolar recruitment/derecruitment [81].
both groups (low and high) are in the injurious range, no Experimental studies found airway pressure was similar in
differences were observed between the two groups with low controlled and assisted MV, whereas esophageal pressure
and high VT [72,73]. When patients were recruited (1996–1999) was different between the two, resulting in severe lung injury
for the ARDS Network trial, there was no discussion about during spontaneous breathing [82,83].
mechanical power, and the contribution of such an increased In addition to lung damage, experimental studies have
RR in causing harm to the respiratory system of critically ill confirmed that up to 70 h of complete diaphragmatic inactiv­
patients was unknown. ity and controlled MV results in marked atrophy of diaphragm
Another study found that MP values >25 J/min were asso­ myofibers [84]. These findings are consistent with increased
ciated with greater lung damage and higher mortality [65], diaphragmatic proteolysis during inactivity, and this may
thus suggesting that, not only in preclinical settings but also in explain difficult weaning in the latest phases [84]. However,
humans, the higher the MP, the greater the lung damage. In assisted MV is not free from possible damage. When using
patients undergoing ECMO, MP > 14.4 J/min within the first 3 a high level of pressure support, transpulmonary pressure can
days of ECMO was associated with 90-day mortality [74]. increase and diaphragm atrophy can still develop as a result of
Recently, the prognostic value of MP has been compared diaphragmatic oxidative stress and protease activation [85].
with the formula of Costa et al. [62] (4 × ΔP + RR). It is not Thus, using assisted-control MV does not mean that the
surprising that this formula gives similar conclusions as for MP, patients will not develop diaphragmatic dysfunction and mus­
given that it shares the same components as the formula for cle atrophy [85]. In animals with severe lung injury, sponta­
MP and is associated with mortality to the same extent. There neous breathing can even worsen diaphragmatic damage, and
 EXPERT REVIEW OF MEDICAL DEVICES 5

muscle paralysis might be more protective for injured lungs by pendelluft, and inhomogeneous distribution of MV can
preventing injuriously high transpulmonary pressure and high increase the risk of tensile and compressive stress with con­
driving pressure [82,83]. sequent VILI [9,24,98]. The BIRDs (NCT01862016) and the
Insights from the LUNG SAFE study suggest that using PreSpon (NCT04228471) trials will probably clarify the role of
a mode of MV that allows spontaneous breathing was asso­ APRV in patients with ARDS.
ciated with more ventilator-free days and shorter ICU stay Recently, new proportional modes of assisted MV have
without affecting mortality [86]. Saddy et al. [87] observed been investigated in patients with ARDS, including neurally
reduced inflammation when comparing different assisted MV adjusted ventilatory assist (NAVA) among others. During
strategies with pressure-controlled ventilation. Despite posi­ NAVA, the breath is initiated in the brainstem respiratory
tive feedback, current guidelines do not provide specific centers and a potential action is transmitted to the respiratory
recommendations on the use of ventilator modes that can motoneurons and respiratory muscles, causing depolarization
enable spontaneous breathing or not [88]. Observational of the diaphragm, which is recorded as an electrical activity of
results from the LUNG SAFE trial show that spontaneous the diaphragm (EAdi) signal.
breathing during MV is linked to more ventilator-free days Kacmarek et al. [99] found that NAVA compared with con­
and a shorter stay in the ICU without having any impact on ventional lung protective MV decreased the duration of MV
hospital mortality [18,86]. However, nowadays, an initial per­ but did not improve survival. Diniz-Silva et al. [100] compared
iod of controlled MV with the possible association of neuro­ NAVA with pressure support ventilation (PSV) in a small trial
muscular blocking agents (NMBAs) is suggested by investigating the ability to maintain VT within a safe threshold
guidelines [88]. for lung protective ventilation in patients with ARDS. They
found that this was feasible for 75% of the patients under
continuous sedation, but 25% were unable to maintain VT
2.6. Alternative modes of assisted mechanical
within a safe range and it was impossible to record the EAdi
ventilation
signal in one patient. A meta-analysis found that NAVA ame­
Airway pressure release ventilation (APRV) is a mode of MV liorates the synchronism between patient and ventilator and
that uses pressure-controlled ventilation with superimposed reduces mortality compared with PSV mode [101]. NAVA ame­
spontaneous breathing and no ventilator pressurization trig­ liorates diaphragmatic efficiency with neuroventilatory effi­
gered by the patient’s effort. APRV uses a continuous positive ciency and neuromuscular efficiency [102]. Another RCT that
airway pressure through which the patient is allowed to compared NAVA with a control group in pressure control-
breath spontaneously, and a short phase of release in expira­ assist control, pressure support, volume control-assist control,
tion during which the patient is not allowed to breathe. This or pressure-regulated volume control showed decreased dura­
mode is set using a long time (4–6 s) at high pressure (up to tion of MV with NAVA but no improvement in survival [103].
28–30 cmH2O) according to the patient’s requirement and This evidence suggests that the type of ventilator mode
a short time at low pressure (typically zero end-expiratory should be individualized according to the patient’s status
pressure), allowing elastic recoil of the lung [9,89–93]. and clinical response, and new RCTs and large observational
Experimental studies reported reduced VILI when using APRV studies are needed to confirm the role of these new modes of
compared with controlled MV, and these benefits seemed to ventilation in patients with ARDS.
be caused by lower transpulmonary pressure in the presence Flow-controlled ventilation (FCV), another new type of ven­
of APRV [87–89]. This is because low pressure is often set at 0 tilation, provides a constant flow and can minimize energy
cmH2O due to the auto-PEEP that arises with APRV. The airway dissipation. It may guarantee more uniform lung opening
pressure is kept above the lower inflection point on the pres­ compared with pressure-controlled ventilation and volume-
sure – volume curve by this auto-PEEP. High pressure is set controlled ventilation [104].
below the upper inflation point. The patient gets tidal volumes In addition, using an animal model, it was found that
on the most compliant part of the curve by maintaining the oxygenation could be better in FCV [105]. More research is
high and low pressures between the two inflection points. An needed to assess this by comparing arterial blood gas results
RCT comparing time-controlled adaptive ventilation (TCAV), obtained under FCV and under conventional ventilation
a specific protocol of APRV using a shorter time at high modes with the same ventilation conditions [106].
pressure than classic APRV mode (around 1–3 s), and lung
protective ventilation with low VT found reduced ICU mortality
and more ventilator-free days in the TCAV group [94]. A recent
2.7. Prone positioning
meta-analysis found that TCAV can improve oxygenation,
compliance, and shortens the ICU length of stay [95]. Other Prone positioning is a well-known rescue strategy for the
recent findings also confirmed more hemodynamic stability management of patients with severe ARDS. The effects of
than conventional modes of lung protective ventilation [94]. In prone positioning include improved oxygenation, increased
addition, TCAV showed improvement in lung recruitment and recruitment of atelectatic areas, and more homogeneous dis­
distribution of ventilation, with less VILI and inflammation in tribution of ventilation and perfusion, potentially limiting VILI.
animal models [96,97]. Although promising, the use of TCAV in The PROSEVA trial demonstrated improvement in 28-day and
patients with ARDS is still under investigation. Nevertheless, 90-day mortality rates in patients with severe ARDS (PaO2/FiO2
we should bear in mind that during assisted MV, increased <150 with 60% FiO2 and 5 cmH2O of PEEP) who underwent
spontaneous breathing effort, patient-ventilator asynchronies, prone positioning for at least 16 h [107,108]. Prone positioning
6 D. BATTAGLINI ET AL.

is not free of complications. Obstruction of the endotracheal not provide information about the type of RM, thus limiting
tube, pressure sores, and loss of venous catheters have been applicability. Currently, a personalized approach assessing
reported [109]. According to some findings, prone positioning lung recruitability at the bedside before proceeding with
can be adopted for more than 16 h without significant com­ RMs is suggested [44]. A potentially recruitable lung has
plications [108]. some regions with open alveoli and others with collapsed
According to the PROSEVA trial, guidelines recommend alveoli that might be opened, reducing shunt, pulmonary
initiating prone positioning in association with lung protective vascular resistance, and edema while also enhancing oxygena­
ventilator strategies within 36 h of meeting the PROSEVA cri­ tion. On the other hand, poorly/non-recruitable lung is mostly
teria. The use of prone positioning during ECMO showed characterized by already opened alveoli and poses
improvement in oxygenation, more homogeneous distribution a significant risk of VILI due to excessive stress and strain,
of ventilation and perfusion, and less hospital mortality [110]. increased dead space, shunting, and potentially high pulmon­
During the COVID-19 pandemic, prolonged prone positioning ary vascular resistance to oxygenation [114].
cycles >12 h have been studied, suggesting that this approach RMs are currently suggested by the Surviving Sepsis
is feasible and beneficial in selected patients [111]. Recent Campaign guidelines only as rescue strategies to improve
ESICM guidelines suggest using prone positioning as the stan­ oxygenation [115]. New ESICM guidelines on ARDS are against
dard of care in patients with moderate-to-severe ARDS a strategy using airway pressure ≥35 cmH2O for at least 1 min
(defined as PaO2/FiO2 <150 mmHg and PEEP ≥ 5 cmH2O) to to reduce mortality.
reduce mortality [2]. Figure 2 shows all the suggested thresh­
olds for ventilating patients with ARDS.
3.2. Neuromuscular blocking agents
3. Rescue strategies The use of NMBAs has been shown to improve oxygenation,
although early active breathing has the advantage of reducing
3.1. Recruitment maneuvers
respiratory muscle atrophy, enhancing oxygenation, and
The open lung approach includes RMs, reducing repeated improving compliance [116]. Papazian et al. [117] found that
opening and closing of alveoli and improving oxygenation. early use of NMBAs (first days of ICU admission) enhanced 90-
Despite potential advantages, several studies have demon­ day survival and liberation from MV without any respiratory
strated that RMs can worsen VILI and cause hemodynamic muscle inactivity. No significant changes in mortality were
impairment. Although there are no data on the ideal fre­ reported in the ROSE trial, which included patients with mod­
quency or precise timing of RMs, they are typically used erate-to-severe ARDS. This trial compared patients who
in situations of rescue and severe hypoxemia. However, in received an early and continuous infusion of NMBAs with
some studies, RMs were used systematically, without evidence those who received standard therapy with less sedation
of severe hypoxemia or a need for additional recruitment [118]. A recent meta-analysis that excluded the ROSE trial
[44,112,113]. The PHARLAP study [43], which evaluated RMs found that although ICU mortality was considerably lower
up to a PPLAT of 28 cmH2O, was halted because some patients using NMBAs, the overall risk of death at 28 days and 90
had hemodynamic instability. The ART trial revealed that high- days was not decreased. The ROSE trial was excluded because
pressure stepwise lung RMs (up to PPLAT of 50–60 cmH2O) different PEEP titration tactics and a moderate sedation
paired with high PEEP titration increased patient mortality approach were used as opposed to the deep sedation strategy
[42]. A meta-analysis investigating the application of RMs did used in the other studies [119]. In light of the mixed findings

Figure 2. Flowchart with the main thresholds used for mechanical ventilation and rescue strategies in patients with mild-to-severe ARDS. ARDS, acute respiratory
distress syndrome; ECMO, extracorporeal membrane oxygenation; iNO, inhaled nitric oxygen; MP, mechanical power; MV, mechanical ventilation; NMBA,
neuromuscular blocking agent; PaO2, arterial partial pressure of oxygen; PBW, predicted body weight; PEEP, of positive end-expiratory pressure; PPLAT, plateau
pressure; RM, recruitment maneuver, SpO2, peripheral saturation of oxygen; VT, tidal volume; VV-ECMO, venous–venous extracorporeal membrane oxygenation.
 EXPERT REVIEW OF MEDICAL DEVICES 7

from RCTs in patients with severe ARDS, NMBAs are useful to tend to become acidotic. The pH decreased from 7.39 (stan­
increase oxygenation and lower the risk of barotrauma, but dard deviation [SD] 0.1) to 7.32 (SD 0.10) despite maximal
without effects on mortality, ventilator-free days, or the dura­ ECCO2R treatment using a sweep gas flow at 10 L/min ((SD
tion of MV. However, although these considerations are valid 0.3 L/min) and blood flow at 421 mL/min (SD 40 mL/min),
at the population level, individual patients might require which are the maximum values tolerated by this tool [126].
NMBAs to achieve acceptable oxygenation, respiratory Combes et al. [127] performed a large multicenter study to
mechanics, and patient-ventilator synchrony. Current ESICM confirm the feasibility and safety of the ECCO2R device to
guidelines recommend against routine use of NMBAs in mod­ facilitate lung protective ventilation. They found that 78% of
erate-to-severe ARDS, but the evidence is uncertain in cases of the patients achieved an ultraprotective MV strategy between
ARDS due to COVID-19 [2]. 8 and 24 h from initiation of the therapy with a lower CO2
extraction device (0.3–0.5 L/min), and 82% with a higher CO2
extraction device (flow 0.8–1 L/min). Seventy-three percent of
3.3. Inhaled nitric oxide
patients were alive at day 28, and 62% at hospital discharge.
Patients with ARDS who are not responding to standard treat­ Thus, the authors concluded that ECCO2R is feasible to obtain
ments can also get rescue therapy from selective pulmonary optimal gas exchange, without compromising lung protec­
vasodilators, such as inhaled nitric oxide (iNO) [120]. iNO acts tive MV.
by selectively dilating the capillaries in well-oxygenated Despite positive feedback, a recent analysis of RCTs and
alveoli, thus increasing oxygenation and decreasing ventila­ observational studies concluded that there is insufficient evi­
tion/perfusion mismatch, pulmonary vascular resistances, and dence to support the conventional use of ECCO2R to improve
right ventricular output [121]. Trials on iNO have some draw­ outcomes in ARDS [128].
backs, such as a significant risk of bias, a small sample size, Another promising technique combines continuous renal
and dubious compliance with protective mechanical breath­ replacement therapy (CRRT) and CO2 removal. A pilot study on
ing, restricting their interpretability [122,123]. Given the pau­ 11 patients on MV with renal failure using CRRT and very low
city of positive evidence on mortality, a meta-analysis of RCTs flow (0.3 L/min) CO2 removal found that, with this approach,
did not confirm its routine use, and increased renal damage the removal of CO2 was not enough and the reduction in
was found. Inhaled epoprostenol has been proposed as an ventilatory pressure was not sufficient [129].
iNO substitute. Compared with iNO, inhaled epoprostenol had A European consensus on the use of ECCO2R in patients
the advantages of fewer possible side effects, simpler admin­ with ARDS recommended that this strategy should be asso­
istration, and cheaper cost. New, well-designed, and suffi­ ciated with lung protective MV. Criteria for initiation of ECCO2
ciently powered clinical investigations on iNO are still R include PPLAT >25 cmH2O and driving pressure >14 cmH2
required. According to the most recent recommendations, O. Clinical targets to identify the failure or usefulness of ECCO2
notwithstanding the use of prone positioning and the adop­ R treatment include pH >7.30, respiratory rate <25 or 20 bpm,
tion of lung protective strategies, iNO should only be utilized driving pressure <14 cmH2O, and PPLAT <25 cmH2O [130].
in cases of ARDS with severe hypoxemia before the initiation Recent ESICM guidelines recommend against the use of
of venous-venous ECMO [16]. ECCO2R for patients with non-COVID-19 and COVID-19 ARDS
(with a strong level of recommendation) [2]. This technique is
allowed within the context of RCTs.
3.4. Extracorporeal carbon dioxide removal
Extracorporeal carbon dioxide removal (ECCO2R) has been
3.5. Extracorporeal membrane oxygenation
proposed as a treatment for both hypoxemic and hypercapnic
respiratory failure. ECCO2R is a rescue strategy for patients Due to the conflicting results, venous–venous ECMO has been
with severe ARDS. Blood flow rates of 0.5–1.5 L/min are used proposed only as a rescue treatment for patients with severe
to remove low flow CO2 and regulate pH without the inva­ ARDS. The CESAR trial compared patients with ECMO and
siveness of ECMO. Bein et al. [124] compared an MV strategy patients without, finding improvement in quality of life at 6
using low VT (6 mL/kg PBW) and very low VT (3 mL/kg PBW) months in those who underwent ECMO [131]. The EOLIA trial
during ECCO2R and found that the use of very low VT had the did not find improvement in mortality for patients undergoing
greatest potential to further reduce VILI, without negative ECMO despite a trend toward statistical significance [132].
effects. Morris et al. [125] found no difference in survival A sub-analysis of the EOLIA trial found that early initiation of
between a group undergoing only MV and a group using ECMO can improve mortality [133]. In 2006, a meta-analysis of
ECCO2R in association with MV. In addition, ECCO2R did not individual patient data confirmed benefits on 90-day mortality
provide advantages in oxygenation compared with rates for patients treated with ECMO [131]. Another meta-
a conventional MV strategy only. The most recent feasibility analysis of individual patient data found that ECMO support
and safety pilot study of 20 patients with moderate or severe with low driving pressure and lung protective ventilation in
ARDS who underwent ECCO2R with the new standalone plat­ the first 3 days was associated with less in-hospital mortality
form (Prismalung; Gambro-Baxter), integrated on the [134]. ECMO plus ultra-protective mechanical ventilation for
Prismaflex platform (Gambro-Baxter), demonstrated 24 h reduces lung damage and the fibroproliferative response
a decrease in VT from 6 to 4 mL/kg PBW and in PPLAT <25 in a severe ARDS model [135]. Some protocols suggest venti­
cmH2O, achieving ultraprotective ventilation. However, this lating patients with ARDS and ECMO using a volume-
study demonstrates that patients ventilated at 4 mL/kg PBW controlled mode with the following initial settings: VT of 3–4
8 D. BATTAGLINI ET AL.

mL/kg BPW, FiO2 on ventilator at 100%, PEEP of 12–15 cmH2O, caused by pulmonary edema and lung injury [144]; (3)
I:E ratio of 1:1.5–1:2.0, and respiratory rate of 10 breaths/min intrathoracic pressure increases and the diaphragm lowers
[136]. A recent international multicenter study found no into the abdominal cavity during positive-pressure ventilation;
impact of ventilatory settings during ECMO on patient out­ thus, the pressure gradient for venous return is compromised.
comes. They adopted a mean VT of 3.7 mL/kg PBW, plateau Moreover, left ventricular afterload is compromised, increasing
pressure of 24 cmH2O, driving pressure of 14 cmH2O, respira­ left ventricular ejection. In the case of hypervolemic heart
tory rate 14 breaths/min, and mechanical power of 6.6 J/min, failure, left ventricular ejection can improve, increasing cardiac
and all the parameters were significantly reduced compared output and reducing the O2 demand to the myocardium. On
with pre-ECMO ventilatory settings [137]. the contrary, in a hypovolemic setting, a small increase in PEEP
Although current knowledge does not provide specific can cause relatively large decreases in preload and cardiac
recommendations about MV settings during ECMO weaning, output. This can be mitigated by increasing the mean systemic
an increase in pulmonary blood flow is expected and rigorous filling pressure [145], which depends on volume status and
attention to the ventilator values is required [138]. In this case, vasomotor tone (i.e. fluids infusion and vasopressors) [140].
titration of PEEP and VT should be performed, and the
mechanical ventilation setting should be changed to values
5. Conclusions
that are acceptable for non-ECMO patients. No consensus
about the mode of ventilation in this critical phase has been MV strategies are continuously being developed for patients
reached; however, the application of assist control mechanical with ARDS. Current guidelines and clinical practice suggest
ventilation with pressure support seems to be useful when using low VT, PPLAT, ΔP, and MP, all of which should be kept
weaning [139]. as low as clinically feasible. New modes of assisted MV are
Current guidelines for the management of patients with currently under investigation, but there is no definitive evi­
ARDS give a weak recommendation to implement ECMO for dence yet on their influence on outcomes in patients with
severe ARDS. In addition, ECMO has several concerns related ARDS. Rescue strategies are fundamental steps to manage
to costs, the need for experienced staff, and the necessity to patients with severe ARDS who are not easily managed with
centralize ECMO procedures, thus limiting its easy applicability standard lung protective MV. The risk of VILI remains high
in patients who could benefit from the treatment [88]. ESICM regardless of the MV strategy used; therefore, personalized
guidelines recommend using ECMO in specialized centers with MV is a promising therapeutic approach in ARDS.
strict adherence to the EOLIA management strategy [2].
6. Expert opinion
Personalized medicine is a new concept focusing on treatment
4. Other considerations: heart–lung interaction
tailored to the individual characteristics of patients and the
The hemodynamic effects of mechanical ventilation in patients pattern of lung disease. This concept has been adopted
with ARDS can be summarized as follows: (1) after starting recently in the mechanical ventilation field; personalization
mechanical ventilatory assistance, O2 supply can increase of ventilator parameters aims to prevent overdistention,
because the work of breathing is less than that during spon­ inflammation, damage of extracellular matrix, and lung injury.
taneous breathing; (2) changes in lung volume can alter the Thus, one patient could benefit more from lower VT and lower
autonomic tone, pulmonary vascular resistances, and the com­ PEEP than another. It is important to better understand each
pression of the heart in the cardiac fossa at high lung volumes patient’s lung condition to modify the standardized ventila­
[140]. The increased lung volume leads to an increased differ­ tion settings appropriately to reduce VILI and promote
ence between airway and pleural pressures that, when pul­ a better outcome.
monary artery pressure is overcome, pulmonary vessels To date, current recommended lung protective mechanical
collapse, and pulmonary vascular resistances increase. Right ventilation strategies include the use of low VT (4–6 mL/kg
ventricular ejection is hampered by hyperinflation because it PBW), which can be increased to 8 mL/kg PBW according to
increases pulmonary vascular resistance. Alveolar collapse the patient’s condition; PPLAT <27 cmH2O; ΔP < 13 cmH2O;
caused by decreased end-expiratory lung volume increases PEEP individualized according to hemodynamic status, oxyge­
pulmonary vasomotor tone via hypoxic pulmonary vasocon­ nation, and clinical response; and MP maintained as low as
striction. Pulmonary artery pressure can be lowered via recruit­ possible, at least within the safe threshold of 17 J/min. In the
ment maneuvers that restore alveolar oxygenation without next future, automated systems and artificial intelligence may
overdistention [141]. However, if lung-protective mechanical enable better selection of these variables.
ventilation or lower PEEP levels are applied, the effects of Current guidelines do not provide detailed recommenda­
overinflation on pulmonary vascular resistances are mitigated. tions on the use of ventilator modes that allow sponta­
The delivery of positive pleural pressure can create more neous breathing instead of controlled mechanical
zones 1 and 2 of West, altering blood flow to zone 3 and ventilation. Preclinical and clinical studies suggest that
increasing both resistance and right ventricle afterload [142]. a mechanical ventilation strategy allowing spontaneous
This may lead to increased dead space ventilation and shunt breathing led to reduced inflammation, ICU length of stay,
[143]. The increased pulmonary arterial pressure seen in ARDS and mortality. These new modes of assisted mechanical
is usually independent of mechanical ventilation, increasing ventilation are under investigation. Among them, APRV
right ventricle afterload because of hypoxic vasoconstriction seems to be promising compared with conventional
 EXPERT REVIEW OF MEDICAL DEVICES 9

modes of lung protective ventilation, leading to improve­ Acknowledgments

ments in oxygenation, compliance, and shorter ICU length
The authors would like to express their gratitude to Moira Elizabeth
of stay. However, during assisted ventilation, when the Shottler and Lorna O’Brien (authorserv.com) for editing assistance.
patient’s respiratory effort is increased, excessive transpul­
monary pressure may result in overdistension and inhomo­
geneous distribution of transpulmonary pressure variations ORCID
across the lung, which yields cyclic opening/closing of non­ Lorenzo Ball http://orcid.org/0000-0002-3876-4730
dependent regions and pendelluft, as well as an increase in Patricia R. M. Rocco http://orcid.org/0000-0003-1412-7136
the transvascular pressure, thus worsening pulmonary
edema. Moreover, patient-ventilator asynchronies can also
increase the risk of VILI. Two ongoing trials (the BIRDs and
the PreSpon) may clarify the role of APRV in patients with References
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