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97]

Review Article

Strategies to Prevent Ventilator‑associated Lung Injury in

Critically Ill Patients
Alex Joseph1, Muhammad Faisal Khan2, Rajkumar Rajendram3,4
1
Department of Anaesthesia and Surgical Intensive Care, Changi General Hospital, Simei, Singapore, 2Department of Anaesthesiology, Aga Khan University, Karachi,
Pakistan, 3Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia, 4Department of Anaesthesia and
Intensive Care, Stoke Mandeville Hospital, Aylesbury, UK

Abstract
Life‑saving mechanical ventilation (MV) induces or exacerbates a range of pulmonary pathologies, collectively known as ventilator‑induced
lung injury if there is evidence of direct causation (i.e., in the research laboratory). However, in clinical practice, the term ventilator‑associated
lung injury (VALI) is more appropriate. While several factors are involved, the main drivers of the pathogenesis are regional overdistention and
clinical atelectasis. This understanding has led to search for strategies to attenuate VALI and improve survival. The current approaches focus
on reduction of lung stress and strain by limitation of alveolar–plateau pressure and tidal volume. Recent data suggest that control of driving
pressure (plateau pressure–positive end‑expiratory pressure) and mechanical power applied during ventilation may also be beneficial. More
exciting are the various new techniques for MV (e.g., airway pressure release ventilation and neurally adjusted ventilatory assist), emerging
alternative modalities for gas exchange (e.g., extracorporeal membrane oxygenation), and novel biological therapies (e.g., anti‑inflammatory
stem cells) that promise to revolutionize the management of respiratory failure and relegate VALI to the ash heap of history. However, there
are currently insufficient data to recommend their use in routine clinical practice.

Keywords: Acute respiratory distress syndrome, ventilator, ventilator‑associated lung injury, ventilator‑induced lung injury

Introduction compromise. [2] However, MV also causes more subtle

injuries.[2,3] This more subtle VALI manifests microscopically
Mechanical ventilation (MV) enables oxygenation and
as increased vascular permeability, inflammatory infiltrates,
clearance of carbon dioxide in critically ill patients who require
alveolar hemorrhage, hyaline membrane formation, surfactant
advanced respiratory support. There is no doubt that MV is
dysfunction, interstitial and alveolar edema, and alveolar
life‑saving in this context. Unfortunately, the application of MV
collapse.[3]
can induce or exacerbate a range of pulmonary pathologies.
If it can be proved that this damage was directly induced by At the beginning of this century, the clinical significance
MV alone, then it is ventilator‑induced lung injury (VILI). of VALI was confirmed by the publication of the Acute
However, outside of the research laboratory, it is virtually Respiratory Distress Syndrome (ARDS) Network’s trial of
impossible to prove direct causation. In clinical practice, it is protective ventilation strategies in ARDS.[4] This showed that
more appropriate to use the term ventilator‑associated lung MV can itself exacerbate pulmonary injury.[4] This landmark
injury (VALI).[1] Hence, in this review of clinical strategies to trial also demonstrated that ventilation with high tidal
prevent this type of lung injury, the term “VILI” will be used volumes (VT) increases mortality in ARDS in comparison to
when experimental data or pathophysiology are described, lung protective ventilation. However, VALI also develops in
but when clinical management is discussed, the term “VALI”
will be used instead. Address for correspondence: Dr. Rajkumar Rajendram,
Department of Anaesthesia and Intensive Care,
The pathogenesis of VILI is multifactorial and includes Stoke Mandeville Hospital, Aylesbury, Buckinghamshire, UK.
clinically apparent side effects of MV such as gross E-mail: rajkumarrajendram@doctors.org.uk
barotrauma (e.g., pneumothorax) and hemodynamic
This is an open access article distributed under the terms of the Creative Commons
Access this article online Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak,
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DOI: How to cite this article: Joseph A, Khan MF, Rajendram R. Strategies to
10.4103/ijrc.ijrc_6_17 prevent ventilator-associated lung injury in critically ill patients. Indian J
Respir Care 2018;7:4-13.

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Rajendram, et al.: Prevention of ventilator‑associated lung injury

nearly a quarter of patients who receive MV for indications Pulmonary edema also develops in animals ventilated with
other than ARDS.[5] high VT, unless abdominal and chest binders are used to limit
VT.[7] Hence, lung distention (i.e., strain) is more damaging
The clinical presentation of VALI is indistinguishable from
than airway pressure (stress). However, stress‑induced and
progressive ARDS. However, in practice, the management of
strain‑induced lung injuries (i.e., barotrauma and volutrauma,
VALI and ARDS is the same. This review discusses various
respectively) are clearly interrelated.
clinical strategies to prevent VALI. To understand the rationale
behind these strategies, it is important to understand the The relationship between barotrauma and volutrauma
pathogenesis of VALI. The pressure required to inflate lungs includes as follows:
1. Pressure needed to overcome airway resistance and
Pathogenesis of Ventilator‑associated Lung inertia (i.e., for gas flow)
2. Pressure needed to overcome pulmonary elastance.
Injury
There are four main mechanisms involved in the pathogenesis The force distending the lung is not the peak airway pressure,
of VALI. but the TPP (i.e., alveolar pressure–pleural pressure). The
1. Barotrauma lung is deformed above its resting volume (strain) by the
2. Volutrauma difference between the alveolar pressure and the pleural
3. Atelectrauma pressure (stress).[8] Thus, barotrauma and volutrauma are two
4. Biotrauma. faces of the same VALI. Barotrauma reflects excessive stress
while volutrauma reflects excessive strain (overdistention).
Several other factors (e.g., body temperature, respiratory rate,
and acidemia) are involved in the pathogenesis of VALI but The ratio of change in lung volume to the pulmonary volume
are less important than these. at rest is used to estimate lung strain. In experimental models,
VILI develops when alveoli are exposed to a lung strain >2. In
Barotrauma healthy animals, this requires delivery of VT over 20 ml/kg.[8,9]
The effects of excessive transpulmonary pressure
However, smaller lung volumes are under more strain during
(TPP; lung stress) were recognized soon after MV was
any given change (i.e., inspiration/inflation). At low pulmonary
first used. Therapeutic targets were normal blood gases,
volumes, MV may induce harm by regional amplification of
prevention of dyssynchrony, and avoidance of muscle
these forces.[10,11] Although alveolar overdistention cannot
relaxants.[2‑5] Consequently, VT and respiratory rates were
be measured, reducing inflation pressure should minimize
typically high (e.g., 12 ml/kg and 20 breaths/min).[2‑5] Although
regional overdistention.
most patients “tolerated” the ventilator, gross barotrauma was
common. The term “barotrauma” was used to describe the Lung volume, TPP, alveolar distention, and VALI are clearly
clinically recognizable problems of macroscopic gas escape: interrelated. Although alveolar overdistention cannot be
pneumothorax, pneumomediastinum, interstitial emphysema, measured, reducing inflation pressure should minimize
and gas embolism.[3] However, barotrauma also includes more regional overdistention. However, there are several limitations
subtle forms of VALI induced by high airway pressures. to the measurement of pulmonary pressures in routine
clinical practice. Pleural pressure can only be estimated in
Volutrauma
mechanically ventilated patients by the measurement of
Ventilation at high (absolute) lung volume (i.e., overdistension;
esophageal pressure.[12] Not only is this measurement complex,
strain) can rupture alveoli, resulting in air leaks and
difficult, and inaccurate, but because pleural pressure has a
gross barotrauma (e.g., pneumomediastinum).[3] Regional
gravitational gradient, it also varies throughout the lung.
overdistention may occur despite ventilation at low (absolute)
lung volumes. This causes more subtle VALI that manifests In contrast, alveolar pressure can be estimated easily. For
as pulmonary edema. As regional overdistention of alveoli is example, TPP maintains inflation during a period of zero
far more relevant to VALI than excessive airway pressures, flow (e.g., at end inspiration) in mechanically ventilated
the description of VALI as “barotrauma” can be confusing. patients who are not making any spontaneous respiratory
effort. Although the alveolar plateau pressure can easily be
The relevance of pulmonary regional overdistention has
measured at end inspiration, calculation of TPP also requires
been demonstrated in rodents.[6] Hypoxemia and pulmonary
the pleural pressure.
edema develop when regional overdistention is induced. Such
regional overdistention occurs if MV is applied with extremely Hence, alveolar–plateau pressure is usually considered in
high peak airway pressures without positive end‑expiratory isolation. However, if the patient does not make any effort
pressure (PEEP). However, regional overdistention and to breathe, the plateau pressure inflates the chest wall as well
pulmonary edema can be prevented by the addition of 10 cm as the lungs. If the chest wall is stiff (e.g., due to obesity,
H2O PEEP to the same peak airway pressure. Hence, VALI large pleural effusions, or ascites), inflation of the chest wall
from overdistention is worse at low end‑expiratory lung requires significant power and dissipates a large proportion
volumes. The mechanics of this relationship remain unclear. of this pressure. Thus, in a mechanically ventilated patient

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Rajendram, et al.: Prevention of ventilator‑associated lung injury

who is not making any spontaneous respiratory effort, a high parenchymal homogeneity, and regional differences in lung
plateau pressure may not indicate high TPP (i.e., excessive stress or strain. Once these challenges are overcome, it is
pulmonary stretch). However, during noninvasive ventilation, certainly plausible that a threshold of MV power could direct
a distressed patient can generate very large negative pleural the delivery of respiratory support.
pressures. These patients may have very high TPP, despite
having low airway pressures. Hence, the focus of prevention
Tidal atelectasis and atelectrauma
Ventilation at low (absolute) lung volumes can cause tidal
of VALI has recently shifted from plateau pressure to driving
atelectasis and thereby result in “atelectrauma.” This is due
pressure (i.e., plateau pressure minus PEEP).
to frequent collapse and re‑opening of alveoli,[16] effects on
Driving pressure surfactant,[17] and regional hypoxia. This atelectrauma amplifies
Amato et al. found that reduction in MV driving pressure was the pulmonary damage caused by the initial injury. It manifests
an independent variable (mediator) associated with better as a mosaic‑like pattern of collapsed and edematous alveoli
survival in their landmark retrospective multilevel “causal” interspersed with “normal,” open alveoli. This disorganization
mediation analysis of studies on ARDS.[13] Both allocations concentrates stressors at the borders between aerated and
to the intervention (i.e., randomization to the lower VT group) atelectatic regions. At these points, the stress and strain on
and lower driving pressure were associated with significantly lung parenchyma are up to 4–5 times higher than in other lung
better survival. However, when analyzed together, only the regions.[10] Atelectrauma is further increased if ventilation is
reduction in driving pressure was independently associated heterogeneous.
with lower mortality.[13]
The transition from a normal homogenously ventilated
While clearly thought‑provoking, these data cannot be used lung into a collection of heterogeneously ventilated alveoli
to recommend that MV should be titrated to target low clearly exacerbates VALI. Hence, the delivery of MV should
driving pressures. Even Amato et al. acknowledge that the aim to restore or maintain homogeneous gas flow and limit
evidence is indirect and does not establish a direct causal atelectrauma by maintaining adequate lung volumes.
link between a specific driving pressure and outcome.[13]
Biotrauma
Furthermore, driving pressure is mathematically coupled
Exposure to MV (i.e., regional overdistention) triggers the
with VT and elastance (driving pressure = VT × elastance) and
release of a pantheon of inflammatory mediators within
compliance (driving pressure = VT/compliance). Hence, the
the lungs. These mediators are both pro‑inflammatory and
influence of driving pressure on outcome may be confounded
anti‑inflammatory. Their release results in self‑propagating
by differences in elastance (severity of the disease) or
“biotrauma” because these mediators may then damage
VT (degree of strain).[14,15] Change in elastance or compliance
lung directly, initiate pulmonary fibrosis, or recruit cells
indicates a change in pulmonary mechanics, which is of far
such as neutrophils into lung tissue which then release more
greater significance than the choice of a specific value of
inflammatory mediators.[18]
driving pressure.[15] Furthermore, the focus on driving pressure
alone ignores the role of PEEP in VALI. A theoretically “safe” The physical stress of MV may cause the release of these
driving pressure can still induce VALI if delivered with a PEEP mediators either:
that was set either too high or too low.[15,16] 1. Directly releasing mediators from damaged cells
2. Indirectly by activating cell‑signaling pathways
Mechanical power (mechanotransduction).
A series of laboratory experiments found that application
of MV with a pulmonary strain that should be lethal to Direct cellular trauma
healthy animals (i.e., above 2) only actually resulted in Direct damage from the physical stress of MV to the cell
death if delivered at 15 breaths/min.[15] Application of this disrupts cell walls. Deformation of alveolar cells by mechanical
level of pulmonary strain was not fatal if delivered at rates forces results in direct damage and structural changes to cell
of 3–6/min.[15] The VILI was more closely related to tidal membrane molecules. This activates downstream messenger
strain and rate of gas flow than to pulmonary strain at rest systems. Hence, alveolar overinflation induces cellular
(i.e., static strain).[15] Given these data, the cause of VILI could proliferation and inflammation. As a consequence, cytokines
be described by the mechanical power applied during MV; a are released into the alveoli, pulmonary circulation, and even
single physical entity which combines volume, pressures, and the systemic circulation.[18]
flow and respiratory rate.[15]
Mechanotransduction
However, the clinical relevance of targeting mechanical power Most lung cells produce and release cytokines in response to
during MV lacks direct evidence of improved outcomes in cyclical stretching and relaxation in vitro.[19] In vivo animal
humans.[15] The same MV power could have very different models have identified several genes that are either up‑ or
consequences when applied to damaged lungs rather than down‑regulated when pulmonary tissues are exposed to MV.
healthy lungs. [15] It is therefore important to be able to These include genes that are involved with many complex
standardize MV power for an individual patient taking into pathways including immunity and inflammation, metabolism,
consideration the size of their lungs, degree of pulmonary and gene transcription.[20] However, the processes by which

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Rajendram, et al.: Prevention of ventilator‑associated lung injury

these physical forces are detected and transduced into signals Several studies have evaluated the effect of various approaches
that regulate this plethora of intracellular pathways are unclear. to limit alveolar distention and cyclic atelectasis in patients
receiving MV for ARDS.[24]
These mediators obviously affect local tissue healing and
injury. However, interestingly, these mediators can also initiate Various approaches to MV are used to minimize pulmonary
or propagate a profound generalized systemic response that damage in patients with ARDS:
causes multiorgan dysfunction or failure. 1. Delivering low VT and while maintaining a low plateau
pressure to prevent overdistention. This is often referred
MODS as a result of VALI to as “lung protective ventilation”
Although multiorgan dysfunction syndrome (MODS) 2. High PEEP to reduce cyclical atelectasis
commonly coexists with ARDS and VALI, it is unclear how 3. Recruitment maneuvers
these biotraumatic mediators affect distal organs. More 4. Open lung approach to MV
importantly, clinical trials of protective ventilation strategies 5. Airway pressure release ventilation (APRV)
have demonstrated that this intervention reduces serum 6. High‑frequency oscillatory ventilation (HFOV).
cytokines, [21] extrapulmonary organ dysfunction, [21] and
mortality in patients with ARDS.[4] These interventions have varying degrees of data from human
studies on their use in patients with ARDS. For example,
The systemic release of inflammatory mediators,[21] bacteria, or ARDS Network ventilation which combines low VT, limitation
lipopolysaccharide[22] from the alveoli may occur in the lungs of plateau pressure under 30 cm H2O, and titration of PEEP
of patients with increased alveolar–capillary permeability. to FiO2 improves mortality such that only 11 patients had to
The pathogenesis of ARDS is fundamentally dependent on be treated to prevent one death (i.e., the number needed to
increased permeability of the alveolar–capillary interface. The treat [NNT] was 11).[4]
permeability of this interface is also increased by volutrauma
induced by MV. The systemic release of mediators facilitated Yet, few trials have examined these interventions in patients
by this increase in permeability may precipitate MODS and who do not have ARDS. However, while the data from clinical
death. trials help intensivists make difficult decisions, the literature
will never fully address the complexity of many clinical
Hence, VALI reflects the endpoint of volutrauma, barotrauma, situations. Hence, because these strategies are considered
atelectrauma, and biotrauma. The primary injury induced by safe, they are often also used in patients who require MV but
MV (i.e., volutrauma, barotrauma, and atelectrauma) results in do not have ARDS.
the release of inflammatory mediators. This results in both local
and systemic effects which can have profound consequences. It is important to highlight that the ventilation strategies listed
The recognition of the significance of VALI transformed the above deliberately excludes references to driving pressure
approach to MV in routine clinical practice. and mechanical power. This is because driving pressure
mathematically correlates with VT, elastance, compliance, and
plateau pressure.[13‑15] Hence, when plateau pressure, VT, and
Prevention PEEP are set for a protective ventilation strategy, limitation
The focus on VALI has distracted clinicians from the management of driving pressure per se does not confer any additional
of many other stressors which cause alveolar overdistention and benefit.[14,15] Similarly, while limitation of mechanical power
cyclical atelectasis. For example, marked increases in minute applied during ventilation may also be beneficial, there is
ventilation also result in alveolar overdistention. Increasing currently insufficient evidence to advocate this.
minute ventilation by injecting sodium salicylate into the
Preventing alveolar overdistention with low tidal volume
cisterna magna of sheep breathing spontaneously induces
changes similar to VILI and hypoxemia.[23] This was prevented mechanical ventilation and limitation of plateau pressure
by controlling ventilation to limit lung stretch. Low tidal volume ventilation
Lung regions that are dependent, i.e., lower in terms of their
Thus, the focus of clinical strategies to prevent worsening gravitational position (e.g., lower lobes in the supine patient),
of lung injury in patients requiring MV should be on the are more likely to collapse. Hence, in patients receiving MV,
reduction of alveolar overdistention and cyclical atelectasis. dependent lung is often less well aerated than the nondependent
The reduction of this primary insult should reduce secondary lung regions. Hence, a smaller volume is available for
biotrauma. ventilation.[25]
Alveolar overdistention is limited by delivering small VT,
Clinical Practice maintaining a low plateau pressure, and using pressure‑limited
The current strategies to prevent VALI include lung protective ventilation. The advantages of this MV strategy in ARDS
ventilation strategies, adjunctive strategies (e.g., prone were confirmed by the landmark randomized controlled trial
positioning, nitric oxide), and extracorporeal gas exchange conducted by the ARDS Network investigators who compared
(to avoid invasive MV) or a combination of these. These a high VT (12 ml/kg predicted body weight) with a low VT MV
strategies are described below. strategy (6 ml/kg).[4] The low VT MV strategy reduced mortality

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Rajendram, et al.: Prevention of ventilator‑associated lung injury

by 9% (12 ml/kg, 39.8%; 6 ml/kg, 31.0%). This is referred to a threshold variable but rather a continuous variable. This may
as low VT ventilation. be because lower plateau airway pressures are associated with
less alveolar distension. Hence, lower the plateau pressure,
The optimal VT for patients without ARDS who require MV
the better. Pressure‑limited ventilation (e.g., pressure control)
is not known. However, some studies suggest that MV using
reduces alveolar overdistention by ensuring that airway
low VT may also benefit patients without ARDS.[26] In one
pressure does not rise above the set limit.[32]
randomized clinical trial (RCT) of intraoperative MV which
compared 6–8 ml/kg ideal body weight (IBW) (i.e., low VT) However, limiting plateau pressure to 30 cm H2O may be too
with 10–12 ml/kg IBW (i.e., high VT), patients who received low in some cases. If the chest wall is very stiff (e.g., because
6–8 ml/kg IBW had fewer pulmonary complications of large pleural effusions or ascites), overdistention of the
(e.g., pneumonia), extrapulmonary complications (e.g., sepsis), alveoli may not occur even at plateau pressures well above
and reintubations than those receiving higher VT.[23,24] There 30 cm H2O. If a patient with a stiff chest wall is hypoxemic,
was no difference in the development of ARDS or death. the use of higher plateau pressures should be considered.
However, the study was not sufficiently powered to detect this. However, there is no literature to guide ventilator settings in
these situations. In these situations, intensivists must apply
One meta‑analysis (15 RCT and 5 observational studies)
physiological principles alongside the data available from
reported that patients receiving MV with V T around
6 ml/kg IBW had less risk of VALI (risk ratio [RR] 0.33, trials.
95% confidence interval [CI] 0.23–0.47) and death (RR 0.64,
95% CI 0.46–0.89) than those ventilated with higher VT.[27] Methods to Prevent Cyclic Atelectasis
Another meta‑analysis (7 studies) found that fewer patients The use of positive end‑expiratory pressure to prevent
on low VT ventilation (≤7 ml/kg) progressed to ARDS, cyclic atelectasis
developed pneumonia, or died than patients receiving higher The use of sufficient PEEP to prevent de‑recruitment at
VT (>7 ml/kg).[28] However, both analyses were limited by end‑expiration should reduce atelectrauma. Pulmonary edema
the methodological flaws of the RCT and the inclusion of and end‑expiratory alveolar collapse are involved in the
observational data. pathogenesis of several causes of respiratory failure. The use
However, as regional hyperinflation can still occur with VT of PEEP splints alveoli open and reduces cyclic atelectasis.
around 6 ml/kg IBW, it may be better to use lower VT,[6] However, higher PEEP may have adverse effects (e.g., reduced
despite plateau pressures already below 30 cm H2O.[7] Low venous return and pulmonary overdistention).
VT ventilation often results in hypercapnea.[22] In the absence Higher levels of PEEP are protective in animal models of
of raised intracranial pressure or right heart failure, PaCO2 ARDS, but human data are inconsistent.[31] The failure of
up to 70 mmHg with pH >7.2 are safe[29] and may even be these in studies in humans to demonstrate beneficial effects
beneficial. The rationale for permissive hypercapnea includes from the application of PEEP may be because MV was not
the beneficial effects of acidosis on tissue oxygenation
tailored to the specific characteristics of a patient’s lungs.
(i.e., right shift in hemoglobin oxygen dissociation, increase
Most of these clinical trials used a fixed protocol to select
in cardiac output, and potentiation of hypoxic pulmonary
PEEP. Most PEEP titration protocols used airway pressure
vasoconstriction). [29] However, unfortunately, low V T
and gas exchange parameters to select PEEP but do not take
ventilation is sometimes difficult to achieve without increased
pleural pressure or lung recruitability into consideration. The
sedation or neuromuscular blockade, which have other risks.[30]
failure to consider the characteristics of a patient’s lungs when
Hence, large RCT is required to extend the use of low VT selecting PEEP may result in selection of an inappropriate
ventilation to all patients receiving MV. Until such data are level of PEEP. Underapplication or overapplication of PEEP
available, based upon extrapolation from the limited data that can both predispose to VALI.
are currently available, a VT of 6–8 ml/kg IBW is reasonable
A recent meta‑analysis considered these conflicts in the
to use as a starting point for MV in patients with and without
management of ARDS.[32] This reported that an absolute
ARDS.
reduction of 5% in the mortality of moderate and severe
Plateau pressure limitation ARDS (PaO2:FiO2 under 200 mmHg) was associated with
Several studies have investigated plateau pressure in patients higher PEEP.[31] However, an optimal PEEP has not been
with ARDS receiving MV. Although no absolute preferred established.
plateau pressure has been identified, mortality is improved when
The myth of “optimal” positive end‑expiratory pressure
plateau pressures during MV are maintained below 30 cm H2O.
The aim of the application of PEEP is to improve oxygenation
[4]
One observational study of 30 patients with ARDS receiving
and facilitate open‑lung ventilation (i.e., minimize cyclical
MV suggested that if the amount of nonaerated lung is large, it
atelectasis). However, there is no such thing as an “optimal”
may be better to maintain plateau pressure under 28 cm H2O.[31]
PEEP, so there is no optimal method to determine this mythical
Although there are no studies in patients without ARDS, these value of PEEP. However, at some point, MV parameters must
data suggest that, in the context of VALI, plateau pressure is not be set. Hence, the PEEP setting is said to be optimal when:

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1. Oxygenation is best alveoli open and reduces cyclical atelectasis. However, this
2. There is minimal end‑expiratory atelectasis (i.e., maximal strategy alone does not improve clinically relevant outcomes
end‑expiratory recruitment) and the appropriate amount of PEEP to apply is difficult to
3. There is minimal end‑inspiratory overdistention. determine because to plot the MV pressure–volume curve
accurately usually requires neuromuscular blockade.
Several methods are used to select PEEP in routine clinical
practice [Table 1]. Some aim to optimize oxygenation as their Recruitment maneuvers
primary goal, while others prioritize lung protection. Atelectasis occurs as a result of de‑recruitment which may
Role of esophageal pressure monitoring in setting positive itself reflect low VT ventilation, inadequate PEEP, or absorption
atelectasis after administration of high inspired concentrations
end‑expiratory pressure
of oxygen. Recruitment maneuvers involve delivery of a high
When setting MV, TPP (alveolar pressure–pleural pressure)
airway pressure (i.e., >35 cm H20) for at least 40–60 s. These
should be considered. However, pleural pressure cannot be
maneuvers aim to reinflate atelectatic lung and minimize
measured directly. Esophageal pressure is a surrogate for
ventilation heterogeneity.
pleural pressure and can be measured by esophageal balloon
manometry. However, interpretation is difficult because of Recruitment maneuvers should reduce VALI and have been
artifacts from cardiac contraction, gravitational pleural pressure studied.[33,34] However, their role in clinical practice remains
gradient, and distortion and contraction of the esophagus.[12] uncertain. This is primarily because there is no evidence that
Despite these limitations, use of esophageal manometry has lung recruitment improves outcomes. Furthermore, there
been studied in a pilot study involving patients with ARDS.[12] are valid concerns regarding the potential complications
In this study, PEEP was adjusted to keep TPP under 10 cm H2O at of sustained high airway pressures (e.g., cardiovascular
end‑expiration. End‑inspiratory TPP was limited to 25 cm H2O. compromise and air leaks).[34]
Oxygenation improved. There was also a nonsignificant trend Open lung ventilation
toward lower 28‑day mortality. However, this small pilot study Open lung ventilation combines delivery of small VT with the
was not adequately powered to detect a mortality benefit. While application of PEEP above the low inflection point on the MV
tantalizing, a larger trial confirming that this strategy improves pressure–volume curve and recruitment maneuvers. Several
clinically important outcomes is needed before the use of TPP studies have suggested improved oxygenation, reduced need
to guide MV can be recommended in routine clinical practice. for rescue therapies and more ventilator‑free days using this
Independent of TPP, the beneficial effects of high levels approach.[35] However, a recent international multicenter RCT
PEEP around 15 cm H2O appear to outweigh the potentially of 1013 patients with moderate‑to‑severe ARDS reported that
detrimental effects due to alveolar strain, particularly if there 28‑day all‑cause mortality was increased by a high PEEP
is recruitable lung volume.[4] open lung MV strategy (55.3%) in comparison to a low
PEEP ARDSNet MV strategy (49.3%).[35] Hence, while some
Clinicians often set PEEP above the lower inflection point of subgroups may benefit from open lung MV with recruitment
the patient’s MV pressure–volume curve. This should splint maneuvers, the evidence of benefit is weak, and there a clear
risk of harm in comparison to ARDS Network MV.

Table 1: Methods used to set positive end‑expiratory Airway pressure release ventilation
pressure APRV is pressure‑controlled, intermittent mandatory MV
Set arbitrarily high PEEP (15-20 cm H2O; CT studies support use of a
with an extreme inverse ratio that allows spontaneous
PEEP of around 16 cm H2O) breathing throughout the respiratory cycle. This mode of
Set PEEP according to oxygen requirement (e.g., use the ARDSNet MV is based on open lung MV. A high continuous‑positive
PEEP/FiO2 titration protocol) airway pressure (CPAP) is delivered for a prolonged period
Set PEEP to avoid cyclic atelectasis (above the lower inflection point of (e.g., 4.5–6 s) to recruit lung and is only released briefly
the pressure–volume curve)
(e.g., 0.5–0.8 s) to zero PEEP to allow ventilation without
Set PEEP during a staircase recruitment maneuver
de‑recruitment.[36] As the prevention of VALI focuses on
To provide the highest static compliance
“opening the lung and keeping it open,” this is a conceptually
To maintain best oxygenation (i.e., best SpO2)
ideal mode of ventilation.[36]
To maintain least VT dead space (i.e., lowest arterial minus end‑tidal
CO2 gradient) Ventilator manufacturers have caused significant confusion
To maintain lowest intrapulmonary shunt (i.e., highest SvO2) about MV by developing several different terminologies
Set PEEP to provide the greatest amount of aerated lung
for similar modes. This is particularly relevant for APRV
Using electrical impedance tomography
which has not been clearly or consistently defined. Indeed, a
Using sequential CT scans to see lung volume at end‑expiration
significantly underinvestigated aspect of VALI is the influence
Set PEEP, so transpulmonary pressure is 0-10 at end‑expiration (requires
esophageal manometry) of the brand and model of ventilator. Each ventilator has a
PEEP: Positive end‑expiratory pressure, ARDS: Acute respiratory distress unique specification. The resistances built into the MV gas
syndrome, CT: Computed tomography flow circuit, the responses to spontaneous ventilation, and the

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Rajendram, et al.: Prevention of ventilator‑associated lung injury

software which differ between brands and models of ventilator On NAVA, innate reflexes limit VT if lungs are overstretched. This
all influence the delivery of each breath. Further research is allows patients to “regulate” their delivered VT. Hence, NAVA
therefore urgently required to evaluate the effect of the model can prevent overdistention and limit VALI, unload the muscles of
of ventilator on VALI. respiration while improving tolerance of the ventilator.[43,44] To the
degree that self‑regulating ventilatory defense mechanisms can
More problematic than the different terminology that ventilator
prevent lung overinflation, NAVA may improve patient outcomes
manufacturer’s use for similar modes of ventilation is the wide
by tailoring delivery of MV breath by breath.[45]
variation in their delivery of these modes. As a result, the MV
settings used by researchers and clinicians vary significantly. This mode of MV was studied in rabbits with ARDS induced
One APRV variant, P‑APRV recruits alveoli homogeneously by administration of hydrochloric acid. The rabbits were
during a 90% CPAP phase that inflates the lung.[37] This is randomized to one of the three groups. They received NAVA
followed by a brief release phase personalized to the patient’s or volume‑controlled MV with either high (15 ml/kg) or
lung mechanics. This results in an almost static yet ventilated conventional (6 ml/kg) VT.[45] This study demonstrated that
lung. Cyclical atelectasis is minimized and thereby dynamic NAVA and standard low V T ventilation provide similar
tissue strain is reduced.[36] lung protection. However, whether the protective feedback
mechanism observed in rabbits is relevant to severe respiratory
A meta‑analysis reported that the incidence of ARDS was reduced failure in humans is unclear. Hence, these data require
by a factor of 10 and mortality was reduced by a factor of three confirmation by randomized controlled clinical trials in humans
in trauma patients treated with this mode of MV (P‑APRV) in before use in routine practice can be recommended.
comparison to trauma patients with similar injuries treated with
standard ventilation.[37] Of all the currently available literature, Mechanical ventilation in the prone position
only this study[37] has reported the precise P‑APRV settings that Oxygenation increases in about 70% of hypoxemic patients
were used. Despite showing promise, all of the human data with ARDS when MV is delivered in a prone position.[46]
on P‑APRV are retrospective, so a large RCT demonstrating Reasons for this include increased end‑expiratory lung volume,
improvement in clinical outcomes is necessary before any form reduced compression of the lower lobes by the heart and
of APRV can be recommended in routine practice. improved regional ventilation.[46] The net result of these
changes is better ventilation–perfusion matching. The delivery
High‑frequency oscillatory ventilation of MV in the prone position should also limit VALI by
HFOV delivers tiny VT (less VT than the anatomical dead space) decreasing pulmonary heterogeneity.[47,48]
at frequencies up to 15/s. A meta‑analysis (eight trials
It is important to note that proning is not without risk. Patients
involving 419 adults with ARDS)[38] reported that mortality
who are “proned” have more complications, including
was significantly lower in those treated with HFOV than
pressure ulcers, endotracheal tube obstruction, and chest tube
those treated with standard MV. However, in two recent large
dislodgment. However, these complications are potentially
multicenter trials (OSCAR and OSCILLATE), use of HFOV
preventable. Hence, despite these adverse events, prone
did not benefit patients with ARDS.[39,40] Hence, HFOV should
positioning has been shown to significantly reduce absolute
not be used in patients with ARDS. Furthermore, it has not
mortality in patients with severe ARDS.[49] In a recent trial of
been studied in patients without ARDS.
proning in patients with moderate and severe ARDS, 28‑day
Physiological strategies to minimize ventilator‑associated mortality was significantly higher (32.8%) in those treated
lung injury supine than in those who were proned (16.0%).[50] The absolute
Neurally adjusted ventilatory assist reduction in mortality with proning was 16%, so the NNT to
Inspiratory diaphragmatic electrical activity (EAdi) reflects prevent one death was remarkably only 6.2. Prone positioning
feedback loops travelling via the vagus nerve that collate data is therefore an important intervention that should be strongly
from pulmonary mechanoreceptors (which detect stretch) and considered in patients with refractory hypoxia.
chemoreceptors.[41] In patients receiving MV EAdi increases Partial or total extracorporeal support
if the VT delivered by MV is less than the patient’s respiratory An innovative approach is to avoid MV using extracorporeal
requirement. The EAdi decreases if the VT delivered is more membrane oxygenation (ECMO) or carbon dioxide removal.[51]
than the patient’s respiratory requirement. If MV is combined with partial extracorporeal support, the MV
Neurally adjusted ventilatory assist (NAVA) delivers MV required to provide adequate oxygenation and carbon dioxide
pressure support in proportion to EAdi. A specific nasogastric removal is reduced by that provided by the extracorporeal
tube measures EAdi and the intensivist sets the proportion circuit.[52] This hybrid approach has fewer complications than
on the ventilator. When respiratory demand is satisfied, full ECMO and reduces VALI as VT can be reduced.
VT is stable despite increases in the support proportion.[42] Some (predominantly observational) data support this
This synchronized breath‑by‑breath support in proportion management strategy.[53,54] However, further randomized data
to respiratory demand is particularly beneficial if work of are necessary to determine which patients require extracorporeal
breathing is increased and/or respiratory muscles are weak. support and indeed when and which technique to use.

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Rajendram, et al.: Prevention of ventilator‑associated lung injury

Sedation, neuromuscular blocking agents, and control Conflicts of interest

of fever There are no conflicts of interest.
The main purpose of MV is to allow gas exchange
(i.e., oxygenation and clearance of CO2). A nonspecific References
approach to limit VALI is to reduce patients’ metabolic 1. International consensus conferences in intensive care medicine:
demands (e.g., by sedation, neuromuscular blockade [NMB], Ventilator‑associated lung injury in ARDS. This official conference
and prevention of fever) and thereby the required minute report was cosponsored by the American thoracic society, the European
Society of Intensive Care Medicine, and the Societé de Réanimation de
ventilation for gas exchange. Langue Française, and was approved by the ATS board of directors, July
1999. Am J Respir Crit Care Med 1999;160:2118‑24.
Ventilator synchrony and metabolic demands are improved by
2. Nash G, Blennerhassett J, Pontoppidan H. Pulmonary lesions
NMB. This allows reduction of VT and pressure. In an animal associated with oxygen therapy and artificial ventilation. Laval Med
model of lung injury, spontaneous breathing improved lung 1968;39:59‑64.
recruitment if the lung injury was mild but was associated with 3. Avignon PD, Hedenstrom G, Hedman C. Pulmonary complications in
respirator patients. Acta Med Scand Suppl 1956;316:86‑90.
more cyclic atelectasis/atelectrauma and tidal hyperinflation 4. Acute Respiratory Distress Syndrome Network, Brower RG,
than NMB.[55,56] Matthay MA, Morris A, Schoenfeld D, Thompson BT, et al. Ventilation
with lower tidal volumes as compared with traditional tidal volumes for
A multicenter, placebo‑controlled, RCT reported that 90‑day acute lung injury and the acute respiratory distress syndrome. N Engl J
mortality in patients with moderate and severe ARDS was Med 2000;342:1301‑8.
reduced after NMB for 48 h.[57] Interestingly, the benefit on 5. Gajic O, Dara SI, Mendez JL, Adesanya AO, Festic E, Caples SM, et al.
Ventilator‑associated lung injury in patients without acute lung injury at
mortality was only apparent approximately 16 days after the the onset of mechanical ventilation. Crit Care Med 2004;32:1817‑24.
initiation of NMB. Serum cytokine levels are lower in patients 6. Webb HH, Tierney DF. Experimental pulmonary edema due to
receiving NMB.[58] Hence, the delayed mortality benefit seen intermittent positive pressure ventilation with high inflation pressures.
with NMB could reflect reduced biotrauma‑induced multiorgan Protection by positive end‑expiratory pressure. Am Rev Respir Dis
1974;110:556‑65.
failure.[57] Importantly, there was no increase in critical care 7. Dreyfuss D, Soler P, Basset G, Saumon G. High inflation pressure
myopathy with NMB therapy. pulmonary edema. Respective effects of high airway pressure, high
tidal volume, and positive end‑expiratory pressure. Am Rev Respir Dis
Anti‑inflammatory agents and stem cells 1988;137:1159‑64.
Anti‑inflammatory agents[58] and mesenchymal stem cells[59] 8. Chiumello D, Carlesso E, Cadringher P, Caironi P, Valenza F,
Polli F, et al. Lung stress and strain during mechanical ventilation
have been studied in VILI in laboratory studies in animals.
for acute respiratory distress syndrome. Am J Respir Crit Care Med
The main potential benefit of these agents in the prevention 2008;178:346‑55.
of VILI, over their role in other inflammatory diseases, is that 9. Protti A, Cressoni M, Santini A, Langer T, Mietto C, Febres D,
treatment could be initiated before the patient is exposed to the et al. Lung stress and strain during mechanical ventilation: Any safe
threshold? Am J Respir Crit Care Med 2011;183:1354‑62.
causative factor (i.e., before administration of MV). However, 10. Mead J, Takishima T, Leith D. Stress distribution in lungs: A model of
no reports of the use of any of these treatments in humans are pulmonary elasticity. J Appl Physiol 1970;28:596‑608.
currently available. 11. Muscedere JG, Mullen JB, Gan K, Slutsky AS. Tidal ventilation at low
airway pressures can augment lung injury. Am J Respir Crit Care Med
1994;149:1327‑34.
Conclusion 12. Zin WA, Milic‑Emili J. Esophageal pressure measurement. In: Hamid Q,
Shannon J, Martin J, editors. Physiologic Basis of Respiratory Disease.
Improved understanding of VILI and VALI has led to the Hamilton, ON, Canada: Bc Decker; 2005. p. 639‑47.
development of protective MV strategies to reduce VALI and 13. Amato MB, Meade MO, Slutsky AS, Brochard L, Costa EL,
improve patient outcomes. The current focus on prevention Schoenfeld DA, et al. Driving pressure and survival in the acute
respiratory distress syndrome. N Engl J Med 2015;372:747‑55.
of VALI has shifted to consideration of driving pressure and
14. Guérin C, Papazian L, Reignier J, Ayzac L, Loundou A, Forel JM, et al.
mechanical power. However, the relevance of these variables Effect of driving pressure on mortality in ARDS patients during lung
over VT and plateau pressure lacks direct proof. There are several protective mechanical ventilation in two randomized controlled trials.
emerging modalities (e.g., ECMO, NAVA, P‑APRV, and NMB) Crit Care 2016;20:384.
15. Tonetti T, Vasques F, Rapetti F, Maiolo G, Collino F, Romitti F,
and novel approaches (e.g., anti‑inflammatory stem cells) that et al. Driving pressure and mechanical power: New targets for VILI
promise to revolutionize the management of respiratory failure prevention. Ann Transl Med 2017;5:286.
and relegate VALI to the ash heap of history. However, there 16. Bilek AM, Dee KC, Gaver DP 3rd. Mechanisms of surface‑tension‑induced
is currently insufficient data to recommend their use in routine epithelial cell damage in a model of pulmonary airway reopening.
J Appl Physiol (1985) 2003;94:770‑83.
practice. Indeed, the recurring theme of this review is that further 17. Albert RK. The role of ventilation‑induced surfactant dysfunction and
randomized controlled trials are required. However, while the atelectasis in causing acute respiratory distress syndrome. Am J Respir
data from clinical trials certainly help intensivists make difficult Crit Care Med 2012;185:702‑8.
18. Tremblay LN, Slutsky AS. Ventilator‑induced injury: From barotrauma
decisions, the literature can never fully addresses the conflicting
to biotrauma. Proc Assoc Am Physicians 1998;110:482‑8.
priorities of many clinical scenarios. 19. Vlahakis NE, Schroeder MA, Limper AH, Hubmayr RD. Stretch
induces cytokine release by alveolar epithelial cells in vitro. Am J
Financial support and sponsorship Physiol 1999;277:L167‑73.
Nil. 20. Nonas SA, Moreno‑Vinasco L, Ma SF, Jacobson JR, Desai AA,

Indian Journal of Respiratory Care ¦ Volume 7 ¦ Issue 1 ¦ January-June 2018 11

[Downloaded free from http://www.ijrc.in on Wednesday, November 16, 2022, IP: 122.180.177.97]

Rajendram, et al.: Prevention of ventilator‑associated lung injury

Dudek SM, et al. Use of consomic rats for genomic insights into 38. Sud S, Sud M, Friedrich JO, Meade MO, Ferguson ND, Wunsch H,
ventilator‑associated lung injury. Am J Physiol Lung Cell Mol Physiol et al. High frequency oscillation in patients with acute lung injury and
2007;293:L292‑302. acute respiratory distress syndrome (ARDS): Systematic review and
21. Ranieri VM, Suter PM, Tortorella C, De Tullio R, Dayer JM, Brienza A, meta‑analysis. BMJ 2010;340:c2327.
et al. Effect of mechanical ventilation on inflammatory mediators 39. Ferguson ND, Cook DJ, Guyatt GH, Mehta S, Hand L, Austin P, et al.
in patients with acute respiratory distress syndrome: A randomized High‑frequency oscillation in early acute respiratory distress syndrome.
controlled trial. JAMA 1999;282:54‑61. N Engl J Med 2013;368:795‑805.
22. Murphy DB, Cregg N, Tremblay L, Engelberts D, Laffey JG, Slutsky AS, 40. Young D, Lamb SE, Shah S, MacKenzie I, Tunnicliffe W, Lall R, et al.
et al. Adverse ventilatory strategy causes pulmonary‑to‑systemic High‑frequency oscillation for acute respiratory distress syndrome.
translocation of endotoxin. Am J Respir Crit Care Med 2000;162:27‑33. N Engl J Med 2013;368:806‑13.
23. Mascheroni D, Kolobow T, Fumagalli R, Moretti MP, Chen V, 41. Allo JC, Beck JC, Brander L, Brunet F, Slutsky AS, Sinderby CA,
Buckhold D, et al. Acute respiratory failure following pharmacologically et al. Influence of neurally adjusted ventilatory assist and positive
induced hyperventilation: An experimental animal study. Intensive Care end‑expiratory pressure on breathing pattern in rabbits with acute lung
Med 1988;15:8‑14. injury. Crit Care Med 2006;34:2997‑3004.
24. Petrucci N, De Feo C. Lung protective ventilation strategy for the 42. Sinderby C, Navalesi P, Beck J, Skrobik Y, Comtois N, Friberg S, et al.
acute respiratory distress syndrome. Cochrane Database Syst Rev Neural control of mechanical ventilation in respiratory failure. Nat Med
2013;2:CD003844. 1999;5:1433‑6.
25. Gattinoni L, Pesenti A. The concept of “baby lung”. Intensive Care Med 43. Piquilloud L, Vignaux L, Bialais E, Roeseler J, Sottiaux T, Laterre PF,
2005;31:776‑84. et al. Neurally adjusted ventilatory assist improves patient‑ventilator
26. Ladha K, Vidal Melo MF, McLean DJ, Wanderer JP, Grabitz SD, interaction. Intensive Care Med 2011;37:263‑71.
Kurth T, et al. Intraoperative protective mechanical ventilation and 44. Mauri T, Bellani G, Grasselli G, Confalonieri A, Rona R, Patroniti N,
risk of postoperative respiratory complications: Hospital based registry et al. Patient‑ventilator interaction in ARDS patients with extremely low
study. BMJ 2015;351:h3646. compliance undergoing ECMO: A novel approach based on diaphragm
27. Serpa Neto A, Cardoso SO, Manetta JA, Pereira VG, Espósito DC, electrical activity. Intensive Care Med 2013;39:282‑91.
Pasqualucci Mde O, et al. Association between use of lung‑protective 45. Brander L, Sinderby C, Lecomte F, Leong‑Poi H, Bell D, Beck J, et al.
ventilation with lower tidal volumes and clinical outcomes among Neurally adjusted ventilatory assist decreases ventilator‑induced lung
patients without acute respiratory distress syndrome: A meta‑analysis. injury and non‑pulmonary organ dysfunction in rabbits with acute lung
JAMA 2012;308:1651‑9. injury. Intensive Care Med 2009;35:1979‑89.
28. Neto AS, Simonis FD, Barbas CS, Biehl M, Determann RM, Elmer J, 46. Piedalue F, Albert RK. Prone positioning in acute respiratory distress
et al. Lung‑protective ventilation with low tidal volumes and the syndrome. Respir Care Clin N Am 2003;9:495‑509.
occurrence of pulmonary complications in patients without acute 47. Broccard A, Shapiro RS, Schmitz LL, Adams AB, Nahum A, Marini JJ,
respiratory distress syndrome: A Systematic review and individual et al. Prone positioning attenuates and redistributes ventilator‑induced
patient data analysis. Crit Care Med 2015;43:2155‑63. lung injury in dogs. Crit Care Med 2000;28:295‑303.
29. Hickling KG, Henderson SJ, Jackson R. Low mortality associated with 48. Valenza F, Guglielmi M, Maffioletti M, Tedesco C, Maccagni P, Fossali T,
low volume pressure limited ventilation with permissive hypercapnia et al. Prone position delays the progression of ventilator‑induced lung
in severe adult respiratory distress syndrome. Intensive Care Med injury in rats: Does lung strain distribution play a role? Crit Care Med
1990;16:372‑7. 2005;33:361‑7.
30. Hraiech S, Yoshida T, Papazian L. Balancing neuromuscular blockade 49. Sud S, Friedrich JO, Taccone P, Polli F, Adhikari NK, Latini R, et al.
versus preserved muscle activity. Curr Opin Crit Care 2015;21:26‑33. Prone ventilation reduces mortality in patients with acute respiratory
31. Terragni PP, Rosboch G, Tealdi A, Corno E, Menaldo E, Davini O, failure and severe hypoxemia: Systematic review and meta‑analysis.
et al. Tidal hyperinflation during low tidal volume ventilation in Intensive Care Med 2010;36:585‑99.
acute respiratory distress syndrome. Am J Respir Crit Care Med 50. Guérin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, et al.
2007;175:160‑6. Prone positioning in severe acute respiratory distress syndrome. N Engl
32. Briel M, Meade M, Mercat A, Brower RG, Talmor D, Walter SD, et al. J Med 2013;368:2159‑68.
Higher vs. lower positive end‑expiratory pressure in patients with acute 51. Brodie D, Bacchetta M. Extracorporeal membrane oxygenation for
lung injury and acute respiratory distress syndrome: Systematic review ARDS in adults. N Engl J Med 2011;365:1905‑14.
and meta‑analysis. JAMA 2010;303:865‑73. 52. Gattinoni L, Kolobow T, Agostoni A, Damia G, Pelizzola A, Rossi GP,
33. Talmor D, Sarge T, Malhotra A, O’Donnell CR, Ritz R, Lisbon A, et al. et al. Clinical application of low frequency positive pressure ventilation
Mechanical ventilation guided by esophageal pressure in acute lung with extracorporeal CO2 removal (LFPPV‑ECCO2R) in treatment
injury. N Engl J Med 2008;359:2095‑104. of adult respiratory distress syndrome (ARDS). Int J Artif Organs
34. Brower RG, Morris A, MacIntyre N, Matthay MA, Hayden D, 1979;2:282‑3.
Thompson T, et al. Effects of recruitment maneuvers in patients 53. Terragni PP, Del Sorbo L, Mascia L, Urbino R, Martin EL, Birocco A,
with acute lung injury and acute respiratory distress syndrome et al. Tidal volume lower than 6 ml/kg enhances lung protection:
ventilated with high positive end‑expiratory pressure. Crit Care Med Role of extracorporeal carbon dioxide removal. Anesthesiology
2003;31:2592‑7. [Erratum, Crit Care Med 2004;32:907]. 2009;111:826‑35.
35. Writing Group for the Alveolar Recruitment for Acute Respiratory 54. Bein T, Weber‑Carstens S, Goldmann A, Müller T, Staudinger T,
Distress Syndrome Trial (ART) Investigators, Cavalcanti AB, Brederlau J, et al. Lower tidal volume strategy (≈3 ml/kg) combined
Suzumura ÉA, Laranjeira LN, Paisani DM, Damiani LP, et al. with extracorporeal CO2 removal versus ‘conventional’ protective
Effect of lung recruitment and titrated positive end‑expiratory ventilation (6 ml/kg) in severe ARDS: The prospective randomized
pressure (PEEP) vs. low PEEP on mortality in patients with acute xtravent‑study. Intensive Care Med 2013;39:847‑56.
respiratory distress syndrome: A Randomized clinical trial. JAMA 55. Forel JM, Roch A, Marin V, Michelet P, Demory D, Blache JL, et al.
2017;318:1335‑45. Neuromuscular blocking agents decrease inflammatory response in
36. Jain SV, Kollisch‑Singule M, Sadowitz B, Dombert L, Satalin J, patients presenting with acute respiratory distress syndrome. Crit Care
Andrews P, et al. The 30‑year evolution of airway pressure release Med 2006;34:2749‑57.
ventilation (APRV). Intensive Care Med Exp 2016;4:11. 56. Yoshida T, Uchiyama A, Matsuura N, Mashimo T, Fujino Y. The
37. Andrews PL, Shiber JR, Jaruga‑Killeen E, Roy S, Sadowitz B, comparison of spontaneous breathing and muscle paralysis in two
O’Toole RV, et al. Early application of airway pressure release ventilation different severities of experimental lung injury. Crit Care Med
may reduce mortality in high‑risk trauma patients: A systematic review 2013;41:536‑45.
of observational trauma ARDS literature. J Trauma Acute Care Surg 57. Papazian L, Forel JM, Gacouin A, Penot‑Ragon C, Perrin G, Loundou A,
2013;75:635‑41. et al. Neuromuscular blockers in early acute respiratory distress

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Rajendram, et al.: Prevention of ventilator‑associated lung injury

syndrome. N Engl J Med 2010;363:1107‑16. 59. Needham DM, Colantuoni E, Mendez‑Tellez PA, Dinglas VD,
58. Curley GF, Hayes M, Ansari B, Shaw G, Ryan A, Barry F, et al. Sevransky JE, Dennison Himmelfarb CR, et al. Lung protective
Mesenchymal stem cells enhance recovery and repair following mechanical ventilation and two year survival in patients with acute lung
ventilator‑induced lung injury in the rat. Thorax 2012;67:496‑501. injury: Prospective cohort study. BMJ 2012;344:e2124.

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