REVIEW

CURRENT
OPINION Lung protection in acute respiratory distress
syndrome: what should we target?
Jeremy R. Beitler a,b

Purpose of review
Most clinical trials of lung-protective ventilation have tested one-size-fits-all strategies with mixed results.
Data are lacking on how best to tailor mechanical ventilation to patient-specific risk of lung injury.
Recent findings
Risk of ventilation-induced lung injury is determined by biological predisposition to biophysical lung injury
and physical mechanical perturbations that concentrate stress and strain regionally within the lung. Recent
investigations have identified molecular subphenotypes classified as hyperinflammatory and
hypoinflammatory acute respiratory distress syndrome (ARDS), which may have dissimilar risk for
ventilation-induced lung injury. Mechanically, gravity-dependent atelectasis has long been recognized to
decrease total aerated lung volume available for tidal ventilation, a concept termed the ‘ARDS baby lung’.
Recent studies have demonstrated that the aerated baby lung also has nonuniform stress/strain distribution,
with potentially injurious forces concentrated in zones of heterogeneity where aerated alveoli are adjacent
to flooded or atelectatic alveoli. The preponderance of evidence also indicates that current standard-of-care
tidal volume management is not universally protective in ARDS. When considering escalation of lung-
protective interventions, potential benefits of the intervention should be weighed against tradeoffs of
accompanying cointerventions required, for example, deeper sedation or neuromuscular blockade. A
precision medicine approach to lung-protection would weigh.
Summary
A precision medicine approach to lung-protective ventilation requires weighing four key factors in each
patient: biological predisposition to biophysical lung injury, mechanical predisposition to biophysical injury
accounting for spatial mechanical heterogeneity within the lung, anticipated benefits of escalating lung-
protective interventions, and potential unintended adverse effects of mandatory cointerventions.
Keywords
acute lung injury, acute respiratory distress syndrome, mechanical ventilation, precision medicine,
ventilator-induced lung injury

INTRODUCTION clinically important factor in assessing VILI risk

The vital importance of ventilation-induced lung [7–9], although bedside ascertainment remains a
injury (VILI) is striking. To date, all interventions challenge [10]. Integration of both biological and
found in a multicenter trial to improve survival from mechanical predisposition to VILI, weighed against
acute respiratory distress syndrome (ARDS) are risks of the lung-protective therapy and mandatory
thought to exert their effect by preventing VILI:
lower tidal volumes [1,2], prone positioning [3],
a
and, most controversially, neuromuscular blockade Center for Acute Respiratory Failure and bDivision of Pulmonary, Allergy,
[4]. and Critical Care Medicine, Columbia University College of Physicians
and Surgeons, NewYork-Presbyterian Hospital, New York, New York,
Equally striking is the small body of evidence to
USA
guide personalization of ventilatory support to
Correspondence to Jeremy R. Beitler, MD, MPH, Center for Acute
patient-specific risk of VILI. Investigations histori- Respiratory Failure; Division of Pulmonary, Allergy, and Critical Care
cally have focused on pulmonary mechanics, pro- Medicine, Columbia University College of Physicians and Surgeons,
viding invaluable insights for tailoring support to NewYork-Presbyterian Hospital, 622W 168th Street, PH 8 East-101,
minimize mechanical stress both globally and New York, NY 10032, USA. E-mail: [email protected]
regionally within the lung [5,6]. Increasingly, bio- Curr Opin Crit Care 2020, 26:26–34
logical heterogeneity also is recognized as a DOI:10.1097/MCC.0000000000000692

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 Lung protection in acute respiratory distress syndrome Beitler

described mechanical phenomena precipitating

KEY POINTS VILI can be framed in these terms.
 A precision medicine approach to lung-protective Since lung insufflation is managed from a single
ventilation requires weighing four key factors in each airway opening at the endotracheal tube, mechani-
patient: cal ventilation targets historically have emphasized
global mechanics, using whole-lung pressure and
o Biological predisposition to biophysical lung injury.
volume changes as surrogates of stress and strain,
o Presence and severity of spatial mechanical respectively [19,20]. The preponderance of preclini-
heterogeneity within the lung. cal and human literature now support a central role
for regional mechanical perturbations in VILI path-
o Anticipated benefits of escalating lung-
protective interventions. ogenesis as well [21–24]. Indeed, much of what has
been understood previously as stress/strain acting
o Potential unintended adverse effects of global across the lung, including hyperinflation
cointerventions, for example, deeper sedation, from high tidal volumes, is correctly depicted only
required to escalate the lung-protective strategy.
through consideration of regional mechanics.

cointerventions, is essential for titrating ventilatory

Aerated lung volume is reduced in acute
support to optimize therapeutic benefit.
respiratory distress syndrome
In patients with ARDS, global mechanics are grossly
abnormal: higher airway pressures occur regularly
BIOLOGICAL HETEROGENEITY AND despite modest tidal volumes. This lower respiratory
VENTILATION-INDUCED LUNG INJURY system compliance has often been interpreted as
RISK stiffness, but in fact functional volume loss appears
Biological heterogeneity has long been recognized as to be the main driver. The added weight of cell-rich
a central feature of ARDS. Trajectory of the ARDS pulmonary edema fluid, paired with inflammation-
patient unquestionably depends in part on ARDS risk associated surfactant deactivation, causes gravity-
factor [11–13]. Historical subtyping of ARDS often dependent atelectasis, a classic finding on computed
has classified patients by perceived precipitant, as tomography (CT) of many ARDS patients. Thus, the
‘direct’ or ‘indirect’ lung injury [14]. Subsequent work functional aerated volume of the ARDS lung is
identified molecular biological differences [15] and smaller than normal, a phenomenon often termed
dissimilar genetic predisposing correlates [16] of the ‘ARDS baby lung’ [25,26].
direct versus indirect ARDS, but this classification Importantly, compliance of the still-aerated
scheme fails to account for severity or duration of lung volume, termed specific compliance (compli-
risk exposure, leaving obvious residual within-class ance normalized to volume of functional aerated
heterogeneity. lung) appears relatively preserved [25,27,28].
More recently, novel modeling approaches have Because atelectatic lung tends to stay collapsed dur-
identified two distinct molecular subphenotypes, ing tidal insufflation [29–31], volume is distributed
hyperinflammatory and hypoinflammatory ARDS almost entirely to the aerated baby lung (Fig. 1). This
[8]. Post-hoc analyses of multiple clinical trials sug- aerated baby lung may readily suffer overdistension
gest subphenotypes classified in this manner may given its near-normal specific compliance.
exhibit differential response to therapies [8,17,18 ],
&&
The smaller aerated lung volume available for
raising the prospect that they may also predispose tidal ventilation provides compelling mechanism of
differentially to VILI. action for lower tidal volumes. This rationale was
A detailed review of ARDS subphenotyping was noted explicitly in the ARDS Network tidal volume
published recently elsewhere in this journal [7]. trial: ‘Since atelectasis and edema reduce aerated
lung volumes in patients with [ARDS], inspiratory
airway pressures are often high, suggesting the pres-
MECHANICAL DETERMINANTS OF ence of excessive distension, or ‘stretch,’ of the
VENTILATION-INDUCED LUNG INJURY aerated lung’ [2].
The mechanical determinants of VILI are best Yet, this mechanistic understanding also high-
understood in terms of stress and strain. Mechanical lights a key shortcoming of the current standard-of-
stress is defined as the force per unit area within an care approach to tidal volumes. Targeting 6  2 ml/
object that occurs due to an externally applied force. kg predicted body weight for height and sex scales
Strain is a measure of deformation, the change in tidal volume to presumed healthy lung size, which,
shape relative to its resting form. All currently depending on degree of atelectasis in the ARDS lung,

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Respiratory system

Superimposed Helical Spring p < .001

Pressure
(cmH2O)

Volume (mL/kg PBW)

0

ARDS “baby
+2.5
lung” volume

+5

+7.5

+10
} Atelectatic
lung

Measured Predicted
Insp Capacity Insp Capacity

FIGURE 1. Functional aerated lung volume is decreased in acute respiratory distress syndrome. As a result, the volume of
aerated lung available for gas exchange and mechanical insufflation is reduced; this smaller aerated region is termed the
baby lung. Left: Computed tomography chest of representative patient with acute respiratory distress syndrome. Ventral
regions are well aerated with patchy ground-glass opacities and few areas of focal consolidation from pneumonia. Dorsal
regions show dense dependent atelectasis caused by superimposed pressure from gravity on the edematous acute respiratory
distress syndrome lung above. The effect of gravity on dependent atelectasis in the lung is analogous to that of gravity on a
helical spring oriented vertically in gravity, such as observed with a Slinky (Poof-Slinky, Inc, Hollidaysburg, PA, USA), the
classic children’s toy. The spring coils are distanced farther apart in nondependent regions while the spring is near fully
collapsed in gravity-dependent regions. Reprinted with permission [6]. Right: Measured inspiratory capacity is significantly
reduced compared with their predicted normal values in patients with acute respiratory distress syndrome (mean difference,
29.5  8.6 ml/kg predicted body weight; P < 0.001). Box plots illustrate the median and interquartile range (boxes), mean
(diamond), and maximum and minimum values (whiskers). Reprinted with permission [33].

can yield wildly different exposure to stress and interdependence [21,24], a mechanism by which
strain [19,32]. ventilation at low absolute lung volumes seemingly
A precision medicine approach instead would paradoxically can cause VILI [38].
scale tidal volumes to functional lung size, that is, the The pulmonary radiographic correlate of this
ARDS baby lung volume [33–36]. special heterogeneity may be the diffuse but patchy
‘ground glass’ opacities on CT. In-vivo studies in
animals and humans have found heterogeneous
Spatial heterogeneity of stress/strain consolidation correlate strongly with markers of
distribution in acute respiratory distress high regional strain [22,24], which map to regional
syndrome lung inflammation [23,39–41], and are associated
Stress and strain are spatially heterogeneously dis- with elevated plasma markers of alveolar epithelial
tributed within the aerated ARDS baby lung. Neigh- injury [42].
boring alveoli share an interalveolar septum and A precision medicine approach therefore would
thus are mechanically interdependent. When one also seek to minimize spatial heterogeneity of stress/
alveolus becomes fluid-filled or collapsed, the strain distribution when present, precisely the pur-
neighboring alveolus also is deformed [21]. This ported mechanism of benefit of prone positioning
phenomenon has been observed in real-time via [43–47].
confocal microscopy, wherein shrinkage of a single
fluid-filled alveolus causes the interalveolar septum
to stretch and bulge into that fluid-filled space, High shear stress/strain in small airways
producing deformation and local overexpansion High shear forces may occur in small airways and
of the adjacent air-filled alveolus. During insuffla- alveolar ducts susceptible to tidal opening and col-
tion, near the flooded alveolus, air-filled alveoli lapse [48]. Inflammation-mediated surfactant dys-
become more deformed, presumably predisposing function and edema weight favor small airways
to mechanical failure from high shear stress/strain collapse at low lung volumes, particularly in grav-
[37] (Fig. 2). Through a similar mechanism, shear ity-dependent zones [49–51]. During inspiration,
stress on aerated lung at the border of regional collapsed but recruitable lung units may assume
atelectasis may be orders of magnitude greater than an unzippering-like conformation as the air bolus
elsewhere in the lung due to alveolar mechanical propagates along the airway, generating high local

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 Lung protection in acute respiratory distress syndrome Beitler

surface that contributes to lung injury [56–58].

Regardless of precise mechanism, the repetitive
exposure to locally injurious forces with each inspi-
ratory–expiratory cycle causes injury to small air-
ways, often described as atelectrauma.
While it remains controversial the extent to
which atelectrauma occurs and causes clinically
significant injury in the nonzero end-expiratory
pressure era, a precision medicine strategy would
minimize small airways stress/strain by identifying
and mitigating atelectrauma. Preventing atelec-
trauma is an area for which precise positive end-
expiratory pressure (PEEP) titration, among other
interventions, may offer benefit [59].

MECHANISMS OF ACTION FOR PROVEN

VENTILATION-INDUCED LUNG INJURY-
PREVENTIVE INTERVENTIONS
All three interventions found in multicenter trials to
improve survival in patients with ARDS share a
common mechanism: prevention of VILI.
Lower tidal volumes directly mitigate overdisten-
sion of the aerated baby lung, decreasing plasma
membrane wounding and rupture, disruption of cell
junctions, and detachment of basement membranes
[58,60–62]. Lower tidal volumes also attenuate shear
strain from spatial mechanical heterogeneity by lim-
iting the magnitude of shear deformation with each
inspiratory cycle. Finally, lower tidal volumes may
attenuate atelectrauma by decreasing likelihood of
tidal recruitment with each inspiratory cycle.
Prone positioning distributes gravitational forces
within the lung to favor ventral compression. Con-
formational shape-matching of the lung within the
chest cavity favors ventral expansion regardless of
FIGURE 2. Spatial heterogeneity increases stress and strain. In position. Thus, with proning, gravitational and con-
the isolated perfused rat lung, confocal microscopy with optical formational forces act in opposing directions, yield-
sections 2-mm thick permits direct visualization of alveoli. Top: ing more homogenous aeration throughout the lung.
Adjacent alveoli share a common septum and are mechanically Prone positioning therefore decreases shear strain
interdependent. In normal conformation, strain is minimized and regional ventral hyperinflation [43,45,46]. To
across neighboring air-filled alveoli. Bottom: In a single-alveolus the extent that lung recruitment occurs, prone posi-
model of pulmonary edema, the effects on local strain tioning also may mitigate atelectrauma [63].
distribution of heterogeneous parenchymal consolidation and Neuromuscular blockade prevents several
flooding can be appreciated. The liquid-filled alveolus shrinks patient–ventilator interactions that may cause
due to micromechanical effects of meniscus formation. As a mechanical injury. Inhibiting active inspiration
result, the adjacent air-filled alveolus bulges and overdistends. may attenuate unintended high tidal volumes from
Reprinted with permission of the American Thoracic Society. breath stacking dyssynchrony [64,65] and transient
Copyright ß 2019 American Thoracic Society [37]; The regional hyperinflation from pendelluft [66]. Inhib-
American Journal of Respiratory Cell and Molecular Biology is iting active expiration may facilitate lung recruit-
an official journal of the American Thoracic Society. ment for a given PEEP by maintaining higher
end-expiratory transpulmonary pressure, thereby
shear forces that may be injurious [52–55]. It has decreasing atelectrauma [67]. Conflicting trial results
been proposed also that creation and rupture of around clinical efficacy of neuromuscular blockade
foam microbubbles at the air–liquid interface may in ARDS might be explained by differences in seda-
generate high interfacial stress at the epithelial tion management and dyssynchrony [4,68,69].

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Respiratory system

LUNG VERSUS PATIENT PROTECTION Such tradeoffs of mandatory cointerventions may

Maximizing lung protection is not necessarily syn- limit the role for so-called ultra-low tidal volume
onymous with maximizing patient benefit, even ventilation or ‘lung rest’, in which tidal volume and
when the lung-protective intervention itself has a respiratory rate are reduced to levels prohibitive for
favorable side-effect profile. Most established lung- maintaining adequate gas exchange without extracor-
protective interventions require other therapies be poreal life support (ECLS). While a growing body of
instituted concomitantly to institute the lung-pro- literature suggests tidal volumes below 6 ml/kg pre-
tective strategy. These mandatory cointerventions may dicted body weight may confer additional lung protec-
&&

carry their own untoward effects that change the tion [79,80,81 ], the extent to which the totality of
risk–benefit calculation when therapeutic effect is interventions required for ultra-low tidal volume strat-
framed not in terms of lung protection but rather egies benefits patients again likely depends on poten-
the more appropriate target – net benefit to the tial downsides of ECLS, including bleeding, hemolysis,
patient (Table 1). limb ischemia, immobility, infection, and unknown
For example, lowering tidal volumes or permit- pharmacokinetic effects of key medications [82–84].
ting hypercapnia may increase patient discomfort As cumulative experience refines ECLS management,
and/or respiratory drive, which often are managed risks may decrease, changing the risk–benefit calcula-
by increasing sedatives or analgesics [70]. Deep seda- tion, and potentially expanding populations for
tion also accompanies prone positioning as rou- whom the net patient-level effect may be beneficial.
tinely instituted [3], and certainly neuromuscular
blockade [4,68]. PROPOSED VENTILATION TARGETS
Excess suppression of respiratory drive may con- To be clear, existing data do not justify precise
tribute to diaphragm disuse atrophy and respiratory ventilation targets that are universally appropriate
muscle weakness that prolong invasive ventilation for all patients. There is no one-size-fits-all strategy
&
[71,72,73 ,74]. Regardless of its effects on drive, esca- for lung-protective ventilation. Rather, ventilation
lating sedation may impair extubation readiness, targets should be individualized according to
delay ventilator liberation, prevent early patient clinical assessment of VILI risk, tradeoffs of cointer-
mobilization and physical therapy [74–76], unin- ventions, and considering likely biological subphe-
tended effects of mandatory cointerventions which notype [9,10]. For patients at low risk of VILI, strict
may contribute to morbidity and mortality. Sedatives adherence to the most protective ventilation targets
and analgesics may have medication-specific iatro- often may be outweighed by adverse effects of coin-
genic effects as well, including contributing to delir- terventions and a strategy of liberal targets with
ium, hemodynamic instability, and gastrointestinal permissive dyssynchrony may be most appropriate.
complications [75–78]. In contrast, for patients at highest risk of VILI,

Table 1. Potential adverse effects of cointerventions often employed with lung-protective strategiesa

Cointervention Associated lung-protective strategies Unintended potential adverse effects

Deep sedation Lower tidal volumes Delayed spontaneous awakening trial

Prone positioning Delayed spontaneous breathing trial
Neuromuscular blockade Delayed mobilization and physical therapy
Diaphragm disuse atrophy
Hemodynamic instability
Delirium
Neuromuscular blockade Lower tidal volumes with dyssynchrony intolerance All sedation-associated side-effects above
Prone positioning Neuromuscular weakness
Neuromuscular blockade
Extracorporeal life support Ultra-low tidal volumes Catheter site hemorrhage
Lung rest Gastrointestinal hemorrhage
Intracranial hemorrhage
Limb ischemia
Hemolysis and thrombocytopenia
Delayed mobilization
Infection

VILI, ventilation-induced lung injury.

a
For VILI-preventive interventions, the net therapeutic effect depends not only on the extent to which lung protection is afforded but also the unintended adverse
effects of cointerventions routinely administered with the lung-protective strategy.

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 Lung protection in acute respiratory distress syndrome Beitler

complete control of ventilation may be necessary to Also clearly important is the maximum global
safely institute maximally protective ventilation stretch experienced by the lungs during tidal venti-
despite the risks of associated cointerventions. lation. Airway plateau pressure, measured during a
While several potential targets exist for lung- relaxed end-inspiratory pause, is most often used for
protective ventilation, they are not of equal impor- this purpose, but there is no threshold effect for
tance. Cyclic stretch during tidal ventilation appears safety [86]. Plateau pressure fails to distinguish the
to be the most important driver of clinically significant contribution of lung versus chest wall recoil, and
lung injury [1,2,36,79,80]. Tidal volume per predicted chest wall mechanics can vary widely between
body weight is the most widely used target but it does patients [87,88]. Transpulmonary pressure can be
not scale to patient-specific aerated lung volume used to overcome this limitation and distinguish the
accounting for volume loss from atelectasis and con- contributions of lung from chest wall [89–91], but
solidation (i.e., baby lung), and thus is increasingly esophageal manometry is not widely available.
recognized as an imperfect strategy [19,33,34,36]. Proposed specific target ranges for several
Moreover, with patient–ventilator interactions such parameters relevant to lung-protective ventilation
as double triggering and reverse triggering that lead to are presented in Table 2.
breath stacking dyssynchrony [64,85], volume-preset
ventilator modes do not ensure the intended tidal
volume is delivered in the patient with dyssynchro- CONCLUSION: PRECISION MEDICINE FOR
nous spontaneous effort. Airway driving pressure (pla- VENTILATION-INDUCED LUNG INJURY
teau pressure minus PEEP) has been advocated as a Personalizing lung-protective ventilation requires
strategy for scaling tidal volume to respiratory system assessing each patient’s risk of VILI and the risk/
compliance and thus baby lung size [36]. Pressure- benefit of possible interventions to mitigate VILI.
targeted, time-cycled ventilation targeting a specific To gauge VILI risk, one must evaluate both biological
driving pressure again risks misinterpretation if predisposition and mechanical predisposition,
patient respiratory effort is not considered, as patient including global and regional lung mechanics
effort may augment transpulmonary pressure swings accounting for spatial heterogeneity of stress/strain
during tidal ventilation. distribution within the lung. The decision on

Table 2. Suggested targets for lung-protective ventilation according to ventilation-induced lung injury riska

Parameter Low VILI risk High VILI risk Priority

Cyclic stretch
Tidal volume 6–8 ml/kg PBW 3–6 ml/kg PBW Highest
Driving pressure 15 cmH2O 10 cmH2O Highest
Maximal stretch at end-inspiration
Plateau airway pressure 30 cmH2O 27 cmH2O High
Plateau transpulmonary pressureb 20 cmH2O 15 cmH2O High
Spatial stress/strain heterogeneity
Prone positioning Not currently recommended Strongly recommended High
PEEP 5–15 cmH2O 10–24 cmH2O Moderate
End-expiratory transpulmonary pressureb – 0–3 cmH2O Moderate
Control of breathing
Patient-ventilator interaction Permissive dyssynchrony Consider synchronous ventilation Moderate
c
P0.1 >1 cmH2O 0–3 cmH2O Low
Frequency of cyclic exposure
Respiratory rate 15–35 bpm 5–35 bpm Low
Gas exchange
Oxygen saturation 88–95% 88–95% High
Arterial CO2 35–45 mmHg 45–70 mmHg Low

PEEP, positive end-expiratory pressure; PBW, predicted body weight; VILI, ventilation-induced lung injury.
a
Proposed target ranges and prioritization are based on available evidence at time of publication. They should be considered in context of the individual patient
and adjusted accordingly based on clinically ascertained risk of VILI and cointerventions prescribed to help achieve targets.
b
Where esophageal manometry is available to estimate pleural pressure and calculate transpulmonary pressure.
c
P0.1 is the airway occlusion pressure, the decrease in airway pressure during the first 100 ms (0.1 s) of inspiration against an occluded airway.

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Respiratory system

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