The Mechanism of Ventilator-induced Lung Injury:
Role of Dynamic Alveolar Mechanics
J. DiRocco, D. Carney, and G. Nieman
z Introduction
Supportive therapy with mechanical ventilation is critical for survival of all patients
with the acute respiratory distress syndrome (ARDS) [1]. We now recognize ventilator-induced lung injury (VILI) as a potential complication of this therapy. VILI
occurs when improper methods of mechanical ventilation exacerbate the primary
lung injury in ARDS [2]. Indeed, VILI significantly increases mortality from ARDS,
yet the mechanism of VILI remains ill-defined [2±4]. No proven remedy for the inflammatory response associated with ARDS has yet been developed. An improved
understanding of VILI will limit mortality from ARDS. Known bedside measures to
guide the clinician when adjusting mechanical ventilation to minimize VILI are
crude and limited [5±8]. In order to investigate the mechanism of VILI, first the
dynamic behavior of alveolar inflation and deflation (i.e., alveolar mechanics) during tidal ventilation in the normal and injured lung must be understood.
Currently, there are believed to be three mechanisms of VILI:
1) Atelectrauma is an alveolar shear stress-induced injury caused by alveolar recruitment-derecruitment
2) Volutrauma is an alveolar overexpansion injury caused by high lung pressures
and volumes, and
3) Biotrauma is an alveolar, inflammatory injury caused by cytokine release from
the pulmonary parenchyma secondary to mechanical injury induced by atelectrauma or volutrauma [9].
Since VILI-induced injury occurs mainly at the level of the alveolus or alveolar
duct, understanding dynamic alveolar mechanics is critical to clarify the mechanism of VILI. Despite extensive research, the mechanics of alveolar inflation are
poorly understood [10±39].
In this chapter, we will move from a review of the dynamic changes in alveoli
during ventilation to postulates regarding changes in alveolar mechanics in the
acutely injured lung. Finally we will discuss how improper ventilation with preservation of abnormal alveolar mechanics may cause VILI. We will not discuss the role
of pulmonary surfactant, the elastin/collagen support tissue, or the three dimensional architecture of the alveolus, all of which may play an important role in normal and abnormal alveolar mechanics as discussed elsewhere [40].
Currently, there is no technique available to measure the three-dimensional
changes in the alveolus and alveolar duct during tidal ventilation. However, it is
possible to study two-dimensional dynamic alveolar mechanics in subpleural alveo-
The Mechanism of Ventilator-induced Lung Injury: Role of Dynamic Alveolar Mechanics
li. Our laboratory utilizes in vivo microscopy to study the two-dimensional changes
in subpleural alveoli in real-time with lung inflation and deflation. In order to assess dynamic mechanics in both the normal and acutely injured lung, we will integrate data from our in vivo microscopic assessment of alveolar mechanics with
those generated from static models (histologic assessment at varying lung volumes)
or surrogate measurements (quasi-static pressure/volume [P/V] curve, computed tomography [CT] scan, impedance tomography).
z Dynamic Alveolar Ventilation
Alveoli are not physically independent structures but rather are interconnected
with shared walls containing elastin and collagen fibers [41]. This is disparate to
common descriptions in current medical textbooks that depict alveoli as individual
balloon-like structures bunched together as a cluster of grapes [42]. Histological
studies have contributed substantially to our understanding of alveolar ducts and
alveoli, but these studies have focused on two-dimensional static structures with little extrapolation to three-dimensional, dynamically moving structures. This is a
critical oversight, for understanding dynamic change is essential to define normal
alveolar mechanics and to interpret how alterations in alveolar mechanics in the
acutely injured lung may lead to a VILI.
Numerous experimental techniques have been used to study dynamic alveolar
mechanics. In the normal lung, four models of dynamic alveolar size change have
been proposed (Table 1):
z isotropic balloon-like expansion and contraction of alveoli;
z expansion and contraction of the alveolar ducts with little change in alveolar
volume;
z successive alveolar recruitment and derecruitment; and
z alveolar crumpling and un-crumpling along septa similar to a paper bag [18,
19].
There is no consensus as to which of the above mechanisms predominates [10±25].
Isotropic Balloon-like Alveolar Mechanics
Early depictions of alveoli as grape clusters led to a belief that each alveolus was a
functionally independent unit. Therefore, it was thought that morphometric measurement of the change in alveolar surface area could be used to determine the
mechanism by which alveoli change size during lung expansion [10, 12, 14, 16, 17,
21]. In addition, this thought would allow for mathematical verification since if alveoli truly expand isotropically (i.e., balloon-like stretching), the surface area of the
lung should change predictably with change in lung volume. Indeed, early reports
indicated that uniform, isotropic alveolar expansion and contraction were responsible for the majority of changes in lung volume [10, 12, 16]. Studies on fresh lung
tissue frozen at various levels of inflation and deflation [10, 11, 14±17] indicate that
alveolar shape remains relatively unchanged with changes in lung volume, supporting conventional morphometric data that alveoli change by means of isotropic expansion and contraction. Further mathematical interpretation came from Dunnill's
comparison of the regression line of alveolar surface area/alveolar volume to the re-
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Table 1. Measurement of dynamic alveolar ventilation
Species
Protocol
Methods
z Rabbit
In vivo & Freezing
Point count & Lm
z Rat
In vivo & Freezing
z Dog
z Dog
Formalin vapor
Excised lungs
z Guinea
pig
Rapidly Frozen
z Cats
Freeze + Freeze dry
z Cats
Freeze + Freeze dry
z Cats
z Rat
Freeze + Freeze dry
Vascular perfusion
z Rabbit
Vascular perfusion
z Rat
z Dog
Airway instillation
In vivo
z Dog
In vivo
z Gerbil
Freeze + Freeze dry
z Rat
Vascular perfusion
z Human
Excised lung
z Rat
In vivo microscopy
z Rabbits
Excised lung
Conclusions
Isotropic alveolar expansion,
Interior alveoli also isotropic
Dynamic 2 point
Geometric hysteresis
count
Subpleural alveoli same size
in vivo and in frozen tissue
Lm
Isotropic alveolar expansion
Alveolar septae and New method for calculating
area with map reader surface tension in situ
Point count & Lm
Alveolar volume : linear
Duct volume : at 40% VL
No alveolar folding
Thickness of A-B barrier ; 33%
D/MD ratio
No D in alveolar shape FRC ? TLC
Alveoli collapse like a accordion
Alveolar microholes
Isotropic alveolar expansion
Alveoli & duct D proportionally
Morphometry
Alveoli & duct D proportionally
Morphometry
No D in alveolar diameter and
Stereology
alveolar walls pleat.
R/D is a major mechanism of VLD
The entire alveolus does not collapse
Morphometry
Multiple possible mechanisms
of alveolar volume change:
1) Sequential alveolar derecruitment
2) Balloon-like reduction in size
3) Change in size and shape
4) Crumpling of alveolar surface
Morphometry
Anisotropic alveolar expansion
Morphometry
Little change in alveolar volume
Lung volume change by R/D
Monodispersed
Little change in alveolar volume
Aerosol
Lung volume change by R/D
Lm
Little change in alveolar volume
Lung volume change by R/D
3D reconstruction
Alveolar shape Ds with deflation
Little D in alveolar diameter
until very low lung volume
P/V curve
Alveolar collapse without Pflex
Mathematical model Lung volume change by R/D
Morphometry
11% D in alveolar diameter
during tidal ventilation
P/V curve
Alveolar diameter ; with
: in lung volume, R/D important
Reference
10
11
12
13
14
15
16
17
18
19, 20
21
22
23
24
25
26
27
28
The Mechanism of Ventilator-induced Lung Injury: Role of Dynamic Alveolar Mechanics
Table 1 (continued)
Species
Protocol
Methods
Conclusions
Reference
z Rats
Excised lung
z Mice
Freeze substitution
In situ
Airway fixation
z Rats
Airway fixation
Morphometry
z Human
Frozen section
Morphometry
z Rat
Glutaraldehyde
Morphometry
Light & EM
z N/A
Math model
Math P/V curve
z N/A
Math model
Math P/V curve
z Dog
Oleic acid
lung injury
CT scan
z Human
ALI/ARDS
CT scan
z Dog
Rabbit
Rat
Normal Excised
Lungs
Morphometry
Small airway (< 300 lm) D length
& diameter with lung volume D
Alveoli : in size with lung volume D
No maximum lung volume
No D in alveolar size with
D in lung volume
Lung volume D due to :; in
alveolar number not size
Alveolar wall stretched and thus
carry force. Alveolar ducts and
alveolar walls in mechanical
equailibrium
At low lung volume alveoli expand
either by unfolding or expansion of
alveolar ducts. At high lung volumes
the basement membrane and
attached cells deform
Alveoli recruit throughout lung
inflation not only at lower Pflex.
The P/V curve did not predict
optimal ventilator setting
Best compliance during decremental,
but not incremental, PEEP is related
to open-lung PEEP
Recruitment throughout lung
inflation not just at Pflex. More
alveoli open on expiration than
inspiration at the same airway
pressure
Recruitment throughout lung
inflation not just at Pflex.
Derecruitment did not parallel
deflation
Lung folding appeared in all species
with some protocols but absent in
others. Folding depends on lung
volume history
29
z Mice
Microfocal X-ray
tomography
Lm
P/V curve
Lm
30
31
32
33
34
35
36
37
38
39
Lm: mean linear intercept; A-B: air-blood barrier; R/D: alveolar recruitment/derecruitment; P/V: lung pressure/volume curve; Pflex: inflection point on the P/V curve; N/A: not applicable; VL: Lung volume; FRC:
Functional residual capacity; TLC: Total lung capacity; D: Change
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gression line of alveolar surface area/lung volume [12]. His mathematical comparison supported uniform, isotropic alveolar expansion, however repeat calculations of
his data could not distinguish either recruitment/derecruitment or isotropic alveolar volume change as the most important mechanism of lung inflation. Subtle modifications to the postulate of isotropic change followed including ideas that alveoli
increase in volume in linear fashion with lung volume [14], alveoli undergo anisotropic expansion (i.e., unequal or asymmetrical alveolar expansion) [21], or a combination of isotropic expansion of the alveolus and alveolar duct [16]. None of
these early postulates are easily defended.
Alveolar Folding
Rather than balloon-like elastic expansion and contraction, the alveolus could
change size by folding and unfolding of the alveolar walls similar to an accordion.
An early study by Forest suggested that alveoli did not fold [14]. This work was followed by several studies that disagreed and concluded that alveoli do indeed change
volume by complex folding [15, 18±20, 34, 39]. In a theoretical model of complex
alveolar folding, alveolar surface area would not significantly change with lung inflation and thus alveolar volume and alveolar surface area would not necessarily be
related. If the alveolar surface area increased with lung expansion alveoli would
change either be stretching or recruiting.
The first demonstration of septal folding in the rabbit was by Gil and Weibel
who found ªcrumplingº of the alveolar surface and showed that the epithelium
folds back onto adjacent epithelium [18]. Gil et al. demonstrated the presence of
septal folding in fixed tissue [19]. Their photomicrographs showed heavy thickened
septa with capillaries piled upon each other. This demonstrated the potential anatomic mechanism for alveolar septal folding. Klingele and Staub [15] demonstrated
that there is no change in alveolar shape from functional residual capacity (FRC) to
total lung capacity (TLC) but at low lung volumes alveoli collapse from side to side
similar to folding of an accordion.
Oldmixon and Hoppin demonstrated that alveolar folding was seen in rat but not
dog and rabbit lungs fixed over a range of inflation pressures and inflation histories
[39]. They noted that the presence of septal folding was more related to lung volume
history that lung pressure at fixation and that there was temporal component to the
unfolding process. A transient inflation pressure of 22 cmH2O did not resolve septal
folding, but holding the pressure at 22 cmH2O (or cycling the pressure at 30 cmH2O)
did eliminate folding. The possibility of septal folding is anatomically feasible since
the curvature of the air-liquid interface in the corners of the alveolar space would allow enough ªslacknessº in the alveolus to allow septal folding [16].
Septal folding may be the prime mechanism causing distinctive inflection points
(Pflex) on the quasi-static P/V curve that are the hallmarks of lung reopening.
Tschumperlin and Margulies [34] found that at low volumes lung inflation is by
either septal unfolding or expansion of the alveolar ducts without a change in alveolar volume. At high lung volume, their data suggests that the basement membrane and attached cells deform as the lung nears physiological limits. An electron
microscope (EM) photomicrograph clearly demonstrates an alveolar fold at low
lung volume (Fig. 1). This biphasic change in alveolar size by one mechanism at
low lung volume (septal folding) and a different mechanism at high lung volume
(alveolar stretching) was support by the data obtained by Klingele and Staub [15].
The Mechanism of Ventilator-induced Lung Injury: Role of Dynamic Alveolar Mechanics
Fig. 1. Electron micrograph demonstrating septal folding (arrow) between an
alveolus (alv) and capillary (cap) at low
lung volume. Septal folding would allow
alveoli to change volume greatly without
a change in basement membrane surface area. An alternate interpretation is
volume change exclusively in the alveolar duct without a change in alveolar
volume or surface area. From [34] with
permission
Alveolar Recruitment/Derecruitment
Another possibility is that the lung changes volume by recruitment and derecruitment of large populations of alveoli. Alveoli are either open or collapsed and do
not change size with ventilation, other than by rapid opening or total collapse. To
prove the above, it would have to be shown that open alveoli do not change size
with ventilation and that there are more alveoli open at inspiration than at expiration. A number of studies have concluded that the lung changes volume primarily
by alveolar recruitment/derecruitment [22±24, 26, 28, 32].
Smaldone and coworkers [23] developed a unique technique in which they filled
excised lungs with a mono-dispersed aerosol and measured its deposition in alveoli
at zero airflow. By evaluating the relationship of particle deposition and morphometric assessment of alveolar size, they concluded that the lung inflates by a progressive recruitment of alveoli and deflates by alveolar derecruitment. In addition
they noted that at low lung volume alveoli were large and actually got smaller during inflation concomitant with an increase in alveolar number. Data from Lum and
coworkers suggested that the predominant mechanism of lung volume change is alveolar recruitment. They also observed a temporal recruitment of alveoli with application of 30 cmH2O airway pressure [24]. Specifically, alveoli recruit over time
as long as elevated airway pressure was maintained. Although not directly observed
with EM in this studies, the authors postulate that the anatomical mechanism of alveolar recruitment is septal pleating akin to previously described studies [18, 19].
Using data from postmortem, excised human lungs, Salmon et al. [26] created a
mathematical model of a P/V curve and concluded that reopening of collapsed alveoli during lung inflation is responsible for the majority of hysteresis in the P/V
curve. Boyle et al. [28] showed that the mean air space diameter declined with increased volume in rabbit lungs. This suggests that a significant amount of alveolar
recruitment had occurred. Direct visualization of subpleural alveoli during large
changes in lung volume in the living animal also suggests that the lung changes
volume by alveolar recruitment/derecruitment [22]. In vivo photomicrographs
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Fig. 2. In vivo photomicrographs of normal subpleural alveoli at residual volume
(RV), inflation to 80% of total lung capacity (TLC) and deflation to a second RV
(RV #2). The number of alveoli changed
greatly with lung volume change whereas
alveolar size changed very little. This suggests that the normal lung changes volume by alveolar recruitment/derecruitment rather than balloon-like expansion
and contraction. From [22] with permission
showed that the size of alveoli at residual volume, as compared to 80% TLC, was
not significantly different suggesting that lung volume change is due to either recruitment/derecruitment or changes in the alveolar duct (Fig. 2).
In a recent morphometric study, it was determined that changes in lung volume
are due to changes in the number of alveoli (recruitment/derecruitment) without a
change in alveolar size [32]. They further postulated that the mechanism of the
hysteresis between the inflation and deflation limb of the P/V is due to a difference
in the number of open alveoli.
Another method to determine if alveolar recruitment/derecruitment occurs is to
measure the change in alveolar size with lung inflation. If alveoli do not change size
then it can be inferred that recruitment/derecruitment may be taking place. Several
studies looked at alveolar size change with lung inflation with variable results. Mercer et al. did a three-dimensional reconstruction of alveoli and found that there
was little change in alveolar volume except at low lung volume [25]. In two recent
studies by Soutiere et al., [30, 31] it was found that the observation of alveolar size
change during lung inflation was dependent on whether fixation was by freezing
The Mechanism of Ventilator-induced Lung Injury: Role of Dynamic Alveolar Mechanics
(change) [30] or airway fixation (no change) [31]. Thus, these experiments yield
variable results in support of the lung changing volume by alveolar recruitment.
Summary of Normal Alveolar Mechanics
Although there are excellent studies suggesting that alveoli change volume in a balloon-like fashion [10±12, 14±17], we believe the best available data support the theory that the lung changes volume by either alveolar folding [15, 18±20, 34, 39] or
alveolar recruitment/derecruitment [22±24, 26, 28, 32]. Alveolar folding and recruitment/derecruitment need not be mutually exclusive. The studies investigating alveolar recruitment/derecruitment did not considered the mechanism by which the
alveolus recruits and derecruits. It is very conceivable that lung volume change is
by recruitment/derecruitment and the mechanism of alveolar collapse and opening
is through septal folding. Hopefully, new techniques such as CT will yield dynamic
three-dimensional images of alveoli and alveolar ducts to resolve this long standing
controversy [29].
z Abnormal Alveolar Mechanics
Although we are still unsure of how the normal lung changes volume, most of the
literature favors relatively stable alveoli and that other mechanisms (e.g., duct volume change, normal recruitment/derecruitment, crumpling and pleating) account
for normal lung volume change. Thus, unstable alveoli that collapse and expand
with each breath will be considered abnormal.
Early studies by both Gil et al. [19] and Bachofen et al. [20] demonstrated that
derecruitment was the dominant mechanism of lung deflation in a surfactant deactivation model of ARDS. These data are supported by a mathematical model of the
P/V curve that suggested that in ARDS the lung changes volume primarily by recruitment/derecruitment [35, 36]. Two studies measuring alveolar recruitment via a
CT scan, one in a dog model of ARDS [37], the other in humans with ARDS [38],
both support the above hypothesis that in the acutely injured lung volume change
is predominately by alveolar recruitment/derecruitment.
More recently, alveolar recruitment/derecruitment has been shown to be the predominant mechanism of lung volume change in the acutely injured lung inflated to
near TLC [18±22] as well as during tidal ventilation [43, 44]. Indirect techniques
have been used to study dynamic alveolar stability during tidal ventilation [43, 44].
Dynamic alveolar collapse and recruitment following lung injury by oleic acid, saline lavage, and endotoxin was assessed utilizing CT [43]. In all three injuries, alveoli collapse and reopen rapidly (as fast as 0.6 seconds following a breath hold)
(Fig. 3).
Grasso et al. utilized P/V curves during tidal ventilation and hypothesized that
increase in slope indicated tidal alveolar recruitment, decrease in slope indicated tidal alveolar over-inflation and a linear curve indicates normal aerated alveoli [44].
These data support those of Neumann [43] and suggest that dynamic alveolar inflation is altered in acute lung injury (ALI) during tidal ventilation.
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The Mechanism of Ventilator-induced Lung Injury: Role of Dynamic Alveolar Mechanics
Ventilator Injury and Dynamic Alveolar Mechanics
Regardless of how normal alveoli change volume with tidal ventilation, in ALI dynamic alveolar mechanics are dramatically altered [43±46]. Atelectrauma is caused
when unstable alveoli result in a shear stress induced lung injury [41]. Ventilator
settings that presumably cause alveolar recruitment/derecruitment are known to
cause VILI (i.e., high peak inspiratory pressure and low positive end-expiratory
pressure [PEEP]) [47]. Reducing tidal volume, which presumably reduces alveolar
recruitment/derecruitment has been shown to reduce mortality in patients with
ARDS [1, 5]. Our lab directly measured dynamic alveolar mechanics utilizing in
vivo microscopy and demonstrated that inappropriate ventilation of unstable alveoli
results in VILI (Fig. 4) [46].
Fig. 4. In vivo photomicrographs of the same normal alveoli at peak inspiration (a) and end expiration
(b). Normal alveoli are very stable with little change in size during tidal ventilation (dots). Injurious mechanical ventilation (High peak inspiratory pressure, low PEEP) causes a ventilator induced lung injury resulting in alveolar instability. Abnormal alveoli in an injured lung at peak inspiration (c) and end expiration (d) demonstrating severe instability with alveoli open on inspiration (dots) and collapsed on expiration (arrows)
3
Fig. 3. Computed tomography (CT) scans of lungs injured by 3 different mechanisms (Oleic acid, top; Saline Lavage, middle; Endotoxin, bottom). CT scans were obtained after 4 seconds of inspiratory hold (right)
and 4 seconds of expiratory hold (left). Note that there was more collapse during both the expiratory
and inspiratory hold in the oleic acid injured lungs (top). This suggests that the etiology of injury has an
impact on alveolar instability. From [43] with permission
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Altered dynamic alveolar mechanics may cause VILI by two mechanisms: 1)
large gross tears could be ripped in the alveolar wall, or 2) the cell membrane
maybe injured without gross tears [48±50]. In a patient subjected to very high-pressure mechanical ventilation during support for ARDS, Hotchkiss et al. found multiple large tears in the alveolar wall [48]. Gajic et al. demonstrated that injurious mechanical ventilation damaged pulmonary cell membranes and that the injury was
reversible if injurious ventilation was discontinued [49]. Injury to the cell membrane was confirmed utilizing electron microscopy that revealed ultra-structural
disruption to both pulmonary epithelium and endothelium [50]. VILI caused destruction of epithelial cells and denudation of the basement membrane. These studies suggest that altered alveolar mechanics are a primary mechanism of VILI and
that alveolar injury ranges from gross tearing to ultrastructural damage.
z Conclusion
The exact mechanism of dynamic lung volume change at the alveolar level is unknown. Postulated mechanisms of alveolar mechanics include `normal' alveolar recruitment/derecruitment, change in the size of the alveolar duct with little change
in alveolar size, and crumpling/uncrumpling of the alveolus similar to a paper bag
and balloon-like alveolar size change. It appears that normal alveoli are stable and
that with ALI alveoli become unstable and will often collapse and re-open with
every breath. This recruitment/derecruitment causes a shear stress injury that damages lung tissue leading to VILI.
More knowledge of normal and abnormal alveolar mechanics is necessary to
better understand the mechanism of VILI. This knowledge will ultimately improve
ventilator strategies leading to reduced morbidity and mortality associated with
VILI.
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