American Journal of Respiratory and Critical Care Medicine

Rationale: Improved ventilation strategies have been the mainstay for reducing mortality in acute respiratory distress syndrome. Their unique clinical effectiveness is, however, unmatched by our understanding of the underlying mechanobiology, and their impact on alveolar dynamics and gas exchange remains largely speculative.

Objectives: To assess changes in alveolar dynamics and associated effects on local gas exchange in experimental models of acute lung injury (ALI) and their responsiveness to sighs.

Methods: Alveolar dynamics and local gas exchange were studied in vivo by darkfield microscopy and multispectral oximetry in experimental murine models of ALI induced by hydrochloric acid, Tween instillation, or in antibody-mediated transfusion-related ALI.

Measurements and Main Results: Independent of injury mode, ALI resulted in asynchronous alveolar ventilation characteristic of alveolar pendelluft, which either spontaneously resolved or progressed to a complete cessation or even inversion of alveolar ventilation. The functional relevance of the latter phenomena was evident as impaired blood oxygenation in juxtaposed lung capillaries. Individual sighs (2 × 10 s at inspiratory plateau pressure of 30 cm H2O) largely restored normal alveolar dynamics and gas exchange in acid-induced ALI, yet not in Tween-induced surfactant depletion.

Conclusions: We describe for the first time in detail the different forms and temporal sequence of impaired alveolar dynamics in the acutely injured lung and report the first direct visualization of alveolar pendelluft. Moreover, we identify individual sighs as an effective strategy to restore intact alveolar ventilation by a mechanism independent of alveolar collapse and reopening.

Scientific Knowledge on the Subject

Mechanical ventilation strategies are the mainstay of treatment to ensure sufficient oxygen delivery to systemic organs in patients with acute respiratory distress syndrome but may concurrently amplify lung injury. Refinement of ventilation maneuvers and strategies to alleviate ventilation-induced lung injury is, however, hampered by our lack of insight into the dynamic changes in alveolar mechanics in injured lungs.

What This Study Adds to the Field

In injured murine lungs, we identified a range of asynchronous alveolar dynamics ranging from alveolar pendelluft to complete immobilization (“stunning”) and inverse ventilation of individual alveoli. The latter phenomena negatively impact alveolocapillary gas exchange but can be rapidly reversed by individual sighs. Our findings identify asynchronous alveolar ventilation as an important cause of impaired oxygenation that can be reversed by recruitment maneuvers independent of alveolar collapse and reopening.

Impaired lung mechanics are a critical hallmark of injured lungs resulting from the combined effects of interstitial and alveolar fluid accumulation, the infiltration of inflammatory cells, and surfactant depletion on the functional unit of the lung (the alveolus) (1). Mechanical ventilation aims to counteract the detrimental effects of impaired lung mechanics on pulmonary gas exchange by appropriate ventilator settings; however, mechanical ventilation may itself further impair lung mechanics and tissue damage. Alveolar overdistention with traumatic (barotrauma/volutrauma) or proinflammatory (biotrauma) sequelae, redistribution of tidal volumes from diseased to healthy lung areas (baby lung concept), and repetitive opening and collapse of individual alveoli (atelectrauma) have been proposed to mediate such ventilator-induced lung injury (2, 3). To counteract these effects, ventilator strategies, such as high positive end-expiratory pressure (PEEP) to prevent alveolar collapse, or recruitment maneuvers to open atelectatic lung units have been developed, and are commonly used in the routine clinical setting (4). However, the functional correlates of impaired lung mechanics and the mechanistic effects of targeted ventilation maneuvers at the alveolar level have so far not been well characterized.

Currently, intravital microscopy is the only established approach with sufficient temporal and spatial resolution to assess the biomechanics of mechanical ventilation at the alveolar level. Intravital microscopic observations through an open chest preparation in rats, dogs, and pigs revealed the presence of alveolar instability, defined as repetitive recruitment and derecruitment of alveoli with each respiratory cycle, in injured lungs (57), a notion that was recently indirectly supported by magnetic resonance imaging of inhaled hyperpolarized helium in healthy human volunteers (8). Yet, our own studies in mice using a closed chest preparation revealed an overall decrease of alveolar compliance in injured lungs, but no cyclic alveolar opening and collapse (9).

To obtain a more comprehensive picture of alveolar dynamics in acute lung injury (ALI) and to assess their functional consequences on local gas exchange and their response to recruitment maneuvers, we analyzed alveolar dynamics in different murine models of ALI using our previously reported thoracic window technique (10) in combination with darkfield microscopy (9) and multispectral oxygen saturation (So2) imaging (11). Although alveolar dynamics in healthy lungs were largely uniform, we found a spectrum of alterations in injured lungs that ranged from loss of ventilation-dependent dynamics (termed alveolar stunning) to paradoxical ventilation including interalveolar pendelluft. Here, we provide a comprehensive characterization of these asynchronous alveolar ventilation patterns and show their progression along a common pathway that correlates inversely with local gas exchange, yet can be reversed for certain types of ALI by short individual sighs. Some of the results of these studies have been previously reported in the form of abstracts (12, 13).

Animals, Surgical Preparation, and Intravital Microscopy

Details are provided in the online supplement. Experiments were performed in male Balb/c and severe combined immunodeficient mice. Lung intravital microscopy was performed in anesthetized mice through a resealed thoracic window as described (911). Alveolar dynamics and local blood So2 were visualized by darkfield microscopy (9) and multispectral oximetry (11).

Experimental Protocols

ALI was induced by intratracheal instillation of hydrochloric acid (pH, 1.5; 2 ml/kg body weight) (9); surfactant depletion by instillation of Tween (1.6%, 2 ml/kg body weight) (14); or as model of transfusion-related ALI, by intravenous injection of 31-1-2s monoclonal antibody against H-2Kd and H-2Dd major histocompatibility class I molecules (2 mg/kg) into severe combined immunodeficient mice (15). Alveolar dynamics were imaged at baseline, and after ALI induction for 90–150 minutes. In randomly selected regions of interest, the focal plane was sequentially set for the end-expiratory and end-inspiratory plateau phases, and image series of alveolar dynamics were obtained for each plateau phase. The frequency of asynchronous alveolar ventilation was determined as percentage of all visualized alveoli 15 minutes after ALI induction. For temporal profiles, single regions of interest were continuously recorded for 150 minutes. To analyze the response to recruitment maneuvers, baseline alveolar dynamics and So2maps were recorded at baseline and 90 minutes after induction of ALI, followed by two successive sighs at 30 cm H2O pressure for 10 seconds each and a third data recording. PEEP was maintained at 1 cm H2O throughout all protocols.

Data Analysis

Intravital microscopy recordings from intact and injured lungs were analyzed off-line, and the subpleural area (A) of each alveolar cluster was planimetrically measured (9). Alveolar cluster volume (V) was estimated as V = 4/3 · π · A3/2 assuming spherical geometry. Alveolar tidal volume (Vta) was calculated as difference between end-inspiratory and end-expiratory volume. Alveoli were classified according to their volume change during the respiratory cycle (Table 1): at baseline, alveoli showed the previously reported characteristic expansion during inspiration and retraction during expiration (i.e., end-inspiratory > end-expiratory volume), whereas alveolar size remained unchanged during the end-inspiratory and end-expiratory plateau phases (9). This behavior was defined as normal. In injured lungs, some alveoli showed paradoxical motions during the inspiratory and expiratory plateau phase (and between inspiration and expiration, vide infra), which was classified as pendelluft.

Table 1. Classification of Alveolar Dynamics

    

Definition of abbreviation: Vta = alveolar tidal volume.

Alveoli were classified according to their dynamics during the inspiratory or expiratory plateau phase, or according to their individual change in tidal volume (Vta) relative to baseline, respectively. At baseline, most alveoli showed expansion during inspiration and no change in size during the plateau phases, which was defined as normal alveolar dynamics. In injured lungs, pendelluft was evident as paradoxical motion during both the end-inspiratory and the end-expiratory plateau phase. Classification based on changes in Vta discriminated between unimpaired alveoli (Vta > 25% of baseline), alveoli with stunning (−25% < Vta < 25% of baseline), and alveoli with inverse ventilation (Vta < −25%).

Alveoli were further classified into three groups based on their Vta after injury relative to their individual Vta at baseline (100%): unimpaired describes alveoli with a Vta greater than 25% of the individual baseline, stunning alveoli in which Vta decreased to less than 25%, and inverse ventilation alveoli with negative Vta of greater than 25% of the individual baseline. Notably, the latter phenomenon also reflects a form of paradoxical motion, yet we deliberately reserved the term pendelluft for those alveoli where the paradoxical motion also occurred during the plateau phases (rather than between inspiration and expiration) and thus, could be directly visualized. Two-dimensional So2 maps were generated as previously described (11), and mean So2 in the juxtaposed capillary network was measured.

ALI Causes Alveolar Pendelluft in Murine Lungs

Darkfield intravital microscopy of mechanically ventilated mouse lungs allowed for direct visualization of subpleural alveolar clusters and their dynamics. In intact lungs, all visualized alveoli underwent cyclic changes in size in synchrony with the ventilatory cycle, whereas alveolar recruitment/derecruitment or asynchronous alveolar dynamics were absent. This coordinated pattern changed within 10 minutes after ALI induction by acid instillation, because individual alveoli started to display paradoxical motion in that they slowly inflated during the end-expiratory plateau phase and deflated during the end-inspiratory plateau (Figures 1A and 1B; see Video E1 in the online supplement). Temporal profile analyses showed that paradoxical volume changes in individual alveoli during the plateau phase were inversely opposed to those of normal alveoli within the same observation field (Figure 2A).

This behavior is in-line with the classic hypothetical concept of alveolar gas transfer between groups of alveoli with asynchronous ventilation (16), and we accordingly termed it alveolar pendelluft. Paradoxical air movement in pendelluft alveoli was not only evident during the plateau phases, but also over the full respiratory cycle, in that pendelluft alveoli had a lesser volume in end-inspiration than in end-expiration, whereas normal alveoli showed the characteristic higher volume in end-inspiration as compared with end-expiration (Figure 2B). Normal alveoli directly adjacent to pendelluft alveoli showed a trend toward higher volume changes as compared with more remote alveoli, which were separated from pendelluft alveoli by at least one intermittent alveolus (Figure 2B). This finding is essentially in line with the concept of pendelluft that implies a functional pair of reciprocally inflating/deflating units. Yet, the difference between adjacent and remote normal alveoli did not reach statistical significance, presumably because the combined volume of adjacent normal alveoli exceeds that of a single pendelluft alveolus by far. At rare occasions, however, a reciprocating displacement of gas volume could be seen between a pair of juxtaposed alveoli during the plateau phase (see Video E2), consolidating that the observed phenomenon truly reflects a pendulum-like shift between two adjacent units.

Alveoli with pendelluft behavior were detectable at roughly comparable frequencies in three different models of ALI: (1) acid aspiration injury, (2) Tween-lavage injury, and (3) antibody-mediated transfusion-related ALI (Figure 2C). Lavage with varying Tween concentrations resulted in a dose-dependent increase in pendelluft events over a range of 0.5–3%, suggesting that the prevalence of pendelluft is related to the severity of lung injury (Figure 2D). To determine the time course of alveolar pendelluft, we continuously recorded alveolar dynamics in a defined region of interest on the surface of an acid-injured lung over 2.5 hours. In most cases, alveolar pendelluft was a transient phenomenon that appeared within 10 minutes after ALI induction and resolved again over the subsequent 5–60 minutes (Figure 3A). Occasionally, alveolar pendelluft developed at later time points (>1 h), either in alveoli that had earlier shown pendelluft, or in previously normal alveoli. Alveolar pendelluft had no direct impact on alveolar gas exchange as revealed by multispectral So2 mapping, which showed no decrease in hemoglobin So2 in the vicinity of pendelluft alveoli (Figure 3B). After transient episodes of pendelluft, alveoli would typically return to a physiologic motion in synchrony with the respiratory cycle; yet occasionally alveoli with pendelluft would come to a complete stop (i.e., maintain a fixed volume over the entire respiratory cycle) and were then classified as alveolar stunning (Figure 3C; see Video E3).

Alveolar Stunning and Inverse Ventilation

Ninety minutes after induction of acid-induced ALI, we compared Vta of alveolar clusters with their individual baseline. At baseline, more than 95% of alveoli showed Vta greater than zero (i.e., motion in synchrony with the respiratory cycle) (Figure 4A). Acid-induced ALI caused a distinct reduction in mean Vta, evident as a left shift in the frequency histogram with a substantial percentage (27.6%) of alveoli showing Vta less than zero indicating asynchronous ventilation. We classified each alveolus in injured lungs based on its Vta relative to baseline as either unimpaired if Vta in the injured alveolus exceeded 25% of its baseline; stunning if Vta was less than 25% of the baseline value, or as inverse ventilation if Vta was greater than 25% but inverse to the respiratory cycle (i.e., higher Vta at end-expiration than end-inspiration). In control lungs instilled with 2 ml/kg saline, more than 90% of alveoli showed unimpaired dynamics after 2 hours; in acid-injured lungs, however, almost 50% of alveoli showed either stunning or inverse ventilation (Figure 4B).

To test the functional consequences of such impaired alveolar dynamics on local alveolocapillary gas exchange, we again applied multispectral So2 mapping (Figure 4C). As previously reported (11), So2 maps of the in vivo mouse lung showed pulmonary arteriolar vessel trees carrying deoxygenated blood (in blue or green) that became rapidly oxygenated (red) in the densely capillarized alveolar area in intact lungs. In acid-injured lungs with impaired alveolar dynamics (either alveolar stunning or inverse ventilation), alveolar gas exchange was significantly impaired resulting in reduced and heterogeneous oxygenation (Figure 4D), which was paralleled by a drop in PaO2 from 427 ± 9 to 189 ± 39 mm Hg (P < 0.05) and a concomitant increase in PaCO2 from 29.7 ± 2.6 to 45.2 ± 4.7 mm Hg (P < 0.05).

Effect of Individual Sighs on Alveolar Dynamics

To probe for the effects of simple recruitment maneuvers on alveolar dynamics in the acid-injured lung, we next performed two successive sighs (30 cm H2O pressure) for 10 seconds each, 90 minutes after acid instillation. These individual sighs markedly reduced the relative frequency of alveoli with stunning or inverse ventilation, whereas unimpaired alveolar dynamics increased proportionally (Figure 4B). Accordingly, ventilation-synchronous Vta increased in response to sighs, as demonstrated by a right shift and normalization of the respective frequency distribution (Figure 4A). This restoration of alveolar dynamics and tidal volume was associated with an improvement in local and global gas exchange as signified by higher hemoglobin So2 in alveolar capillary networks (Figures 4C and 4D), a reduction in PaCO2 from 45 ± 4.7 to 30.1 ± 4.4 mm Hg (P < 0.05), and a trend toward an increase in PaO2 from 189 ± 39 to 219 ± 37 mm Hg (P = 0.08). The association between improvements in alveolar dynamics and gas exchange is highlighted by a near-linear correlation between the respective changes in both parameters in response to ALI induction and sighs, respectively (Figure 4E).

To further probe the effectiveness of sighs to reverse impaired alveolar dynamics, we applied a second model of ALI induced by alveolar instillation of 1.6% Tween. Similar to acid instillation, Tween impaired alveolar dynamics (i.e., it induced inverse ventilation and stunning in a subset of alveoli that was associated with reduced alveolar gas exchange) (Figures 5A–5D). However, in this model of surfactant depletion, sighs failed to correct alveolar dynamics (no significant difference between Tween and sighs in Figures 5A and 5B) and achieved only a minor improvement in lung capillary oxygenation (1.0%) that was significantly (P < 0.001) lower compared with the rescue of oxygenation in acid-induced ALI (4.6%) (Figure 5D).

Here, we report different forms of asynchronous alveolar ventilation and their functional consequences on gas exchange in experimental ALI. Individual alveoli of injured lungs show asynchronous ventilation consistent with the classic concept of pendelluft, which we demonstrate for the first time at the alveolar level. Alveolar pendelluft was evident in all studied forms of ALI without directly impacting on alveolar gas exchange, is transient in nature, and either spontaneously resolves or progresses to a relative immobilization of alveoli termed alveolar stunning. Ninety minutes after ALI induction, approximately 30–50% of alveoli show either stunning or inverse ventilation, which at this stage is associated with impaired capillary oxygenation and total gas exchange. Individual sighs restore normal alveolar dynamics and improve gas exchange in acid-induced ALI, pointing toward a previously unrecognized beneficial effect of recruitment maneuvers that is independent of alveolar collapse and reopening.

Impaired Alveolar Dynamics

Altered alveolar dynamics are a key pathologic feature in ALI that not only impairs respiratory mechanics and alveolar gas exchange, but by requiring high distending pressures, and by excessive strain and shear forces between and within alveoli, contributes to the progression and aggravation of lung disease. Previous stereometric analyses have identified the aerated rather than the atelectatic lung regions as predominant site of alveolar injury (17). Accordingly, concepts of impaired alveolar dynamics and appropriate ventilator strategies have focused at large on alveolar overdistention, or on cyclic opening and collapse of injured alveoli where alveoli are either fully collapsed or liquid-filled in expiration but become cyclically aerated during inspiration. The latter phenomenon has been studied by intravital microscopy (18) and magnetic resonance imaging of hyperpolarized gases (8) in experimental animals or computed tomography in ventilated patients (19). However, biomechanical considerations (20) and direct visualization of alveolar dynamics (9) have recently challenged the regular occurrence of cyclic alveolar opening and collapse in injured lungs.

In contrast, we report here a new set of asynchronous alveolar dynamics that are common to various forms of ALI and range from transient paradoxical motions to complete stops or even inversions of regular alveolar dynamics. Transient paradoxical motions were evident during both the end-inspiratory and end-expiratory plateau phase. As flow from the ventilator is stopped during the plateau phases, these motions reflect gas transfer between adjacent respiratory units rather than in and out of the lung. The existence of such paradoxical gas transfer was originally postulated by Otis and colleagues (16) for conditions of heterogeneous time constants, and was termed pendelluft (i.e., a pendulum-like movement of air between adjacent respiratory units). Here, we report the first direct observation of pendelluft at the level of individual alveoli. Notably, we reserved the term pendelluft for asynchronous alveolar dynamics during the end-inspiratory or -expiratory plateau phase, following the definition by Otis and colleagues (16) who related this phenomenon to end-inspiration or -expiration when tracheal flow has dropped to zero.

Although pendelluft is nowadays also used to describe asynchronous gas transfer during the dynamic phase of the respiratory cycle, we termed the later phenomenon inverse ventilation (discussed later) to differentiate it from pendelluft. Overt pendelluft with paradoxical motion during both the end-inspiratory and the end-expiratory phase was regularly observed in all tested models of ALI, but never in healthy control lungs. Alveolar pendelluft was, however, not directly associated with impaired local gas exchange. This result may seem surprising, because air reciprocating between respiratory units by definition changes alveolar gas composition and increases functional dead space. However, alveolar pendelluft is generally a solitary event that affects only 5% of alveoli. The effect on alveolar gas composition of the surrounding alveoli and capillary oxygenation is hence modest, in particular during ventilation with 100% O2. Notably, this situation is in stark contrast to the subsequent development of inverse ventilation, which similarly reflects paradoxical alveolar ventilation, yet together with coincidental alveolar stunning affects approximately 50% of alveoli and thus, ultimately results in an oxygenation deficit.

Alveolar pendelluft is transient in nature and commonly reversible, yet occasionally proceeds to a second stage where alveolar ventilation virtually stops or inverts. Video E3 catches the very moment where an alveolus converts from pendelluft to stunning. The limited area of microscopic observation at any single time point did not allow us to determine whether all alveoli with stunning or inverse ventilation had previously shown pendelluft. However, because alveolar pendelluft only affects 5% of alveoli at a given time point and in most cases reverts back to normal ventilation, it seems probable that alveoli also switch directly from normal dynamics to stunning or inverse ventilation, although such a transition was not directly captured. Ninety minutes after induction of ALI, 30–45% (in Tween- and acid-induced ALI, respectively) of alveoli showed severely impaired motion, which compromised regional alveolar gas exchange. Approximately half of these alveoli had very small Vta (stunning), whereas the other half showed negative Vta (inverse ventilation). The mechanisms underlying alveolar stunning and inverse ventilation are probably multifactorial involving mechanical interdependence of air spaces (21), surfactant depletion, interstitial edema, and occlusion of proximal airways to varying degrees depending on the model and time course of ALI.

Taken together, ALI causes progressive impairment of alveolar dynamics from intact motion to alveolar pendelluft to stunning and inverse ventilation (Figure 6). Asynchronous alveolar ventilation may not only contribute to increased dead space, low ventilation-perfusion matching, and gas exchange abnormalities in acute respiratory distress syndrome (ARDS), but also promote the progression of lung injury. Asynchronous alveolar dynamics can involve cyclic opening of collapsed bronchi, fracture of liquid bridges, and/or displacement of foam plugs proximal to an alveolus during the respiratory cycle. The mechanical forces exerted by the resulting interfacial stresses would suffice to cause significant biophysical cell injury (22, 23). Consistent with this view, adult lungs show more heterogeneous alveolar distention than infant lungs, which arguably predisposes them for asynchronous ventilation, and are concomitantly more susceptible for ventilator-induced lung injury (24).

Effect of Sighs

Sighs are commonly defined as brief increases in inspiratory ventilation pressure that have been shown to improve oxygenation and lung mechanics in patients with ARDS or animal models of ALI, respectively (2527). Specifically, sighs of 30 cm H2O as used in the present study have been demonstrated to improve lung function and reduce inflammation in ventilated mice (28). Sighs are considered to act as brief recruitment maneuvers in that they counteract alveolar collapse at low tidal volume ventilation, and open up atelectatic lung areas. Here, we report a previously unrecognized mechanism by which sighs can improve local lung mechanics and gas exchange in that two individual sighs delivered in short succession restored normal alveolar dynamics in acid-injured lungs. These beneficial effects were not attributable to opening of collapsed alveoli and did not require high PEEP levels. Reversal of alveolar stunning or inverse ventilation to unimpaired alveolar dynamics was closely associated with improvements in both regional and total gas exchange.

Several mechanisms may account for the normalization of alveolar dynamics. First, sighs may open up collapsed airways, and/or disrupt fluid bridges, thereby reestablishing an air continuum between the alveolus and the upper airways (29). Second, sighs may remove fluid from partially liquid-filled alveoli (30), thereby increasing the effective gas-filled diameter of the alveolus, decreasing alveolar surface tension, and increasing alveolar compliance (31). Third, similarly, sighs may remove fluid from the interstitial space, thereby improving alveolar compliance and alveolocapillary gas exchange. PEEP levels of 10–20 cm H2O have been shown to reduce extravascular lung water and increase lymphatic flow through the thoracic duct (32). Although sighs in the present study were only transient, similar mechanisms may theoretically apply. Finally, sighs may stimulate surfactant secretion via stretch-dependent release of lamellar bodies from alveolar type II cells (33, 34). Surfactant secretion in spontaneously breathing cats correlates directly with the frequency of spontaneous large “gasps,” the physiologic equivalent of sighs (35). The notion of sigh-induced surfactant release is in line with the fact that sighs failed to restore alveolar dynamics and gas exchange in Tween-induced ALI. As Tween is instilled and remains in the alveolar space in this model, it deactivates not only surfactant in the epithelial lining fluid at the time of injury induction, but also all subsequently released surfactant. However, the situation is probably more complex because 90 minutes after Tween lavage the model has likely progressed from one of alveolar surface tension reduction to one of ventilator-induced lung injury (36), and because sighs alone not always suffice to increase surfactant production or release as compared with conventional ventilation (37).

Several model-immanent restrictions should be considered that may potentially impact our findings. First, intravital microscopy, while capturing alveolar dynamics with unmatched spatial and temporal resolution, is restricted to the analysis of subpleural alveoli. To address this limitation, we previously compared intravital microscopic images from the lung surface with alveolar dynamics in deeper or more central lung regions as obtained by optical coherence tomography (9) or endoscopic confocal laser scanning microscopy (38). Importantly, all three techniques yielded essentially similar and comparable data on alveolar size and shape changes during the respiratory cycle. That notwithstanding, frequency and extent of heterogeneous and asynchronous alveolar ventilation may differ quantitatively between superficial and more central lung areas as a result of the different biomechanical environment.

Second, mice were ventilated in left decubitus position with relatively low PEEP levels of 1 cm H2O, which bear the risk for progressive formation of atelectasis (39), preferentially in dependent lung zones. Because dependent atelectasis may become recruited by sighs, this effect can have contributed to the beneficial effects of sighs on global gas exchange in acid-injured lungs. Dependent atelectasis, however, did not impact on the intravital microscopic analyses, because (1) mice were ventilated in a pressure- rather than volume-controlled mode; (2) intravital microscopic observations were performed on the apical surface of the lung; and (3) our study highlights the development of asynchronous alveolar dynamics in individual alveoli, which cannot be explained by global changes in lung biomechanics. Third, caution is generally warranted when extrapolating data from short-term, well-defined animal models to the clinical situation. Although basic morphologic and physiologic principles of respiratory dynamics equally apply across all mammalian species, important variables affecting alveolar dynamics, such as fluid accumulation, inflammation, and disease heterogeneity, may vary considerably between animal models and clinical settings.

In view of these limitations, any translation of the present data to the clinical scenario has to be considered with due caution. Our findings suggest that individual sighs may provide physiologic benefit in clinical scenarios of impaired alveolar dynamics independent of their ability to open-up collapsed alveoli. In the past, recruitment maneuvers of various amplitude, duration, and frequency have been tested in numerous clinical trials in ARDS with mixed results (40, 41). As a consequence, the routine use of recruitment maneuvers is currently not recommended. Short individual sighs in the absence of high PEEP may potentially provide a safe and effective way to restore normal alveolar dynamics with a reduced risk for the adverse effects associated with classic recruitment maneuvers, such as overdistention or hemodynamic alterations. However, deep inflation maneuvers essentially similar to our sighs, albeit higher in amplitude, have also been found to exert detrimental effects in that they can sustain inflammatory responses, exacerbate lung vascular dysfunction (42), and cause hyperinflation and apoptosis of renal and pulmonary cells in severe, yet not in moderate lung injury (43). That notwithstanding, asynchronous alveolar ventilation should be taken into account as an important, previously unrecognized mechanism of impaired lung function and gas exchange that may potentially be counteracted by appropriate ventilatory maneuvers, such as sighs.

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Correspondence and requests for reprints should be addressed to Wolfgang M. Kuebler, M.D., Dr. Med., Keenan Research Centre for Biomedical Science, St. Michael's Hospital, 209 Victoria Street, Toronto, ON, M5B 1W8 Canada. E-mail:

Supported by grant KU 1218/4-2 as part of the package application “Protective Ventilation” by the German Research Foundation (W.M.K.) and by Health Canada/Canadian Blood Services Priority Research grants (W.M.K. and J.W.S.).

Author Contributions: Conception and study design, A.T. and W.M.K. Data acquisition, analysis, and interpretation, A.T., H.T.N., M.K., J.W.S., E.K., L.B., A.S.S., A.R.P., and W.M.K. Drafting manuscript, A.T., L.B., A.S.S., and W.M.K.

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Originally Published in Press as DOI: 10.1164/rccm.201505-0901OC on October 29, 2015

Author disclosures are available with the text of this article at www.atsjournals.org.

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