Strain heterogeneity in the injured lung: cause or consequence?

ventilation heterogeneity is an established marker of pulmonary dysfunction in asthma and other conditions such as acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI). The nonuniform delivery of inspired gas leads to regional over- and under-ventilation causing a ventilation-perfusion mismatch and a reduction in gas transfer efficiency. Ventilation heterogeneity is also an important pathogenic mechanism in VILI with the unequal distribution of gas volumes leading to localized over-distension (strain heterogeneity) at the regional, alveolar, and cellular levels even when whole lung strain is below a safe threshold. In this issue of the Journal of Applied Physiology, Paula et al. (3) use computed tomography (CT) to investigate how combinations of tidal volume (Vt) and positive end expiratory pressure (PEEP) affect different measures of strain heterogeneity in healthy pigs. The key question posed by the authors is how to define the strain responsible for lung injury. Should this metric be based on the unstressed gas volume of alveoli at zero pressure or at the expiratory pressure to which the alveoli periodically return at end-expiration?

Strain heterogeneity in the mechanically ventilated lung is a multiscale phenomenon that is represented at the organ scale by the well-established concept of “baby lung” where the collapse of small airways and alveoli (derecruitment) divides the lung into two compartments: patent and collapsed tissue. In this case it is clear that as more parenchyma is lost to atelectasis the distension (and strain) of the remaining open lung will be greater at a given tidal volume. The addition of PEEP may increase the open fraction, leading to a reduction in tidal strain referenced to the end-expiratory volume and insignificant change in strain referenced to FRC (3). Just as increases in PEEP may result in a greater volume of aerated tissue, changes in airway pressure during the ventilator cycle may lead to intratidal recruitment. This is a critical consideration in image-based assessments of regional strain that is elucidated by Paula et al. (3); without this accommodation, even in the healthy lung, the strain will be overestimated in dependent regions where intratidal recruitment occurs.

The analysis techniques provided by Paula et al. allow estimation of regional strain and regional intratidal recruitment. The combination of these metrics with quantification of regional edema, inflammation, and cellular injury may provide the key to addressing a long-standing and contentious question in the pathogenesis of lung injury—the nature of the mechanical forces that lead to injury and disruption of the blood-gas barrier. Is static strain, dynamic strain, atelectrauma, or some combination of these (or other) stimuli responsible for injury?

Ample evidence has been provided indicating that a threshold volume or pressure must be surpassed to generate injury in initially healthy animals (6). Our own work in mice has shown a tidal volume-dependent rate of injury once a threshold level of distension has been exceeded (8). At first glance this seems to indicate that the total degree of overdistension (strain referenced to FRC) is the critical factor in generating VILI, at least in initially healthy lungs. However, these studies were conducted with zero end-expiratory pressure. The addition of PEEP during high-Vt ventilation progressively reduces (5) or prevents (7, 9) injury despite similar inspiratory pressures, suggesting that the dynamic strain may be culpable for distension-induced injury.

Another possible explanation for the synergy between low PEEP and high Vt in VILI pathogenesis is that alveolar-scale heterogeneity and interdependence cause localized tissue distension and injury greater than would be predicted simply from regional or whole lung volume changes (2, 10). It is also possible that VILI is due predominantly to atelectrauma; low PEEP is necessary to allow decruitment, whereas high inspiratory pressures are required to cyclically reopen collapsed units (4). These conditions also provide high dynamic strain, of course. Nevertheless, cell membrane disruption caused by high Vt, PEEP = 0 is avoided during total liquid ventilation with similar global dynamic strain (1), further implicating atelectrauma in VILI pathogenesis.

Determining the mechanisms responsible for blood-gas barrier disruption, inflammation, and cell necrosis is a critical step in improving mechanical ventilation strategies. Without this mechanistic information we are left with the two conflicting goals of using PEEP to prevent atelectrauma and using low Vt to prevent volutrauma. Fortunately, the different mechanisms involved in these two types of injury have unique spatial distributions under different ventilatory conditions that can be identified using the techniques developed by Paula et al. (3). This provides an exciting opportunity to correlate the spatial density of lung injury to regions of high strain (referenced to both FRC and end-expiration) and cyclic recruitment, which may provide definitive evidence of the mechanistic origins of VILI.

GRANTS

This work was supported by National Heart, Lung, and Blood Institute Grant K99HL128944

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author(s).

AUTHOR CONTRIBUTIONS

B.J.S. drafted manuscript; B.J.S. edited and revised manuscript; B.J.S. approved final version of manuscript.