Do More Injured Lungs Need More Protection? Let’s Test It

Driving pressure, calculated as the difference between plateau pressure and positive end-expiratory pressure (PEEP) during mechanical ventilation in a relaxed subject, has an independent association with the risk of death in patients with acute respiratory distress syndrome (ARDS) (1, 2), suggesting that interventions in these patients such as PEEP titration are beneficial only if associated with a decrease in driving pressure. Lung computed tomography demonstrating heterogonous aeration in ARDS typically reveals dependent nonaerated lung, which is central to both our current understanding of ventilation strategies (3) and the typical increase in respiratory system stiffness (static elastance) estimated as the driving pressure divided by the Vt. Perhaps readers will be more familiar with compliance (the inverse of elastance); both static respiratory system elastance and compliance are largely influenced by the volume of aerated lung. As both the stress and strain resulting in ventilation-induced lung injury reflect Vt and end-expiratory lung volume, targeting driving pressure makes sense, as driving pressure, in effect, scales Vt to the magnitude of the reduced lung volume for a given patient with ARDS.

In this issue of the Journal, Goligher and colleagues (pp. 1378–1385) now provide supporting data, with a secondary analysis from five randomized trials, demonstrating a significant interaction of elastance and the effect of randomized Vt on mortality (4). With the use of Bayesian multivariable logistic regression and long-term (60-d mortality) as the primary outcome, patients with higher elastance (and hence higher driving pressures) are likely to accrue a greater mortality benefit with lower Vt compared with patients with lower elastance (and hence lower driving pressures), who are likely to accrue less mortality benefit. A Subpopulation Treatment Effect Pattern Plot analysis confirmed heterogeneity of the Vt treatment effect. Although their analysis provides credence that lung-protective ventilation strategies, and perhaps PEEP selection, should primarily target driving pressure, several considerations are required to reconcile this with earlier studies.

Lower Vt appears beneficial in both healthy and injured lungs. In the pivotal ARDS Network study examining lower versus higher Vt ventilation (5), the interaction between the randomized Vts and the quartile of static compliance at baseline was not significant. Further analysis by Hager and colleagues of the ARDS Network data confirmed the lack of interaction and concluded that the benefit of lower Vt ventilation strategy was not associated with plateau pressure (6), suggesting that lower Vt was beneficial even when plateau pressure was low (and by extension, there was benefit when the elastance was also low). Analyzing a larger cohort than Hager and colleagues, Goligher and colleagues’ analysis failed to find this relationship, perhaps because of the larger sample size and more sensitive analytic approaches. The elastance-dependent effect of Vt reduction is consistent with the observation in models of ventilation-induced lung injury, in which damage is exacerbated by the degree of preexisting lung dysfunction (7). Taken together, this suggests the maximum benefit of lowering Vt is found in the most severely injured lungs.

Goligher and colleagues and Amato and colleagues used Day 1 postrandomization respiratory system elastance and driving pressure values, respectively; ideally prerandomization elastance would be used, but these values are not available for many patients in this database. This is important, as ventilation with either higher or lower Vt could alter the post-treatment elastance. For example, randomization to higher Vt overnight could result in either tidal recruitment (and reduced elastance) or early ventilator-induced lung injury (and increased elastance) and introduce bias. Moreover, respiratory system elastance in patients with ARDS is not static; it changes over time, perhaps suggesting that a prospective study examining this concept would also need to be dynamic, reflecting regular assessments of elastance.

Respiratory system elastance is composed of both lung and chest wall compliance, making it a poor surrogate for transpulmonary pressure. Multiple factors such as increased body weight, chest wall deformity, markedly positive cumulative fluid balance, and raised intraabdominal pressure, among others, can all affect the chest wall elastance and, consequently, the respiratory system elastance. The respiratory system elastance was adjusted either to the predicted or the actual body weight based on data availability in the five examined studies, but as discussed by Goligher and colleagues, the driving pressure may need to be reconsidered when chest wall elastance is abnormally elevated.

The association presented in the present article, and multiple sensitivity analyses to address some of these concerns, provide some compelling data, but design and implementation of high-quality prospective randomized clinical trials testing these findings to better inform management will be difficult. Theoretical analysis of mechanical power applied during ventilation (8), another newer approach to understanding ventilator-induced lung injury, groups driving pressure and Vt together, suggesting that it will be hard to separate the two during a clinical study. Furthermore, higher inspiratory flow rates increase mechanical power transmission, adding additional complexity to clinical trials of optimal lung protective ventilation. A contemporary usual care arm will include lower Vt ventilation and PEEP titration, noting that today’s patients are more likely to also receive prone ventilation and restrictive fluid therapy. Early appropriate antibiotics, resuscitation and mobilization, reduced transfusion-related lung injury, and early corticosteroids (9) in appropriate patients with ARDS are among many other practice changes that reduce lung damage and improve outcomes, requiring even larger clinical trial enrollment to achieve adequate power.

The current analysis suggests that elastance (and thus driving pressure) predicts the effect of treatment with lower Vt and provides additional support for targeting an upper limit for driving pressure of 15 cm H₂O. Prospective testing of such a strategy could also stratify patients based on their respiratory system elastance; those with a high elastance could then be randomized to an ultra-low Vt strategy to decrease driving pressure further, possibly coupled with the use of extra corporeal carbon dioxide removal. Similarly, patients with low elastance could be randomized to higher Vts that may be better tolerated. Until such studies are complete, the simplicity of repeated titration based on driving pressure is an attractive personalized approach as we strive to further improve outcomes from ARDS.