How we deliver energy to the lung matters: Mechanistic clues for safer ventilation

Mechanical ventilation remains a life-saving intervention for patients with severe respiratory failure, yet the very forces that facilitate gas exchange can also injure the lung. Ventilator-induced lung injury (VILI) develops when excessive stress and strain are imposed on vulnerable alveoli, and despite decades of progress in lung-protective ventilation, preventing this harm remains a central challenge in critical care. Among ventilatory parameters, driving pressure, a surrogate for tidal strain, has emerged as a key determinant of clinical outcomes, with re-analysis of previous randomized clinical trials and observational data suggesting a strong association between higher driving pressure and mortality in acute respiratory distress syndrome (ARDS) (Aoyama et al., 2018). This has prompted interest in understanding how driving pressure interacts with respiratory rate, mechanical power and energy delivery to modulate injury risk. In this issue of The Journal of Physiology, a new experimental study provides important insight into this question by examining how different combinations of driving pressure and respiratory rate influence lung injury even when a composite index is held constant (Cominesi et al., 2025). In a design reminiscent of the classic experiments by Dreyfuss et al. (1988) exploring the independent contributions of pressure and volume to pulmonary oedema, the authors employed an elegant approach to disentangle the components of mechanical energy delivery. By systematically varying driving pressure (DP) and respiratory rate (RR) across multiple ventilatory strategies, while constraining the composite index 4DP + RR to a fixed target, they were able to examine how distinct combinations of strain amplitude and frequency influence the trajectory of lung injury. Using healthy and acid-injured rat lungs, the investigators evaluated functional and structural outcomes including gas exchange, respiratory mechanics, imaging, bronchoalveolar lavage for analysis of the immune response, and histology, enabling an integrated assessment of early inflammation and tissue damage. This factorial manipulation of pressure and rate, under equivalent composite load, provides a rare opportunity to tease out the mechanistic interplay between strain magnitude and the effects of rate in the evolution of VILI. The authors observed that in both rat populations, the ventilation strategy with the highest driving pressure and lowest respiratory rate (and lowest mechanical power) resulted in the greatest degree of lung injury. These findings hold translational relevance for how clinicians conceptualize lung-protective ventilation. Although mechanical power has been proposed as an integrative marker of VILI risk, and higher mechanical power has been associated with mortality in ARDS (Costa et al., 2021), the present results challenge the assumption that ventilatory strategies with equivalent mechanical power (or the simplified surrogate 4DP + RR) necessarily produce equivalent biological injury. In these experiments, conditions with higher driving pressure and lower respiratory rate induced more inflammation and structural damage despite a constant composite load, suggesting that the pattern of energy delivery may be as important as its magnitude. It should be noted that rodent lungs differ from human lungs in size, mechanics and injury susceptibility, and some ventilatory combinations used in this study would have no correlate at the bedside. Additionally, this study did not address whether increasing respiratory rate worsens VILI for a given injurious level of driving pressure, because its design maintained a fixed 4DP + RR. Notwithstanding this, the demonstration that driving pressure may carry disproportionate injurious potential aligns with trial re-analyses indicating that mechanical power may add little information to guide protective ventilation beyond driving pressure alone (Dianti et al., 2021). Together, these observations encourage a focus on limiting tidal strain over limiting respiratory frequency at the bedside, and caution against assuming that all energy delivered to the lung is equal. This study emphasizes the need for continued investigation examining how strain amplitude and cycle frequency should be balanced in clinical ventilation strategies. If driving pressure confers a disproportionate risk relative to respiratory rate, then trials that explicitly target lower driving pressure may offer a path toward better mechanical ventilation strategies for critically ill patients. Prospective randomized trials are needed to determine whether prioritizing driving pressure reduction improves outcomes beyond conventional lung-protective ventilation. Notably, the ongoing DRIVE trial within the PRACTICAL platform is directly addressing this question by evaluating a driving pressure-limited approach in acute hypoxaemic respiratory failure (practicalplatform.org; clinicaltrials.gov/study/NCT05440851). Such trials will be essential to determine whether mechanistic insights from preclinical models translate into reductions in VILI, shorter ventilation duration and improved survival in patients. In sum, this study underscores that the risk of injury to the mechanically ventilated lung depends not only on the magnitude of energy delivered, but also the amplitude, frequency and spatial distribution of that energy. As the field moves towards precision ventilation, these findings remind us that limiting tidal strain to safe levels should remain the primary target for protective ventilation. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. No competing interests are declared. R.G.: Conception or design of the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work. G.P.: Conception or design of the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work. E.G.: Conception or design of the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work. R.A.G. was supported by an NIH/NHLBI T32 Ruth L. Kirschstein Institutional National Research Service Award (NIH 5T32HL105323-14).