Effect of varying driving pressure and respiratory rate on ventilator‐induced lung injury in healthy and injured lungs: An experimental animal study

Ventilator-induced lung injury (VILI) is a major complication of mechanical ventilation. A combined index of driving pressure (DP) and respiratory rate (RR), expressed as 4DP+RR, has been proposed to predict VILI risk. We investigated whether different combinations of DP and RR, whilst keeping 4DP+RR constant, result in different degrees of VILI in healthy (Series 1) and hydrochloric acid-injured rat lungs (Series 2). Rats were ventilated for 4 h (Series 1) or 2 h (Series 2) using five combinations of DP and RR, targeting a constant 4DP+RR equal to 140. We assessed gas exchange, partitioned respiratory mechanics, lung micro-computed tomography (microCT), bronchoalveolar lavage (BAL) and alveolar tissue histology. In Series 1, the highest DP with the lowest RR, led to impaired gas exchange, compliance reduction and increased inflammation, with evidence of a threshold effect in clinical parameters and a progressive increase in histological damage. In Series 2, the lung damage progressed linearly with increasing DP and decreasing RR. Despite a constant 4DP+RR, mechanical power (MP) paradoxically decreased as DP increased. In Series 1, inflammation occurred before detectable tissue damage. A threshold effect in clinical markers (oxygenation, compliance and microCT) alongside progressively increasing histological injury suggests that early lung injury may follow a two-phase progression. In Series 2, VILI progressed linearly with increasing DP and decreasing RR despite a constant 4DP+RR load. These findings support a complex interplay between DP, RR and the spatial distribution of energy dissipation as key determinants of VILI. KEY POINTS: Ventilator-induced lung injury (VILI) is a major complication of mechanical ventilation; the index combining driving pressure (DP) and respiratory rate (RR) - 4DP+RR - has been proposed to estimate the risk of VILI. Different combinations of DP and RR, while keeping 4DP+RR constant, may exert distinct effects on lung injury. We show that higher DP with lower RR exacerbates lung injury, despite a fixed 4DP+RR, and pre-injured lungs exhibit heightened vulnerability as compared to healthy lungs. Transpulmonary DP correlates strongly with structural injury as assessed by lung micro-Computed Tomography and histology, whereas mechanical power shows an unexpected inverse trend as DP increases and RR decreases. These findings demonstrate that a fixed 4DP+RR does not ensure lung protection and highlight DPRR interactions and spatial energy dissipation as key determinants of VILI progression.