The study population consisted of 121 healthy female pigs included in previous experiments on VILI [10,11,12]. A detailed explanation of the ventilatory settings for each experiment is provided in Table 1.

The following variables were collected in each experiment at baseline, at 0.5 h after protocol initiation, and at 6 h intervals until the 48th hour. For each variable we calculated the average over the experimental period, excluding the baseline measurement, with the exception of the outcome variables, which were collected at the end of the experiment.

The respiratory mechanics variables were computed as follows:

$$\text\left(}_}, }_\text\cdot }^\right)=\frac}_}-\text}},$$

$$\text }_}, }_\text\cdot }^)=\frac}_}-}_}}},$$

$$\text \left(\text, }_\text\cdot }^\right)=\text-\text,$$

where Pawplat is plateau airway pressure, PEEP is the end-expiratory airway pressure, Pesplat is esophageal pressure measured at inspiratory plateau pause, Pesee is end-expiratory esophageal pressure measured at PEEP. Pressures are expressed in cmH2O, and tidal volume (Vt) in litres.

$$\text \left(}_},\text\cdot }_}^\right)=\frac}}_}-\text},$$

where Vt is the tidal volume (ml) and the pressures at the denominator are the same explained in the elastance formulas.

Autopsy was performed immediately after euthanasia. Lung weight was measured immediately, and six samples were collected for the lung wet-to-dry measurement. End-experiment lung weight and lung wet-to-dry ratio were used as primary outcome given that they represent and reflect the degree of lung damage induced by the ventilation. The lung wet-to-dry ratio was calculated as the ratio between the weight of the sample and its weight after 24 h of drying at 50 Celsius degrees in an oven. Ten tissue samples were obtained from each lung, equally distributed, for histological analysis. For each sample, the presence of given alterations (i.e. alveolar rupture, inflammation, alveolar oedema, and atelectasis) was expressed according to the prevalence at which the alteration was observed in the field and a score was assigned (prevalence 0–0.25, score 2; 0.25–0.50, score 4; 0.50–0.75, score 8; 0.75–1.00, score 16). The total histological score was then calculated as the sum of every singular score.

Driving pressure was computed as:

where DP is driving pressure (cmH2O), Vt is tidal volume (ml), Crs is the compliance of the respiratory system (ml · cmH2O−1).

4DPRR was computed as:

$$4\text=4\times \text+\text,$$

where DP is driving pressure (cmH2O), RR is the respiratory rate (breaths · min−1).

Mechanical power was computed as:

$$\text=0.098\times \text\times \}_}}^\times \left[\frac\times }_}+\text\times \frac:\text}:\text}\times }_}\right]+}_}\times \text\},$$

where RR is respiratory rate (breaths · min−1), Vt is the tidal volume (litres), Ers is the elastance of the respiratory system (cmH2O · l−1), Raw is the resistance of the airways (cmH2O · l−1), PEEP is the positive end-expiratory pressure (cmH2O).

Note that driving pressure is present in all the three variables (Vt times elastance equals Vt · Crs−1, i.e. driving pressure), the respiratory rate is present into 4DPRR and mechanical power; PEEP times Vt is present exclusively into mechanical power.

Mechanical power ratio was computed as:

where the expected mechanical power is computed using the normal physiological values of healthy adult pigs in according to De Robertis [13]: RR of 20 breaths · min−1, Vt of 10 ml · kg−1, Ers of 0.75 cmH2O · l−1 · kg−1, I:E of 0.5, Raw of 3.9 cmH2O · l−1 · kg−1, PEEP = 0 cmH2O.

Continuous variables are presented as mean and standard deviation. A linear regression model was employed to assess the relationship between continuous variables (predictive variables as a function of outcome variables). A multiple linear regression model, with a forward method, was used to assess the relationship between the constitutive variables of the predictive ones (i.e. tidal volume, respiratory rate and positive end-expiratory pressure) against the outcome variables. For statistical analysis R 4.3.1 (R Studio, ver. 2023.09.1 + 494, by Posit Software) was used.