Rationale: Unphysiologic strain (the ratio between tidal volume and functional residual capacity) and stress (the transpulmonary pressure) can cause ventilator-induced lung damage. Objectives: To identify a strain–stress threshold (if any) above which ventilator-induced lung damage can occur. Methods: Twenty-nine healthy pigs were mechanically ventilated for 54 hours with a tidal volume producing a strain between 0.45 and 3.30. Ventilator-induced lung damage was defined as net increase in lung weight. Measurements and Main Results: Initial lung weight and functional residual capacity were measured with computed tomography. Final lung weight was measured using a balance. After setting tidal volume, data collection included respiratory system mechanics, gas exchange and hemodynamics (every 6 h); cytokine levels in serum (every 12 h) and bronchoalveolar lavage fluid (end of the experiment); and blood laboratory examination (start and end of the experiment). Two clusters of animals could be clearly identified: animals that increased their lung weight (n = 14) and those that did not (n = 15). Tidal volume was 38 ± 9 ml/kg in the former and 22 ± 8 ml/kg in the latter group, corresponding to a strain of 2.16 ± 0.58 and 1.29 ± 0.57 and a stress of 13 ± 5 and 8 ± 3 cm H₂O, respectively. Lung weight gain was associated with deterioration in respiratory system mechanics, gas exchange, and hemodynamics, pulmonary and systemic inflammation and multiple organ dysfunction. Conclusions: In healthy pigs, ventilator-induced lung damage develops only when a strain greater than 1.5–2 is reached or overcome. Because of differences in intrinsic lung properties, caution is warranted in translating these findings to humans.

Tidal volume (VT) and volume of gas caused by positive end-expiratory pressure (VPEEP) generate dynamic and static lung strains, respectively. Our aim was to clarify whether different combinations of dynamic and static strains, resulting in the same large global strain, constantly produce lung edema. Laboratory investigation. Animal unit. Twenty-eight healthy pigs. After lung computed tomography, 20 animals were ventilated for 54 hours at a global strain of 2.5, either entirely dynamic (VT 100% and VPEEP 0%), partly dynamic and partly static (VT 75–50% and VPEEP 25–50%), or mainly static (VT 25% and VPEEP 75%) and then killed. In eight other pigs (VT 25% and VPEEP 75%), VPEEP was abruptly zeroed after 36–54 hours and ventilation continued for 3 hours. Edema was diagnosed when final lung weight (balance) exceeded the initial weight (computed tomography). Mortality, lung mechanics, gas exchange, pulmonary histology, and inflammation were evaluated. All animals ventilated with entirely dynamic strain (VT 825 ± 424 mL) developed pulmonary edema (lung weight from 334 ± 38 to 658 ± 99 g, p < 0.01), whereas none of those ventilated with mainly static strain (VT 237 ± 21 mL and VPEEP 906 ± 114 mL, corresponding to 19 ± 1 cm H2O of positive end-expiratory pressure) did (from 314 ± 55 to 277 ± 46 g, p = 0.65). Animals ventilated with intermediate combinations finally had normal or largely increased lung weight. Smaller dynamic and larger static strains lowered mortality (p < 0.01), derangement of lung mechanics (p < 0.01), and arterial oxygenation (p < 0.01), histological injury score (p = 0.03), and bronchoalveolar interleukin-6 concentration (p < 0.01). Removal of positive end-expiratory pressure did not result in abrupt increase in lung weight (from 336 ± 36 to 351 ± 77 g, p = 0.51). Lung edema forms (possibly as an all-or-none response) depending not only on global strain but also on its components. Large static are less harmful than large dynamic strains, but not because the former merely counteracts fluid extravasation.

Venovenous extracorporeal membrane oxygenation (vv-ECMO) has been classically employed as a rescue therapy for patients with respiratory failure not treatable with conventional mechanical ventilation alone. In recent years, however, the timing of ECMO initiation has been readdressed and ECMO is often started earlier in the time course of respiratory failure. Furthermore, some centers are starting to use ECMO as a first line of treatment, i.e., as an alternative to invasive mechanical ventilation in awake, non-intubated, spontaneously breathing patients with respiratory failure (“awake” ECMO). There is a strong rationale for this type of respiratory support as it avoids several side effects related to sedation, intubation, and mechanical ventilation. However, the complexity of the patient–ECMO interactions, the difficulties related to respiratory monitoring, and the management of an awake patient on extracorporeal support together pose a major challenge for the intensive care unit staff. Here, we review the use of vv-ECMO in awake, spontaneously breathing patients with respiratory failure, highlighting the pros and cons of this approach, analyzing the pathophysiology of patient–ECMO interactions, detailing some of the technical aspects, and summarizing the initial clinical experience gained over the past years.

Objective: Lungs behave as viscoelastic polymers. Harms of mechanical ventilation could then depend on not only amplitude (strain) but also velocity (strain rate) of lung deformation. Herein, we tested this hypothesis. Design: Laboratory investigation. Setting: Animal unit. Subjects: Thirty healthy piglets. Interventions: Two groups of animals were ventilated for 54 hours with matched lung strains (ratio between tidal volume and functional residual capacity) but different lung strain rates (ratio between strain and inspiratory time). Individual strains ranged between 0.6 and 3.5 in both groups. Piglets ventilated with low strain rates had an inspiratory-to-expiratory time ratio of 1:2–1:3. Those ventilated with high strain rates had much lower inspiratory-to-expiratory time ratios (down to 1:9). Respiratory rate was always 15 breaths/min. Lung viscoelastic behavior, with ventilator setting required per protocol, was “quantified” as dynamic respiratory system hysteresis (pressure-volume loop [in Joules]) and stress relaxation (airway pressure drop during an end-inspiratory pause [in cm H₂O]). Primary outcome was the occurrence of pulmonary edema within 54 hours. Measurements and Main Results: On average, the two study groups were ventilated with well-matched strains (2.1 ± 0.9 vs 2.1 ± 0.9; p = 0.864) but different strain rates (1.8 ± 0.8 vs 4.6 ± 1.5 s^–1; p < 0.001), dynamic respiratory system hysteresis (0.6 ± 0.3 vs 1.4 ± 0.8 J; p = 0.001), and stress relaxation (3.1 ± 0.9 vs 5.0 ± 2.3 cm H₂O; p = 0.008). The prevalence of pulmonary edema was 20% among piglets ventilated with low strain rates and 73% among those ventilated with high strain rates (p = 0.010). Conclusions: High strain rate is a risk factor for ventilator-induced pulmonary edema, possibly because it amplifies lung viscoelastic behavior.

High tidal volume can cause ventilator-induced lung injury (VILI), but positive end-expiratory pressure (PEEP) is thought to be protective. We aimed to find the volumetric VILI threshold and see whether PEEP is protective per se or indirectly. In 76 pigs (22 ± 2 kg), we examined the lower and upper limits (30.9–59.7 mL/kg) of inspiratory capacity by computed tomography (CT) scan at 45 cmH2O pressure. The pigs underwent a 54-h mechanical ventilation with a global strain ((tidal volume (dynamic) + PEEP volume (static))/functional residual capacity) from 0.45 to 5.56. The dynamic strain ranged from 18 to 100 % of global strain. Twenty-nine pigs were ventilated with end-inspiratory volumes below the lower limit of inspiratory capacity (group “Below”), 38 within (group “Within”), and 9 above (group “Above”). VILI was defined as death and/or increased lung weight. “Below” pigs did not develop VILI; “Within” pigs developed lung edema, and 52 % died before the end of the experiment. The amount of edema was significantly related to dynamic strain (edema 188–153 × dynamic strain, R 2 = 0.48, p < 0.0001). In the “Above” group, 66 % of the pigs rapidly died but lung weight did not increase significantly. In pigs ventilated with similar tidal volume adding PEEP significantly increased mortality. The threshold for VILI is the lower limit of inspiratory capacity. Below this threshold, VILI does not occur. Within these limits, severe/lethal VILI occurs depending on the dynamic component. Above inspiratory capacity stress at rupture may occur. In healthy lungs, PEEP is protective only if associated with a reduced tidal volume; otherwise, it has no effect or is harmful.