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Background We hypothesized that as CARDS may present different pathophysiological features than classic ARDS, the application of high levels of end-expiratory pressure is questionable. Our first aim was to investigate the effects of 5–15 cmH 2 O of PEEP on partitioned respiratory mechanics, gas exchange and dead space; secondly, we investigated whether respiratory system compliance and severity of hypoxemia could affect the response to PEEP on partitioned respiratory mechanics, gas exchange and dead space, dividing the population according to the median value of respiratory system compliance and oxygenation. Thirdly, we explored the effects of an additional PEEP selected according to the Empirical PEEP-FiO 2  table of the EPVent-2 study on partitioned respiratory mechanics and gas exchange in a subgroup of patients. Methods Sixty-one paralyzed mechanically ventilated patients with a confirmed diagnosis of SARS-CoV-2 were enrolled (age 60 [54–67] years, PaO 2 /FiO 2  113 [79–158] mmHg and PEEP 10 [10–10] cmH 2 O). Keeping constant tidal volume, respiratory rate and oxygen fraction, two PEEP levels (5 and 15 cmH 2 O) were selected. In a subgroup of patients an additional PEEP level was applied according to an Empirical PEEP-FiO 2  table (empirical PEEP). At each PEEP level gas exchange, partitioned lung mechanics and hemodynamic were collected. Results At 15 cmH 2 O of PEEP the lung elastance, lung stress and mechanical power were higher compared to 5 cmH 2 O. The PaO 2 /FiO 2 , arterial carbon dioxide and ventilatory ratio increased at 15 cmH 2 O of PEEP. The arterial–venous oxygen difference and central venous saturation were higher at 15 cmH 2 O of PEEP. Both the mechanics and gas exchange variables significantly increased although with high heterogeneity. By increasing the PEEP from 5 to 15 cmH 2 O, the changes in partitioned respiratory mechanics and mechanical power were not related to hypoxemia or respiratory compliance. The empirical PEEP was 18 ± 1 cmH 2 O. The empirical PEEP significantly increased the PaO 2 /FiO 2  but also driving pressure, lung elastance, lung stress and mechanical power compared to 15 cmH 2 O of PEEP. Conclusions In COVID-19 ARDS during the early phase the effects of raising PEEP are highly variable and cannot easily be predicted by respiratory system characteristics, because of the heterogeneity of the disease.

Positive end-expiratory pressure in COVID-19 acute respiratory distress syndrome: the heterogeneous effects