Patients with severe COVID-19 may develop acute respiratory failure requiring mechanical ventilation.(1) Prone positioning is a rescue therapy for ARDS patients with hypoxemia refractory to protective mechanical ventilation with high FIO2.(2)
 
In non-COVID-19 ARDS, prone positioning has been shown to improve oxygenation and is associated with improved outcomes. The improvement in oxygenation and the reduction in the risk of ventilation-induced lung injury have been explained by a more homogeneous distribution of transpulmonary pressures, which opens the dorsal atelectatic areas, thus reducing regional lung stress.(3)
 
In COVID-19 ARDS, different phenotypes have been proposed.(1) In phenotype 1, lung weight and lung compliance may be relatively normal, alveolar recruitment is minimal, and hypoxemia is mainly due to increased lung regions with low ventilation/perfusion ratios.(4) On the other hand, in phenotype 2, lung weight is increased, lung compliance is markedly reduced, alveolar recruitment is variable, and hypoxemia is mainly due to increased true shunting. Both phenotypes are characterized by increased wasted ventilation (high dead space ventilation and lung regions with high ventilation/perfusion ratios).(5) Therefore, the effects of prone positioning in COVID-19 ARDS may differ from those seen in non-COVID-19 ARDS. To date, few randomized controlled trials have reported benefits of prone positioning in COVID-19 ARDS.
 
In a study published in this issue of Jornal Brasileiro de Pneumologia, Cunha et al.(6) aimed to identify factors that lead to a positive oxygenation response and predictors of mortality after prone positioning in mechanically ventilated patients with COVID-19. A multicenter cohort study was performed across seven hospitals in Brazil, including patients with a suspected or confirmed diagnosis of COVID-19 who were on invasive mechanical ventilation, had a PaO2/FIO2 < 150 mmHg, and were prone positioned. An improvement in the PaO2/FIO2 ratio of at least 20 mmHg after the first prone positioning session was defined as a positive response. Of the 574 patients studied, 412 (72%) responded positively to the first prone positioning session. Multiple logistic regression showed that “responders” had lower Simplified Acute Physiology Score III and SOFA scores, lower D-dimer levels, and lower baseline PaO2/FIO2 ratios. Age, time to the first prone positioning session, number of sessions, pulmonary impairment, and immunosuppression were associated with increased mortality. Overall, although prone positioning led to an improvement in oxygenation, this improvement was not associated with better survival.
 
The definition of “responders” in COVID-19 patients is heterogeneous across studies,(7-9) including the use of different thresholds for response in oxygenation (e.g., a PaO2/FIO2 increase ≥ 20 mmHg; a PaO2/FIO2 increase ≥ the median percent change in PaO2/FIO2; a PaO2/FIO2 ≥ 150 mmHg after returning to the supine position) and the use of ventilatory ratio.
 
The impact of improvement in oxygenation during prone positioning on ultimate outcomes is controversial. A beneficial effect of early prone positioning on survival has been reported in patients with a PaO2/FIO2 ≤ 150 mmHg or a PaO2/FIO2 ≤ 100 mmHg.(7) Other authors(8,9) found higher mortality in nonresponders (Table 1). In the study by Cunha et al.,(6) prone positioning increased oxygenation and respiratory rate, but it was not associated with improvement in respiratory system mechanics (compliance, driving pressure, or plateau pressure).

 
In responders, prone positioning promotes alveolar recruitment with higher regional perfusion of dorsal areas. In nonresponders, prone positioning does not redistribute lung densities, and perfusion is mainly redistributed toward dependent lung regions. In COVID-19 phenotype 2, oxygenation may improve due to the redistribution of pulmonary blood flow from dorsal to ventral lung regions but not due to effective alveolar recruitment.(10)
 
Data suggest that early use of prone positioning, as well as the number of prone positioning sessions, may be associated with better outcomes.(11,12) In the study by Cunha et al.,(6) the time to prone positioning was not fixed nor was it defined a priori, which may account for the nonresponders whose first prone positioning session occurred late in the course of COVID-19, even though the number of sessions did not differ between nonresponders and responders. This can be explained by the fact that clinicians play a crucial role in decision making, individualizing the timing and number of sessions. In most previous studies, the decision to prone patients was at the discretion of the attending physician rather than being standardized across centers (Table 1).
 
Data on timing of intubation have not been reported. Yet, optimal timing of intubation has become a cornerstone in COVID-19 management and is known to be associated with outcomes. Patients with COVID-19 phenotype 1 can initially benefit from noninvasive respiratory support, since they respond better to the higher oxygen fraction and moderate PEEP levels delivered by noninvasive CPAP.(13) On the other hand, worsening of oxygenation during noninvasive respiratory support or the presence of COVID-19 phenotype 2 requires prompt and early intubation and invasive mechanical ventilation.
 
Cunha et al.(6) listed some limitations of their study, including its retrospective design (not all data could be found in the electronic medical records, and they were unable to control for the prescription and timing of prone positioning), the absence of an a priori power analysis or preplanned protocol, the small sample size, the lack of control groups, and the lack of description of other rescue therapies (e.g., inhaled nitric oxide, recruitment maneuvers, and extracorporeal membrane oxygenation), which may affect patient outcomes.
 
Overall mortality in the study by Cunha et al.(6) was 69.3%, which suggests that those patients with severe COVID-19 are at high risk of death. This mortality rate is high compared with those reported in other studies involving COVID-19 patients who underwent prone positioning (Table 1). Prone positioning is just one part of a therapeutic concept including a sophisticated ventilation strategy, strict fluid balance control, and dedicated hemodynamic management, all of which may affect outcomes.(3)
 
In conclusion, the study by Cunha et al.(6) improves our knowledge about the use of prone positioning in COVID-19 patients with severe hypoxemic respiratory failure, suggesting that this maneuver should be used early regardless of oxygenation response. However, their findings cannot be generalized without confirmation in larger randomized controlled trials.
 
AUTHOR CONTRIBUTIONS
 
DB: review and approval of the final manuscript. PP and PRMR: senior authorship and approval of the final manuscript.
 
CONFLICT OF INTEREST
 
None declared.
 
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