Acute respiratory failure is the most common cause of death in patients with coronavirus disease 2019 (COVID-19) (1). Comparable with non-COVID-19–related acute respiratory distress syndrome (ARDS) formation of consolidated atelectasis with concomitant hypoxemia refractory to conventional mechanical ventilation with high Fio2 has been considered as the most decisive pathophysiologic mechanism (2). Accordingly, widely accepted recommendations for the treatment of ARDS such as prone positioning have been applied for the treatment of COVID-19–related respiratory failure in the absence of specific therapeutic options despite a lack of evidence (3).
In ARDS, prone positioning has been shown to improve gas exchange in several studies (4). The most important underlying mechanism is probably a homogenization of transpulmonary pressures resulting in a recruitment of dorsal atelectatic areas thereby reducing ventilation-perfusion mismatch and intrapulmonary right-to-left shunt. In a landmark study by Guérin et al (5), prone positioning within 36 hours after the onset of mechanical ventilation reduced mortality from 33% to 16% in severe ARDS with a Pao2/Fio2 less than 150 mm Hg. Notably, prone positioning in this so-called Proning Severe ARDS Patients (PROSEVA) trial was conducted in well experienced ARDS centers and performed for at least 16 hours. Since then, early prone positioning for at least 16 hours is regularly recommended as an important therapeutic measure in severe ARDS. Unfortunately, prone positioning is still underused in clinical practice, possibly due to limited expertise and the fear of hemodynamic instability (6). Indeed, only a few contraindications such as cardiogenic shock or unstable spine fractures should be accepted.
In non-COVID-19–related respiratory failure, prone positioning can be expected to effect similar beneficial effects in view to the above-mentioned pathophysiologic similarities. On the other hand, certain pathophysiologic particularities of COVID-19–related respiratory failure have been described recently (7). Most relevant, the frequency of thromboembolic complications resulting in fulminant lung embolism is increased (8), and extrapulmonary endothelial dysfunction may contribute to myocardial damage and cardiac failure (9). Furthermore, different phenotypes of COVID-19–related respiratory failure have been suggested (10). In some COVID-19 patients, normal lung compliance and minimal recruitability but a loss of hypoxic pulmonary vasoconstriction with impaired regulation of pulmonary blood flow have been identified as the main reason for hypoxemia. Therefore, effects of prone positioning may differ from conventional ARDS. Until today, evidence for prone positioning in COVID-19–related respiratory failure is lacking.
With the study presented by Mathews et al (11) in this issue of Critical Care Medicine, the authors aimed at closing this gap of evidence. In a retrospective analysis of 2,338 COVID-19 patients with moderate to severe respiratory failure and Pao2/Fio2 less than 200 mm Hg, prone positioning within the first 2 days of ICU admission in 702 patients was associated with a lower risk of hospital mortality compared with 1,636 patients without or later onset of prone positioning. The beneficial effect of early prone positioning was also present in subgroup analyses regarding different levels of hypoxemia with Pao2/Fio2 less than 150 mm Hg and Pao2/Fio2 less than 100 mm Hg.
Data were derived from a multicenter cohort study of critically ill adults with COVID-19 (Study of the Treatment and Outcomes in Critically Ill Patients with Coronavirus Disease [STOP-COVID]) and elaborately processed to compensate for statistical bias arising from the uncontrolled observational design of that study. After weighting the data, baseline and severity of illness characteristics were well-balanced between the groups in view to 25 covariates including severity of illness variables and treatment such as neuromuscular blockade and corticosteroid therapy.
In view to the high number of included patients with a focus on early prone positioning within the first 2 days and successful statistical weighting of the groups, the authors should be congratulated on this successful analysis and presentation of scientifically and clinically meaningful data, thereby confirming recently published results derived from smaller cohorts (12).
Nonetheless, important limitations remain: Most important, prone positioning is part of a therapeutic concept in experienced ARDS centers including a sophisticated ventilation strategy, a strict fluid balance control, and a dedicated hemodynamic management. Certainly, the performance of such a concept might have influenced outcome. Unfortunately, ventilation data and hemodynamics are missing, and duration of prone positioning is unknown as well. Therefore, it is impossible to differentiate between different phenotypes of respiratory failure according to lung compliance and recruitability. At the least, different incidences of fulminant lung embolism seem unlikely in view to comparable d-dimer levels in both groups. However, missing values remain an important limitation of the study.
Interestingly, only 50% of patients with Pao2/Fio2 less than 200 were put in prone position. It is yet unclear, whether contraindications or other factors such as poor experience influenced indication. It could be hypothesized that patients without prone positioning were treated in less-experienced centers with an overall reduced quality of treatment. However, this hypothesis cannot be derived from the results of the study: Units with fewer beds and higher regional COVID-19 density used prone positioning more often. One possible explanation is a limited provision of extracorporeal membrane oxygenation (ECMO) in small centers with many COVID-19 patients (13).
In summary, the present study by Mathews et al (11) strongly supports the strategy for early prone positioning in COVID-19–related respiratory failure and is therefore highly relevant for clinical practice. Accordingly, effectiveness of ECMO has been demonstrated recently in a retrospective cohort of COVID-19 patients (14): The estimated probability of death 60 days post ECMO initiation was 31% in 83 patients which is comparable with data from non-COVID-19–related ARDS. Thus, it is increasingly clear that COVID-19–related lung failure can and should be treated comparable with ARDS in view to the support of lung function and pulmonary gas exchange despite some interesting pathophysiologic differences (15). Vice versa, most recently evaluated promising strategies of awake prone positioning during spontaneous breathing in COVID-19 may further improve outcome not only in COVID-19–related but also in non-COVID–related ARDS (16). The results of appropriate controlled studies may be awaited with baited breath!
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