The lung response to prone positioning was variable in patients with early ARDS due to COVID-19. In general, the volume of the non-aerated and over-aerated tissue decreased, and the distribution of aeration became more homogeneous; arterial oxygenation improved, but compliance and PaCO2 did not.
In ARDS unrelated to COVID-19, prone positioning decreases the alveolar collapse and hyperinflation and homogenizes the distribution of end-expiratory aeration and tidal inflation [3-5]. As a result, mechanical ventilation generates less alveolar deformation and tension and less pulmonary damage [20-25]. This is the strongest rationale for prone positioning in ARDS: making mechanical ventilation safer [6-25]. Increasing arterial oxygenation is probably less important except for the unusual case of life-threatening hypoxemia. In several studies, the survival benefit of prone positioning was not associated with a higher arterial oxygen tension [26-28]. In some of them [26,27], it was instead associated with a lower PaCO2, a sign of more homogeneous ventilation.
In early ARDS due to COVID-19, the lung morphological response to prone positioning resembled that in other ARDS. Alveolar collapse and hyperinflation decreased, and the distribution of aeration became more homogeneous. As long as the regional gas content is associated with the local distending pressure, the distribution of pleural and transpulmonary pressure became more homogeneous [29-31]. In the supine position, and from sternum to vertebra, the regional gas-to-tissue ratio ranged from 3.1 (2.5-4.0) to 0.1 (0.1-0.2) ml/g; in the prone position, and from vertebra to sternum, from 1.5 (0.8-1.9) to 0.6 (0.2-1.3) ml/g (Figure 3). Therefore, the peak value and dispersion of inflation along the vertical axis were smaller in prone than supine position. Changes in the horizontal distribution of aeration were usually minor. Based on these findings, prone positioning may protect patients with COVID-19 from secondary lung damage [32], as it does in other ARDS.
Several factors probably contributed to redistributing lung aeration with prone positioning. As shown in Figure E5, one of these factors was the superimposed pressure [19]: the gas-to-tissue ratio increased, did not change, or decreased where the superimposed pressure decreased, remained constant, or increased respectively [3]. Other possible factors include (i) the shape of the lung and the chest wall [29,33,34]; (ii) the compression of the lung by the heart and the abdomen [35,36]; (iii) the compliance of the non-dependent and dependent rib cage [37]; and (iv) the distribution of the lung mass along the vertical axis [6].
With prone positioning, arterial oxygenation almost always increased while the volume of the non-aerated lung decreased. Nonetheless, these two responses were unrelated in magnitude. With ARDS, hypoxemia is primarily due to decreased ventilation-to-perfusion ratio, down to zero in the non-aerated lung [38,39]. The improved oxygenation with prone positioning is classically attributed to net recruitment and better ventilation-to-perfusion matching [40,41]. With COVID-19, the distribution of the pulmonary blood flow can be very heterogeneous [42,43], affecting the response to prone positioning. For a given lung recruitment, oxygenation will increase more or less if the newly aerated alveoli are hyper or hypo-perfused. This can be why, in our study population, the reversal of alveolar collapse was not always associated with a proportional increase in arterial oxygenation.
Changes in compliance and PaCO2 were partly associated with those in hyperinflation. With a larger decrease in the volume of the over-aerated lung compartment, the respiratory system compliance increased. As the chest wall compliance reasonably decreased [37], lung compliance probably increased even more. At the same time, the PaCO2 tended to decrease in the face of constant minute ventilation. With ARDS, hypercapnia is primarily due to increased ventilation-to-perfusion ratio up to infinity in the over-distended lung [38,39]. A decrease in PaCO2 may then signal a decrease in the dead space and predict survival [26,27,44]. These data suggest that hyperinflation at lung CT was associated with overdistention and that prone positioning decreased both. However, several poorly predictable factors can confound the interpretation of the functional response to prone positioning in an individual subject. For example, for a given morphological response, the change in the respiratory system compliance will depend on the behaviour of the chest wall and the change in the dead space and PaCO2 on the distribution of the pulmonary blood flow [6]. If prone positioning ameliorates survival by diminishing the harms of mechanical ventilation, it may be indicated even in patients with large and potentially reversible alveolar collapse and/or hyperinflation at the lung CT, and no better gas exchange or respiratory system mechanics while prone [28].
Hyperinflation is common in patients with COVID-19, even in those ventilated with low tidal volume and airway pressure [16,45,46]. In the seven patients with a larger (than the median) volume of the over-aerated compartment, tidal volume was 6.1 (5.7-6.5) ml/kg of predicted body weight, and plateau airway pressure 23 (21-23) cmH2O (Table E5). Hyperinflation is a well-known risk factor for secondary damage [47,48]. In our previous study [16], increasing PEEP from 5 to 15 cmH2O in the supine position decreased the volume of the non-aerated lung by 168 (110-202) ml but increased the volume of the over-aerated lung by 121 (63-270) ml. Hyperinflation increased with a higher PEEP in all (100%) patients. Herein, prone positioning decreased the volume of the non-aerated lung by 82 (26-147) ml and the volume of the over-aerated compartment by 28 (11-186) ml. Hyperinflation decreased in all patients but one (93%), especially in those with a larger over-aerated compartment when supine. Therefore, prone positioning may recruit the lung with less hyperinflation than a higher PEEP.
So far, the morphological and functional response to prone positioning in COVID-19 has been investigated only partially [49,50]. In a study conducted with electrical impedance tomography, ventilation increased dorsally and decreased ventrally in the lung section below the belt, while the local ventilation-to-perfusion matching and arterial oxygenation improved [49]. In another study conducted with the CT, the volume of the non-aerated tissue variably decreased dorsally and increased ventrally, in line with the superimposed pressure. A positive response, defined as a rise in PaO2:FiO2 ≥20 mmHg, was the rule in the early, but not late, phase of the disease, possibly due to the development of pulmonary fibrosis [50]. Our findings complement these previous ones by showing that with prone positioning: (i) aeration is globally more evenly distributed so that harms of mechanical ventilation should be reduced; (ii) a “beneficial” morphological response cannot be predicted from changes in gas exchange and respiratory system mechanics; (iii) the decrease in hyperinflation is frequently larger than recruitment. This can be particularly important in patients with COVID-19, who are at an increased risk of ventilator-induced lung damage [46].
Some of the limitations of this study deserve a comment. First, the sample size was based on feasibility limitations. During the first pandemic wave, we could not enrol all consecutive eligible patients, which may have been a source of bias (see Table E1). Second, the lung CTs were obtained at end-expiration, and we did not study the distribution of tidal volume in the supine and prone positions. Third, our findings may not be valid for patients with late COVID-19 [50]. Finally, we did not study the impact of prone positioning on patient-centered outcomes, such as survival or duration of mechanical ventilation. Further studies are needed to address these critical issues.