Computed tomography assessment of PEEP-induced alveolar recruitment in patients with severe COVID-19 pneumonia

Over the last months, the global pandemic from coronavirus disease 2019 (COVID-19) has posed important challenges to intensive care unit (ICU) physicians [1, 2]. A significant proportion of COVID-19 patients develop severe hypoxemic respiratory failure requiring invasive mechanical ventilation [2, 3]. Although COVID-19 meets the clinical criteria for acute respiratory distress syndrome (ARDS) [4], peculiar pathophysiological features [5] and phenotypes have been identified in this disease [6]. In COVID-19 patients, chest computed tomography (CT) findings typically include ground glass opacities overlapping with areas of lung consolidation, not always reflecting the severity of gas-exchange impairment [7]. In this context, severe hypoxemia might be related not only to loss of aeration, but also to highly perfused ground-glass areas [8, 9]. In COVID-19 patients with high respiratory system compliance and low ventilation-perfusion ratio (\({\dot{V}}_{A}/\dot{Q}\)), hypoxemia is primarily due to the \({\dot{V}}_{A}/\dot{Q}\) mismatch, which is more related to lung perfusion regulation impairment than to an increase in non-aerated tissue; therefore, lung recruitability is probably low [8, 9].

To date, no specific recommendations are available concerning the optimal PEEP levels in invasively ventilated COVID-19 patients [10]. It has been suggested that COVID-19-associated ARDS might share common features with ordinary ARDS [11], in which the use of higher PEEP levels is frequently advocated [12], even if this strategy is not supported by the findings of recent trials [13]. Nevertheless, the pathophysiology of COVID-19 seems to differ from that of ARDS [9] and limited physiological data is available on PEEP response in severe COVID-19 patients. We therefore conducted an observational study with the aim to investigate the effect of two levels of PEEP (8 and 16 cmH₂O) on alveolar recruitment in severe COVID-19 patients. We hypothesized that the PEEP increase resulted in limited alveolar recruitment in COVID-19 patients.

This cohort study was carried out in a university-affiliated hospital in Genoa, Italy. The ethics review board approved the protocol of the study (Comitato Etico Regione Liguria, protocol n. 163/2020) and the need for written informed consent was waived for retrospectively collected data. According to local regulations, consent was delayed after discharge for prospectively collected data in unconscious patients.

The main findings of this study were that, in critically ill mechanically ventilated patients with severe COVID-19 pneumonia, alveolar recruitment induced by changes of PEEP from 8 cmH2O to 16 cmH2O was: (1) minimal and independent of the respiratory system compliance; (2) prevalent in the dependent and caudal lung regions; (3) not correlated with the excess lung weight; and (4) not associated with changes in gas-exchange, respiratory mechanics and laboratory parameters. Higher PEEP improved oxygenation at FiO₂ 0.5 but not 1.0 and decreased respiratory system compliance.

Patients included in the present study had severe hypoxemic respiratory failure at ICU admission and at the time of CT scan. We assessed alveolar recruitment as changes in the non-aerated compartment, using classically adopted CT attenuation thresholds [21, 23‐25]. The two levels of PEEP selected in the present study, i.e., 8 and 16 cmH₂O, were the boundaries of the range of PEEP received by most COVID-19 patients [26], and similar to previous studies investigating alveolar recruitment in ARDS, where 5 and 15 cmH₂O were used [25]. The lower level of PEEP in our study was set at 8 cmH₂O due to safety concerns related to the reduction in PEEP to 5 cmH₂O in severely hypoxemic COVID-19 patients.

Spontaneously breathing healthy subjects have an average lung weight of around 930 g [22]. In our cohort, lung weight was 1500 g and end-expiratory gas volume 1360 ml, values similar to those reported in studies on ARDS not related to COVID-19 [21, 25]. The gas volume was similar to that reported in a recent study, showing that when classical ARDS was compared at similar PaO₂/FiO₂ or compliance, the gas volume was higher in COVID-19 [5]. This is in line with a recent study comparing twenty-seven COVID-19 patients with an historical cohort of classical ARDS [11]. However, another study comparing COVID-19 ARDS with ARDS from other causes concluded that, when patients were matched based on their PaO₂/FiO₂ ratio or respiratory system compliance, the two pathologies had substantial differences with potential implications to the optimal ventilator management [5]. In patients with classical ARDS, the overall lung weight is increased compared to normal patients, due to increased edema distributed along a ventral-dorsal gradient [27]. This leads to increased pressures acting on the dependent lung regions and progressive atelectasis formation [27, 28]. The application of PEEP counterbalances the effects of increased superimposed pressure on most dependent alveoli [29], keeping them open and improving respiratory system compliance and gas-exchange. The median amount of alveolar recruitment from 8 to 16 cmH₂O PEEP in our COVID-19 cohort was less than 3% of the total lung mass. This value is lower than the lung tissue recruited from 5 to 15 cmH₂O PEEP in classical ARDS, which ranged from 8 to 15% of lung weight [21, 25] or 21% of lung volume [23] in early studies. Moreover, these studies reported high inter-subject variability in classical ARDS, while we observed a homogeneously low recruitment potential in our cohort. In line with our results, previous studies found that PEEP-induced alveolar recruitment was lower in patients with primary as compared to a secondary insult to the lung [30]. In a study in ten COVID-19 patients measuring recruitment from 5 to 15 cmH₂O PEEP with electric impedance tomography, the recruited lung volume was around 300 ml with high inter-individual variability [31]. However, it is difficult to compare this value to our results because of the different imaging technique adopted, analyzing only one juxta-diaphragmatic slice. The application of PEEP 16 cmH₂O also increased hyperaeration, especially in presence of less excess lung weight, as reported in classical ARDS patients [23]. As a consequence, the increase in PEEP from 8 to 16 cmH₂O yielded  a worsening of the respiratory system compliance in our cohort of COVID-19 patients. Alveolar recruitment was not associated with higher levels of inflammatory markers, D-dimer and respiratory system compliance.

These findings support the concept that PEEP might improve oxygenation in COVID-19 by altering the \(\dot{V}/\dot{Q}\) matching in areas with low \({\dot{V}}_{A}/\dot{Q}\), rather than through recruitment. This suggests caution in applying PEEP levels higher than those strictly necessary to maintain oxygenation. We observed a decrease in respiratory system compliance among patients at more advanced stages of the disease, not reflected by increased recruitment. This is compatible with a natural history of the disease based on fibrotic mechanisms, rather than worsening of edema. Our findings suggest that COVID-19 pneumonia acts as a typical primary pneumonia [32], as also confirmed by autopsy findings, which reported injury in the alveolar epithelial cells, hyaline membrane formation, and hyperplasia of type II pneumocytes, diffuse alveolar damage and consolidation due to fibroblastic proliferation with extracellular matrix and fibrin forming clusters in airspaces and capillary vessel [33]. We speculate that, differently from classical ARDS, in COVID-19 pneumonia, the non-aerated lung regions are poorly recruitable due to the fact that they do not represent atelectasis, but alveolar spaces substituted by fibrosis and mucinous filling, cellular debris and necrotic tissue reflecting pneumo-and vascular lysis [34‐36].

Some limitations of our study should be addressed. In our center, CT scan and evaluation of PEEP was routinely performed in a high proportion of patients with COVID-19 pneumonia for clinical purposes, but only when CT was indicated and in sufficiently stable patients. The main reasons for exclusion were clinical instability and need for contrast-enhanced CT. The timing of CT scans was based on clinical indication, resulting in heterogeneity of included patients, and we cannot rule out that, in a proportion of patient, bacterial co-infection might have played a role in defining the radiological findings and the response to PEEP [37]. However, this is representative of the population of a COVID-19 ICU. Only two arbitrary levels of PEEP were investigated for technical reasons and patient safety concerns. While we cannot exclude that different ventilator setting or the addition of a recruitment maneuver may have led to different results, previous studies reported that the response to PEEP at two low and moderate PEEP levels correlated with the maximal lung recruitment achievable at higher PEEP [25]. Moreover, venous admixture was estimated from central venous line blood samples, not a pulmonary artery catheter.

In critically ill patients with severe COVID-19 pneumonia, increasing PEEP from 8 cmH₂O to 16 cmH₂O did not lead to major alveolar recruitment while worsened respiratory mechanics. This suggests limiting PEEP strictly to those levels necessary to maintain oxygenation, thus avoiding the use of higher PEEP levels. Lung imaging techniques might be considered in the next future to better assess clinical alterations in critically ill patients with COVID-19 pneumonia.