Introduction
Acute respiratory distress syndrome (ARDS)—as currently defined—is a syndrome which broadly includes diverse conditions grouped on the basis of an oxygenation deficit of acute onset and bilateral radiographic infiltrates that cannot be attributed solely to a cardiovascular cause [
1]. The severity of ARDS is classified by a single criterion only: oxygenation deficit, expressed as PaO
2/FiO
2 ratio. By this broad definition, hypoxemic patients with coronavirus disease 2019 (COVID-19) and bilateral chest X-ray infiltrates clearly satisfy the definition of ARDS. We have reported [
2,
3] that severe hypoxemia with relatively well-preserved respiratory system compliance (Crs) measured under standard conditions is characteristic of COVID-19-ARDS, and it differs from ARDS of other causes (typical ARDS), while others did not recognize consistent differences [
4‐
7]. However, the increased frequency of higher Crs in COVID-19-ARDS was noted by some of the same authors [
4,
5], and a significantly higher Crs associated with severe hypoxemia was recently documented [
8]. The heterogeneous nature of ARDS allows that—at the population level—there may be wide overlap between COVID-19-ARDS and typical ARDS, and these observations continue to drive a debate [
6,
9]. It is worth remembering that during the Berlin conference, the experts’ panel initially agreed on using an upper threshold of 40 ml/cmH
2O of respiratory system compliance (Crs) to qualify as severe ARDS. This variable was not implemented, however, as it did not add further prognostic value to bilateral infiltrates and PaO
2/FiO
2 ratio [
10]. In other words, the PaO
2/FiO
2 ratio and the Crs deteriorated together in typical ARDS. This pairing may not occur in COVID-19-ARDS, where a discrepancy between the severities of hypoxemia and respiratory mechanics may be the key issue, rather than their individual absolute values per se.
Indeed, this discrepancy could be due to the underlying pathogenesis of COVID-19-ARDS, which is highly atypical and quite distinct from most other forms of typical ARDS that are routinely encountered [
2,
11,
12]. In typical ARDS, the primary site ‘hit’ is the alveolar space, particularly in pulmonary ARDS. In contrast, in COVID-19-ARDS, the prevalent pathophysiological mechanism is initiated on the vascular side of the pulmonary unit. In addition, the endothelialitis, typical of COVID-19 patients, results in a powerful activation of the coagulation cascade, with micro and macro thrombosis occurring in pulmonary tissues and throughout the body [
13‐
15]. Undoubtedly, microthromboses are recognized autopsy findings [
16], and pulmonary artery filling defects (vascular occlusion or compression) have been described in typical ARDS for decades [
17,
18]. A striking difference between typical ARDS and COVID-19-ARDS, however, is the remarkable frequency and extent to which pulmonary [
15,
19] and extrapulmonary thrombosis [
20] occur in the latter. While regional atelectasis, edema and fibrosis may coexist, disrupted vasoregulation strikingly alters the matching of perfusion to ventilation, a pathophysiologic mechanism which may be the predominant contributor to hypoxemia in the early phase of this evolving disease [
12,
21].
To investigate whether and to what degree, COVID-19-ARDS differs from typical ARDS, we compared the physio-anatomical characteristics of COVID-19-ARDS patients with two historically matched cohorts of typical ARDS. Quantitative CT scan analysis, and measurements of respiratory system mechanics and gas exchange were performed under standardized and identical conditions, both in COVID-19-ARDS and typical ARDS, thus avoiding the biases of acquiring CT scans and physiological variables under highly heterogeneous “clinical” conditions.
Methods
Study population
Thirty-two COVID-19-ARDS patients, consecutively admitted to the ICU of ASST Santi Paolo e Carlo Hospital, Milan over the period between February 21st, 2020 and May 7th, 2020 were prospectively enrolled. This study was conducted in accordance with the pre-existing Ethics Committee approval that allows physiological and CT scan studies for all patients with severe respiratory failure admitted to our critical care unit (ethics committee numbers: 42937/2016 and 9890/2017). All had documented COVID-19 positive RT-PCR o nasal or pharyngeal swab and bilateral infiltrates documented by chest X-ray. This COVID-19-ARDS population was matched with cohorts from two separate non-COVID ARDS populations: one matched 1:1 for PaO2/FiO2 (PaO2/FiO2-matched-ARDS) and a second one matched 1:1 for respiratory system compliance (Compliance-matched-ARDS). The values of PaO2/FiO2 ratio and Crs used for matching these cohorts were the ones measured in COVID-19-ARDS at 5 cmH2O of PEEP during mechanical ventilation, immediately before the CT scan. The PaO2/FiO2 ratio and Crs of the two historical non-COVID ARDS cohorts were measured under exactly the same conditions.
The two matched, entirely independent population samples were extracted from our ARDS dataset which includes 232 patients studied between 2003 and 2018. These patients had previously been screened and included in clinical physiopathologic studies performed by our group over the same time span. Therefore, they met all criteria that define ARDS and underwent a common and standardized intervention (e.g., CT scan, PEEP trials, measurement of respiratory mechanics and gas exchange) and a standardized data collection protocol.
Measurements
In every studied patient (of both COVID-19-ARDS and the matched non-COVID ARDS populations), gas exchange, respiratory mechanics, hemodynamics and CT scan variables were recorded under standardized conditions (Volume Controlled ventilation, tidal volume 7–8 ml/kg of Ideal Body Weight (IBW), muscle relaxation, 5 cmH2O of Positive End-Expiratory Pressure, PEEP). Both COVID-19-ARDS and non-COVID ARDS population cohorts underwent CT scanning and PEEP testing within a median of 3 [IQR 1—4] days after the admission to ICU.
Gas exchange
We measured FiO
2, PO
2, PCO
2, hemoglobin saturation and derived variables (using arterial and central venous blood) and end-tidal PCO
2 (P
ETCO
2). Venous admixture was computed using central venous blood values as surrogates for the mixed venous ones [
22].
Respiratory system mechanics
We measured plateau pressure, PEEP, driving pressure and respiratory system compliance at the standardized value of 5 cmH2O.
CT-quantitative anatomical variables
In each patient, the whole lung CT was performed under static conditions during an end-expiratory hold at 5 cmH
2O of PEEP. Lung profiles of each CT scan slice were manually contoured, excluding hilar structures. Then, quantitative analysis was performed with dedicated software (Maluna [
23]). We estimated lung weight, gas volume, amount of over-inflated tissue (voxel density − 1000 to − 900 Hounsfield Units, HU), well-aerated tissue (− 899 to − 500 HU), poorly aerated tissue (− 499 to − 100 HU) and non-aerated tissue (− 100 to + 100 HU). Analyses were performed on each whole slice as well as on ten equally spaced segments along the sterno-vertebral axis.
PEEP response
All patients underwent a “PEEP-test” in which PEEP was raised from 5 to 15 cmH2O while keeping constant respiratory rate, tidal volume and FiO2. Gas exchange, hemodynamics and mechanical variables were re-measured at 15 cmH2O of PEEP after a 15-min equilibration period (See Supplement for details.)
Statistical analysis
The one-to-one matching procedure was performed with the nearest-neighboring method using the optimal algorithm, without replacement, with the MatchIt package for R (R Foundation for Statistical Computing version 4.0.2) [
24]. Data are presented as mean ± standard deviation. Student’s
t test assessed the statistical significance of the difference between group means when data were distributed normally; otherwise, the Wilcoxon test was used. Chi square test or Fisher’s exact test was used to construct the contingency tables. Linear regression tested the relationship between continuous variables. Two-way analysis of variance allowing interaction was used to evaluate the gas volume distribution along the segments of sterno-vertebral axis. These statistical analyses were performed with R (R Foundation for Statistical Computing version 4.0.2) and its package Tidyverse.
Discussion
In this study, which compares COVID-19-ARDS patients with two different non-COVID-19 ARDS populations, we found the following: (1) COVID-19-ARDS patients, compared to PaO2/FiO2-matched ARDS (i.e., similar oxygenation), had consistently better respiratory system compliance and nearly double the end-expiratory gas volume as their counterparts in the comparison groups; (2) COVID-19-ARDS patients, compared to a separate population of non-COVID-19 ARDS patients matched on Crs (i.e., with similar respiratory system mechanics) had consistently worse oxygenation variables; (3) COVID-19-ARDS, PaO2/FiO2-matched-ARDS, and Compliance-matched-ARDS experienced similar oxygenation improvement when raising PEEP from 5 to 15 cmH2O. Importantly, however, while that oxygenation improvement in the PaO2/FiO2-matched-ARDS population was associated with significantly improved CO2 clearance and respiratory mechanics, these variables did not change or deteriorated in both COVID-19-ARDS patients and Compliance-matched-ARDS patients.
Patient populations
A single matching variable was used for each matching procedure. No other variables were included, due to the limited size of our ARDS dataset. The anthropometric characteristics of the three populations were not statistically different. Bilateral pneumonia was the only cause of lung injury in COVID-19-ARDS patients. By comparison, pneumonia accounted for 53.1% and 43.8% in PaO
2/FiO
2-matched-ARDS and Compliance-matched-ARDS cohorts, respectively, incidence frequencies similar to the LUNG-SAFE study (59.4%) of 3022 patients (
p = 0.16) [
25]. The prevalence of sepsis was also similar among LUNG-SAFE, PaO
2/FiO
2-matched-ARDS and Compliance-matched-ARDS (16%, 18.7% and 25% in, respectively;
p = 0.36). Therefore, our sample of matched ARDS patients appears representative of the ARDS populations enrolled in pre-COVID ARDS clinical trials. The distribution of mild, moderate and severe ARDS (as measured at 5 cmH
2O of PEEP [
26]) in COVID-19-ARDS and in our PaO
2/FiO
2-matched-ARDS subgroup was identical (Table
2) [
1]. In contrast, the overall severity of Compliance-matched-ARDS patients was lower, as the prevalence of severe ARDS category was only 18.8% vs 68.7% in COVID-19-ARDS. The general clinical severity, as indicated by SAPSII, tended to be lower in COVID-19-ARDS patients, compared to the two non-Covid ARDS populations, perhaps accounting for their shorter length of stay in the ICU.
Oxygenation, lung mechanics and the mechanism of hypoxemia
Differently from typical ARDS, where the decrease of PaO
2/FiO
2 ratio is associated with a decrease in Crs, in our COVID-19-ARDS population PaO
2/FiO
2 ratio and Crs were unrelated. This has also been found in a recent larger study comparing typical ARDS with COVID-19-ARDS [
8]. This contrasts with the decision taken in Berlin to exclude Crs from the ARDS definition as unnecessary, as it added no prognostic value to the PaO
2/FiO
2 ratio alone [
10]. It is then possible that the mechanisms leading to hypoxemia are somehow different between COVID-19-ARDS and typical ARDS. Hypoxemia due to venous admixture [
27] originates from two potential mechanisms: true right to left shunt (i.e., perfusion of non-aerated tissue) and/or low ventilation–perfusion (
VA/
Q) ratio (perfusion of poorly ventilated lung regions). In typical ARDS, the primary component of venous admixture is right-to-left shunt. Accordingly, the greater the fraction of non-aerated tissue, the greater the venous admixture [
28,
29]. In COVID-19-ARDS the venous admixture was unrelated to the non-aerated tissue fraction; indeed, it was very high even when the fraction of non-aerated tissue was very low (Fig.
3). This observation strongly suggests that the major component of the venous admixture in COVID-19-ARDS is ventilation–perfusion mismatch, rather than true right-to-left shunt. The important role of
VA/
Q mismatch in COVID-19-ARDS is consistent with (but not entirely explained by) the reported high incidence of micro and macro thrombosis in this disease [
11,
14,
30,
31] and with the importance of markers of immune-thrombosis (e.g.,
d-dimers) in the outcome of COVID-19-ARDS [
8].
Respiratory system compliance and lung gas volume
The relative importance of
VA/
Q mismatching as opposed to right-to-left shunt in COVID-19-ARDS is consistent with its relatively higher lung gas volume, which correlates with the respiratory system compliance (see Figure E4). Moreover, the gas volume was remarkably higher in COVID-19-ARDS compared to PaO
2/FiO
2-matched-ARDS for each lung section along the gravitational axis, including the most dependent ones, which are almost gasless in typical ARDS (Fig.
2). Again, this difference, likely due to the vasocentric nature of COVID-19-ARDS (as compared to ‘gas space-centered’ nature of typical ARDS), is not entirely surprising. Unexpectedly, however, we found that Compliance-matched-ARDS patients had lower gas volume than did COVID-19-ARDS patients, despite having similar values of respiratory system mechanics. The interpretation of these findings is currently only speculative. However, it is tempting to hypothesize that the increased gas volume in COVID-19-ARDS is caused by newly formed emphysema-like functional regions that may develop as a consequence of the ischemic changes and diffuse micro thromboses described in autopsy findings [
11,
14].
Response to PEEP
The improved oxygenation in our PaO
2/FiO
2-matched-ARDS patient cohort in response to the PEEP test was likely due recruitment. Indeed, these patients were more recruitable, as indicated by higher baseline non-aerated tissue mass in conjunction with a significant decrease of plateau pressure and an improvement of Crs when PEEP was raised. In contrast, Compliance-matched-ARDS and COVID-19-ARDS patients, with lower baseline non-aerated tissue mass, showed unaltered or worsened respiratory system mechanics and PaCO
2 in response to the PEEP test (Table
3). These findings suggest—in line with previous observations—[
32,
33] that the primary mechanism of oxygenation improvement was a decrease/redistribution of blood flow away from airless zones rather than recruitment.
Atypical features of COVID-19-ARDS
Our data suggest that COVID-19-ARDS is an atypical subset of ARDS. We may then wonder why, for a given severity of hypoxemia, the Crs values of our COVID-19-ARDS patients appear higher than those reported by other authors [
6,
34]. As the virus is the same worldwide, its manifestations everywhere should be more or less consistent. The differences observed among various reports may depend on two main factors: the timing of the observations and the conditions of measurement. Indeed, COVID-19-ARDS evolves rather rapidly with time, as reflected by a CT scan appearance that shifts progressively from bilateral ground glass opacities to overt consolidations/collapse [
35]. Crs changes accordingly [
36]. It is not surprising that, with passing time, Crs may decrease to impressively low values. The conditions of measurement are also important. Most studies, such as the largest one yet published on COVID-19 pathophysiology [
8], report Crs values measured under the prevailing “clinical conditions”. In all cohorts of our COVID-19-ARDS, PaO
2/FiO
2-matched-ARDS and Compliance-matched-ARDS populations, all measurements were performed at a standard PEEP of 5 cmH
2O. It is obvious that Crs measured at 10–15 cmH
2O of PEEP may lead to different values than those we report here.
Clinical implications
Our COVID-19-ARDS patients were studied 9.6 ± 4 days after the onset of symptoms and were compared with “early” historical ARDS patients (within 1 week from admission). Within this initial timeframe, the sharp physio-anatomic distinctions between non-COVID-ARDS and COVID-19-ARDS suggest the need to modify our standard practice of ARDS management for COVID-19 patients. Specifically, the dramatically greater gas volume and better compliance of COVID-19 lungs, when present, discourage interventions intended to further inflate the lungs. Indeed, for a similar marginal improvement of oxygenation in response to a PEEP increment, signs of overdistension became manifest in our COVID-19 patients. In contrast, respiratory mechanics improved and PaCO2 decreased in the PaO2/FiO2-matched-ARDS cohort. Attempts to aggressively recruit the lung to improve O2 exchange by applying higher than customary levels of mean airway pressure seem ill-advised during this early disease phase. We must stress, however, that COVID-19 pneumonia rapidly evolves with time. Consequently, the safest ventilatory strategy could well be different at different stages which range from initial modest ground-glass opacities with preserved Crs to an intermediate stage (as described in the present study), to a final stage characterized by extensive opacities, prevalent fibrosis, and very low Crs.
Limitations
These data are unique in documenting physiologic measurements and quantitative images under identical conditions in closely matched COVID-19-ARDS and non-COVID-ARDS patients. However, our study has several limitations: first, the limited size of our historical ARDS dataset. Second, patients were enrolled in a single center, within a limited time frame of their illnesses. Earlier or later stages may present sharply different behaviors. In addition, we did not perform a second CT scan at 15 cmH2O. Finally, a comprehensive set of hemodynamic data were not acquired, preventing full characterization of the mechanisms underlying the gas exchange variations we observed.
Conclusion
COVID-19-ARDS and non-COVID ARDS patients differ significantly in their radiological and physiological features, both in terms of the relationship between oxygenation and lung mechanics and their responses to PEEP. The different stages of the disease call for a rethinking of the traditional lung protective ventilation targets which take into account the peculiarities of this novel ARDS variant.
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