Pathophysiology of COVID-19-associated acute respiratory distress syndrome: a multicentre prospective observational study

Giacomo Grasselli, Tommaso Tonetti, Alessandro Protti, Thomas Langer, Massimo Girardis, Giacomo Bellani, John Laffey, Gianpaolo Carrafiello, Luca Carsana, Chiara Rizzuto, Alberto Zanella, Vittorio Scaravilli, Giacinto Pizzilli, Domenico Luca Grieco, Letizia Di Meglio, Gennaro de Pascale, Ezio Lanza, Francesco Monteduro, Maurizio Zompatori, Claudia Filippini, Franco Locatelli, Maurizio Cecconi, Roberto Fumagalli, Stefano Nava, Jean-Louis Vincent, Massimo Antonelli, Arthur S Slutsky, Antonio Pesenti, V Marco Ranieri, collaborators, Alfredo Lissoni, Nicola Rossi, Amedeo Guzzardella, Carlo Valsecchi, Fabiana Madotto, Francesca Bevilacqua, Marco Di Laudo, Lorenzo Querci, Carmen Seccafico, Giacomo Grasselli, Tommaso Tonetti, Alessandro Protti, Thomas Langer, Massimo Girardis, Giacomo Bellani, John Laffey, Gianpaolo Carrafiello, Luca Carsana, Chiara Rizzuto, Alberto Zanella, Vittorio Scaravilli, Giacinto Pizzilli, Domenico Luca Grieco, Letizia Di Meglio, Gennaro de Pascale, Ezio Lanza, Francesco Monteduro, Maurizio Zompatori, Claudia Filippini, Franco Locatelli, Maurizio Cecconi, Roberto Fumagalli, Stefano Nava, Jean-Louis Vincent, Massimo Antonelli, Arthur S Slutsky, Antonio Pesenti, V Marco Ranieri, collaborators, Alfredo Lissoni, Nicola Rossi, Amedeo Guzzardella, Carlo Valsecchi, Fabiana Madotto, Francesca Bevilacqua, Marco Di Laudo, Lorenzo Querci, Carmen Seccafico

Abstract

Background: Patients with COVID-19 can develop acute respiratory distress syndrome (ARDS), which is associated with high mortality. The aim of this study was to examine the functional and morphological features of COVID-19-associated ARDS and to compare these with the characteristics of ARDS unrelated to COVID-19.

Methods: This prospective observational study was done at seven hospitals in Italy. We enrolled consecutive, mechanically ventilated patients with laboratory-confirmed COVID-19 and who met Berlin criteria for ARDS, who were admitted to the intensive care unit (ICU) between March 9 and March 22, 2020. All patients were sedated, paralysed, and ventilated in volume-control mode with standard ICU ventilators. Static respiratory system compliance, the ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air, ventilatory ratio (a surrogate of dead space), and D-dimer concentrations were measured within 24 h of ICU admission. Lung CT scans and CT angiograms were done when clinically indicated. A dataset for ARDS unrelated to COVID-19 was created from previous ARDS studies. Survival to day 28 was assessed.

Findings: Between March 9 and March 22, 2020, 301 patients with COVID-19 met the Berlin criteria for ARDS at participating hospitals. Median static compliance was 41 mL/cm H2O (33-52), which was 28% higher than in the cohort of patients with ARDS unrelated to COVID-19 (32 mL/cm H2O [25-43]; p<0·0001). 17 (6%) of 297 patients with COVID-19-associated ARDS had compliances greater than the 95th percentile of the classical ARDS cohort. Total lung weight did not differ between the two cohorts. CT pulmonary angiograms (obtained in 23 [8%] patients with COVID-19-related ARDS) showed that 15 (94%) of 16 patients with D-dimer concentrations greater than the median had bilateral areas of hypoperfusion, consistent with thromboembolic disease. Patients with D-dimer concentrations equal to or less than the median had ventilatory ratios lower than those of patients with D-dimer concentrations greater than the median (1·66 [1·32-1·95] vs 1·90 [1·50-2·33]; p=0·0001). Patients with static compliance equal to or less than the median and D-dimer concentrations greater than the median had markedly increased 28-day mortality compared with other patient subgroups (40 [56%] of 71 with high D-dimers and low compliance vs 18 [27%] of 67 with low D-dimers and high compliance, 13 [22%] of 60 with low D-dimers and low compliance, and 22 [35%] of 63 with high D-dimers and high compliance, all p=0·0001).

Interpretation: Patients with COVID-19-associated ARDS have a form of injury that, in many aspects, is similar to that of those with ARDS unrelated to COVID-19. Notably, patients with COVID-19-related ARDS who have a reduction in respiratory system compliance together with increased D-dimer concentrations have high mortality rates.

Funding: None.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
Static compliance of the respiratory system and total lung weight of patients with COVID-19-associated ARDS or classical ARDS, Boxes show medians and IQRs; whiskers show the tenth to 90th percentiles. ARDS=acute respiratory distress syndrome.
Figure 2
Figure 2
Distribution of perfusion through CT angiogram coronal slices of patients representative of each D-dimer and compliance subgroup (A–D) CT angiogram in patients with COVID-19. (A) A 42-year-old man from the LDLC group (static compliance 38 mL/cm H2O; D-dimer 1260 ng/mL; PaO2/FiO2 144). (B) A 70-year-old man from the LDHC group (static compliance 46 mL/cm H2O; D-dimer 587 ng/mL; PaO2/FiO2 114). (C) A 62-year-old man from the HDLC group (static compliance 32 mL/cm H2O; D-dimer 15 430 ng/mL; PaO2/FiO2 52). (D) A 75-year-old man from the HDHC group (static compliance 50 mL/cm H2O; D-dimer 21 010 ng/mL; PaO2/FiO2 76). Purple-blue colouring indicates hypoperfusion. (E) Three-dimensional reconstruction of the pulmonary vascular arterial tree from the patient in panel D. Red (arrows) shows thromboembolic lesions. HDHC=high D-dimers, high compliance. HDLC=high D-dimers, low compliance. LDHC=low D-dimers, high compliance. LDLC=low D-dimers, low compliance. PaO2/FiO2=ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air.
Figure 3
Figure 3
Kaplan-Meier analysis of 28-day survival in the four D-dimer and static compliance subgroups HDHC=high D-dimers, high compliance. HDLC=high D-dimers, low compliance. LDHC=low D-dimers, high compliance. LDLC=low D-dimers, low compliance.

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