An appraisal of respiratory system compliance in mechanically ventilated covid-19 patients.

BACKGROUND: Heterogeneous respiratory system static compliance (CRS) values and levels of hypoxemia in patients with novel coronavirus disease (COVID-19) requiring mechanical ventilation have been reported in previous small-case series or studies conducted at a national level.
METHODS: We designed a retrospective observational cohort study with rapid data gathering from the international COVID-19 Critical Care Consortium study to comprehensively describe CRS-calculated as: tidal volume/[airway plateau pressure-positive end-expiratory pressure (PEEP)]-and its association with ventilatory management and outcomes of COVID-19 patients on mechanical ventilation (MV), admitted to intensive care units (ICU) worldwide.
RESULTS: We studied 745 patients from 22 countries, who required admission to the ICU and MV from January 14 to December 31, 2020, and presented at least one value of CRS within the first seven days of MV. Median (IQR) age was 62 (52-71), patients were predominantly males (68%) and from Europe/North and South America (88%). CRS, within 48 h from endotracheal intubation, was available in 649 patients and was neither associated with the duration from onset of symptoms to commencement of MV (p = 0.417) nor with PaO2/FiO2 (p = 0.100). Females presented lower CRS than males (95% CI of CRS difference between females-males: - 11.8 to - 7.4 mL/cmH2O p < 0.001), and although females presented higher body mass index (BMI), association of BMI with CRS was marginal (p = 0.139). Ventilatory management varied across CRS range, resulting in a significant association between CRS and driving pressure (estimated decrease - 0.31 cmH2O/L per mL/cmH20 of CRS, 95% CI - 0.48 to - 0.14, p < 0.001). Overall, 28-day ICU mortality, accounting for the competing risk of being discharged within the period, was 35.6% (SE 1.7). Cox proportional hazard analysis demonstrated that CRS (+ 10 mL/cm H2O) was only associated with being discharge from the ICU within 28 days (HR 1.14, 95% CI 1.02-1.28, p = 0.018).
CONCLUSIONS: This multicentre report provides a comprehensive account of CRS in COVID-19 patients on MV. CRS measured within 48 h from commencement of MV has marginal predictive value for 28-day mortality, but was associated with being discharged from ICU within the same period. Trial documentation: Available at https://www.covid-critical.com/study . TRIAL REGISTRATION: ACTRN12620000421932.

Background

Millions of people have been infected by SARS-CoV-2 worldwide, and many of those have been hospitalized for respiratory complications associated with coronavirus disease-2019 (COVID-19). Many of those COVID-19 hospitalised patients have received mechanical ventilation (MV), due to the development of acute hypoxemic respiratory failure and acute respiratory distress syndrome (ARDS) [1-4]. To date, several landmark studies [5-8] have improved our understanding of COVID-19 pulmonary pathophysiology, but pulmonary derangement in COVID-19 and appropriate ventilatory management remains incompletely characterized.

Earlier reports on the pulmonary pathophysiology of COVID-19 patients reported conflicting results and extreme heterogeneity in levels of pulmonary shunting, static respiratory system compliance (CRS), [9-12] and substantial heterogeneity in lung recruitability [13, 14]. Adding further to the controversy over CRS in COVID-19 patients, Grasselli and collaborators [7] have compared findings from an Italian repository of COVID-19 ARDS with previous ARDS cases of different etiologies. They found statistically significant higher CRS in patients with COVID-19 ARDS. In addition, they found that patients who presented with lower CRS and higher D-dimer values had the greatest mortality risk. In line with these figures, in a small-case series, Chiumello and collaborators found that COVID-19 patients presented higher CRS levels in comparison with patients with ARDS from other etiologies and matched levels of hypoxemia [12]. Regrettably, those previous reports did not provide any information on how CRS progressed beyond a punctual assessment during the period of MV. In contrast, in another landmark study by Ferrando et al. [6], CRS figures from a Spanish database were very similar to previously published cohorts of ARDS patients. The authors also found that intensive care unit (ICU) discharge and mortality were not influenced by the initial levels of CRS.

In a pandemic caused by a novel virus, access to international data is vital, because it may help account for differences in populations, access to medical care, equipment and critical variations in clinical managements among countries. Thus, analysis of international repositories improves the overall understanding of a novel disease and helps establishing best practices to enhance outcome. One example of how single-center or single-country studies can influence medical care early in a pandemic, before being contradicted by subsequent international findings is the issue of CRS. Indeed, as this parameter can be markedly impacted by fine variations in ventilatory management, extrapolations from mono-center or single-country studies may be challenging. In early January 2020, the COVID-19 Critical Care Consortium incorporating the ExtraCorporeal Membrane Oxygenation for 2019 novel Coronavirus Acute Respiratory Disease (COVID-19–CCC/ECMOCARD) group was founded to investigate patients presenting to ICUs worldwide.

Here, we present a comprehensive appraisal of CRS in mechanically ventilated COVID-19 patients enrolled into the COVID-19–CCC/ECMOCARD international study, in order to understand the dynamics of CRS during the first week of mechanical ventilation and its potential impact on patient outcomes.

Materials and methods

Study design and oversight

The COVID-19-CCC/ECMOCARD is an international, multicentre, cohort observational study ongoing in 351 hospitals across 53 countries. The full study protocol is available elsewhere [15]. To summarize, participating hospitals obtained local ethics committee approval and a waiver of informed consent was granted in all cases. ISARIC/SPRINT-SARI data collection began at admission to hospital, while data collection for the COVID-19–CCC observational study commenced at admission to the ICU. De-identified patient data were collected retrospectively and stored via the REDCap electronic data capture tool, hosted at the University of Oxford, United Kingdom or Monash University, Melbourne, Australia.

Study population

We reviewed data of all patients admitted to the ICU at a COVID-19–CCC collaborating site, from January 14 through September 30, 2020, with a clinically suspected or laboratory confirmed diagnosis of SARS-CoV-2 infection, through naso-pharyngeal swab for real-time PCR SARS-CoV-2 detection. Of note, suspicion of SARS-CoV-2 infection was based on symptoms and onset of infection and was confirmed by the clinician when COVID-19 infection was the most likely cause of the symptoms experienced. Patients excluded were those under the age of 15 years or admitted to an ICU for other reasons. We focused our analysis on patients on controlled MV and with a computed CRS value within 48 h of MV commencement.

Definitions and pulmonary mechanics computations

CRS was calculated as: tidal volume (mL)/[(airway plateau pressure-PEEP (cmH2O))]. Of note, we provided to data collectors a detailed data dictionary, with instructions on how to collect airway plateau pressure values, via an inspiratory pause of approximately 3 s. We computed CRS using the first measured tidal volume, airway plateau pressure and PEEP values, within 48 h of MV commencement. In the sub-population of patients on controlled MV, without ECMO support, we analysed key pulmonary variables, such as tidal volume, positive end expiratory pressure (PEEP), static driving pressure, inspiratory fraction of oxygen (FiO2), and gas exchange, recorded during routine clinical practice and only. Tidal volume was reported in mL/kg of predicted body weight (PBW) [16].

Data collection

After enrolment, data on demographics, comorbidities, clinical symptoms and laboratory results were collected by clinical and research staff of the participating ICUs in an electronic case report form [15]. Details of respiratory and hemodynamic support, physiological variables, and laboratory results were collected daily. Of note, the worst daily values were preferentially recorded. The duration of MV and ICU stay, and hospital mortality were recorded. Analysis of daily data was restricted to the first seven days from commencement of MV.

Statistical analyses

Descriptive statistics summarised demographics, clinical signs on ICU admission, ICU management and clinical outcomes for the overall study cohort and subjects with baseline compliance measured within the first 48 h of controlled MV. Statistics were reported as medians (interquartile range) for continuous variables and numbers (percentage) for categorical variables. Linear regression was applied to summarise associations between baseline compliance with body mass index (BMI) (including interaction between BMI and sex), days from symptom onset to MV commencement and PaO2/FiO2, adjusted for BMI. Linear mixed modelling was used to investigate trends in compliance over time and associations with key respiratory parameters during the first 7 days of controlled MV. Models assumed a linear effect for days and a random intercept per subject to account for repeated measures. Consistent with exploratory analyses, BMI was included as a fixed effect to adjust for potential confounding in the clinical characteristics and management of patients with different BMI. Hypothesis testing was applied to all fixed effects, assuming a 5% level of statistical significance. Results were summarised graphically with uncertainty in estimated trends represented by 95% prediction intervals. Expected patient outcomes including length of ICU stay, duration of MV and risk of ICU mortality versus discharge were examined using multi-state modelling [17]. Compared with exploratory analyses of clinical outcomes, the multistate model accounted for ICU discharge and death as competing events and allowed data from all patients to be included, regardless of study follow-up time. The model comprised of four states, to describe patients prior to commencement of MV (non MV), on mechanical ventilation (MV), ICU discharged (Discharge) and mortality (Death). States were presented as percentage and standard error (SE) in the text. Patients extubated before death or discharge were assumed to transition between MV an non-MV states. State transitions were modelled by Cox proportional hazards, with patients censored at last known follow-up, up to 28 days from ICU admission. Follow-up analysis considered Cox proportional hazard regression to examine associations between baseline compliance and competing risks of ICU mortality and discharge, following commencement of MV. Baseline compliance was included as a linear effect, with age, sex, BMI and comorbidities (hypertension, chronic cardiac disease, chronic kidney disease) as additional covariates and adjusted for recruiting centre. A shared frailty term (Gamma distributed) was included to account for residual variation between study sites. Analyses were conducted using R version 3.6.2 or higher (The R Foundation).

Results

We studied 745 patients from 22 countries, who required admission to the ICU and MV from January 14 to December 31, 2020, and presented at least one value of CRS within the first seven days of MV. Among those, 597 (80%) had laboratory-confirmed diagnosis of SARS-CoV2 infection, while in 148 (20%), infection was clinically suspected. Enrolment rate, since January 2020, is reported in Fig. 1. CRS, within 48 h from endotracheal intubation, was available in 649 patients (Fig. 2). No association between CRS and days from onset of symptoms to commencement of MV was found (Fig. 3). Median CRS (IQR), within the first 48 h of mechanical ventilation, was 34.1 mL/cmH2O (26.4–44.0) and PaO2/FiO2 113.0 mmHg (84.0–161.3), without any linear association between these parameters. In particular, 16%, 46% and 38% of the patients presented with mild, moderate or severe hypoxemia, respectively (Fig. 4a). Female sex was associated with a significantly lower CRS than in males (95% CI of difference between genders: − 11.8 to − 7.4 mL/cmH2O p < 0.001) (Fig. 4b). Females also presented higher body mass index (BMI) (95% CI of difference between males and females: − 1.9 to − 5.5, p < 0.001), but as shown in Fig. 5, CRS and BMI were not linearly associated. Our model estimated that CRS was 37.57 cmH2O/mL (95% CI 36.5–38.6) upon commencement of MV (Fig. 6), with further worsening in the first seven days of MV (estimated decrease − 0.31 cmH2O/mL per day, 95% CI − 0.48 to − 0.14, p < 0.001). In addition, as detailed in Fig. 7, PaCO2, tidal volume, PEEP, driving pressure and FiO2 significantly varied across the range of CRS, and a significant association was found between inspiratory plateau pressure and CRS changes (Fig. 8).

Fig. 1

Patient enrolment rate from January 14 through December 31, 2020

Fig. 2

Patient population flow chart. The analysis of 1505 COVID-19 patients on mechanical ventilation identified 649 patients with static respiratory system compliance within 48 h from commencement of mechanical ventilation

Fig. 3

Linear regression analysis of days from onset of symptoms to commencement of mechanical ventilation and static respiratory system compliance, based on the first measurement obtained within 48 h from commencement of mechanical ventilation, adjusted for body mass index. Dark black horizontal bar depicts median value, and upper and lower horizontal light black bars show 90th and 10th percentile. Days of onset of symptoms to commencement of mechanical ventilation was not associated with static respiratory system compliance (estimate 0.92 mL/cmH2O, 95% CI − 0.31–0.31 p = 0.417)

Fig. 4

a Linear regression analysis of arterial partial pressure of oxygen (PaO2/FiO2) and respiratory system compliance (CRS), based on the first measurement obtained within 48 h from commencement of mechanical ventilation, with an interaction of gender and adjusted for body mass index (BMI). No statistically significant association was found between PaO2/FiO2 and CRS (estimate 0.49, 95% CI − 0.09–1.07 p = 0.100). Typical acute respiratory distress syndrome stratification groups [35] (severe, moderate and mild based on levels of hypoxemia) are highlighted in dark, medium and light grey, respectively. b Static respiratory system compliance (CRS) distribution by sex, based on the first measurement obtained within 48 h from commencement of mechanical ventilation. Dashed black lines depict median values for females and males

Fig. 5

Linear regression analysis of static respiratory system compliance, based on the first measurement obtained within 48 h from commencement of mechanical ventilation, and body mass index with an interaction for sex. Per each graph, fitted line of the model is depicted and the upper and lower lines display the 95% predictive interval. Dark grey dots depict female patients, while light grey dots males. Static respiratory system compliance did not vary according to the body mass index (estimate − 0.12 cmH2O/mL, 95%CI − 0.29 to − 0.04, p = 0.139), but was associated with female sex (estimate − 10.73 cmH2O/mL, 95%CI − 18.54 to − 2.92, p = 0.007)

Fig. 6

Static respiratory system compliance dynamics. Evolution of static respiratory system compliance over the first 7 days of mechanical ventilation, adjusted for body mass index. Under each day, the number of analysed patients is reported in parenthesis. Fitted line of the model is depicted, and the upper and lower lines display the 95% predictive interval. Respiratory system compliance varied during the first seven days of mechanical ventilation (estimate − 0.31 cmH2O/mL, 95%CI − 0.48 to 0.14, p < 0.001)

Fig. 7

Linear Mixed model analysis of respiratory system compliance vs. crucial pulmonary variables during the first 7 days of mechanical ventilation (grey-scale coded bar for day 1 through 7 is reported on the right section of each graph and in parenthesis is reported the number of analysed patients). Per each graph, fitted line of the model is depicted and the upper and lower lines display the 95% predictive interval. All analyses are adjusted for body mass index. Static compliance of respiratory system was found to be associated with PaCO2 (estimated decrease − 0.11 mmHg, 95% CI − 0.15 to − 0.06, p < 0.001), tidal volume (estimated increase 0.04 mL/Kg of predicted body weight per day, 95% CI 0.03–0.04, p < 0.001), PEEP (estimated increase − 0.03 cmH2O, 95% CI 0.02–0.04, p < 0.001), driving pressure (estimated decrease − 0.31 cmH2O/L, 95% CI − 0.48 to 0.14, p < 0.001) and FiO2 (estimated decrease − 0.15%, 95% CI − 0.23 to − 0.06, p < 0.001). While PaO2/FiO2, was not significantly associated with static compliance of respiratory system (estimated increase 0.29 mmHg, 95% CI − 0.03 to 0.61, p = 072) PaO2/FiO2, ratio between arterial partial pressure of oxygen and inspiratory fraction of oxygen; PaCO2 arterial partial pressure of carbon dioxide; PEEP, positive end-expiratory pressure

Fig. 8

Association of airway inspiratory plateau pressure with static respiratory system compliance. Linear Mixed model analysis of the association of respiratory system compliance with airway inspiratory plateau pressure during the first 7 days of mechanical ventilation (grey-scale coded bar for day 1 through 7 is reported on the right section of each graph and in parenthesis is reported the number of analysed patients). Fitted line of the model is depicted, and the upper and lower lines display the 95% predictive interval. Analysis is adjusted for body mass index. The model highlights significant association between respiratory system compliance and airway plateau pressure (estimated decrease − 0.22 cmH2O/L, 95% CI − 0.23 to − 0.21, p < 0.001), but based on the model prediction, airway plateau pressure remained predominantly below 30 cmH2O

Baseline characteristics upon ICU admission, applied interventions and outcomes, are summarized in Table 1. The most common interventions applied to the study population were use of antibiotics (96%), neuromuscular blocking agents (81%) and prone position (61%). The overall hospital mortality of the study population was 40%, and among those patients who died in the hospital or were discharged alive, the median (IQR) duration of MV was 11 days (6–18) and 14 days (8–23), respectively. Overall, 28-day ICU mortality, accounting for competing risks, was 35.6% (SE 1.7) and estimated 28-day mortality from commencement of MV was 37.1% (SE 1.7) (Fig. 9b). Cox proportional hazard analysis (Fig. 9c) demonstrated that age (hazard ratio 1.37, 95% CI 1.19–1.59, p < 0.001) and chronic cardiac diseases (HR 1.62, 95% CI 1.14–2.29, p < 0.001) were the only baseline factors associated with 28-day mortality risk. In addition, age (HR 0.77, 95% CI 0.66–0.83, p < 0.001), male sex (HR 0.59, 95% CI 0.44–0.79, p < 0.001), BMI (HR 0.86, 95% CI 0.79–0.95, p = 0.003) and CRS (+ 10 mL/cm H2O) (HR 1.14, 95% CI 1.02–1.28, p = 0.018) were associated with the chance of being discharge from the ICU within 28 days.

Table 1

Only patients with the following characteristics were included in this analysis: (1) on controlled mechanical ventilation; (2) airway plateau pressure, tidal volume and positive-end-expiratory pressure recorded within 48 h from commencement of mechanical ventilation

Characteristic	Full cohort (n = 745)	First CRS recorded within 48 hr of MV (n = 649)
Age, years: n; median (IQR)	745; 62 (52–71)	649; 62 (53–71)
Male: n (%)	510 (68)	445 (69)
Geographic region: n (%)
Africa	19 (3)	14 (2)
Asia	63 (8)	57 (9)
Australia and New Zealand	6 (1)	4 (1)
Europe	326 (44)	295 (45)
Latin America and the Caribbean	108 (14)	92 (14)
Northern America	223 (30)	187 (29)
Time from onset of symptoms, days: n; median (IQR)
Onset of symptoms to hospital admission	735; 7 (3–9)	643; 7 (3–9)
Onset of symptoms to ICU admission	735; 7 (5–11)	643; 7 (5–11)
Onset symptoms to mechanical ventilation	735; 8 (5–11)	643; 8 (5–11)
Clinical signs on ICU admission: n; median (IQR)
WBC count, 103/µL	604; 8.9 (6.3–12.8)	540; 9.0 (6.6–13.0)
Lymphocyte count, 103	459; 0.7 (0.5–1.1)	402; 0.7 (0.5–1.1)
Temperature, °C	329; 37.4 (36.5–38.1)	293; 37.4 (36.5–38.2)
Creatinine, mg/dL	613; 1.0 (0.7–1.4)	543; 1.0 (0.7–1.4)
CRP, mg/dL	216; 118.1 (29.4–206.7)	194;121 (29.1–205.6)
Lymphocyte count to CRP ratio	167; 0.01 (0–0.03)	147; 0.01 (0–0.03)
Neutrophil to Lymphocyte ratio	414; 10.1 (5.6–16.6)	364;10.2 (5.9–16.6)
D-dimer level mg/L	237; 1.3 (0.8–4.7)	207; 1.4 (0.8–4.4)
Clinical management during first 28 days of ICU admission: n (%)
Antibiotics	713 (96)	621 (96)
Antivirals	288 (50)	245 (49)
Continuous renal replacement therapy	110 (15)	92 (15)
Vasoactive drugs	411 (58)	365 (58)
Cardiac-assist devices	54 (7)	48 (7)
ECMO	72 (10)	61 (9)
Prone positioning	451 (61)	392 (60)
Inhaled nitric oxide	72 (10)	66 (10)
Neuromuscular blockadea	599 (81)	524 (81)
Recruitment manoeuvres	295 (40)	266 (41)
Clinical outcomes
Outcome at study end: n (%)
Died in hospital	300 (40)	266 (41)
Discharged alive	400 (54)	339 (52)
Transferred to another facility	7 (1)	7 (1)
Still in hospital/outcome not finalised	38 (5)	37 (6)
Died in hospital
Duration of ICU stay, days: n; median (IQR)	300; 12 (6–20)	266; 12 (6–20)
Duration of hospital stay, days: n, Median (IQR)	294; 13 (7–22)	260; 14 (7–22)
Duration of MV, days: n; Median (IQR)	300; 11 (6–18)	266; 11 (5–18)
Died within 28 days from ICU admission: n (%)	258 (86)	231 (87)
Discharged alive
Duration of ICU stay, days: n; median (IQR)	399; 19 (12–30)	339; 19 (11–3)
Duration of hospital stay, days: n; Median (IQR)	396; 30 (21–46)	336; 30 (21–45)
Duration of MV, days: n; Median (IQR)	400; 14 (8–23)	339; 14 (8–23)
Discharged alive within 28 days from ICU admission: n (%)	195 (49)	165 (49)

Percentages are calculated for non-missing data

CRS, static compliance of respiratory system; CRP, c-reactive protein; MV, mechanical ventilation; ICU, intensive care unit; IQR, interquartile range; ECMO, extracorporeal membrane oxygenation

aAdministration of neuromuscular blockade drugs administered during the first day of invasive mechanical ventilation was not included in the analysis

Fig. 9

Multistate modelling and Cox regression analysis outcomes for patient with static compliance recorded within 48 h of commencing mechanical ventilation. a Multistate model structure for estimating expected outcomes up to 28 days from admission to intensive care unit (ICU). Modelled health states include not on invasive mechanical ventilation (non-MV), on mechanical ventilation (MV), ICU discharge and death. Patients start in the non-MV state if not mechanically ventilated upon or prior to ICU admission, or in the MV state otherwise. b Predicted probabilities of occupying health states up to 28 days from ICU admission. c Results of Cox proportional hazards modelling for risk of death and ICU discharge from commencement of mechanical ventilation. Covariates comprise age, body mass index (BMI), selected comorbidities (hypertension, chronic cardiac disease, chronic kidney disease) and baseline static compliance. Parameter estimates are presented as estimated hazard ratios with 95% confidence intervals (CI). Further details on factors significantly associated with assessed outcomes are available in the results section

Discussion

This large observational report from intensive care units throughout the world found that initial static respiratory system compliance was only associated with hazard of being discharged from the ICU within 28 days. The duration from onset of symptoms to commencement of MV did not influence CRS, and interestingly lower CRS was found in female patients. In the evaluated population, neuromuscular blocking agents and prone position were commonly applied and ventilatory management across CRS levels varied in terms of tidal volume, PEEP and FiO2, throughout the first 7 days of MV.

In comparison with previous reports on ARDS patients without COVID-19 [18], we similarly found that the majority of patients exhibited moderate hypoxemia, even when presented higher CRS. We also noted a larger range of CRS in line with previous studies [7, 8], but in contrast with values from a larger COVID-19 ARDS series from Spain [6]. Considering that we focused our analysis on static compliance of the respiratory system, without partitioning into the pulmonary and chest wall components [19, 20], it is interesting that CRS was not associated with BMI, suggesting that patients with higher BMI potentially presented also with higher lung compliance. Irrespective, we found lower CRS in female patients, who also presented higher BMIs. To the best of our knowledge, no studies have systematically investigated the effects of gender/BMI on COVID-19 severity; thus, whether obesity might be a crucial risk factor for ICU admission and mechanical ventilation, specifically in female patients, and its effects on lung compliance should be further explored. We also found that throughout the range of CRS values, plateau pressure was within what is typically presumed as lung protective ranges [21], but this resulted in potentially harmful driving pressures, specifically for patients with the lowest CRS values. As many of these patients were obese, this raises the question of whether these modest pressures might have increased the risk of pulmonary derecruitment, or in patients with normal BMI, the resulting driving pressure might have been related to pulmonary overdistention. These factors could have contributed to sustained hypoxemia and impaired lung function throughout the study period. In such circumstances, it is questionable whether MV guided by oesophageal pressure monitoring may have some benefits [22], but more research is needed to corroborate such reasoning.

Phenotypic subsets of COVID-19-associated ARDS have been proposed [9, 13, 23–25]. Recent study has also explored whether CRS—related phenotype patterns existed among patients with ARDS before the COVID-19 pandemic [26]. Various investigators [7, 27], who did not find significant CRS variability among COVID-19 patients requiring MV, questioned the overall clinical value of CRS in the COVID-19 population. In a very small case series, Gattinoni et al [9] found an initial CRS of 50 mL/cmH2O, but high levels of shunt fraction that could have explained the resulting severe hypoxemia. In subsequent study, Chiumello and collaborators found higher CRS in patient with COVID-19 ARDS and ARDS caused by other injuries, while matching for similar levels of PaO2/FiO2 [12]. Interestingly, these findings were in line with computed tomography studies results, corroborating higher proportion of normally aerated tissue in COVID-19 ARDS. In similar reports, heterogeneous pathophysiology among patients with different levels of pulmonary compliance has been implied [10, 25]. As corroborated by landmark post-mortem studies [28] and clinical studies [7, 29], SARS-CoV-2 heterogeneously affects pulmonary ventilation and perfusion. Hence, it could be argued that the use of CRS as key pathophysiological parameter to predict clinical evolution might be over simplistic and in-depth characterization of pulmonary pathophysiology should be recommended for COVID-19 patients, specifically when obese. Interestingly, our report is the first that specifically focused on the dynamics of CRS, rather than only baseline CRS. We found that CRS was not related to the duration from the onset of symptoms to commencement of MV, emphasising the need for inclusive data on mechanisms of lung injury in not ventilated COVID-19 patients [30]. The median CRS value found in our population was 34.1 mL/cmH2O, similar to findings by Ferrando et al. [6], not dissimilar to findings by Bellani et al. on patients with non-COVID-19 ARDS [31], but lower than figures recently reported by Grasselli [7] and Grieco [32] in COVID-19 patients. In addition, we found a further decrease in CRS during the first week of MV. This could have been related to the specific ventilatory management in our reported population, but such discrepancy further highlights the need of a comprehensive appraisal of pulmonary and chest wall mechanics in COVID-19 patients [20].

One of the most striking results was the continued use of high PEEP over the first seven days of MV, even in patients with high compliance. This seems counterintuitive, given that current recommendations in ARDS suggest decreasing PEEP, especially in the face of high compliance. As hypoxemia persisted even with high PEEP and high compliance, our results add to the hypothesis that maintaining high PEEP may worsen gas exchange from lung overdistension, resulting in increased dead space and intrapulmonary shunting. Other authors have speculated that using high levels of PEEP in COVID-19 patients with low recruitability may be detrimental, and that lowering PEEP may improve gas exchange and limit ventilator-induced lung injury [33]. Our results in this large cohort of patients from multiple global areas support this theory. Finally, we found that patients required two weeks of MV, and 28-day mortality in the overall population was 35.6%, with hospital mortality up to 40%. These figures are in line with mortality rates reported by Grasselli [7] in the subgroups characterized by low D-dimer, and mortality in severe-moderate COVID-19 ARDS, as corroborated by Ferrando [6]. Nevertheless, we found that CRS was only associated with the discharge from ICU within 28 days. Thus, the marginal clinical value of CRS as a predictor of mortality in COVID-19 patients calls for urgent identification of valuable markers that could inclusively describe pulmonary derangement and guide personalized treatment.

Strengths and limitations

Collaborations between international data collection efforts have the ability to answer many questions related to COVID 19 and to pave the way for future novel diseases to achieve rapid and global data access to help guide best practice. The international COVID-19 Critical Care Consortium study [15], in collaboration with the ISARIC/SPRINT-SARI networks [34], provides inferences not limited by ventilatory management specific to small patient cohort or single-country studies. In addition, in comparison with previous studies, we provided more granular data to inclusively appraise the dynamics of CRS in COVID-19 patients on MV and to study its association with laboratory, and clinical features. A few limitations of our observational study should also be emphasized. First, we centred our analysis on COVID-19 patients, without comparisons against previous repositories of patients with ARDS from different aetiologies. Yet, we provided a wide-ranging discussion of the characteristics of our population in the context of previous analyses in ARDS patients. Second, inferences on pulmonary perfusion disorders in our population can only be speculative, since D-dimer was only available in a small subset of patients (Table 1). Third, as reported by the enrolment rate (Fig. 1 Supplemental Digital Content), patients were mostly enrolled in the early phase of the pandemic, hence extrapolations from our findings should take into account potential biases related to overwhelmed critical care services. Fourthly, it is important to emphasise that we centred our analysis on CRS, but due to the complex respiratory pathophysiology in COVID-19 patients and the high percentage of patients with increased BMI, the use of oesophageal pressure monitoring to fully describe lung and chest wall compliances is advisable and should be prioritised in future investigations. Fifth, the majority of patients were admitted in centers located in North America, Europe and South America. Although these findings are in line with the global distribution of COVID-19 cases, extrapolations of our findings in other regions should be applied cautiously.

Conclusions

Our comprehensive appraisal of COVID-19 patients on MV from a large international observational study implies that expected CRS within 48 h from commencement of MV is not influenced by the duration from onset of symptoms to commencement of MV, but after intubation, a further decrease in CRS might be expected during the first week of ventilation. In addition, baseline CRS is associated with the chance of being discharged from the ICU within 28 days, but it is not a predictive marker of 28-day mortality. Based on potential inferences from our findings, future studies that could provide an in-depth characterization of lungs and chest wall compliance in COVID-19 patients will be critical to guide best practice in ventilatory management.

Prefix/First name/Last name	Site name
Tala Al-Dabbous	Al Adan Hospital
Dr Huda Alfoudri
Dr Mohammed Shamsah
Dr Subbarao Elapavaluru Ashley Berg Christina Horn	Allegheny General Hospital
Dr Stephan Schroll	Barmherzige Bruder Regansburg
Dr Jorge Velazco Wanda Fikes Ludmyla Ploskanych	Baylor Scott & White Health—Temple
Dr Dan Meyer Maysoon Shalabi-McGuire Trent Witt Ashley Ehlers	Baylor University Medical Centre, Dallas
Dr Lorenzo Grazioli	Bergamo Hospital
Dr E. Wilson Grandin Jose Nunez Tiago Reyes	Beth Israel Deaconess Medical Centre
Dr Mark Joseph Dr Brook Mitchell Martha Tenzer	Carilion Clinic
Dr Ryuzo Abe Yosuke Hayashi	Chiba University Graduate School of Medicine
Dr Hwa Jin Cho Dr In Seok Jeong	Chonnam National University Hospital
Dr Nicolas Brozzi Dr Jaime Hernandez-Montfort	Cleveland Clinic—Florida
Omar Mehkri Stuart Houltham	Cleveland Clinic—Ohio
Dr Jerónimo Graf Rodrigo Perez	Clinica Alemana De Santiago
Dr Roderigo Diaz Camila Delgado Joyce González Maria Soledad Sanchez	Clinica Las Condez
Dr Diego Fernando Bautista Rincón Melissa Bustamante Duque Dr Angela Maria Marulanda Yanten	Clinica Valle de Lilli
Dr Dan Brodie	Columbia University Medical Centre
Dr Desy Rusmawatiningtyas	Dr Sardjito Hospital (Paediatrics)
Gabrielle Ragazzo	Emory University Healthcare System
Dr Azhari Taufik Dr Margaretha Gunawan Dr Vera Irawany Muhammad Rayhan Dr Elizabeth Yasmin Wardoyo	Fatmawati Hospital
Dr Mauro Panigada Dr Chiara Martinet Dr Sebastiano Colombo Dr Giacomo Grasselli Dr Michela Leone Dr Alberto Zanella	Fondazione IRCCS Policlinico of Milan (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico)
Prof Massimo Antonelli Dr Simone Carelli Domenico L. Grieco	Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Motohiro Asaki	Fujieda Municipal General Hospital
Dr Kota Hoshino	Fukuoka University
Dr Leonardo Salazar Laura Duarte	Fundación Cardiovascular de Colombia
Dr Joseph McCaffrey Allison Bone	Geelong Hospital
Dr David Thomson Dr Christel Arnold-Day Jerome Cupido Zainap Fanie Dr Malcom Miller Dr Lisa Seymore Dawid van Straaten	Groote Schuur Hospital
Dr Ibrahim Hassan Dr Ali Ait Hssain Jeffrey Aliudin Al-Reem Alqahtani Khoulod Mohamed Ahmed Mohamed Darwin Tan Joy Villanueva Ahmed Zaqout	Hamad General Hospital—Weill Cornell Medical College in Qatar
Dr Ethan Kurtzman Arben Ademi Ana Dobrita Khadija El Aoudi Juliet Segura	Hartford HealthCare
Dr Gezy Giwangkancana	Hasan Sadikin Hospital (Adult)
Dr Shinichiro Ohshimo	Hiroshima University
Dr Koji Hoshino Saito Hitoshi Dr Yuka Uchinami	Hokkaido University Hospital
Dr Javier Osatnik	Hospital Alemán
Dr Anne Joosten	Hospital Civil Marie Curie
Dr Antoni Torres Ana Motos Dr Minlan Yang	Hospital Clinic, Barcelona
Carlos Luna	Hospital de Clínicas
Francisco Arancibia	Hospital del Tórax
Virginie Williams Alexandre Noel	Hospital du Sacre Coeur (Universite de Montreal)
Dr Nestor Luque	Hospital Emergencia Ate Vitarte
Dr Trieu Huynh Trung Sophie Yacoub	Hospital for Tropical Diseases
Marina Fantini	Hospital Mater Dei
Dr Ruth Noemi Jorge García Dr Enrique Chicote Alvarez	Hospital Nuestra Señora de Gracia
Dr Anna Greti Oscar Lomeli	Hospital Puerta de Hierro
Dr Adrian Ceccato	Hospital Universitari Sagrat Cor
Dr Angel Sanchez	Hospital Universitario Sant Joan d’Alacant
Dr Ana Loza Vazquez	Hospital Universitario Virgen de Valme
Dr Ferran Roche-Campo	Hospital Verge de la Cinta de Tortosa
Dr Divina Tuazon Dr Toni Duculan	Houston Methodist Hospital
Hiroaki Shimizu	Kakogawa Acute Care Medical Center, Hyogo
Marcelo Amato Luciana Cassimiro Flavio Pola Francis Ribeiro Guilherme Fonseca	INCOR (Universidade de São Paulo)
Dr Heidi Dalton Dr Mehul Desai Dr Erik Osborn Hala Deeb	INOVA Fairfax Hospital
Dr Antonio Arcadipane Claudia Bianco Raffaele Cuffaro Gennaro Martucci Giovanna Occhipinti Matteo Rossetti Chiara Vitiello	ISMETT
Dr Sung-Min Cho Kate Calligy Dr Glenn Whitman	Johns Hopkins
Dr Hiroaki Shimizu Dr Naoki Moriyama	Kakogawa Acute Care Medical Center
Dr Jae-Burm Kim	Keimyung University Dong San Hospital
Dr Nobuya Kitamura Takashi Shimazui	Kimitsu Chuo Hospital
Dr Abdullah Al-Hudaib Dr Alyaa Elhazmi	King Faisal Specialist Hospital and Research Center
Dr Johannes Gebauer	Klinikum Passau
Dr Toshiki Yokoyama	Kouritu Tousei Hospital
Dr Abdulrahman Al-Fares Esam Alamad Fatma Alawadhi Kalthoum Alawadi Dr Sarah Buabbas	Al-Amiri and Jaber Al-Ahmed Hospitals, Kuwait Extracorporeal Life Support Program
Dr Hiro Tanaka	Kyoto Medical Centre
Dr Satoru Hashimoto Masaki Yamazaki	Kyoto Prefectural University of Medicine
Tak-Hyuck Oh	Kyung Pook National University Chilgok Hospital
Dr Mark Epler Dr Cathleen Forney Jared Feister Katherine Grobengieser Louise Kruse Joelle Williamson	Lancaster General Health
Dr Eric Gnall Dr Mara Caroline Sasha Golden Colleen Karaj Sherry McDermott Lynn Sher Dr Timothy Shapiro Lisa Thome Mark Vanderland Mary Welch	Lankenau Institute of Medical Research (Main Line Health)
Prof Luca Brazzi	Le Molinette Hospital (Ospedale Molinette Torino)
Dr Tawnya Ogston	Legacy Emanuel Medical Center
Dr Dave Nagpal Karlee Fischer	London Health Sciences Centre
Dr Roberto Lorusso Maria de Piero	Maastricht University Medical Centre
Prof Mariano Esperatti	Mar del Plata Medical Foundation Private Community Hospital
Dr Diarmuid O’Briain	Maroondah Hospital
Dr Edmund G. Carton	Mater Misericordiae University Hospital
Ayan Sen Amanda Palacios Deborah Rainey	Mayo Clinic College of Medicine
Cassandra Seefeldt Dr Lucia Durham Dr Octavio Falcucci Amanda Emmrich Jennifer Guy Carling Johns Emily Neumann	Medical College of Wisconsin (Froedtert Hospital)
Dr Nina Buchtele Dr Michael Schwameis	Medical University of Vienna
Dr Stephanie-Susanne Stecher Delila Singh Dr Michaela Barnikel Lukas Arenz	Medical Department II, LMU Hospital Munich
Dr Akram Zaaqoq Lan Anh Galloway Caitlin Merley	MedStar Washington Hospital Centre
Dr Marc Csete Luisa Quesada Isabela Saba	Mount Sinai Medical Centre
Dr Daisuke Kasugai Hiroaki Hiraiwa Taku Tanaka	Nagoya University Hospital
Dr Eva Marwali Yoel Purnama Dr Santi Rahayu Dewayanti Dr Ardiyan Dr Debby Siagian	National Cardiovascular Center Harapan Kita
Yih-Sharng Chen	National Taiwan University Hospital
Prof John Laffey Dr Bairbre McNicholas Dr David Cosgrave	Galway University Hospitals
Marlice VanDyk Sarah MacDonald	Netcare Unitas ECMO Centre
Dr Ian Seppelt	Nepean Hospital
Dr Indrek Ratsep Lauri Enneveer Kristo Erikson Dr Getter Oigus Andra-Maris Post Piret Sillaots	North Estonia Medical Centre
Frank Manetta	Northwell Health
Mamoru Komats	Obihiro-Kosei General Hospital
Dr S. Veena Satyapriya Dr Amar Bhatt Marco Echeverria Juan Fiorda Alicia Gonzalez Dr Nahush A. Mokadam Johnny McKeown Joshua Pasek Haixia Shi Alberto Uribe	Ohio State University Medical Centre
Dr Rita Moreno	Oklahoma Heart Institute
Bishoy Zakhary Hannah Johnson Nolan Pow	Oregon Health and Science University Hospital (OHSU)
Dr Marco Cavana Dr Alberto Cucino	Ospedale di Arco (Trento hospital)
Prof Giuseppe Foti Dr Marco Giani Dr Vincenzo Russotto	Ospedale San Gerardo
Prof Davide Chiumello Valentina Castagna Silvia Coppola	Ospedale San Paolo
Dr Andrea Dell’Amore	Padua University Hospital (Policlinico of Padova)
Dr Hoi-Ping Shum	Pamela Youde Nethersole Eastern Hospital
Dr Alain Vuysteke	Papworth Hospitals NHS Foundation Trust
Dr Asad Usman Andrew Acker Blake Mergler Nicolas Rizer Federico Sertic Benjamin Smood Alexandra Sperry Dr Madhu Subramanian	Penn Medicine (Hospital of the University of Pennsylvania)
Dr Erlina Burhan Dr Navy Lolong Dr Ernita Akmal Prof Menaldi Rasmin Bhat Naivedh Dr Faya Sitompu	Persahabatan General Hospital
Dr Peter Barrett Julia Daugherty Dr David Dean	Piedmont Atlanta Hospital
Dr Antonio Loforte	Policlinico di S. Orsola, Università di Bologna
Dr Irfan Khan Olivia DeSantis Dr Mohammed Abraar Quraishi	Presbyterian Hospital Services, Albuquerque
Dr Gavin Salt	Prince of Wales
Dr Dominic So Darshana Kandamby	Princess Margaret Hospital
Dr Jose M. Mandei Hans Natanael	Prof Dr R. D. Kandou General Hospital—Paediatric
Eka YudhaLantang Anastasia Lantang	Prof Dr R. D. Kandou General Hospital—Adult
Anna Jung Dr Terese Hammond	Providence Saint John's Health Centre
George Ng Dr Wing Yiu Ng	Queen Elizabeth Hospital, Hong Kong
Dr Pauline Yeung	Queen Mary Hospital
Dr Shingo Adachi	Rinku general medical center (and Senshu trauma and critical care center)
Dr Pablo Blanco Ana Prieto Jesús Sánchez	Rio Hortega University Hospital
Dr Meghan Nicholson	Rochester General Hospital
Dr Michael Farquharson	Royal Adelaide Hospital
Dr Warwick Butt Alyssa Serratore Carmel Delzoppo	Royal Children’s Hospital
Dr Pierre Janin Elizabeth Yarad	Royal North Shore Hospital
Dr Richard Totaro Jennifer Coles	Royal Prince Alfred Hospital
Robert Balk Samuel Fox James Hays Esha Kapania Pavel Mishin Andy Vissing Garrett Yantosh	Rush University, Chicago
Saptadi Yuliarto Dr Kohar Hari Santoso Dr Susanthy Djajalaksana	Saiful Anwar Malang Hospital (Brawijaya University) (Paediatrics)
Dr Arie Zainul Fatoni	Saiful Anwar Malang Hospital (Brawijaya University) (Adult)
Dr Masahiro Fukuda	Saiseikai Senri Hospital
Prof Keibun Liu	Saiseikai Utsunomiya Hospital
Prof Paolo Pelosi Dr Denise Battaglini	San Martino Hospital
Dr Juan Fernando Masa Jiménez	San Pedro de Alcantara Hospital
Dr Sérgio Gaião Dr Roberto Roncon-Albuquerque	São João Hospital Centre, Porto
Jessica Buchner	Sentara Norfolk General Hospital
Dr Young-Jae Cho Dr Sang Min Lee	Seoul National University Hospital
Dr Su Hwan Lee	Severance Hospital
Dr Tatsuya Kawasaki	Shizuoka Children's Hospital
Dr Pranya Sakiyalak Prompak Nitayavardhana	Siriraj Hospital
Dr Tamara Seitz	Sozialmedizinisches Zentrum Süd—Kaiser-Franz-Josef-Spital
Rakesh Arora David Kent	St Boniface Hospital (University of Mannitoba)
Dr Swapnil Parwar Andrew Cheng Jennene Miller	St George Hospital
Daniel Marino Jillian E Deacon	St. Christopher's Hospital for Children
Dr Shigeki Fujitani Dr Naoki Shimizu	St Marianna Medical University hospital
Dr Jai Madhok Dr Clark Owyang	Stanford University Hospital
Dr Hergen Buscher Claire Reynolds	St Vincent’s Hospital
Dr Olavi Maasikas Dr Aleksandr Beljantsev Vladislav Mihnovits	Tartu University Hospital
Dr Takako Akimoto Mariko Aizawa Dr Kanako Horibe Ryota Onodera	Teine Keijinkai Hospital
Prof Carol Hodgson Meredith Young	The Alfred Hospital
Timothy Smith Cheryl Bartone	The Christ Hospital
Dr Timothy George	The Heart Hospital Baylor Plano, Plano
Dr Kiran Shekar Niki McGuinness Lacey Irvine	The Prince Charles Hospital
Brigid Flynn Abigail Houchin	The University of Kansas Medical Centre
Dr Keiki Shimizu Jun Hamaguchi	Tokyo Metropolitan Medical Center
Leslie Lussier Grace Kersker Dr John Adam Reich	Tufts Medical Centre (and Floating Hospital for Children)
Dr Gösta Lotz	Universitätsklinikum Frankfurt (University Hospital Frankfurt)(Uniklinik)
Dr Maximilian Malfertheiner Esther Dreier Dr Lars Maier	Universitätsklinikum Regensburg (Klinik für Innere Medizin II)
Dr Neurinda Permata Kusumastuti	University Airlangga Hospital (Paediatric)
Dr Colin McCloskey Dr Al-Awwab Dabaliz Dr Tarek B Elshazly Josiah Smith	University Hospital Cleveland Medical Centre (UH Cleveland hospital)
Dr Konstanty S. Szuldrzynski Dr Piotr Bielański	University Hospital in Krakow
Dr Yusuff Hakeem	University Hospitals of Leicester NHS Trust (Glenfield Hospital)
Dr Keith Wille Rebecca Holt	University of Alabama at Birmingham Hospital (UAB)
Dr Ken Kuljit S. Parhar Dr Kirsten M. Fiest Cassidy Codan Anmol Shahid	University of Calgary (Peter Lougheed Centre, Foothills Medical Centre, South Health Campus and Rockyview General Hospital)
Dr Mohamed Fayed Dr Timothy Evans Rebekah Garcia Ashley Gutierrez Hiroaki Shimizu	University of California, San Francisco-Fresno Clinical Research Centre
Dr Tae Song Rebecca Rose	University of Chicago
Dr Suzanne Bennett Denise Richardson	University of Cincinnati Medical Centre
Dr Giles Peek Dalia Lopez-Colon	University of Florida
Dr Lovkesh Arora Kristina Rappapport Kristina Rudolph Zita Sibenaller Lori Stout Alicia Walter	University of Iowa
Dr Daniel Herr Nazli Vedadi	University of Maryland—Baltimore
Dr Lace Sindt Cale Ewald Julie Hoffman Sean Rajnic Shaun Thompson	University of Nebraska Medical Centre
Dr Ryan Kennedy	University of Oklahoma Health Sciences Centre (OU)
Dr Matthew Griffee Dr Anna Ciullo Yuri Kida	University of Utah Hospital
Dr Ricard Ferrer Roca Cynthia Alegre Dr Sofia Contreras Dr JordI Riera	Vall d'Hebron University Hospital, Barcelona
Dr Christy Kay Irene Fischer Elizabeth Renner	Washington University in St. Louis/Barnes Jewish Hospital
Dr Hayato Taniguci	Yokohama City University Medical Center
Gabriella Abbate Halah Hassan Dr Silver Heinsar Varun A Karnik Dr Katrina Ki Hollier F. O'Neill Dr Nchafatso Obonyo Dr Leticia Pretti Pimenta Janice D. Reid Dr Kei Sato Dr Kiran Shekar Aapeli Vuorinen Dr Karin S. Wildi Emily S. Wood Dr Stephanie Yerkovich	COVID-19 Critical Care Consortium

Prefix/First name/Last name	Site name
Dr Emma Hartley	Aberdeen Royal Infirmary (Foresterhill Health Campus)
Bastian Lubis	Adam Malik Hospital
Takanari Ikeyama	Aichi Childrens Health and Medical Center
Balu Bhaskar	American Hospital
Dr Jae-Seung Jung	Anam Korea University Hospital
Sandra Rossi Marta Fabio Guarracino	Azienda Ospedaliero Universitaria Parma
Prof Fabio Guarracino	Azienda Ospedaliero Universitaria Pisana
Stacey Gerle	Banner University Medical Centre
Emily Coxon	Baptist Health Louisville
Dr Bruno Claro	Barts Hospital
Dr. Gonzo Gonzalez-Stawinski	Baylor All Saints Medical Centre, Forth Worth
Daniel Loverde	Billings Clinic
Dr Vieri Parrini	Borgo San Lorenzo Hospital
Dr Diarmuid O’Briain Stephanie Hunter	Box Hill Hospital
Dr Angela McBride	Brighton and Sussex Medical School
Kathryn Negaard Dr Phillip Mason	Brooke Army Medical Centre
Dr Angela Ratsch	Bundaberg Hospital
Dr Mahesh Ramanan Julia Affleck	Caboolture Hospital
Ahmad Abdelaziz	Cairo University Hospital
Dr Sumeet Rai Josie Russell-Brown Mary Nourse	Canberra Hospital
Juan David Uribe	Cardio VID
Dr Adriano Peris	Careggi Hospital
Mark Sanders	Cedar Park Regional Medical Center
Dominic Emerson	Cedars-Sinai Medical Centre
Muhammad Kamal	Cengkareng Hospital
Prof Pedro Povoa	Centro Hospitalar de Lisboa
Dr Roland Francis	Charite-Univerrsitatsmedizi n Berlin
Ali Cherif	Charles Nicolle University Hospital
Dr Sunimol Joseph	Children’s Health Ireland (CHI) at Crumlin
Dr Matteo Di Nardo	Children’s Hospital Bambino Gesù
Micheal Heard	Children's Healthcare of Atlanta-Egleston Hospital
Kimberly Kyle	Children's Hospital
Ray A Blackwell	Christiana Care Health System's Centre for Heart and Vascular Health
Dr Michael Piagnerelli Dr Patrick Biston	CHU de Charleroi
Hye Won Jeong	Chungbuk National University Hospital
Reanna Smith	Cincinnati Children's
Yogi Prawira	Cipto Mangunkusumo Hospital
Dr Giorgia Montrucchio Dr Gabriele Sales	Città della Salute e della Scienza Hospital—Turin, Italy
Nadeem Rahman Vivek Kakar	Cleveland Clinic, Abu Dhabi
Dr Michael Piagnerelli Dr Josefa Valenzuela Sarrazin	Clinica Las Condes
Dr Arturo Huerta Garcia	Clínica Sagrada Família
Dr Bart Meyns	Collaborative Centre Department Cardiac Surgery, UZ Leuven
Marsha Moreno	Dignity Health Medical Group-Dominican
Rajat Walia	Dignity Health St. Joseph's Hospital and Medical Center (SJHMC)
Dr Annette Schweda	Donaustauf hospital
Cenk Kirakli	Dr. Suat Seren Chest Diseases and Surgery Practice and Training Centre
Estefania Giraldo	Fundación Clinica Shaio (Shaio Clinic)
Dr Wojtek Karolak	Gdansk Medical University
Dr Martin Balik	General University Hospital
Elizabeth Pocock	George Washington University Hospital
Evan Gajkowski	Giesinger Medical Centre
Dr James Winearls Mandy Tallott	Gold Coast University Hospital
Kanamoto Masafumi	Gunma University Graduate School of Medicine
Dr Nicholas Barrett	Guy's and St Thomas NHS Foundation Trust Hospital
Yoshihiro Takeyama	Hakodate City Hospital
Sunghoon Park	Hallym University Sacred Heart Hospital
Faizan Amin	Hamilton General Hospital
Dr Erina Fina	Hasan Sadikin Hospital
Dr Serhii Sudakevych	Heart Institute Ministry of Health of Ukraine
Dr Angela Ratsch	Hervey Bay Hospital
Patrícia Schwarz Ana Carolina Mardini	Hospital de Clínicas de Porto Alegre
Ary Serpa Neto	Hospital Israelita Albert Einstein
Dr Andrea Villoldo	Hospital Privado de Comunidad
Alexandre Siciliano Colafranceschi	Hospital Pro Cardíaco
Dr Alejandro Ubeda Iglesias	Hospital Punta de Europa
Lívia Maria Garcia Melro Giovana Fioravante Romualdo	Hospital Samaritano Paulista
Diego Gaia	Hospital Santa Catarina
Helmgton Souza	Hospital Santa Marta
Dr Diego Bastos	Hospital Cura D’ars Fortaleza
Filomena Galas	Hospital Sirio Libanes
Dr Rafael Máñez Mendiluce	Hospital Universitario de Bellvitge
Alejandra Sosa	Hospital Universitario Esperanza (Universidad Francisco Marroquin)
Dr Ignacio Martinez	Hospital Universitario Lucus Augusti
Hiroshi Kurosawa	Hyogo Prefectural Kobe Children's Hospital
Juan Salgado	Indiana University Health
Dr Beate Hugi-Mayr	Inselspital University Hospital
Eric Charbonneau	Institut Universitaire de Cardiologie et de Pneumologie de Quebec—Universite Laval
Vitor Salvatore Barzilai	Instituto de Cardiologia do Distrito Federal—ICDF
Veronica Monteiro	Instituto de Medicina Integral Prof. Fernando Figueira (IMIP)
Rodrigo Ribeiro de Souza	Instituto Goiano de Diagnostico Cardiovascular (IGDC)
Michael Harper	INTEGRIS Baptist Medical Center
Hiroyuki Suzuki	Japan Red Cross Maebashi Hospital
Celina Adams	John C Lincoln Medical Centre
Dr Jorge Brieva	John Hunter Hospital
George Nyale	Kenyatta National Hospital (KNH)
Jihan Fatani Dr Faisal Saleem Eltatar	King Abdullah Medical City Specialist Hospital
Dr. Husam Baeissa	King Abdullah Medical Complex
Ayman AL Masri	King Salman Hospital NWAF
Yee Hui Mok	KK Women's and Children's Hospital
Masahiro Yamane	KKR Medical Center
Hanna Jung	Kyung Pook National University Hospital
Dr Matthew Brain Sarah Mineall	Launceston General Hospital
Rhonda Bakken	M Health Fairview
Dr Tim Felton	Manchester University NHS Foundation Trust—Wythenshawe
Lorenzo Berra	Massachusetts General Hospital
Gordan Samoukoviv Dr Josie Campisi	McGill University Health Centre
Bobby Shah	Medanta Hospital
Arpan Chakraborty	Medica Super speciality Hospital
Monika Cardona	Medical University of South Carolina
Harsh Jain	Mercy Hospital of Buffalo
Dr Asami Ito	Mie University Hospital
Brahim Housni	Mohammed VI University hospital
Sennen Low	National Centre for Infectious Diseases
Dr. Koji Iihara	National Cerebral and Cardiovascular Center
Joselito Chavez	National Kidney and Transplant Institute
Dr Kollengode Ramanathan	National University Hospital, Singapore
Gustavo Zabert	National University of Comahue
Krubin Naidoo	Nelson Mandela Children's Hospital
Singo Ichiba	Nippon Medical School Hospital
Randy McGregor	Northwestern Medicine
Teka Siebenaler	Norton Children's Hospital
Hannah Flynn	Novant Health (NH) Presbyterian Medical Centre
Julia Garcia-Diaz Catherine Harmon	Ochsner Clinic Foundation
Kristi Lofton	Ochsner LSA Health Shreveport
Toshiyuki Aokage	Okayama University Hospital
Kazuaki Shigemitsu	Osaka City General Hospital
Dr Andrea Moscatelli	Ospedale Gaslini
Dr Giuseppe Fiorentino	Ospedali dei Colli
Dr Matthias Baumgaertel	Paracelsus Medical University Nuremberg
Serge Eddy Mba	Parirenyatwa General Hospital
Jana Assy	Pediatric and Neonatal Cardiac intensive care at the American University
Holly Roush	Penn State Heath S. Hershey Medical Centre
Kay A Sichting	Peyton Manning Children's Hospital
Dr Francesco Alessandri	Policlinico Umberto, Sapienza University of Rome
Debra Burns	Presbyterian Hospital, New York/Weill Cornell Medical Centre
Ahmed Rabie	Prince Mohammed bin Abdulaziz Hospital
Carl P. Garabedian	Providence Sacred Heart Children's Hospital
Dr Jonathan Millar Dr Malcolm Sim	Queen Elizabeth II University Hospital
Dr Adrian Mattke	Queensland Children’s Hospital
Dr Danny McAuley	Queens University of Belfast
Jawad Tadili	Rabat university hospital
Dr Tim Frenzel	Radboud University Medical Centre
Aaron Blandino Ortiz	Ramón y Cajal University Hospital
Jackie Stone	Rapha Medical Centre
Dr Alexis Tabah Megan Ratcliffe Maree Duroux	Redcliffe Hospital
Dr Antony Attokaran	Rockhampton Hospital
Dr Brij Patel	Royal Brompton &Harefield NHS Foundation Trust
Derek Gunning	Royal Columbian Hospital
Dr Kenneth Baillie	Royal Infirmary Edinburgh
Dr Pia Watson	Sahlgrenska University Hospital
Kenji Tamai	Saiseikai Yokohamashi Tobu Hospital
Dr Gede Ketut Sajinadiyasa Dr Dyah Kanyawati	Sanglah General Hospital
Marcello Salgado	Santa Casa de Misericordia de Juiz de Fora
Assad Sassine	Santa Casa de Misericórdia de Vitoria
Dr Bhirowo Yudo	Sardjito Hospital
Scott McCaul	Scripps Memorial Hospital La Jolla
Bongjin Lee	Seoul National University Children's Hospital
Yoshiaki Iwashita	Shimane University Hospital
Laveena munshi	Sinai Health Systems (Mount Sinai Hospital)
Dr Neurinda Permata Kusumastuti	Soetomo General Hospital (FK UNAIR)
Dr Nicole Van Belle	St. Antonius Hospital
Ignacio Martin-Loeches	St James’s University Hospital
Dr Hergen Buscher	St Vincent’s Hospital, Sydney
Surya Oto Wijaya	Sulianti Saroso Hospital
Dr Lenny Ivatt	Swansea Hospital
Chia Yew Woon	Tan Tock Seng Hospital
Hyun Mi Kang	The Catholic University of Seoul St Mary Hospital
Erskine James	The Medical Centre Navicent Health
Nawar Al-Rawas	Thomas Jefferson University Hospital
Tomoyuki Endo	Tohoku Medical and Pharmaceutical University
Dr Yudai Iwasaki	Tohoku University
Dr Eddy Fan Kathleen Exconde	Toronto General Hospital
Kenny Chan King-Chung	Tuen Mun Hospital
Dr Vadim Gudzenko	UCLA Medical Centre (Ronald Regan)
Dr Beate Hugi-Mayr	Universitätsspital Bern, Universitätsklinik für Herz- und Gefässchirurgie
Dr Fabio Taccone	Universite Libre de Bruxelles
Dr Fajar Perdhana	University Airlangga Hospital (Adult)
Yoan Lamarche	University de Montreal (Montreal Heart Institute)
Dr Joao Miguel Ribeiro	University Hospital CHLN
Dr Nikola Bradic	University Hospital Dubrava
Dr Klaartje Van den Bossche	University Hospital Leuven
Gurmeet Singh	University of Aberta (Mazankowski Heart Institute)
Dr Gerdy Debeuckelaere	University of Antwerp
Dr Henry T. Stelfox	University of Calgary and Alberta Health Services
Cassia Yi	University of California at San Diego
Jennifer Elia	University of California, Irvine
Shu Fang	University of Hong Kong
Thomas Tribble	University of Kentucky Medical Center
Shyam Shankar	University of Missouri
Dr Paolo Navalesi	University of Padova
Raj Padmanabhan	University of Pittsburgh Medical Centre
Bill Hallinan	University of Rochester Medical Centre (UR Medicine)
Luca Paoletti	University of South Carolina
Yolanda Leyva	University of Texas Medical Branch
Tatuma Fykuda	University of the Ryukus
Jillian Koch	University of Wisconsin & American Family Children's Hospital
Amy Hackman	UT Southwestern
Lisa Janowaik	UTHealth (University of Texas)
Jennifer Osofsky	Vassar Brothers Medical Center (VBMC)
A/Prof Katia Donadello	Verona Integrated University Hospital
Josh Fine	WellSpan Health—York Hospital
Dr Benjamin Davidson	Westmead Hospital
Andres Oswaldo Razo Vazquez	Yale New Haven Hospital