Risk Factors for 28-Day in-Hospital Mortality in Mechanically Ventilated Patients with COVID-19: An International Cohort Study

doi:10.21203/rs.3.rs-751869/v1

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Risk Factors for 28-Day in-Hospital Mortality in Mechanically Ventilated Patients with COVID-19: An International Cohort Study

https://doi.org/10.21203/rs.3.rs-751869/v1

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Background: Risk factors associated with mortality in patients with coronavirus disease 2019 (COVID-19) on mechanical ventilation are still not fully elucidated. Thus, we aimed to identify patient-level factors, readily available at the bedside, associated with the risk of in-hospital mortality within 28 days from commencement of invasive mechanical ventilation (28-day IMV mortality) in patients with COVID-19.

Methods Prospective observational cohort study in 148 intensive care units in the global COVID-19 Critical Care Consortium. Patients with clinically suspected or laboratory confirmed COVID-19 infection admitted to the intensive care unit (ICU) from February 2^nd through December 29th, 2020, requiring IMV. No study-specific interventions were performed. Patient characteristics and clinical data were assessed upon ICU admission, the commencement of IMV and for 28 days thereafter. We primarily aimed to identify time-independent and time-dependent risk factors for 28-day IMV mortality.

Results: A total of 1713 patients were included in the survival analysis, 588 patients died in hospital within 28 days of commencing IMV (34.3%). Cox-regression analysis identified associations between the hazard of 28-day IMV mortality with age (HR 1.27 per 10-year increase in age, 95% CI 1.17 to 1.37, P<0.001), PEEP upon commencement of IMV (HR 0.78 per 5-cmH₂O increase, 95% CI 0.66-0.93, P=0.005). Time-dependent parameters associated with 28-day IMV mortality were serum creatinine (HR 1.30 per doubling, 95% CI 1.19-1.42, P<0.001), lactate (HR 1.16 per doubling, 95% CI 1.06-1.27 P=0.001), PaCO₂ (HR 1.31 per doubling, 95% CI 1.05-1.64, P=0.015), pH (HR 0.82 per 0.1 increase, 95% CI 0.74-0.91, P<0.001), PaO₂/FiO₂ (HR 0.56 per doubling, 95% CI 0.50-0.62, P<0.001) and mean arterial pressure (HR 0.92 per 10 mmHg increase, 95% CI 0.88-0.97, P=0.002).

Conclusions: This international study establishes that in mechanically ventilated patients with COVID-19, older age and clinically relevant variables monitored at the bedside are risk factors for 28-day IMV mortality. Further investigation is warranted to validate any causative roles these parameters might play in influencing clinical outcomes.

Critical Care & Emergency Medicine

COVID-19

Mechanical Ventilation

SARS-CoV-2

Intensive Care Unit

In 2020, outbreaks due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were reported globally [1]. Among patients with coronavirus disease-2019 (COVID-19), a subset developed critical illness, and up to 17% of those severe patients received invasive mechanical ventilation (IMV) [2–5]. Published reports on critically ill patients have been limited to small patient cohorts[6, 7], single-centre reports [8], mixed populations with and without any need of IMV[2, 4, 9], and single-country studies [10]. Early studies have revealed substantial variability in mortality rates — ranging from 30% [11] to 80% [2, 4, 9].

Studies [10–13] that have focused on COVID-19 patients on IMV have identified a variety of demographic and clinical characteristics associated with mortality risk. In COVID-19 patients requiring IMV, routinely measured biochemical parameters could be of significant prognostic value. However, the pattern and value of their clinical trajectory remain unclear. Ignoring changes in biochemical parameters over time when estimating associations with hospital outcomes are likely to produce biased estimates [14]. For clinicians wanting to use model outputs for prognostic purposes, the presence of such biases will have implications for identifying patients at high risk of mortality.

In early January 2020, the COVID-19 Critical Care Consortium (COVID-19–CCC) was founded to provide a global perspective on the management of critically ill COVID-19 patients and resulting outcomes to overcome many of the limitations of single-centre and single-nation studies. In this analysis, we present an inclusive characterization of mechanically ventilated patients to identify baseline and longitudinal factors associated with in-hospital mortality assessed over the first 28 days after the commencement of IMV (28-day IMV mortality).

Study Design and Setting

We analyzed COVID-19–CCC study [15] dataset (Trial registration: ACTRN12620000421932). The study protocol was initially approved by the Alfred Hospital Ethics Committee, Melbourne, Australia (Project: 62066, Local reference: 108/20). Participating hospitals had to obtain local ethics committee approval, and a waiver of informed consent was granted in all cases. De-identified patient data were collected and stored via the REDCap electronic data capture tool, hosted at the University of Oxford, in Oxford, United Kingdom, University College Dublin, in Dublin, Ireland and Monash University, in Melbourne, Australia.

Participants

Patients admitted to a COVID-19–CCC ICU, from February 2nd through December 29th, 2020, with a clinically suspected or laboratory confirmed (by real-time PCR) diagnosis of SARS-CoV-2 infection and requiring IMV for any cause were enrolled. Patients under the age of 15 years and those admitted to the ICU for reasons not related to an acute infection with SARS-CoV-2 were excluded.

Variables, data sources, measurements and definitions

After enrolment, data on demographics, comorbidities, clinical symptoms, and laboratory results were collected by clinical/research staff in all participating ICUs and recorded in an electronic case report form [16]. Details of respiratory and hemodynamic support, physiological variables, and laboratory results were collected daily up to 28 days from commencement of IMV. When multiple results for the same test were available for a single given day, the worst daily value was recorded preferentially. The duration of IMV and ICU stay also were recorded. In this paper, analysis of daily data was restricted to the first 28 days following the initiation of IMV.

Primary outcome

The primary outcome was 28-day IMV mortality. We hypothesized that time-independent factors and temporal trends of continuous parameters, frequently assessed in patients on IMV, could influence the expected risk of 28-day IMV mortality. Not all patients had a final disposition at the time of database lock. Therefore, records in which the last update indicated that the patient had not died, been discharged, or completed 28 days of follow-up after IMV initiation at the same facility were censored at their last known date of daily data collection. In particular: Patients who were discharged alive from the hospital within 28 days were censored on the date of hospital discharge; Patients transferred to another facility, from ICU or hospital within 28 days were censored on the date of transfer; Patients whose outcome was not finalized on day 28 were censored at the last known date of daily data collection.

Secondary outcomes

Variable associations with the hazard of being discharged alive from the hospital were modelled to account for the competing risk. We also describe the overall duration of IMV, hospital stay duration, tracheostomy use, and the occurrence of complications on IMV.

Statistical analysis

We appraised dataset of the COVID-19 Critical Care Consortium, which is a prospective international, multi-centre, observational study in 377 hospitals spanning 53 countries. For each patient, data collection began at the time of hospital admission, using the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) [17] and the Short PeRiod IncideNce sTudy of Severe Acute Respiratory Infection (SPRINT-SARI) [18] case report forms. Data collection for the COVID-19–CCC observational study commenced upon ICU admission. Descriptive statistics included patient demographics, comorbidities, admission signs and symptoms, clinical signs at IMV commencement, and ICU management. Continuous variables were summarised as medians with interquartile ranges. Categorical variables were summarised as frequencies with percentages. Data completeness per variable was also reported in all tables.

For the subset of patients with daily (longitudinal) data collected on clinical parameters, we first examined temporal trends over the first 28 days from commencement of IMV. Data were presented visually as unadjusted means and 95% confidence intervals (CI) and not clustered per survival or discharge outcome. The resulting outputs allowed us to assess changes in clinical parameters during IMV, to inform the formulation of time-to-event models for estimating the hazards of mortality and discharge.

We performed time-to-event analysis to examine associations between critical variables measured on or before the commencement of IMV (time-independent) and variables assessed over time on the hazards of mortality and discharge (28-day IMV discharge) up to 28 days from commencement of IMV [19]. Mortality and discharge were considered as competing events. Associations with each outcome were estimated using cause-specific Cox proportional hazard models. In comparison with logistic regression models, the time-to-event analysis allows all patients to be included when estimating the associations between patient-level factors and the outcomes of interest, regardless of whether their outcome is known by the study end date, as required by logistic regression models. This is a significant strength of the Cox proportional hazard models we applied and an essential consideration for this study. It allowed patients to be censored at their last follow-up date if their outcome was not finalised after 28 days from IMV commencement, e.g., still in the hospital. Importantly, in studies of hospitalised patients, time-to-event analysis is recommended over traditional logistic regression models since the latter introduce selection bias due to the exclusion of patients without an outcome.

Models included fixed effects for age, sex, body mass index, cardiac arrest before IMV and comorbidities reported at hospital admission (diabetes, hypertension, chronic cardiac disease), selected based on previous evidence [8, 10, 11]. Week of ICU admission was also included to account for secular trends in death and discharge hazards over the different months of the pandemic. Based on the results of hypothesis testing for the proportional hazards assumption, a linear trend was chosen. Continuous variables, namely pH, arterial partial pressure of carbon dioxide (PaCO₂), ratio between arterial partial pressure of oxygen and inspiratory fraction of oxygen (PaO₂/FiO₂), lactate, creatinine and mean arterial pressure (MAP) were treated as time-dependent variables in the model to appraise the impact of dynamic changes throughout the 28-day study period on estimated hazard ratios. For each patient, we included daily observations where all time-dependent variables were observed on the same day. Tidal volume and positive end expiratory pressure (PEEP), measured upon commencement of IMV, were also included. Unlike other daily parameters, we considered baseline values for tidal volume and PEEP as these variables are specific to time spent on IMV. Since patients were likely to be extubated before death or discharge, treating these variables as time-dependent may have led to spurious associations since patients were likely to have been extubated and have spent additional time in hospital before death or discharge. Log-2 transformations were applied to serum creatinine, lactate, PaCO₂ and PaO₂:FiO₂ to remove skewness before analysis. The remaining variables were mean centred and appropriate scaled to improve interpretation of the estimated effect. The baseline hazard function was stratified by geographic region (Africa, Asia, Australia/New Zealand, Europe, Latin America and the Caribbean, Northern America) to account for non-proportional effects.

Handling of missing data

Missing data on time-independent covariates, excluding cardiac arrest before IMV, were assumed to be missing at random. Values were imputed with Multiple Imputation using Chained Equations (MICE) [20]. MICE is an iterative algorithm which applies a series of linked regression models to impute missing values for each covariate, conditional on values for remaining variables. Models are fitted to multiple independent runs of the MICE algorithm; results across multiple runs are combined to produce a result. For time-dependent variables, follow-up intervals were constructed using all available daily observations per patient in line with a model specification for time-to-event analyses [14]. Final model results were pooled following ten independent rounds of MICE and model fitting.

All analyses were conducted using R version 4.0.1 or higher (The R Foundation).

A total of 3372 COVID-19 patients, enrolled at 148 collaborating sites across 33 countries, were screened for final analysis (Fig. 1). Among those patients, 2379 (70%) received IMV and were included in the analysis, while 993 (29%) patients who never received IMV were excluded.

Patient characteristics

In the studied cohort, the median age (IQR) was 59 years (50–68), and patients were predominantly white (46%) and from Europe (36%) (Table 1). Hypertension, obesity, smoking and diabetes were the most common comorbidities. The median time from onset of symptom to ICU admission was eight days (IQR: 5–11 days), as was time from symptom onset to commencement of IMV (median 8 days, IQR 5–12 days). IMV was initiated upon ICU admission for 67% of the patients. At the time of IMV commencement (Table 2), median (IQR) creatinine and lactate were 0.9 mg/dL (0.7–1.4) and 1.4 mmol/L (1.0–2.0), respectively. Patients were severely hypoxemic, and their median (IQR) PaO₂/FiO₂ was 106mmHg (75–155), pH was 7.35 (7.28–7.42), and PaCO₂ was 44.8mmHg (37.0-53.7). Patients presented with respiratory system compliance of 33 mL/cmH₂O (25–43) and were ventilated using PEEP of 12 cmH₂O (10–14). Vasopressors were required in 54% of the patients. Common treatment strategies over the first 28 days included antibiotics (96%), neuromuscular blocking agents(81%), prone positioning(55%), corticosteroids(52%), and antivirals(49%) (Table 3).

Table 1

Demographic and clinical characteristics upon ICU admission
Characteristic	All mechanically ventilated patients (n = 2,379)	Patients included in survival analysis (n = 1,713)
Age, years: n; Median (IQR)	2379; 59(49 to 68)	1713; 59(50 to 68)
Female: n (%)	785/2378 (33)	530/1712 (31)
Ethnicity: n (%)
Aboriginal	24/2180 (1)	11/1561 (1)
Arab	56/2180 (3)	47/1561 (3)
Black	265/2180 (12)	188/1561 (12)
East Asian	119/2180 (5)	87/1561 (6)
Latin American	119/2180 (5)	274/1561 (18)
South Asian	172/2180 (8)	71/1561 (5)
West Asian	18/2180 (1)	14/1561 (1)
White	890/2180 (41)	721/1561 (46)
Other	267/2180 (12)	148/1561 (9)
Geographic region: n (%)
Africa	186/2379 (8)	170/1713 (10)
Asia	420/2379 (18)	204/1713 (12)
Australia and New Zealand	36/2379 (2)	24/1713 (1)
Europe	686/2379 (29)	609/1713 (36)
Latin America	322/2379 (14)	258/1713 (15)
Northern America	729/2379 (31)	448/1713 (26)
Healthcare or Lab Worker: n (%)	109/2223 (5)	76/1603 (5)
Comorbidities: n (%)
Smoking	586/1659 (35)	391/1179 (33)
Obese	875/2335 (37)	644/1683 (38)
Hypertension	1166/2351 (50)	869/1692 (51)
Chronic Kidney Disease	220/2333 (9)	140/1675 (8)
Chronic Cardiac Disease	362/2328 (16)	261/1671 (16)
Diabetes	762/2315 (33)	536/1664 (32)
Malignant neoplasm	106/2331 (5)	75/1676 (4)
Chronic pulmonary disease	222/2335 (10)	150/1677 (9)
Severe liver disease	112/2366 (5)	68/1701 (4)
Body Mass Index (BMI): n; Median (IQR)	2083; 28.6(25.3 to 33.6)	1521; 28.7(25.5 to 33.6)
APACHE II: n; Median (IQR)	1054; 16.0(11.0 to 22.8)	821; 17.0(11.0 to 23.0)
SOFA: n; Median (IQR)	1186; 5.0(3.0 to 8.0)	962; 6.0(4.0 to 8.0)
WBC count, 10³/µL: n; Median (IQR)	1621; 10.0(6.8 to 14.1)	1226; 10.0(6.9 to 14.1)
Lymphocyte count, 10³/µL: n; Median (IQR)	1213; 0.8(0.5 to 1.2)	944; 0.8(0.5 to 1.2)
Neutrophils: Lymphocyte ratio: n; Median (IQR)	1108; 10.8(6.0 to 18.2)	868; 10.8(6.1 to 18.0)
Temperature, °C: n; Median (IQR)	1114; 37.0(36.2 to 37.9)	844; 37.0(36.3 to 37.9)
Creatinine, mg/dL: n; Median (IQR)	1661; 1.0(0.7 to 1.4)	1263; 1.0(0.7 to 1.4)
C-reactive protein level, mg/dL: n; Median (IQR)	1144; 88(16 to 185)	917; 92(17 to 191)
D-dimer, mcg/mL: n; Median (IQR)	691; 2(1 to 4)	527; 2(1 to 5)
Lactate, mmol/L: n; Median (IQR)	1394; 1.4(1.0 to 2.1)	1166; 1.4(1.0 to 2.0)
Ferritin; ng/mL: n; Median (IQR)	554; 2.7(1.3 to 4.5)	420; 2.7(1.4 to 4.5)
IL-6; ng/L: n; Median (IQR)	179; 90(38 to 238)	152; 92(44 to 247)

Table 1 caption

Percentages are calculated for non-missing data. BMI, body mass index; APACHE II, Acute Physiology and Chronic Health Evaluation II score; SOFA, Sequential Organ Failure Assessment Score; WBC, white blood cell count; CRP, c-reactive protein; IL-6, interleukin 6.

Table 2

Clinical characteristics upon commencement of invasive mechanical ventilation
Characteristic	All mechanically ventilated patients (n = 2,379)	Patients included in survival analysis (n = 1,713)
Clinical signs and laboratory findings within 24h from commencement of IMV
WBC count, 10³/µL: n; Median (IQR)	1654; 10.5(7.2 to 14.7)	1293; 10.4(7.2 to 14.5)
Lymphocyte count, 10³/µL: n; Median (IQR)	1153; 0.8(0.5 to 1.2)	928; 0.8(0.5 to 1.2)
Neutrophils: Lymphocyte ratio: n; Median (IQR)	1055; 11(6 to 18)	851; 11(6 to 18)
Temperature, °C: n; Median (IQR)	1122; 37(36 to 38)	882; 37(36 to 38)
Creatinine, mg/dL: n; Median (IQR)	1690; 1.0(0.7 to 1.4)	1341; 0.9(0.7 to 1.4)
C-reactive protein level, mg/dL: n; Median (IQR)	1065; 87(16 to 183)	904; 93(18 to 189)
D-dimer, mcg/mL: n; Median (IQR)	642; 1.7(0.8 to 4.7)	510; 1.5(0.8 to 4.5)
Lactate, mmol/L: n; Median (IQR)	1427; 1.4(1.0 to 2.1)	1274; 1.4(1.0 to 2.0)
Ferritin; ng/mL: n; Median (IQR)	507; 2.7(1.4 to 4.5)	406; 2.7(1.5 to 4.8)
IL-6; ng/L: n; Median (IQR)	156; 98(31 to 287)	144; 102(33 to 313)
Gas exchange and level of support within 24h from commencement of IMV
pH: n; Median (IQR)	1741; 7.35(7.28 to 7.42)	1390; 7.35(7.28 to 7.42)
FiO₂, mmHg: n; Median (IQR)	1745; 0.80(0.60 to 1.00)	1386; 0.80(0.60 to 1.00)
PaO₂/FiO₂, mmHg: n; Median (IQR)	1611; 105.20(74.00 to 156.00)	1344; 106.65(75.00 to 155.12)
PaCO₂, mmHg: n; Median (IQR)	1726; 44.00(36.50 to 53.20)	1378; 44.80(37.00 to 53.70)
Static respiratory system compliance, mL/cmH₂O: n; Median (IQR)	714; 33(25 to 42)	616; 33(25 to 42)
Plateau Pressure, cmH₂O: n; Median (IQR)	934; 25(21 to 28)	804; 25(21 to 28)
Driving Pressure, cmH₂O: n; Median (IQR)	931; 12(10 to 15)	802; 12(10 to 15)
Respiratory rate, breaths/min: n; Median (IQR)	1388; 22(18 to 27)	1053; 22(18 to 26)
PEEP level, cmH₂O: n; Median (IQR)	1440; 12(10 to 14)	1114; 12(10 to 14)
Minute ventilation, L/min: n; Median (IQR)	1080; 9(8 to 11)	839; 9(8 to 11)
Ventilatory ratio: n; Median (IQR)	875; 0.74(0.59 to 0.92)	719; 0.76(0.61 to 0.92)
Heart rate, beats/min: n; Median (IQR)	1449; 98(79 to 116)	1064; 98(78 to 114)
Mean Arterial Pressure, mmHg: n; Median (IQR)	1835; 74(64 to 90)	1408; 74(64 to 89)
Vasopressor/Inotropic Support N. (%)	999/1893 (53)	775/1432 (54)
Tracheostomy (N, %)	26/1907 (1)	21/1444 (1)

Table 2 Caption: Percentages are calculated for non-missing data. IQR, interquartile range; WBC, white blood cell count; IL-6, interleukin 6. PaO₂, arterial partial pressure of oxygen; FiO₂, inspiratory fraction of oxygen; PaCO₂, arterial partial pressure of carbon dioxide; PEEP, positive end expiratory pressure; 28-day ventilator free day (VFD) was calculated as following: VFDs = 0 if subject dies within 28 days of mechanical ventilation; VFDs = 28 − x if successfully liberated from ventilation x days after initiation; VFDs = 0 if the subject is mechanically ventilated for >28 days; IMV, invasive mechanical ventilation. Static respiratory system compliance was calculated as: tidal volume (mL)/(static airway plateau pressure-PEEP (cmH₂O)).

Table 3

Intensive Care Unit Clinical management within the first 28 days of ICU admission
Characteristic	All mechanically ventilated patients (n = 2,379)	Patients included in survival analysis (n = 1,713)
Antibiotics, n (%)	2196/2299 (96)	1587/1660 (96)
Any antiviral: n (%)	874/1691 (52)	596/1214 (49)
Ramdesivir: n (%)	261/1069 (24)	166/778 (21)
Corticosteroids: n (%)	873/1697 (51)	645/1245 (52)
Continuous renal replacement therapy: n (%)	339/2271 (15)	236/1656 (14)
Vasoactive drugs: n (%)	1291/2240 (58)	926/1636 (57)
Cardiac-assist devices: n (%)	118/2261 (5)	96/1639 (6)
ECMO: n (%)	449/2339 (19)	343/1702 (20)
Prone positioning: n (%)	1174/2340 (50)	944/1702 (55)
Use of Inhaled Nitric Oxide: n (%)	259/2340 (11)	196/1701 (12)
Use of neuromuscular blockade: n (%)	1767/2341 (75)	1383/1701 (81)
Recruitment maneuvers: n (%)	655/2143 (31)	577/1565 (37)
Tracheostomy inserted	338/2326 (15)	289/1698 (17)
28-day VFD, days: n; Median (IQR)	2023; 0(0 to 15)	1468; 0(0 to 14)
Days from ICU admission to death: n; Median (IQR)	1031; 11(5 to 21)	718; 12(6 to 23)
Days from IMV commencement to death: n; Median (IQR)	1031; 11(5 to 21)	718; 12(6 to 22)
Duration of ICU stay (died), days: n; Median (IQR)	1031; 11(5 to 21)	718; 12(6 to 22)
Duration of ICU stay (discharged), days: n; Median (IQR)	981; 19(12 to 33)	739; 19(12 to 33)
Days from hospital admission to IMV commencement: n; Median (IQR)	2376; 0(0 to 3)	1710; 0(0 to 2)
Days from ICU admission to IMV commencement: n; Median (IQR)	2379; 0(0 to 0)	1713; 0(0 to 0)
Days from first reported symptom to IMV commencement: n; Median (IQR)	2310; 8(5 to 12)	1664; 8(5 to 12)
Commenced IMV on ICU admission: n (%)	1554/2379 (65)	1152/1713 (67)

Table 3 Caption: Percentages are calculated for non-missing data. ECMO, extracorporeal membrane oxygenation; iNO, inhaled nitric oxide; IMV, invasive mechanical ventilation; ICU, intensive care unit. 28-day ventilator free day (VFD) was calculated as following: VFDs = 0 if subject dies within 28 days of mechanical ventilation; VFDs = 28 − x if successfully liberated from ventilation x days after initiation; VFDs = 0 if the subject is mechanically ventilated for >28 days

In 1713 patients with complete daily assessment, 588 patients died in hospital within 28 days of commencing IMV (34.3%), 26 patients (1.5%) were transferred to another hospital. At the study end date, outcomes of 230 patients (13.4%) who were censored at their last known follow-up date were unknown, based on daily data collection. Among patients who died, the median time to death was 12 days (IQR 6–23 days) from ICU admission. For patients with a reported cause of death (n = 648), respiratory failure was the most common (n = 189;45%), while other causes included multi-organ failure (n = 231;36%), septic shock (n = 49; 8%), cardiac failure (n = 38;6%), cerebrovascular accident (n = 13;2%), hemorrhagic shock (n = 6;1%) or other causes (n = 46;7%).

Dynamics of daily clinical parameters

Daily averages for clinical variables, including arterial blood gases, are depicted in Fig. 2. There was a clear improvement in the dynamics of PaO₂/FiO₂ (from 132.7 ± 2.9 mmHg upon start IMV to 198.8 ± 9.2 mmHg at 28 days), pH (from 7.34 ± 0.00 to 7.40 ± 0.00), serum creatine (from 1.39 ± 0.04 mg/dL to 1.18 ± 0.09) and lactate (from 1.98 ± 0.06 mmol/L to 1.15 ± 0.07). Differently, trajectories of PaCO₂ and MAP were more convoluted, with early worsening during the first days of IMV and delayed improvement. Figure 3 shows ventilatory modes throughout the study period. Controlled modes were predominantly used during the first 2 weeks of IMV. Stratification of clinical variables and ventilatory settings for patients with known final outcome within the first 28 days of IMV are reported separately in Figs. 4 and 5. There was an apparent discrepancy between survivors and non-survivors in the applied FiO₂, while tidal volume and PEEP were similar throughout the assessment period.

Primary Outcome

Time-to-event analysis (Fig. 6A) identified older age (HR 1.27 per 10-year increase in age, 95% CI 1.17 to 1.37, P < 0.001) and lower values of PEEP, upon commencement of IMV (HR 0.78 per 5-cmH₂O increase, 95% CI 0.66–0.93, P = 0.005) as statistically significant associations with of the hazard of 28-day IMV mortality. Among time-dependent variables, an increase in serum creatinine (HR 1.3 per doubling, 95% CI 1.19–1.42, P < 0.001), lactate (HR 1.16 per doubling, 95% CI 1.06–1.27, P = 0.001) and PaCO₂ (HR 1.31 per doubling, 95% CI 1.05–1.64, P = 0.015) increased the hazards of 28-day IMV mortality. Conversely, an increase in pH (HR 0.82 per 0.1 increase, 95% CI 0.74–0.91, P < 0.001), PaO₂/FiO₂ (HR 0.56 per doubling, 95% CI 0.50–0.62, P < 0.001) and MAP (HR 0.92 per 10 mmHg increase, 95% CI 0.88–0.97, P = 0.002), decreased the hazards of 28-day IMV mortality. Figure 7A depicts variability in the baseline survival function for 28-day IMV mortality among geographic regions.

Secondary Outcomes

Estimated hazard ratios for the variables as mentioned above and the hazard of discharge are reported in Fig. 6B. Results indicated that older age (HR 0.85 per 10-year increase in age, 95% CI 0.78 to 0.93, P < 0.001), increased creatinine (HR 0.81 per doubling, 95% CI 0.71–0.92, P = 0.001) and PaCO₂ (HR 0.52 per doubling, 95% CI 0.36–0.77, P < 0.001) decreased the hazards of 28-day IMV discharge, while higher PaO₂/FiO₂ (HR 1.54 per doubling, 95% CI 1.33–1.79, P < 0.001) increased the hazard. Similar to IMV 28-day mortality, baseline survival function of 28-day IMV discharge varied between geographic regions (Fig. 7B).

Tracheostomy was carried out in 289/1698 patients (17%) included in the survival analysis (Table 3). During hospitalization, the most common complications in the mechanically ventilated population were cardiac arrhythmia (26%), pleural effusion (20%) and cardiac arrest (17%) (Table 4). The median duration of IMV was 13 days (IQR:7–24 days). Among patients in whom final disposition was available within 28 days of IMV, the median time from ICU to death was 12 days (IQR:6–22 days). Among patients known to be discharged alive from the hospital, the median time from ICU admission to hospital discharge was 19 days (IQR:12–33 days).

Table 4

Cardio-pulmonary complications
Complication at any time during hospitalization n (%)	All mechanically ventilated patients (n = 2,379)	Patients included in survival analysis (n = 1,713)
Cardiac Arrhythmia	471/1955 (24)	356/1393 (26)
Pleural Effusion	359/1932 (19)	280/1377 (20)
Cardiac Arrest	415/1966 (21)	232/1400 (17)
Deep Vein Thrombosis	7/67 (10)	6/45 (13)
Pneumothorax	170/1966 (9)	135/1400 (10)
Pulmonary Embolism	104/1635 (6)	83/1108 (7)
Heart Failure	105/1926 (5)	70/1373 (5)
Cardiac Ischemia	79/1922 (4)	55/1369 (4)
Cardiomyopathy	46/1602 (3)	34/1087 (3)
Cryptogenic organizing pneumonia	50/1906 (3)	38/1357 (3)
Myocardial Infarction	45/1612 (3)	28/1094 (3)
Bronchiolitis	26/1904 (1)	22/1356 (2)
Myocarditis/Pericarditis	44/1610 (3)	25/1094 (2)
Endocarditis	7/1610 (0)	7/1094 (1)

The present international multicentre cohort study from six continents constitutes the most extensive epidemiological investigation of mechanically ventilated patients with severe COVID-19. The study enabled delineation of the clinical course during the first 28 days of IMV, corroborating age and accounting for longitudinal changes in pH, PaO₂/FiO₂, MAP, PaCO₂, lactate and creatinine when assessing associations with 28-day IMV mortality.

Reported average mortality rates in mechanical ventilated COVID-19 patients have varied [2, 4, 9, 13, 21]. Those findings have been potentially biased by highly variable censor dates to define death, and substantial percentages of patients still requiring ICU care at the chosen censor date [2, 4, 6, 8, 9, 22–26]. In our study, among 1713 ventilated patients, we reported an overall 28-day IMV mortality of 34.3%, similar to rates in ventilated patients from the Netherlands [10] and Spain [8] and lower than figures from United Kingdom [27]. Given the observational nature of our study, extrapolations on the mortality figures of our population can only be speculative. Nevertheless, the mortality rate should be interpreted in the context of the enrollment period of February-December 2020, since early dismal survival from outbreak epicenters might have been counterbalanced by lower mortality rates later in the year. In addition, in comparison with previous single-country observational studies [28, 29], corticosteroids were used in fewer patients, due to either differences in practice among geographical regions or inclusion of data acquired early in the pandemic. Nevertheless, we found that period of admission to ICU was not significantly associated with major outcomes, implying consistent burden of the disease throughout periods of the pandemic.

In line with previous reports [9, 10, 13, 30, 31] that found older populations at the highest risk of mortality, age shared a strong positive association with the hazard of 28-day IMV mortality. Of note, we report a slightly younger population than previous investigations [8, 30, 32, 33], possibly because, in 2020, IMV was primarily reserved for younger patients in some of the geographical regions comprising our study network. Irrespective, it is still not fully elucidated why SARS-CoV-2 infection is more lethal in older adults and several theories that detail potential risks associated with age-related changes to the immune cells, inflammasome activity, epigenome, and characteristic comorbidities have emerged [34]. Among the other time-independent factors, only PEEP was found to reduce mortality hazards in our analyses, in contrast with previous evidence associating higher PEEP with mortality [30]. These findings emphasize the challenges in setting the optimal PEEP in COVID-19 patients [35], particularly in light of early controversial reports on heterogeneous static respiratory system compliance in infected patients [36].

We found that several clinical variables increased the risk of 28-day IMV mortality. To the best of our knowledge, our report is the first that applied Cox proportional hazards modelling of 28-day IMV mortality to assess the impact of time-dependent clinical variables, taking into account the competing risk of ICU discharge. Indeed, previous investigations [8–10, 30, 37, 38] focused on risk factors for mortality appraised at a fixed time point, limiting inferences on variables that dynamically change during IMV. By incorporating baseline stratification by geographic region in modelling, we found substantial differences in survival, in line with the most recent reports from low-middle income countries [39]. As expected, the severity of hypoxemia during IMV was strongly associated with both mortality and delayed discharge. In this cohort, patients presented a considerable improvement in PaO₂/FiO₂ during the first 24h of IMV, similarly to previous evidence [8], and potentially related to the prompt pronation, NMBAs and high PEEP after commencement of IMV. However, the data also emphasizes potential long-term respiratory derangement since moderate hypoxemia persisted throughout the assessment period. The study also identified the association of PaCO₂ with the hazard of death, which was not reported in previous studies. Furthermore, an increase in PaCO₂ during the initial days of IMV was evident in this cohort, which could have been related to the initial hypercatabolic state, inadequate ventilatory management, micro or macrovascular pulmonary thrombosis [40–42] or simply to respiratory fatigue, given that on average, patients were intubated eight days from symptom onset. Previous extensive studies [9, 10, 30, 37] failed to corroborate serum lactate and MAP as risk factors for mortality in COVID-19 patients on IMV. In a large critically ill population from the United Kingdom, lactate within 24-h from ICU admission was an early predictor of mortality [37]. However, the evolution of such parameter in this population was unknown, and only 59% required IMV. Cytokine storm and septic shock in COVID-19 are linked with haemodynamic instability and lactic acidosis, and multi-organ failure in the most severe cases. Thus, our original findings imply that haemodynamic impairment could be valuable in risk stratification. Similar to the findings of the PRoVENT-COVID study [10], changes in pH were associated with mortality risk. On average, pH normalization was achieved within one week. It is uncertain whether low pH was driven by refractory hypercapnia, metabolic disturbance or a mixed acid-base disorder. Importantly, interdependence of aforementioned variables should also be considered. Indeed, pH and PaCO₂ coupling may have been present during refractory hypercapnia, and similarly pH and lactate correlation could have been the result of sustained acidemia during severe hypotensive states or other metabolic disturbances. Finally, the association of serum creatinine with the hazards of death is important, because most patients in our cohort did not have chronic kidney disease before hospitalization. Further investigation of the multifactorial etiology of renal impairment in COVID-19 is urgently needed, as the angiotensin converting enzyme-two receptor is critical for SARS-CoV-2 cell entry and widely expressed in the kidneys [43, 44], but IMV and septic shock might have also contributed to the development of kidney injury.

Strengths and limitations

In efforts to inform the field as to characteristics of COVID-19 infection, many early publications limited to small patient series or single-country experiences have appeared. These papers reported conflicting findings related to centre-specific patient populations, resource availability differences, and patient management strategy variations. The current study overcomes some of these limitations by providing a detailed global analysis of demographics and comorbidities associated with mortality and, for the first time, account for the dynamics of a clinically relevant subset of commonly tested variables associated with hazards of 28-day IMV. Limitations of the current report include that our model should not be used for prediction at an individual level, due to the lack of validation in different and larger cohorts. Admission to ICU, indication for IMV were not standardized across countries and could have depended on local practices. In this cohort, patients received IMV in 2020; thus, they may not reflect the current scenarios of ICU ventilatory management across the globe – to which subsequent reports can be compared. Further, many of the early pandemic centers were resource-limited, which may have adversely impacted the noted outcomes. Approximately 50% of the patients received corticosteroids. Consequently, any extrapolation of our findings to patients receiving dexamethasone treatment must be performed with caution [45, 46]. Given that the analyses selectively focused on demographics and comorbidities associated with increased mortality, and time-dependent parameters routinely measurable at the bedside of IMV patients, other unmeasured factors could have biased our inferences about mortality risks. The 28-day timeline could have biased results toward early mortality. Irrespective, we precisely aimed at identifying key associations affecting mortality during the period of IMV, which in COVID-19 patients is approximately ten days [10, 21, 47]. Lastly, information on SARS-CoV-2 variants and patient vaccination status is not accessible from our analyses.

This study represents the most extensive and comprehensive international cohort analyses of patient characteristics associated with mortality, in COVID-19 patients requiring mechanical ventilation. Age and commonly tested parameters in COVID-19 patients on IMV, including pH, blood gases, MAP, serum lactate, and serum creatinine, were associated with the increased hazards 28-day IMV mortality. These original findings offer new avenues for research efforts for the early identification of the patients most at risk and in need of altering clinical management strategies.

Coronavirus disease 2019 (COVID-19)
In-hospital mortality within 28 days from commencement of invasive mechanical ventilation (28-day IMV mortality)
Intensive care unit (ICU)
Hazard Ratio (HR)
Confidence Interval (CI)
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)
Invasive mechanical ventilation (IMV)
COVID-19 Critical Care Consortium (COVID-19–CCC)
International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC)
Short PeRiod IncideNce sTudy of Severe Acute Respiratory Infection (SPRINT-SARI)
Multiple Imputation using Chained Equations (MICE)
Arterial partial pressure of carbon dioxide (PaCO₂)
Ratio between arterial partial pressure of oxygen and inspiratory fraction of oxygen (PaO₂/FiO₂)
Mean arterial pressure (MAP)
Positive end expiratory pressure (PEEP)

Ethics approval and consent to participate

Participating hospitals obtained local ethics committee approval and a waiver of informed consent was granted in all cases.

Consent for publication

Not applicable

Availability of data materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

A/Prof Li Bassi received research support from Fisher & Paykel outside the submitted work. Prof Dalton consults with Innovative ECMO Concepts, Abiomed and Instrumentation Labs, which does not affect the current work. Prof Brodie receives research support from ALung Technologies, and he has been on the medical advisory boards for Baxter, Abiomed, Xenios and Hemovent. A/Prof Fan reports personal fees from ALung Technologies, Baxter, Fresenius Medical Care, Getinge, and MC3 Cardiopulmonary outside the submitted work. Prof Laffey reports consulting fees from Baxter and Cala Medical, both outside the submitted work. Prof Nichol is supported by a Health Research Board of Ireland Award (CTN-2014-012). Prof Fraser receives research support from Fisher & Paykel outside the submitted work. Prof. Grasselli reports personal fees from Draeger Medical, Biotest, Getinge, Fisher & Paykel and MSD outside the submitted work.

Funding: The University of Queensland, The Wesley Medical Research, The Prince Charles Hospital Foundation, The Health Research Board of Ireland; Biomedicine International Training Research Programme for Excellent Clinician-Scientists; The European Union Research and Innovation Programme (Horizon 2020); la Caixa Foundation. Finally, Carol Hodgson is funded by the National Health and Medical Research Council Grant.

Authors’ contribution

GLB conceived of the study, participated in its design and coordination and helped to draft the manuscript; JYS conceived of the study, participated in its design and coordination and helped to draft the manuscript; NW performed the statistical analysis helped to draft the manuscript; HD, participated in its design and coordination and helped to draft the manuscript; JoF participated in collection of data and reviewed the initial draft of the manuscript; AC participated in collection of data and reviewed the initial draft of the manuscript; SS participated in collection of data and reviewed the initial draft of the manuscript; SH participated in collection of data and reviewed the initial draft of the manuscript; SF participated in collection of data and reviewed the initial draft of the manuscript; RP participated in collection of data, helped in the statistical analysis and reviewed the initial draft of the manuscript, JGL participated in collection of data and reviewed the initial draft of the manuscript; EF participated in collection of data and reviewed the initial draft of the manuscript; RB participated in collection of data and reviewed the initial draft of the manuscript; DB participated in collection of data and reviewed the initial draft of the manuscript; AB participated in collection of data and reviewed the initial draft of the manuscript; DC participated in collection of data and reviewed the initial draft of the manuscript; AA participated in collection of data and reviewed the initial draft of the manuscript; GG participated in collection of data and reviewed the initial draft of the manuscript; CH participated in collection of data and reviewed the initial draft of the manuscript; SH participated in collection of data and reviewed the initial draft of the manuscript; CL participated in collection of data and reviewed the initial draft of the manuscript; EM participated in collection of data and reviewed the initial draft of the manuscript; LM participated in collection of data and reviewed the initial draft of the manuscript; SM participated in collection of data and reviewed the initial draft of the manuscript; AN participated in collection of data and reviewed the initial draft of the manuscript; MP participated in collection of data and reviewed the initial draft of the manuscript; PP participated in collection of data and reviewed the initial draft of the manuscript; AT participated in collection of data and reviewed the initial draft of the manuscript; PY participated in collection of data and reviewed the initial draft of the manuscript; MO participated in collection of data and reviewed the initial draft of the manuscript; JF conceived of the study, participated in its design and coordination and helped to draft the manuscript

Statistical Analysis: Nicole White; Rex Person.

Acknowledgments

We recognize the crucial importance of the ISARIC and SPRINT-SARI networks in developing and expanding the global COVID-19 Critical Care Consortium. We thank the generous support we received from the Extracorporeal Life Support Organization (ELSO) and the International ECMO Network (ECMONet). We greatly acknowledge Adrian Barnett for his invaluable contribution to the analysis plan and statistical insights. We greatly acknowledge Bailey Schneider (University of Michigan and University of Queensland) for her input and contribution to the critical revision of the manuscript. We owe Li Wenliang, MD from the Wuhan Central Hospital, an eternal debt of gratitude for reminding the world that doctors should never be censored during a pandemic. Finally, we acknowledge all members of the COVID-19 Critical Care Consortium and various collaborators.

Contributors TO BE LISTED IN PUBMED

Prefix/First Name/Last Name	Site Name
Dr Emma Hartley	Aberdeen Royal Infirmary (Foresterhill Health Campus)
Tala Al-Dabbous	Al Adan Hospital
Dr Subbarao Elapavaluru Ashley Berg Christina Horn	Allegheny General Hospital
Prof Fabio Guarracino	Azienda Ospedaliero Universitaria Pisana
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	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
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 Darryl Abrams Alexis Serra	Columbia University Medical Centre
Gabrielle Ragazzo Dr Jeffrey Javidfar Nisreen Shiban	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 Silvia Coppola 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 Grieco	Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Dr Kota Hoshino	Fukuoka University
Dr Leonardo Salazar Laura Duarte	Fundación Cardiovascular de Colombia
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
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
Marcelo Amato Luciana Cassimiro Flavio Pola	INCOR (Universidade de São Paulo)
Dr Mehul Desai Dr Heidi Dalton 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 Judy Willhide 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 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	Kuwait ECLS program, Al-Amiri & Jaber Al-Ahmed Hospitals
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 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	Medizinische Klinik und Poliklinik II
Dr Marc Csete Luisa Quesada Isabela Saba	Mount Sinai Medical Centre
Dr Daisuke Kasugai Hiroaki Hiraiwa Taku Tanaka	Nagoya University Hospital
Dr Eva Marwali	National Cardiovascular Center Harapan Kita
Yih-Sharng Chen	National Taiwan University Hospital
Prof John Laffey Dr Bairbre McNicholas Dr Aine McCarthy Dr Eibhilin Higgins Ritika Ranjan	National University of Ireland Galway and Galway University Hospitals
Marlice VanDyk Sarah MacDonald	Netcare Unitas ECMO Centre
Dr Indrek Ratsep Lauri Enneveer Kristo Erikson Dr Getter Oigus Andra-Maris Post Piret Sillaots	North Estonia Medical Centre
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	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 Navy Lolong Dr Ernita Akmal Dr Erlina Burhan Prof Menaldi Rasmin Bhat Naivedh	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 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
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
Robert Balk Samuel Fox James Hays Esha Kapania Pavel Mishin Andy Vissing Garrett Yantosh	Rush University, Chicago
Dr Saptadi Yuliarito Dr Arie Zainul Fatoni Dr Kohar Hari Santoso Dr Susanthy Djajalaksana	Saiful Anwar Malang Hospital (Brawijaya University)
Dr Masahiro Fukuda	Saiseikai Senri Hospital
Prof Keibun Liu	Saiseikai Utsunomiya Hospital
Prof Paolo Pelosi Denise Battaglini	San Martino Policlinico Hospital
Dr Juan Fernando Masa Jiménez	San Pedro de Alcantara Hospital
Dr Sérgio Gaião Dr Roberto Roncon-Albuquerque	São João Hospital Centre, Porto
Dr Desy Rusmawatiningtyas	Sardjito Hospital
Dr Young-Jae Cho Dr Sang Min Lee	Seoul National University Bundang 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 Shigeki Fujitani Dr Naoki Shimizu	St Marianna Medical University hospital
Daniel Marino Jillian E Deacon	St. Christopher's Hospital for Children
Dr Jai Madhok Dr Clark Owyang	Stanford University 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
Timothy Smith Cheryl Bartone	The Christ Hospital
Dr Timothy George	The Heart Hospital Baylor Plano, Plano
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 Dr 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
James Lee Daniel Plotkin Barbara Wanjiru Citarella	ISARIC, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK.
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 Bailey Schneider Dr Kiran Shekar Aapeli Vuorinen Dr Karin S. Wildi Emily S. Wood Dr Stephanie Yerkovich	COVID-19 Critical Care Consortium

Collaborators TO NOT BE LISTED IN PUBMED

Prefix/First Name/Last Name	Site Name
Bastian Lubis	Adam Malik Hospital
Takanari Ikeyama	Aichi Childrens Health and Medical Center
Dr Huda Alfoudri	Al-Adan hospital
Balu Bhaskar	American Hospital
Dr Jae-Seung Jung	Anam Korea University Hospital
Sandra Rossi Marta Fabio Guarracino	Azienda Ospedaliero Universitaria Parma
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 Angela McBride	Brighton and Sussex Medical School
Kathryn Negaard Dr Phillip Mason	Brooke Army Medical Centre
Ahmad Abdelaziz	Cairo University 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
Omar Mehkri Stuart Houltham	Cleveland Clinic - Ohio
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
Motohiro Asaki	Fujieda Municipal General Hospital
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
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
Patrícia Schwarz	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
Livia Melro	Hospital Samaritano Paulista
Diego Gaia	Hospital Santa Catarina
Helmgton Souza	Hospital Santa Marta
Dr Diego Bastos	Hospital São Camilo 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
Dr Divina Tuazon Dr Toni Duculan	Houston Methodist Hospital
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
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 Tak-Hyuk Oh	KyungPook National Unviersity Hostpital
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 Superspeciality Hospital
Monika Cardona	Medical University of South Carolina
Dr Akram Zaaqoq Lan Anh Galloway Caitlin Merley	MedStar Washington Hospital Centre
Harsh Jain	Mercy Hospital of Baffalo
Dr Asami Ito	Mie University Hospital
Brahim Housni	Mohammed VI universitary hospital
Dafsah Arifa Juzar	National Cardiovascular Center Harapan Kita
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
Gustavo Zabert	National University of Comahue
Krubin Naidoo	Nelson Mandela Children's Hospital
Singo Ichiba	Nippon Medical School Hospital
Dr Effe Mihelis	Northwell Health
Randy McGregor	Northwestern Medicine
Teka Siebenaler	Norton Children's Hospital
Hannah Flynn	Novant Health (NH) Presbyterian Medical Centre
Julia Garcia-Diaz	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 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 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 For a
Assad Sassine	Santa Casa de Misericórdia de Vitoria
Dr Bhirowo Yudo	Sardjito Hospital
Scott McCaul	Scripps Memorial Hospital La Jolla
Jessica Buchner Jordan Dail Dr Jennifer May	Sentara Norfolk General Hospital
Bongjin Lee	Seoul National University Children's Hospital
Yoshiaki Iwashita	Shimane University Hospital
Dr Neurinda Permata Kusumastuti	Soetomo General Hospital (FK UNAIR)
Dr Nicole Van Belle	St. Antonius Hospital
Dr Hergen Buscher	St Vincent’s Hospital, Sydney
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
Eddy Fan	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
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
Andres Oswaldo Razo Vazquez	Yale New Haven Hospital

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Risk Factors for 28-Day in-Hospital Mortality in Mechanically Ventilated Patients with COVID-19: An International Cohort Study

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