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Figure.  Kaplan-Meier Analysis of Survival of Patients Admitted to the Intensive Care Unit
Kaplan-Meier Analysis of Survival of Patients Admitted to the Intensive Care Unit

Survival is reported for the overall group and stratified by median age (<64 or ≥64 years).

Table 1.  Demographic and Clinical Characteristics, Comorbidities, and Outcomes of 3988 Patients With COVID-19 Admitted to the ICU in Lombardy, Italy
Demographic and Clinical Characteristics, Comorbidities, and Outcomes of 3988 Patients With COVID-19 Admitted to the ICU in Lombardy, Italy
Table 2.  Multivariable Cox Proportional Hazards Regression Analysis of Factors Associated With Mortality
Multivariable Cox Proportional Hazards Regression Analysis of Factors Associated With Mortality
Table 3.  Demographic and Clinical Characteristics, Comorbidities, and Outcomes of the First 1715 Patients
Demographic and Clinical Characteristics, Comorbidities, and Outcomes of the First 1715 Patients
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    1 Comment for this article
    Where are the other variables?
    Joseph DeRose, O.D., M.S. | Private Practice
    There is no mention of obesity nor cigarette smoking in most reports like this one and I find it to be a glaring omission. Other hospital based physicians report that nearly all their deceased patients are overweight or obese. 
    CONFLICT OF INTEREST: None Reported
    Views 33,426
    Citations 0
    Original Investigation
    July 15, 2020

    Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy

    Author Affiliations
    • 1Dipartimento di Anestesia, Rianimazione e Emergenza-Urgenza, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
    • 2Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
    • 3Department of Anaesthesia and Intensive Care Medicine, Humanitas Clinical and Research Center–IRCCS, Rozzano, Italy
    • 4Department of Biomedical Sciences, Humanitas University, Milan, Italy
    • 5Humanitas Gavazzeni, Bergamo, Italy
    • 6Department of Anesthesiology, Intensive Care and Emergency Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
    • 7Dipartimento di Scienze biotecnologiche di base, cliniche intensivologiche e perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy
    • 8Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
    • 9Department of Anesthesia and Intensive Care Medicine, Azienda Socio Sanitaria Territoriale (ASST) Monza–Ospedale San Gerardo, Monza, Italy
    • 10Department of Anaesthesia and Intensive Care, ASST Papa Giovanni XXIII, Bergamo, Italy
    • 11Università degli Studi dell’Insubria, Azienda Ospedaliera Ospedale di Circolo e Fondazione Macchi, Varese, Italy
    • 12Department of Anesthesiology and Intensive Care, ASST Mantova–Ospedale Carlo Poma, Mantova, Italy
    • 13Department of Anaesthesiology, Intensive Care and Perioperative Medicine, Spedali Civili University Hospital, Brescia, Italy
    • 14Direzione Generale (DG) Welfare, Lombardy Region, Milan, Italy
    • 15Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
    • 16Department of Anesthesiology and Intensive Care, ASST Cremona–Ospedale di Cremona, Cremona, Italy
    • 17Department of Anesthesiology and Intensive Care, ASST Lecco–Ospedale di Lecco, Lecco, Italy
    • 18Dipartimento di Anestesia e Rianimazione, Grande Ospedale Metropolitano Niguarda, Milan, Italy
    • 19Department of Intensive Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
    • 20Department of Clinical-Diagnostic, Surgical and Pediatric Sciences, University of Pavia, Pavia, Italy
    • 21Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy
    • 22Department of Anesthesia and Intensive Care, Fondazione Poliambulanza Hospital, Brescia, Italy
    • 23Department of Anesthesia and Intensive Care, ASST Rhodense–Presidio di Rho, Milano, Italy
    • 24Anesthesia and Intensive Care Medicine, Policlinico di Sant’Orsola, Alma Mater Studiorum University of Bologna, Bologna, Italy
    • 25Department of Anesthesiology and Intensive Care, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Polo Universitario, University of Milan, Milan, Italy
    • 26Direzione Scientifica, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
    • 27Dipartimento Emergenza Urgenza, Unità Operativa Complessa (UOC) Anestesia e Rianimazione, ASST, Lodi, Italy
    • 28Division of Pulmonary and Critical Medicine, Massachusetts General Hospital, Boston
    • 29Health Protection Agency of Pavia, Pavia, Italy
    JAMA Intern Med. Published online July 15, 2020. doi:10.1001/jamainternmed.2020.3539
    Key Points

    Question  What are the risk factors associated with mortality among critically ill patients with laboratory-confirmed coronavirus disease 2019 admitted to intensive care units in Lombardy, Italy?

    Findings  In this cohort study that involved 3988 critically ill patients admitted from February 20 to April 22, 2020, the hospital mortality rate as of May 30 was 12 per 1000 patient-days after a median observation time of 70 days. In the subgroup of the first 1715 patients, 865 (50.4%) had been discharged from the intensive care unit, 836 (48.7%) had died in the intensive care unit, and 14 (0.8%) were still in the intensive care unit; 915 patients died in the hospital for overall hospital mortality of (53.4%).

    Meaning  This study found that most critically ill patients with coronavirus disease 2019 in the intensive care unit required invasive mechanical ventilation, and mortality rate and absolute mortality rate were high.

    Abstract

    Importance  Many patients with coronavirus disease 2019 (COVID-19) are critically ill and require care in the intensive care unit (ICU).

    Objective  To evaluate the independent risk factors associated with mortality of patients with COVID-19 requiring treatment in ICUs in the Lombardy region of Italy.

    Design, Setting, and Participants  This retrospective, observational cohort study included 3988 consecutive critically ill patients with laboratory-confirmed COVID-19 referred for ICU admission to the coordinating center (Fondazione IRCCS [Istituto di Ricovero e Cura a Carattere Scientifico] Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy) of the COVID-19 Lombardy ICU Network from February 20 to April 22, 2020. Infection with severe acute respiratory syndrome coronavirus 2 was confirmed by real-time reverse transcriptase–polymerase chain reaction assay of nasopharyngeal swabs. Follow-up was completed on May 30, 2020.

    Exposures  Baseline characteristics, comorbidities, long-term medications, and ventilatory support at ICU admission.

    Main Outcomes and Measures  Time to death in days from ICU admission to hospital discharge. The independent risk factors associated with mortality were evaluated with a multivariable Cox proportional hazards regression.

    Results  Of the 3988 patients included in this cohort study, the median age was 63 (interquartile range [IQR] 56-69) years; 3188 (79.9%; 95% CI, 78.7%-81.1%) were men, and 1998 of 3300 (60.5%; 95% CI, 58.9%-62.2%) had at least 1 comorbidity. At ICU admission, 2929 patients (87.3%; 95% CI, 86.1%-88.4%) required invasive mechanical ventilation (IMV). The median follow-up was 44 (95% CI, 40-47; IQR, 11-69; range, 0-100) days; median time from symptoms onset to ICU admission was 10 (95% CI, 9-10; IQR, 6-14) days; median length of ICU stay was 12 (95% CI, 12-13; IQR, 6-21) days; and median length of IMV was 10 (95% CI, 10-11; IQR, 6-17) days. Cumulative observation time was 164 305 patient-days. Hospital and ICU mortality rates were 12 (95% CI, 11-12) and 27 (95% CI, 26-29) per 1000 patients-days, respectively. In the subgroup of the first 1715 patients, as of May 30, 2020, 865 (50.4%) had been discharged from the ICU, 836 (48.7%) had died in the ICU, and 14 (0.8%) were still in the ICU; overall, 915 patients (53.4%) died in the hospital. Independent risk factors associated with mortality included older age (hazard ratio [HR], 1.75; 95% CI, 1.60-1.92), male sex (HR, 1.57; 95% CI, 1.31-1.88), high fraction of inspired oxygen (Fio2) (HR, 1.14; 95% CI, 1.10-1.19), high positive end-expiratory pressure (HR, 1.04; 95% CI, 1.01-1.06) or low Pao2:Fio2 ratio (HR, 0.80; 95% CI, 0.74-0.87) on ICU admission, and history of chronic obstructive pulmonary disease (HR, 1.68; 95% CI, 1.28-2.19), hypercholesterolemia (HR, 1.25; 95% CI, 1.02-1.52), and type 2 diabetes (HR, 1.18; 95% CI, 1.01-1.39). No medication was independently associated with mortality (angiotensin-converting enzyme inhibitors HR, 1.17; 95% CI, 0.97-1.42; angiotensin receptor blockers HR, 1.05; 95% CI, 0.85-1.29).

    Conclusions and Relevance  In this retrospective cohort study of critically ill patients admitted to ICUs in Lombardy, Italy, with laboratory-confirmed COVID-19, most patients required IMV. The mortality rate and absolute mortality were high.

    Introduction

    As of June 16, 2020, 8 251 224 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and 445 188 coronavirus disease 2019 (COVID-19)–related deaths had been reported worldwide.1 Among active cases, 1.6% (54 593 of 3 503 249) are in severe or critical condition.

    Lombardy, a region of Northern Italy, was the epicenter of the first COVID-19 outbreak in a western country.2 On April 22, 3940 of 69 092 laboratory-confirmed cases (5.7%) required admission to one of the intensive care units (ICUs) of the COVID-19 Lombardy ICU Network.3 Knowledge of baseline patient characteristics and risk factors associated with ICU and hospital mortality is still limited. Male sex, hypertension, cardiovascular disorders, and type 2 diabetes are the most prevalent comorbidities, and they are associated with a high case fatality rate.4-11 The prevalence of chronic obstructive pulmonary disease is typically less than 10%.4,6-8,10-12 It has been hypothesized that the use of drugs acting on the renin-angiotensin system may be associated with the course of the disease, because SARS-CoV-2 enters the host cells by binding to the angiotensin-converting enzyme 2 (ACE2).6,13-17

    Acute respiratory distress syndrome has been diagnosed in 40% to 96%6-8,12,18 of the patients admitted to the ICU. Need for invasive mechanical ventilation (IMV) varied widely between the different case series but is invariably associated with high mortality,4-6,8,10,18,19 with ICU mortality ranging from 16% to 78%.7-9,11,12,18-20 A prior study from the COVID-19 Lombardy ICU Network5 reported an ICU mortality of 25.6% (15% aged 14-63 years; 36% aged 64-91 years); however, 58.2% of patients were still in the ICU at the end of follow-up.

    We herein report ICU and hospital outcomes of the first 3988 patients critically ill with COVID-19 referred to the Coordinating Center (Fondazione IRCCS [Istituto di Ricovero e Cura a Carattere Scientifico] Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy) of the COVID-19 Lombardy ICU Network.2,5 Some data from the first 1591 patients have been previously reported.5 We describe the baseline characteristics of the patients, comorbidities, concomitant treatments at the time of hospital admission, mode and setting of ventilatory support, and the association of these characteristics with time to death.

    Methods
    Patients and Data Collection

    The institutional ethics board of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, approved this study and waived the need for informed consent from individual patients owing to the retrospective nature of the study. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

    This retrospective, observational study enrolled all consecutive patients with confirmed SARS-CoV-2 infection admitted to one of the Network ICUs from February 20 to April 22, 2020. To the best of our knowledge, all the critically ill patients requiring ICU admission in Lombardy have been referred to the Regional Coordinating Center. Laboratory confirmation of SARS-CoV-2 was defined as a positive result of real-time reverse transcriptase–polymerase chain reaction assay of nasal and pharyngeal swabs and, in selected cases, confirmation with reverse transcriptase–polymerase chain reaction assay from lower respiratory tract aspirates.

    The staff of the Regional Coordinating Center contacted each ICU of the Network daily by telephone and recorded on an electronic worksheet the demographic and clinical patient data. The following variables within the first 24 hours of ICU admission were recorded: age, sex, mode of respiratory support (IMV, noninvasive mechanical ventilation [NIV], oxygen mask), level of positive end-expiratory pressure (PEEP), fraction of inspired oxygen (Fio2), arterial partial pressure of oxygen (Pao2), Pao2:Fio2 ratio, use of extracorporeal membrane oxygenation, and prone positioning. Preexisting comorbidities, long-term use of medications, and date of symptom onset were retrieved from the Regional Health System Database, which is based on the prescription of the general practitioners. The definitions of home intake of long-term medications and of each comorbidity, derived from the Regional Database, are presented in the eMethods in the Supplement.

    The ICU and hospital outcomes of each patient were recorded on May 30, 2020. The interval from symptom onset to ICU admission, length of ICU stay, rate of reintubation, and rate of readmission to ICU were also evaluated.

    Statistical Analysis

    Categorical variables are reported as frequencies (percentages with 95% CIs) and continuous variables as means (with SDs) or medians (with interquartile ranges [IQRs] and 95% CIs) according to distribution. Groups were compared with Wilcoxon rank sum tests with Benjamini and Hochberg correction for multiple comparison according to data distribution for continuous variables, and with Pearson χ2 test (Fisher exact test where appropriate) for categorical variables.

    Life status was determined for all patients as of May 30, 2020, from the Regional Health Authority. Time-to-event techniques were used to analyze survival from ICU admission. Overall mortality rate was calculated per 1000 patient-days. The ICU and hospital mortality rates were calculated analogously, taking into account only time until ICU (or hospital) discharge.

    Days from ICU admission to death (event) or May 30, 2020 (censoring), constituted the time of analysis. At the time of censoring, patients might be alive in the ICU, alive in hospital, or alive and discharged. For patients readmitted to the ICU after discharge, the first ICU admission was considered in the analysis.

    We calculated Kaplan-Meier survival estimates and used the log-rank test to compare groups in terms of survival. The association of risk factors with time to death was assessed in univariable and multivariable Cox proportional hazards regression models. The proportional hazard assumption was tested by plotting the Nelson-Aalen cumulative hazard function and Schoenfeld residuals test.21

    Four multivariable models were developed for demographics (model 1), comorbidities (model 2), drugs (model 3), and respiratory parameters (model 4) using variables strongly associated with mortality at univariable analysis, known from previous literature to be strongly associated with outcome and not collinear. We used the Akaike information criterion to compare different regression models and select the most parsimonious model.

    The final model included independent factors from models 1 to 3 only (model 4 was run on a subset of data owing to missing data), with no further selection. The number of patients with missing data were 0 for outcomes, 82 for drugs, 688 for comorbidities, 1053 for Pao2, 984 for Fio2, 1074 for Pao2:Fio2 ratio, and 958 for PEEP on ICU admission. Detailed information about missing data are reported in eFigure 1 in the Supplement.

    A subgroup analysis was performed on the first 1715 patients, most of whom were included in a prior report.6 As of May 30, 2020, 14 (0.8%) of these patients were still in the ICU, and 865 (50.4%) had been discharged from the ICU. A second subgroup analysis was performed on the 1643 patients with hypertension to explore the potential role of ACE inhibitors and antihypertensive drugs in this subset. A third subgroup analysis was performed on the 350 patients treated with NIV in the ICU to assess the association of NIV with patient outcomes. R software, version 4.0 (R CoreTeam, 2020), and STATA computer software, version 16.0 (StataCorp LLC), were used for data analysis. Two-sided P < .05 indicated significance.

    Results
    Description of the Cohort

    From a population of 4209 patients admitted to ICUs in Lombardy with suspected SARS-CoV-2 infection to April 22, 2020, we excluded 127 patients with negative reverse transcriptase–polymerase chain reaction findings for SARS-CoV-2 and 94 patients missing results of reverse transcriptase–polymerase chain reaction for SARS-CoV-2. Data from 3988 patients (median age, 63 [IQR, 56-69] years) were analyzed. Table 1 shows the associations between demographic and baseline characteristics and mortality. Most patients were men (3188 [79.9%; 95% CI, 78.7%-81.1%]), with a median age of 63 (95% CI, 62-63; IQR, 55-69) years. Eight hundred patients were women (20.1%; 95% CI, 18.9%-21.3%]), with a median age of 64 (95% CI, 63-65; IQR, 57-70) years. Median time from symptom onset to ICU admission was 10 (95% CI, 9-10; IQR, 6-14) days. One thousand nine hundred and ninety-eight of 3300 patients (60.5%; 95% CI, 58.9%-62.2%) had at least 1 comorbidity. Hypertension was the most common comorbidity (1643 [42.1%; 95% CI, 40.5%-43.6%]), followed by hypercholesterolemia (545 [16.5%; 95% CI, 15.3%-17.8%]) and heart disease (533 [16.2%; 95% CI, 14.9%-17.4%]).

    Observation Time and Main Outcomes

    Cumulative observation time was 164 305 patient-days from ICU admission to end of follow-up for the 3988 patients (median observation time, 70 [range, 38-112] days; IQR, 61-70 days). After a median follow-up of 69 (IQR, 60-78; range, 38-100) days, there were 1926 deaths (overall mortality, 48.3%) for a mortality rate of 12 (95% CI, 11-12) per 1000 patient-days (Figure). There were 1769 ICU deaths (44.3%), for an ICU mortality rate of 27 (95% CI, 26-29) per 1000 patient-days. At the time of censoring, 91 patients (2.3%; 95% CI, 1.9%-2.8%) were still in the ICU, and 2049 (51.4%; 95% CI, 49.8%-52.9%) had been discharged from the ICU. Among the latter, 1480 patients (37.1%; 95% CI, 35.6%-38.6%) had been discharged from the hospital and 501 (12.6%; 95% CI, 11.6%-13.6%) were still hospitalized; the mortality rate after discharge from the ICU was 2 (95% CI, 1-2) per 1000 patient-days.

    Distribution of patients’ outcomes by ICU admission date is presented in the eFigure 2 in the Supplement. Median ICU stay was 12 (IQR, 6-21; range, 0-87) days, and the median duration of mechanical ventilation was 10 (IQR, 6-17; range, 0-87) days. Median length of stay in hospital was 28 (IQR, 15-48; range, 0-120) days.

    Of the 2049 patients discharged from the ICU, 134 (6.5%) were readmitted to the ICU after discharge. Sixty-four of 3857 patients (1.7%) underwent extracorporeal membrane oxygenation support during the ICU stay, of whom 40 died (62.5%), 13 were discharged home (20.3%), and 11 were still hospitalized (17.2%).

    At ICU admission, 2929 of 3355 patients (excluding 633 with missing data) underwent intubation (87.3%; 95% CI, 86.1%-88.4%). Three hundred and fifty patients underwent noninvasive respiratory support with NIV (10.4%; 95% CI, 9.4%-11.5%), which in most cases consisted of continuous positive air pressure delivered through a helmet or a standard oxygen mask (76 of 3355 patients [2.3%]).

    Univariable Analysis

    A 10-year increase in age was significantly associated with mortality (hazard ratio [HR], 1.86; 95% CI, 1.76-1.96; P < .001). Patients 64 years or older had significantly decreased survival probability compared with younger patients (Figure).

    Hypertension, hypercholesterolemia, heart disease, diabetes, malignant neoplasm, chronic obstructive pulmonary disease, chronic kidney disease, and all the studied medications taken at home before entering the hospital were associated with increased mortality at univariable analysis (Table 1 and eTable 2 in the Supplement). A 10% increase in Fio2 on the first day of ICU admission was associated with increased mortality (HR, 1.24; 95% CI, 1.20-1.27; P < .001), whereas a 100-point increase in Pao2:Fio2 ratio decreased by 44% the hazard for mortality (HR, 0.66; 95% CI, 0.61-0.71; P < .001).

    Multivariable Analysis

    At multivariable analysis, a 10-year increase in age (HR, 1.75; 95% CI, 1.60 -1.92) and male sex (HR, 1.57; 95% CI, 1.31-1.88) were significantly associated with mortality (Table 2 and eFigure 3 in the Supplement). Among comorbidities, history of chronic obstructive pulmonary disease (HR, 1.68; 95% CI, 1.28-2.19), hypercholesterolemia (HR, 1.25; 95% CI, 1.02-1.52), and diabetes (HR, 1.18; 95% CI, 1.01-1.39) were significantly associated with mortality. No long-term use of a medication was independently associated with mortality after controlling for other factors (ACE inhibitors HR, 1.17 [95% CI, 0.97-1.42]; angiotensin receptor blockers [ARBs] HR, 1.05 [95% CI, 0.85-1.29]). Decreased PEEP (HR, 1.04; 95% CI, 1.01-1.06) and Fio2 (HR, 1.14; 95% CI, 1.10-1.19) and increased Pao2:Fio2 ratio (HR, 0.80; 95% CI, 0.74-0.87) at ICU admission were independently associated with improved survival.

    Subgroup Analyses

    In the subgroup analysis of the first 1715 patients (minimum follow-up of 73 days), the hospital mortality was 915 patients (53.4%; 95% CI, 50.9%-55.7%), with 836 (48.7%; 95% CI, 46.4%-51.1%) dying in the ICU and 79 (4.6%; 95% CI, 3.7%-5.7%) dying after ICU discharge. Table 3 shows the univariable associations of baseline characteristics and comorbidities in this subgroup. As of May 30, 2020, 14 patients (0.8%) were still in the ICU and 127 (7.4%) were still hospitalized; the median observation time was 80 (range, 76-112) days. The median ICU length of stay of patients who died in the ICU was 10 (IQR, 5-16) days; for those discharged from the ICU, 15 (IQR, 8-24) days.

    In the subgroup of 1643 patients with a history of hypertension, long-term home treatment with ACE inhibitors, β-blockers, statins, and diuretics was associated with higher mortality at univariable analysis (eTable 2 in the Supplement). The subgroup of 350 patients initially treated with NIV had lower levels of PEEP (eTable 1 in the Supplement) and a lower hazard for mortality (HR, 0.62; 95% CI, 0.52-0.75; P < .001) than patients treated with IMV. The 151 patients initially treated noninvasively and subsequently undergoing intubation (after a median of 3 [IQR, 2-4; range, 0-15] days) had a significantly lower chance of survival compared with the 199 patients who continued to undergo NIV during the entire ICU stay (HR, 1.69; 95% CI, 1.43-1.98; P < .001). The mortality of the patients undergoing subsequent intubation was similar to that for the patients who were treated with mechanical ventilation for ICU admission (HR for IMV vs NIV failure, 1.20; 95% CI, 0.95-1.53; P = .12). eTable 1 and eFigure 4 in the Supplement show the overall survival data for patients in this subgroup.

    Discussion

    In a cohort of 3988 critically ill patients with laboratory-confirmed SARS-CoV-2 infection admitted to an ICU during the first 2 months of the COVID-19 outbreak in Lombardy, Italy, the estimated ICU and hospital mortality rates were 27 and 12 per 1000 patient-days, respectively. In the subset of the first 1715 patients, ICU and hospital mortality were 48.8% and 53.4%, respectively. This mortality is almost double that described in the initial report,6 in which the ICU mortality was 25.6% but 58.2% of the patients were still in the ICU at the end of follow-up. These sobering statistics highlight the long ICU stays, prolonged need for respiratory support, and high mortality of COVID-19 in critically ill patients.

    At the beginning of the COVID-19 outbreak in Lombardy, many patients required ICU admission in a limited period.2,22 Hence, the ICU capacity had to be rapidly increased by establishing a network of COVID-19 ICUs in many hospitals. Experience in the treatment of patients with acute respiratory failure and the physician-to-patient and nurse-to-patient ratios varied widely among the centers, and this might have had an effect on patient outcomes.23,24 Mortality of patients critically ill with COVID-19 varies significantly among the published case series, ranging from 16% to 78%.7,8,10-12,18-20 This wide variability can be explained by different case mixes, different organization, availability of ICU beds among different countries, and different lengths of follow-up. In a case series of ICU patients in China, 28-day ICU mortality was 39% for the entire ICU population (344 patients) but reached 97% in the subgroup of 100 patients requiring IMV.9 In the case series of critically ill patients from Washington State18 and the Seattle region,12 71% and 75% of patients required IMV, respectively. Mortality calculated with a minimum follow-up of 12 days was 67% in Washington State; with a minimum follow-up of 14 days, 50%.

    Importantly, patients included in our series were the sickest patients, those treated in high-intensity (level 3) areas, as demonstrated by the very high proportion of patients (87.3%) undergoing IMV at ICU admission. Many more patients in Italy, not described herein, have been treated in lower-intensity (level 2) areas, created ad hoc for the COVID-19 crisis, with extended monitoring and noninvasive respiratory support.

    Our findings confirm that survival of critically ill patients with COVID-19 is particularly low for older men requiring IMV and with preexisting comorbidities. Hypertension was the most frequent comorbidity, and patients with hypertension had significantly decreased survival. Despite this, in the multivariable analysis, hypertension was not an independent factor associated with mortality. Conversely, a history of chronic obstructive pulmonary disease, hypercholesterolemia, and diabetes, although affecting a smaller percentage of patients, were independently associated with mortality.

    The pathophysiology of acute respiratory failure in patients with COVID-19 is poorly understood. Some reports show a significant mismatch between the degree of hypoxemia and a relatively minor compromise of respiratory system compliance.25 This mismatch may indicate that the optimal setting of mechanical ventilation in these patients may be different from that commonly applied in usual forms of acute respiratory distress syndrome. Levels of PEEP applied in our patients at ICU admission were higher than those reported for the management of moderate to severe acute respiratory distress syndrome in the pre–COVID-19 era.26 High PEEP levels and Fio2 and low Pao2:Fio2 ratio at ICU admission were all independent factors associated with mortality.

    Data on the effect of drugs acting on the renin-angiotensin system are of particular interest because ACE2 is the primary receptor for SARS-CoV-2 entry into the host cells.17 Preclinical data support the hypothesis that long-term intake of ACE inhibitors, ARBs, statins, corticosteroids, and hypoglycemic agents may increase susceptibility to SARS-CoV-2 infection by favoring viral replication owing to upregulation of ACE2 receptors.27-31 On the other hand, in patients with COVID-19, these same drugs may theoretically improve the clinical course by rebalancing the dysregulated renin-angiotensin system and thus reducing vasoconstriction, inflammation, and oxidation. In a recent large case series, mortality of patients with hypertension taking ACE inhibitors or ARBs was higher than that of patients with hypertension not taking these drugs, but no statistic confirmed the association between chronic therapy with ACE inhibitors or ARBs and mortality.10 In our patients, long-term treatment with ACE inhibitors, ARBs, β-blockers, statins, diuretics, antiplatelet drugs, and anticoagulants before ICU admission was associated with higher mortality in an unadjusted analysis only. This finding should be interpreted with caution, because unmeasured confounders could explain this observation, as demonstrated by the fact that the multivariable analysis did not confirm the association between any home therapies and increased mortality.

    Limitations

    This study has several limitations. First, it is a retrospective study based on data mainly collected by telephone primarily for clinical purposes. We were able to cross-link demographic data from other health care databases; however, this was mainly a real-life database made for operational reasons. We could not assess the effect of other important variables, such as weight, body mass index, smoking history, and respiratory system compliance. Second, some variables have missing data (eFigure 1 in the Supplement), mainly owing to the reasons mentioned above. Third, preexisting comorbidities and chronic medications were retrieved from the regional health system database; therefore, the severity of the comorbidities and patient compliance with medical prescriptions could not be evaluated. Moreover, we do not have information on how many patients maintained their long-term medication regimens during the ICU stay, which may be relevant, particularly for drugs acting on the renin-angiotensin system.

    In addition, another important limitation concerns some peculiar organizational aspects of intensive care services of the Italian health care system. During this crisis, we increased the total capacity of both our higher-intensity (level 3) and lower-intensity (level 2) areas to increase our potential for respiratory support. All patients with COVID-19 undergoing intubation were treated in level 3 areas and are described in this report, whereas most patients who did not undergo intubation were treated in level 2 areas. For these reasons, we believe that our data provide important insights about patients requiring IMV but should not be extrapolated to the population of patients requiring other forms of advanced noninvasive respiratory support.

    Conclusions

    SARS-CoV-2 represents a massive challenge for health care systems and the ICUs in Italy and throughout the world.2 A high volume of patients with the same disease required access to intensive treatments at the same time. Until effective and specific therapies are available, supportive care is the mainstay of treatment for critically ill patients.32,33 Providing this care at a high-quality level for the high volume of patients to treat is a challenge for all health care systems.

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    Article Information

    Accepted for Publication: June 18, 2020.

    Corresponding Author: Alberto Zanella, MD, Dipartimento di Anestesia-Rianimazione e Emergenza Urgenza, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca’ Granda Ospedale Maggiore Policlinico, Via Della Commenda 16, 20122 Milano, Italy (alberto.zanella1@unimi.it).

    Published Online: July 15, 2020. doi:10.1001/jamainternmed.2020.3539

    Author Contributions: Drs Grasselli and Greco contributed equally as co–first authors. Drs Pesenti and Cecconi contributed equally as co–last authors. Drs Greco and Zanella had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Grasselli, Greco, Zanella, Antonelli, Cabrini, Langer, Ranieri, Scudeller, Pesenti, Cecconi.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Grasselli, Greco, Zanella, Albano, Bonanomi, Cereda, Colombo, Crescini, Forastieri Molinari, Pessina, Rech, Pesenti, Cecconi.

    Critical revision of the manuscript for important intellectual content: Grasselli, Zanella, Antonelli, Bellani, Cabrini, Carlesso, Castelli, Cattaneo, Coluccello, Foti, Fumagalli, Iotti, Langer, Latronico, Lorini, Mojoli, Natalini, Ranieri, Scudeller, Rosano, Storti, Thompson, Tirani, Villani, Pesenti, Cecconi.

    Statistical analysis: Greco, Zanella, Coluccello, Latronico, Scudeller, Cecconi.

    Administrative, technical, or material support: Grasselli, Bellani, Carlesso, Cattaneo, Forastieri Molinari, Langer, Latronico, Lorini, Rosano.

    Supervision: Grasselli, Zanella, Albano, Antonelli, Bonanomi, Foti, Fumagalli, Iotti, Langer, Latronico, Lorini, Mojoli, Ranieri, Storti, Pesenti, Cecconi.

    Conflict of Interest Disclosures: Dr Grasselli reported receiving personal fees from Getinge Group, Biotest, Draeger Medical Systems, Inc, Thermo Fisher Scientific, and Fisher & Paykel outside the submitted work. Dr Zanella reported holding patents to WO2016189427 and WO2015IB55837 (licensed). Dr Bellani reported receiving grants and personal fees from Draeger Medical Systems, Inc, and Dimar SRL and personal fees from Hamilton Medical Products, Inc, Getinge Group, GE Healthcare, and Intersurgical outside the submitted work. Dr Iotti reported receiving personal fees from Hamilton Medical Products, Inc, Intersurgical, Maquet Italia, Cinisello Balsamo Eurosets, and Burke & Burke outside the submitted work. Dr Mojoli reported receiving fees for lectures from Hamilton Medical Products, Inc, GE Healthcare, and Seda SpA and a consultancy agreement between University of Pavia and Hamilton Medical Products, Inc. Dr Thompson reported receiving personal fees from Bayer AG outside the submitted work. Dr Pesenti reported receiving personal fees from Maquet Italia, Novalung/Xenios AG, Baxter International, Inc, and Boehringer Ingelheim outside the submitted work. Dr Cecconi reported receiving personal fees from Edwards Lifesciences, Directed Systems, and Cheetah Medical, Inc, outside the submitted work. No other disclosures were reported.

    Group Information: The COVID-19 Lombardy ICU Network includes the following participants: Emiliano Agosteo, MD, Clinica “San Carlo” Paderno Dugnano, Milan, Italy; Giovanni Albano, MD, Humanitas Gavazzeni, Bergamo, Italy; Andrea Albertin, MD, Department of Anaesthesia and Intensive Care, San Giuseppe Hospital, Multimedica Group, Milan, Italy; Armando Alborghetti, MD, Department of Anaesthesia and Intensive Care, Policlinico San Pietro–Ponte San Pietro, Italy; Giorgio Aldegheri, MD, Department of Anaesthesiology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Multimedica, Sesto San Giovanni, Milano, Italy; Benvenuto Antonini, MD, Department of Anaesthesia and Intensive Care, Azienda Socio Sanitaria Territoriale (ASST) Garda–Ospedale di Manerbio, Manerbio, Italy; Enrico Barbara, MD, Department of Anaesthesia and Intensive Care, Humanitas Mater Domini Hospital, Castellanza, Varese, Italy; Giulia Bardelloni, MD, Department of Medicine and Surgery, University of Milano-Bicocca, and Department of Anesthesia and Intensive Care Medicine, ASST Monza–Ospedale San Gerardo, Monza, Italy; Sabrina Basilico, MD, Department of Anesthesia and Intensive Care Unit, ASST Lariana, Como, Italy; Nicolangela Belgiorno, MD, Department of Anaesthesia and Intensive Care, Istituto Clinico San Rocco, Ome, Italy; Giacomo Bellani, MD, Department of Medicine and Surgery, University of Milano-Bicocca, and Department of Anesthesia and Intensive Care Medicine, ASST Monza–Ospedale San Gerardo, Monza, Italy; Enrico Beretta, MD, Unit of Anesthesia and Intensive Care, ASST Valtellina e Alto Lario, Ospedale E. Morelli, Sondalo, Italy; Angela Berselli, MD, Department of Anesthesiology and Intensive Care, ASST Mantova–Ospedale Carlo Poma, Mantova, Italy; Leonardo Bianciardi, MD, Department of Anaesthesia and Intensive Care, Hospital of Pieve di Coriano, ASST Mantova, Mantova, Italy; Ezio Bonanomi, MD, Department of Anaesthesia and Intensive Care, ASST Papa Giovanni XXIII, Bergamo, Italy; Stefano Bonazzi, MD, Department of Anaesthesia and Intensive Care, Hospital MOA Locatelli, Piario, ASST Bergamo Est, Bergamo, Italy; Massimo Borelli, MD, Department of Anaesthesia and Intensive Care, Ospedale Treviglio–Caravaggio, Treviglio, Italy; Nicola Bottino, MD, Dipartimento di Anestesia, Rianimazione e Emergenza-Urgenza, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; Nicola Bronzini, MD, Department of Anaesthesia and Intensive Care, Clinical Institute Sant’Anna, Brescia, Italy; Serena Brusatori, MD, Regional Coordinating Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, and University of Milan, Milan, Italy; Luca Cabrini, MD, Università degli Studi dell’Insubria anda Azienda Ospedaliera Ospedale di Circolo e Fondazione Macchi, Varese, Italy; Carlo Capra, MD, Department of Biotechnology and Sciences of Life, ASST–Setteleghi Ospedale di circolo e Fondazione Macchi, University of Insubria, Varese, Italy; Livio Carnevale, MD, Department of Anaesthesia and Intensive Care, ASST Pavia–Ospedale di Vigevano, Vigevano, Italy; Gianpaolo Castelli, MD, Department of Anesthesiology and Intensive Care, ASST Mantova–Ospedale Carlo Poma, Mantova, Italy; Emanuele Catena, MD, Department of Anesthesia and Intensive Care Unit, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Polo Universitario, University of Milan, Milan, Italy; Sergio Cattaneo, MD, Department of Anaesthesiology, Intensive Care and Perioperative Medicine, Spedali Civili University Hospital, Brescia, Italy; Maurizio Cecconi, MD, Department of Pathophysiology and Transplantation, University of Milan, and Department of Anaesthesia and Intensive Care Medicine, Humanitas Clinical and Research Center–IRCCS, Rozzano, Milan, Italy; Simona Celotti, MD, Humanitas Gavazzeni, Bergamo, Italy; Stefania Cerutti, MD, Department of Anaesthesia and Intensive Care, ASST Papa Giovanni XXIII, Bergamo, Italy; Davide Chiumello, MD, SC Anestesia e Rianimazione, Ospedale San Paolo–Polo Universitario, ASST Santi Paolo e Carlo, and University of Milan, Milan, Italy; Silvia Cirri, MD, Department of Anaesthesia and Intensive Care, Istituto Clinico Sant’Ambrogio, Milan, Italy; Giuseppe Citerio, MD, Department of Anaesthesia and Intensive Care, Hospital of Desio, ASST Monza, and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; Sergio Colombo, MD, Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy; Antonio Coluccello, MD, Department of Anesthesiology and Intensive Care, ASST Cremona-Ospedale di Cremona, Cremona, Italy; Davide Coppini, MD, Department of Anaesthesia and Intensive Care, ASST Garda–Ospedale Civile di La Memoria, Gavardo, Italy; Alberto Corona, MD, Department of Anaesthesia and Intensive Care, Ospedale di Valle Camonica Esine, ASST Vallecamonica, Brescia, Italy; Paolo Cortellazzi, MD, Department of Anaesthesia and Intensive Care, Ospedale Città di Sesto San Giovanni, ASST Nord Milano, Milan, Italy; Elena Costantini, MD, Department of Anaesthesia and Intensive Care Medicine, Humanitas Clinical and Research Center–IRCCS, Rozzano, Milan, Italy; Remo Daniel Covello, MD, Anesthesia and Intensive Care Unit, Busto Arsizio Hospital, ASST Valle Olona, Varese, Italy; Giuseppe Crescini, MD, Department of Anesthesiology and Intensive Care, ASST Cremona-Ospedale di Cremona, Cremona, Italy; Gianluca De Filippi, MD, Department of Anesthesia and Intensive Care, ASST Rhodense–Presidio di Rho, Milano, Italy; Marco Dei Poli, MD, Department of General Anesthesia and Intensive Care, IRCCS Policlinico San Donato, Milan, Italy; Paolo Dughi, MD, ASST Franciacorta, Ospedale di Iseo, Iseo, Italy; Fulvia Fieni, MD, Department of Anaesthesia and Intensive Care, Istituto Clinico San Rocco, Ome, Italy; Gaetano Florio, MD, Regional Coordinating Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, and University of Milan, Milan, Italy; Andrea Forastieri Molinari, MD, Department of Anesthesiology and Intensive Care, ASST Lecco, Ospedale di Lecco, Lecco, Italy; Giuseppe Foti, MD, Department of Medicine and Surgery, University of Milano-Bicocca, and Department of Anesthesia and Intensive Care Medicine, ASST Monza–Ospedale San Gerardo, Monza, Italy; Roberto Fumagalli, MD, Department of Medicine and Surgery, University of Milano-Bicocca, and Dipartimento di Anestesia e Rianimazione Grande Ospedale Metropolitano Niguarda, Milan, Italy; Marco Galletti, MD, Department of Anaesthesia and Intensive Care, Ospedale Valduce, Como, Italy; Giorgio Antonio Gallioli, MD, Department of Anaesthesia and Intensive Care, ASST Vimercate–Ospedale di Vimercate, Vimercate, Italy; Hedwige Gay, MD, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy, and Dipartimento di Anestesia e Rianimazione Grande Ospedale Metropolitano Niguarda, Milan, Italy; Marco Gemma, MD, Department of Anaesthesia and Intensive Care, Fatebenefratelli Hospital, ASST Fatebenefratelli Sacco, Milan, Italy; Paolo Gnesin, MD, Department of Anesthesia and Intensive Care, ASST Franciacorta, Chiari, Brescia, Italy; Giacomo Grasselli, MD, Dipartimento di Anestesia, Rianimazione e Emergenza-Urgenza, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, and Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Stefano Greco, MD, Department of Anaesthesia and Intensive Care, ASST Valle Olona-Ospedale di Saronno, Saronno, Italy; Massimiliano Greco, MD, Department of Pathophysiology and Transplantation, University of Milan, and Department of Anaesthesia and Intensive Care Medicine, Humanitas Clinical and Research Center–IRCCS, Rozzano, Milan, Italy; Paolo Grosso, MD, Department of Anaesthesia and Intensive Care, Policlinico di Monza, Monza, Italy; Luca Guatteri, MD, Department of Anaesthesia and Intensive Care, Ospedale Sacra Famiglia Fatebenefratelli, Erba, Italy; Davide Guzzon, MD, Department of Anaesthesia and Intensive Care, ASST Lecco–Ospedale di Merate, Merate, Italy; Giorgio Antonio Iotti, MD, Department of Intensive Medicine, Fondazione IRCCS Policlinico San Matteo, and Department of Clinical-Diagnostic, Surgical and Pediatric Sciences, University of Pavia, Pavia, Italy; Roberto Keim, MD, ASST Bergamo Est, Seriate, Italy; Thomas Langer, MD, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy, and Dipartimento di Anestesia e Rianimazione Grande Ospedale Metropolitano Niguarda, Milan, Italy; Nicola Latronico, MD, Department of Anaesthesiology, Intensive Care and Perioperative Medicine, Spedali Civili University Hospital, and Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy; Andrea Lombardo, MD, Department of Anesthesia and Intensive Care Unit, ASST Lariana, Como, Italy; Ferdinando Luca Lorini, MD, Department of Anaesthesia and Intensive Care, ASST Papa Giovanni XXIII, Bergamo, Italy; Filippo Mamprin, MD, ASST Bergamo Est, Seriate, Italy; Giovanni Marino, MD, Department of Anaesthesia and Intensive Care, ASST Melegnano-Ospedale di Vizzolo Predabissi, Melegnano, Italy; Francesco Marino, MD, Department of Anaesthesia and Intensive Care, Clinical Institute Betato Matteo, Vigevano, Pavia, Italy; Guido Merli, MD, Department of Anesthesia and Intensive Care Unit, Maggiore Hospital, Crema, Italy; Antonio Micucci, MD, Department of Anaesthesia and Intensive Care, Hospital Sant’Antonio Abate of Cantù, ASST Lariana, Como, Italy; Carmine Rocco Militano, MD, Department of Anesthesia and Intensive Care, Fondazione Poliambulanza Hospital, Brescia, Italy; Francesco Mojoli, MD, Department of Intensive Medicine, Fondazione IRCCS Policlinico San Matteo, and Department of Clinical-Diagnostic, Surgical and Pediatric Sciences, University of Pavia, Pavia, Italy; Giacomo Monti, MD, Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy; Stefano Muttini, MD, Department of Anaesthesia and Intensive Care, ASST Santi Paolo e Carlo-Ospedale San Carlo, Milan, Italy; Samantha Nadalin, MD, Humanitas Gavazzeni, Bergamo, Italy; Giuseppe Natalini, MD, Department of Anesthesia and Intensive Care, Fondazione Poliambulanza Hospital, Brescia, Italy; Paolo Perazzo, MD, Department of Anaesthesia and Intensive Care, IRCCS Orthopedic Institute Galeazzi, Scientific Direction, Milan, Italy; Giovanni Battista Perego, MD, Department of Anaesthesia and Intensive Care, Istituto Auxologico San Luca, Milan, Italy; Luciano Perotti, MD, Department of Intensive Medicine, Fondazione I.R.C.C.S. Policlinico San Matteo, Pavia, Italy; Antonio Pesenti, MD, Dipartimento di Anestesia, Rianimazione e Emergenza-Urgenza, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, and Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Carla Maria Pessina, MD, Department of Anesthesia and Intensive Care, ASST Rhodense–Presidio di Rho, Milano, Italy; Nicola Petrucci, MD, Department of Anaesthesia and Intensive Care, ASST Garda–Ospedale di Desenzano D/G, Desenzano del Garda, Italy; Angelo Pezzi, MD, Department of Anaesthesia and Intensive Care, ASST Nord Milano–Ospedale Edoardo Bassini, Cinisello Balsamo, Italy; Simone Piva, MD, Department of Anaesthesiology, Intensive Care and Perioperative Medicine, Spedali Civili University Hospital, Brescia, Italy; Gina Portella, MD, Emergency-NGO, Milan, Italy; Alessandro Protti, MD, Department of Pathophysiology and Transplantation, University of Milan, Department of Anaesthesia and Intensive Care Medicine, Humanitas Clinical and Research Center–IRCCS, Rozzano, Milan, Italy; Milena Racagni, MD, Department of Anaesthesia and Intensive Care, ASST Santi Paolo e Carlo-Ospedale San Carlo, Milan, Italy; Danilo Radrizzani, MD, ASST Ovest Milanese-Ospedale Nuovo di Legnano Hospital, Legnano, Italy; Maurizio Raimondi, MD, Unità Operativa Complessa (UOC) Anestesia e Rianimazione, Ospedale Civile di Voghera ASST provincia di Pavia, Italy; Marco Ranucci, MD, Department of Cardiovascular Anaesthesia and Intensive Care Unit, IRCCS Policlinico San Donato, Milan, Italy; Roberto Rech, MD, Department of Anesthesia and Intensive Care Unit, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Polo Universitario, University of Milan, Milan, Italy; Mario Riccio, MD, Department of Anaesthesia and Intensive Care, Istituti Ospitalieri di Cremona-C.no Ospedale Oglio Po, Casalmaggiore, Italy; Antonio Rosano, MD, Department of Anesthesia and Intensive Care, Fondazione Poliambulanza Hospital, Brescia, Italy; Patrizia Ruggeri, MD, Department of Anesthesiology and Intensive Care, ASST Cremona–Ospedale di Cremona, Cremona, Italy; Giuseppe Sala, MD, Department of Anaesthesia and Intensive Care, Istutito Clinico Città Studi, Milan, Italy; Luca Salvi, MD, Department of Anaesthesia and Intensive Care, Centro Cardiologico Monzino, Milan, Italy; Pietro Sebastiano, MD, Department of Anaesthesia and Intensive Care, Istituto Clinico Città di Brescia-Istituti Ospedalieri Bresciani, Gruppo San Donato, Brescia, Italy; Paolo Severgnini, MD, Department of Biotechnology and Sciences of Life, ASST–Setteleghi Ospedale di circolo e Fondazione Macchi, University of Insubria, Varese, Italy; Donato Sigurtà, MD, Department of Anaesthesia and Intensive Care, Istituto di Cura Città di Pavia, Pavia, Italy; Nino Stocchetti, MD, Dipartimento di Anestesia, Rianimazione e Emergenza-Urgenza, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, and Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Enrico Storti, MD, Dipartimento Emergenza Urgenza, UOC Anestesia e Rianimazione, ASST, Lodi, Italy; Matteo Subert, MD, Department of Anaesthesia and Intensive Care, Hospital of Melzo, ASST Melegnano Martesana, Milan, Italy; Mario Tavola, MD, Department of Anesthesiology and Intensive Care, ASST Lecco, Ospedale di Lecco, Lecco, Italy; Serena Todaro, MS, Regional Coordinating Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, and University of Milan, Milan, Italy; Francesca Torriglia, MD, UOC Anestesia e Rianimazione, Ospedale Civile di Voghera ASST provincia di Pavia, Italy; Daniela Tubiolo, MD, Dipartimento di Anestesia, Rianimazione e Emergenza-Urgenza, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; Roberto Valsecchi, MD, Department of Anaesthesia and Intensive Care, General Hospital Moriggia Pelascini Gravedona, Como, Italy; Pier Giorgio Villani, MD, Dipartimento Emergenza Urgenza, UOC Anestesia e Rianimazione, ASST, Lodi, Italy; Uberto Viola, MD, Department of Anaesthesia and Intensive Care, Ospedale San Pellegrino, Gruppo Mantova Salus, Mantova, Italy; Giovanni Vitale, MD, Department of Anaesthesia and Intensive Care, Policlinico San Marco, Zingonia, Italy; Massimo Zambon, MD, Department of Anaesthesia and Intensive Care, ASST Melegnano–Martesana, Presidio di Cernusco sul Naviglio, Italy; Alberto Zanella, MD, Dipartimento di Anestesia, Rianimazione e Emergenza-Urgenza, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, and Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; and Elena Zoia, MD, Department of Anaesthesia and Intensive Care, Children’s Hospital Vittore Buzzi, ASST FBF Sacco, Milan, Italy.

    Funding/Support: This study was supported in part by institutional funding (Ricerca corrente 2020) from the Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico.

    Role of the Funder/Sponsor: The sponsor had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Additional Contributions: Paolo Cadringher, MSc, Ospedale Maggiore Policlinico, provided support in data management. Chiara Paleari, MD, and Emanule Cattaneo, MD, University of Milan, helped analyze the scientific literature. Marina Leonardelli and Patrizia Minunno, Ospedale Maggiore Policlinico, provided administrative support. We thank all the staff of the COVID-19 Lombardy ICU Network coordination: Caterina Accardo, MD, University of Milan; Alessio Altomare, MD, University of Milan; Chiara Anzanello, MD, University of Milan; Barbara Antonelli, MD, Ospedale Maggiore Policlinico; Andrea Arcari, MS, University of Brescia; Martina Barbieri, MS, University of Parma; Michele Battistin, MSc, Ospedale Maggiore Policlinico; Matteo Bertocchi, MS, University of Brescia; Lucio Caccamo, MD, Ospedale Maggiore Policlinico; Elena Cadone Ughi, MD, University of Milan; Davide Calabretta, MD, University of Milan; Lorenzo Chiaravalli, MD; Daniela Codazzi, MD, DG Welfare Regione Lombardia; Sebastiano Colombo, MD, Ospedale Maggiore Policlinico; Bianca Della Santa, MD, University of Milan; Marianna Di Feliciantonio, MD, University of Milan; Daniele Dondossola, MD, Ospedale Maggiore Policlinico; Giulia Susanna Ferrero, MS, University of Milan; Chiara Fiorentini, MS, University of Milan; Chiara Galimberti, MS, University of Milan; Giorgio Giudici, MD, University of Milan; Giacomo Grisorio, MS, University of Milan; Amedeo Guzzardella, MD, University of Milan; Alessia Kersik, MD, University of Milan; Giacomo Mandarano, MS, University of Milan; Piergiorgio Mandarano, MS, University of Parma; Pier Luca Marazzi, MD, Fondazione Don Carlo Gnocchi; Barbara Marcora, MD, retired; Alessandra Mattioli, MS, University of Milan; Francesca Migliavacca, MD, University of Milan; Chiara Minaudo, MD, University of Milan; Matilde Moro, University of Parma; Luisa Napolitano, MD, Ospedale Maggiore Policlinico; Carolina Negro, MD, University of Milan; Elisa Paoluzzi Tomada, MD, University of Milan; Carolina Perali, MD, University of Milan; Arianna Pieroni, MD, University of Milan; Stefano Poggio, MD, University of Milan; Costanza Pucci, MD, University of Milan; Martina Ratti, MD, University of Milan; Serena Reato, MS, University of Milan; Anna Ribboni, MD, retired; Francesca Rossi, MD, Ospedale Maggiore Policlinico; Daniel Salvetti, MS, University of Parma; Simone Scarpino, MD, University of Milan; Francesco Scarri, MS, University of Milan; Ivan Silvestri, MS, University of Milan; Andrea Sozzi, MS, University of Milan; Camilla Storaci, MS, University of Milan; Lorenzo Tagliaferri, MS, University of Milan; Francesca Terenzi, MD, University of Milan; Martina Uzzo, MS, University of Milan; Clarissa Uslenghi, MS, University of Milan; Valentina Vago, MS, University of Milan; Oliviero Valori, MD, Ospedale Papa Giovanni XXIII; Carlo Valsecchi, MD, Ospedale Maggiore Policlinico; Chiara Vetrano, MS, University of Brescia; Luigi Vivona, MD, University of Milan; and Arianna Zefilippo, MD, Ospedale Maggiore Policlinico. Claudia Ebm, MD, Humanitas University, Pieve Emanuele, Italy, provided a critical review of English. Romina Aceto, MSC, Arianna De Buglio, MS, and Veronica Granone, MS, Humanitas University, Pieve Emanuele, Italy, provided support for data collection. Roberto Cefalà, MD, ASST Ovest Milanese, provided support to the ICU Network. Marco Salmoiraghi, MD, and Aida Andreassi, MD, DG Welfare Regione Lombardia, and all the staff of DG Welfare Regione Lombardia provided logistical and organizational support. We thank all the health care staff of the COVID-19 Lombardy ICU Network. These individuals were not compensated for their role in the study.

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