Question

Findings  In a cohort of 2215 adults with COVID-19 who were admitted to intensive care units at 65 sites, 784 (35.4%) died within 28 days, with wide variation among hospitals. Factors associated with death included older age, male sex, morbid obesity, coronary artery disease, cancer, acute organ dysfunction, and admission to a hospital with fewer intensive care unit beds.

Meaning  This study identified demographic, clinical, and hospital-level factors associated with death in critically ill patients with COVID-19 that may be used to facilitate the identification of medications and supportive therapies that can improve outcomes.

Abstract

Importance  The US is currently an epicenter of the coronavirus disease 2019 (COVID-19) pandemic, yet few national data are available on patient characteristics, treatment, and outcomes of critical illness from COVID-19.

Objectives  To assess factors associated with death and to examine interhospital variation in treatment and outcomes for patients with COVID-19.

Design, Setting, and Participants  This multicenter cohort study assessed 2215 adults with laboratory-confirmed COVID-19 who were admitted to intensive care units (ICUs) at 65 hospitals across the US from March 4 to April 4, 2020.

Exposures  Patient-level data, including demographics, comorbidities, and organ dysfunction, and hospital characteristics, including number of ICU beds.

Main Outcomes and Measures  The primary outcome was 28-day in-hospital mortality. Multilevel logistic regression was used to evaluate factors associated with death and to examine interhospital variation in treatment and outcomes.

Results  A total of 2215 patients (mean [SD] age, 60.5 [14.5] years; 1436 [64.8%] male; 1738 [78.5%] with at least 1 chronic comorbidity) were included in the study. At 28 days after ICU admission, 784 patients (35.4%) had died, 824 (37.2%) were discharged, and 607 (27.4%) remained hospitalized. At the end of study follow-up (median, 16 days; interquartile range, 8-28 days), 875 patients (39.5%) had died, 1203 (54.3%) were discharged, and 137 (6.2%) remained hospitalized. Factors independently associated with death included older age (≥80 vs <40 years of age: odds ratio [OR], 11.15; 95% CI, 6.19-20.06), male sex (OR, 1.50; 95% CI, 1.19-1.90), higher body mass index (≥40 vs <25: OR, 1.51; 95% CI, 1.01-2.25), coronary artery disease (OR, 1.47; 95% CI, 1.07-2.02), active cancer (OR, 2.15; 95% CI, 1.35-3.43), and the presence of hypoxemia (Pao₂:Fio₂<100 vs ≥300 mm Hg: OR, 2.94; 95% CI, 2.11-4.08), liver dysfunction (liver Sequential Organ Failure Assessment score of 2 vs 0: OR, 2.61; 95% CI, 1.30–5.25), and kidney dysfunction (renal Sequential Organ Failure Assessment score of 4 vs 0: OR, 2.43; 95% CI, 1.46–4.05) at ICU admission. Patients admitted to hospitals with fewer ICU beds had a higher risk of death (<50 vs ≥100 ICU beds: OR, 3.28; 95% CI, 2.16-4.99). Hospitals varied considerably in the risk-adjusted proportion of patients who died (range, 6.6%-80.8%) and in the percentage of patients who received hydroxychloroquine, tocilizumab, and other treatments and supportive therapies.

Discussion: This multicenter cohort study of 2215 critically ill adults with COVID-19 admitted to ICUs at 65 hospitals across the US found that 784 patients (35.4%) died in the 28 days after ICU admission. Older age, male sex, higher body mass index, coronary artery disease, and active cancer were independently associated with a higher risk of death, as was the presence of hypoxemia and liver and kidney dysfunction at ICU admission. Patients admitted to hospitals with fewer ICU beds also had a higher risk of death. Hospitals varied widely in the proportion of patients who received medications and supportive therapy for COVID-19 and in the proportion of patients who died.

Prior data on critical illness from COVID-19 derive from cohorts in China and Italy and small case series and regional reports from cohorts in the US.^3-6 Compared with a large cohort of critically ill patients with COVID-19 in Lombardy, Italy, the median age of patients in the cohort in the present study and the proportion who received invasive mechanical ventilatory support were similar.⁴ The mortality in the cohort in the present study was higher than that of critically ill patients with COVID-19 in Italy (26%),⁴ although 58% of the patients in that cohort were still in the ICU at the end of follow-up, but lower than that reported in single-center studies from Wuhan, China (62%)³ and the Seattle region of the US (50%).⁵ These comparisons are limited by different ICU admitting practices and duration of follow-up among studies.

The most common acute organ injuries observed in the cohort in this study were respiratory failure, acute respiratory distress syndrome, and acute kidney injury. Other acute organ injuries were less frequent in this study, with only 230 patients (10.4%) experiencing a clinically detected thromboembolic event. This incidence of thromboembolic events is considerably lower than the 15% to 42% incidence reported in critically ill patients with COVID-19 in Europe^10-14 and is more consistent with the incidence reported in critically ill patients without COVID-19.¹⁵ Understanding the reason for these differences will be important as hypercoagulability in COVID-19 is pursued as a potential therapeutic target.¹⁶

This study identified considerable interhospital variation in the administration of medications and supportive therapies intended to treat COVID-19 and associated organ injury. Sources of this variation may include the limited high-quality evidence on which to base clinical practice, variation in hospital resources to implement personnel-intensive interventions (eg, prone positioning), variation in the availability of certain medications (eg, remdesivir), or unmeasured variation in patient and practitioner characteristics across centers. These data support clinical equipoise for ongoing randomized clinical trials of therapies for COVID-19.

In this study, several patient characteristics were associated with a higher risk of death. Similar to previous reports,^17,18 older age was associated with a higher risk of death, although at least 15% of patients died in every age group, including those younger than 40 years. Two-thirds of the patients were men, and male sex was independently associated with a higher risk of death, supporting a prior report¹⁹ of the association between male sex and adverse outcomes in patients with COVID-19. In addition, we found that higher body mass index was independently associated with a higher risk of death, extending the findings from prior reports^20-22 on the association between obesity and severe illness from COVID-19. We also identified several novel patient-level factors associated with death, including coronary artery disease and active cancer. Finally, we found that patients who were admitted to hospitals with fewer ICU beds had a higher risk of death.

Nearly 1 in 3 patients in the present cohort was Black compared with approximately 13.4% of the US population. Race, however, was not associated with death in multivariable models. These results are similar to those recently reported by a single-center study²³ in Louisiana, which found that Black patients were more likely to be hospitalized but had similar in-hospital mortality compared with White patients. The reasons for potential racial differences in the frequency of ICU admission with COVID-19 are likely multifactorial and may reflect differences in comorbidities, socioeconomic status, and other factors.

Conclusions and Relevance In this multicenter cohort study of critically ill adults with COVID-19 in the US, more than 1 in 3 died within 28 days after ICU admission. We identified several patient- and hospital-level factors that were associated with death and found that treatment and outcomes varied considerably among hospitals. Future research should examine the patients with COVID-19 at the greatest risk of adverse outcomes and seek to identify medications or supportive therapies that improve their outcomes.

a. What was the exposure of interest? What was the main exposure variable (if there were many, pick one)?

b. What was the outcome of interest? What was the main outcome variable (if there were many, pick one)?

c. What was the study design?   Critique the study design. Is possible, propose an alternative.

d. What do you consider to be the primary weakness of the study? Is this weakness sufficient to eliminate it from your evaluation of evidence relevant to the study hypothesis?

e. What do you consider the primary strength of the study? Why is it a strength?

Answer 1

a) The exposure of interest was to assess factors associated with death and to examine inter hospital variations in treatment and outcomes for critically ill patients admitted in ICU with COVID-19.The main exposure variable was older age who was associated with higher risk of death.

b) The outcome of interest was to facilitate the identification of medications and supportive therapies that can improve outcomes.The main outcomes variable was to examine inter hospital variation in treatment and outcomes for patients with COVID-19.

c)The study design was multi center coherent study.As it was multi center study with multiple variables they should have taken a larger sample of participants.

d)Primary weakness of the study was considerable inter hospital variation in the administration of medications and supportive therapies intended to treat COVID-19 and associated organ injury.This variations may include the limited high-quality evidence on which to base clinical practice,variation in hospital resources to implement personal intensive interventions ( eg.prone positioning) variation in the availability of certain medications ( eg.remdesivir), or unmeasured variation in patient and practitioner characteristics across centers.

e) The Primary strength of the study was,it is a multi center study with participants from multiple countries with multiple factors such as racial differences,comorbidities,socioeconomic status, and other factors.