Rate of Intensive Care Unit admission and outcomes among patients with coronavirus: A systematic review and Meta-analysis

Background The rate of ICU admission among patients with coronavirus varied from 3% to 100% and the mortality was as high as 86% of admitted patients. The objective of the systematic review was to investigate the rate of ICU admission, mortality, morbidity, and complications among patients with coronavirus. Methods A comprehensive strategy was conducted in PubMed/Medline; Science direct and LILACS from December 2002 to May 2020 without language restriction. The Heterogeneity among the included studies was checked with forest plot, χ2 test, I2 test, and the p-values. All observational studies reporting rate of ICU admission, the prevalence of mortality and its determinants among ICU admitted patients with coronavirus were included and the rest were excluded Result A total of 646 articles were identified from different databases and 50 articles were selected for evaluation. Thirty-seven Articles with 24983 participants were included. The rate of ICU admission was 32% (95% CI: 26 to 38, 37 studies and 32, 741 participants). The Meta-Analysis revealed that the pooled prevalence of mortality in patients with coronavirus disease in ICU was 39% (95% CI: 34 to 43, 37 studies and 24, 983 participants). Conclusion The Meta-Analysis revealed that approximately one-third of patients admitted to ICU with severe Coronavirus disease and more than thirty percent of patients admitted to ICU with a severe form of COVID-19 for better care died which warns the health care stakeholders to give attention to intensive care patients. Registration This Systematic review and Meta-Analysis was registered in Prospero international prospective register of systemic reviews (CRD42020177095) on April 9/2020.

The global rate of ICU admission, the prevalence of mortality, comorbidities, complication, number of cases demanding mechanical ventilator, length of stay and independent risk factors for ICU mortality are very important variables to be determined to reduce patient mortality and morbidity through varies mitigating strategies including but not limited to increasing number of ICU beds, mechanical ventilator, skilled professionals, integrated monitors and reducing possible risk factors. Therefore, the objectives of this systematic review and Meta-Analysis was to provide global evidence on the rates of ICU admission, the prevalence of mortality, comorbidity, complications, and independent risk factors of mortality among patients with COVID-19 admitted in ICU.

Protocol and registration
The systematic review and meta-analysis were conducted based on the Preferred Reporting Items for Systematic and Meta-analysis (PRISMA) protocols [40]. This Systematic Review and Meta-Analysis was registered in Prospero international prospective register of systemic reviews (CRD42020177095) on April 9/2020.

Inclusion and exclusion criteria
2.2.1. Inclusion criteria. All observational (case series, cross-sectional, cohort, and casecontrol) studies reporting rate of ICU admission, the prevalence of mortality, morbidity, complication, and its determinants among ICU admitted patients with coronavirus (SARS-COV, MERS and SARS-COV 2) were included.

Exclusion criteria.
Studies that didn't report the rate of ICU admission, the prevalence of ICU mortality, and risk factors among patients with coronavirus were excluded. Besides, Randomized controlled trials, case-control studies, Systemic reviews, and Case reports were excluded.

Search strategy
The search strategy was intended to explore all available published and unpublished studies among Coronaviruses infected patients admitted to ICU from December 2002 to May 2020 without language restrictions. A comprehensive initial search was employed in PubMed/Medline, Science direct, and LILACS followed by an analysis of the text words contained in Title/ Abstract and indexed terms. A second search was undertaken by combining free text words and indexed terms with Boolean operators. The third search was conducted with the reference lists of all identified reports and articles for additional studies. Finally, an additional and grey literature search was conducted on Google scholars. The PubMed/Medline database was searched with the following terms:

Data extraction
The data from each study were extracted with two independent authors with a customized format. The disagreements between the two independent authors were resolved by the other two authors. The extracted data included: Author names, country, date of publication, sample size, the rates of ICU admission, mortality, types of Coronavirus, types of comorbidity, complications, and risk factors. Finally, the data were then imported for analysis in R software version 3.6.1 and STATA 14.

Assessment of methodological quality
Articles identified for retrieval were assessed by two independent Authors for methodological quality before inclusion in the review using a standardized critical appraisal Tool adapted from the Joanna Briggs Institute [45,46] (S1 Table). The disagreements between the Authors appraising the articles were resolved through discussion with the other Two Authors. Articles with average scores greater than fifty percent were included for data extraction.

Data analysis
Data analysis was carried out in R statistical software version 3.6.1 and STATA 14. The pooled rates of ICU admission and prevalence of mortality, comorbidity, complication among corona virus-infected patients were determined with a random effect model as there was substantial heterogeneity between the included studies. The Heterogeneity among the included studies was checked with forest plot, χ2 test, I 2 test, and the p-values. Subgroup analysis was conducted by Country, type of coronavirus, types of comorbidity, and complications. Publication bias was checked with a funnel plot and the objective diagnostic test was conducted with Egger's correlation, Begg's regression tests, and Trim and fill method. Furthermore, moderator analysis was carried out to identify the independent predictors of ICU mortality among corona cases. The results were presented based on the Preferred Reporting Items for Systemic Reviews and Meta-Analysis (PRISMA) [40].

Ethics approval and consent to participate
Ethical clearance and approval were obtained from the ethical review board of the College of Health Science and Medicine.

Selection of studies
A total of 646 articles were identified from different databases with an initial search. Fifty articles were selected for evaluation after the successive screening. Thirty-seven Articles with 24983 participants were included in the systematic review and Meta-Analysis while thirteen studies were excluded with reasons (Fig 1).

Characteristics of included studies
Thirty-seven studies conducted on Coronavirus reporting rates of ICU admission and patient outcomes with 24983 participants were included (Table 1). Thirteen studies were excluded with reasons (S1 Table). The methodological quality of included studies was moderate to high quality as depicted with the Joanna Briggs Appraisal tool for observational studies (S2 Table).
Twenty-six of the included studies were conducted on a newly emerged Coronavirus (SARS-CoV-2), COVID-19. Seven studies were conducted during and after the aftermath of The included studies were conducted in different regions of the world. Sixteen studies were conducted in China, seven studies in Saudi Arabia, five studies in the United States of America, three studies in Italy, two studies in Singapore, one study in Holland, the United Kingdom, and France. All of the included studies reported rates of ICU admission and outcomes of patients while staying in ICU. The majority of the included studies reported the presence of comorbidities and complications in ICU such as death, acute respiratory distress syndrome, renal failure, shock, and discharge.

Meta-analysis
3.3.1. Rate of ICU admission. Thirty-seven studies reported ICU admission were included for Meta-analysis. The number of ICU admission was taken for estimation of pooled prevalence of mortality instead of the total sample size because we wanted to know the number of ICU deaths from those Admitted in ICU. However, the rates of ICU admission were estimated with the total sample size. The pooled rate of ICU admission was 32% (95% CI: 26 to 38, 37 studies and 32, 741 participants) (Fig 2). The finding of the subgroup analysis by types of corona revealed that the rate of ICU admission with SARS-COV, MERS and SARS-COV-2 was 32% (95% CI, 23 to 40), 57% 95% CI, 37 to 76) and 26% 95% CI, 20 to 33) respectively (Fig 3).

Regression analysis
The prevalence of mortality among patients with Coronavirus was greatly affected by several factors including the presence of co-morbidities, history of smoking, history of substance use, male gender, older age groups, ICU admission, nosocomial infection, and others. The

Sensitivity analysis and publication bias
Sensitivity analysis was conducted to identify the most influential study on the pooled summary effect and we didn't find significant influencing the summary effect.
Publication bias was investigated with funnel plot asymmetry and egger's regression and Begg's rank correlation were run to investigate publication bias objectively. The funnel plot didn't show significant publication bias. Neither egger's regression nor Begg's rank correlation showed significant publication bias (P-value < 0.1464) (Fig 9).

Discussion
The Meta-Analysis revealed that more than one-third of patients with coronavirus infection were admitted to ICU globally. The subgroup analysis showed that the rate of ICU admission was very high in patients with the Middle East respiratory syndrome (MERS-CoV), 57% (95% CI: 37to 76) as compared to severe acute respiratory syndrome (SARS-CoV-2 and SARS-CoV), 26% (95% CI: 20 to 33) and 32% (95% CI: 23 to 40) respectively. Currently, the total confirmed cases and the death of patients with the SARS-CoV-2 virus is unpredictably high as compared to the previous two outbreaks [13-15, 19, 20, 63, 64, 66-68]. The lower rate of ICU admission in patients with COVID-19 in this systematic review and Meta-Analysis might be due to a small number of studies assessing rates of admission compared to the number of cases and also the majority of studies were case series with small sample size.
This systematic review and Meta-Analysis revealed that the prevalence of mortality among Coronavirus confirmed cases admitted in ICU were, 39% (95% CI: 34 to 43). This finding is interpreted as there is one mortality for every three cases of admission. This finding is in line with individual studies conducted among Coronavirus confirmed cases since the first outbreak in 2002, China [13-15, 19, 20, 63, 64, 66-68]. The possible explanation for a high number of deaths in ICU may be explained in terms of a limited number of mechanical ventilators, adequate laboratory investigation, integrated patient monitors, presence of co-morbidities, hospital-acquired infections, and some others.
The subgroup analysis showed that the prevalence of mortality among COVID-19 patients admitted in ICU was very higher, 31% (95% CI: 26 to 36). But, it is relatively low as compared to MERS-CoV and SARS-CoV, 61% (95% CI: 44 to 78), and 49% (95% CI: 41 to 57) respectively. The possible explanation for the lower prevalence of mortality among COVID-19 patients might be due to better ICU supportive management, skilled ICU professionals, integrated patient monitors, and lessons from previous outbreaks in handling ICU cases.
The pooled prevalence of comorbidity among patients with coronavirus was as high as sixty percent. The subgroup analysis revealed that the prevalence of comorbidity among COVID-19 patients was 59% (95% confidence interval (CI): 39 to 79) which is consistent with findings of subgroup analysis of SARS-COV, MERS-COV, and individual included studies. The regression analysis revealed that presences of comorbidity, male gender, age greater than 50 years, and ARDS were independent predictors of mortality among patients admitted in ICU with coronaviruses.

Quality of evidence
The systematic review and meta-analysis included plenty of studies with adequate sample size. The methodological quality of included studies was moderate to high quality as depicted with Joanna Briggs Institute assessment tool for meta-analysis of observational studies. However, substantial heterogeneity associated with dissimilarities of included studies in sample size, design, and location could affect the allover quality of evidence.

Limitation of the study
The review incorporated plenty of studies with a large number of participants but the majority of studies included in this review didn't report data on comorbidity and risk factors to investigate the independent predictors. Besides, there were a limited number of studies in some countries and it would be difficult to provide conclusive evidence with results pooled from fewer studies.

Implication for practice
Body of evidence revealed that rate of ICU admission; the prevalence of mortality; morbidity and complications were very high among patients with COVID-1. These could be a huge impact particularly for low and middle-income countries with a limited number of ICU beds, mechanical ventilator, integrated patient monitor, skilled professionals combined with malnutrition, and communicable disease. Therefore, a mitigating strategy is required by different stakeholders to combat the catastrophic impacts of COVID-19 pandemic through creating awareness about preventive measures, implementing ICU protocols for supportive management, management of comorbidities, and prevention of complications.

The implication for further research
The meta-analysis revealed that the prevalence of mortality among COVD-19 in ICU was very high and the major independent predictors of mortality were identified. However, the included studies were too heterogeneous, and cross-sectional studies also don't show a temporal relationship between mortality and its determinants. Therefore, further observational and randomized controlled trials are in demand for a specific group of patients by stratifying the possible independent predictors.

Conclusion
The systematic review and Meta-Analysis revealed that approximately one-third of patients admitted to ICU with severe Coronavirus disease. The systematic review also showed that more than thirty percent of patients admitted in ICU with a severe form of COVID-19 for better care died which warns the health care stakeholders to give attention to intensive care patients admitted with COVID-19 through accessing mechanical ventilators, integrated patient monitors, skilled ICU staffs, creation of awareness about infection prevention and more others. Besides, the prevalence of mortality had a strong relation with comorbidity, age, gender, and complication.