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Clinical course and outcomes of critically ill patients with COVID-19 infection: a systematic review

Objectives Coronavirus disease 19 (COVID-19) is a major cause of hospital admission and represents a challenge for patient management during intensive care unit (ICU) stay. We aimed to describe the clinical course and outcomes of COVID-19 pneumonia in critically ill patients. Methods We performed a systematic search of peer-reviewed publications in MEDLINE, EMBASE and the Cochrane Library up to 15th August 2020. Preprints and reports were also included if they met the inclusion criteria. Study eligibility criteria were full-text prospective, retrospective or registry-based publications describing outcomes in patients admitted to the ICU for COVID-19, using a validated test. Participants were critically ill patients admitted in the ICU with COVID-19 infection. Results From 32 articles included, a total of 69 093 patients were admitted to the ICU and were evaluated. Most patients included in the studies were male (76 165/128 168, 59%, 26 studies) and the mean patient age was 56 (95%CI 48.5–59.8) years. Studies described high ICU mortality (21 145/65 383, 32.3%, 15 studies). The median length of ICU stay was 9.0 (95%CI 6.5–11.2) days, described in five studies. More than half the patients admitted to the ICU required mechanical ventilation (31 213/53 465, 58%, 23 studies) and among them mortality was very high (27 972/47 632, 59%, six studies). The duration of mechanical ventilation was 8.4 (95%CI 1.6–13.7) days. The main interventions described were the use of non-invasive ventilation, extracorporeal membrane oxygenation, renal replacement therapy and vasopressors. Conclusions This systematic review, including approximately 69 000 ICU patients, demonstrates that COVID-19 infection in critically ill patients is associated with great need for life-sustaining interventions, high mortality, and prolonged length of ICU stay.


Introduction
Since the first case of coronavirus disease , identified in December 2019 and caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the disease has spread rapidly, infecting millions of people worldwide and causing a major challenge for healthcare systems [1]. Although in most cases the disease is mild or asymptomatic, a subset of patients develop moderate to severe COVID-19 pneumonia requiring intensive care unit (ICU) admission [2e4]. As an exceptionally high number of cases have required hospitalization, emergency departments and ICUs have been strained and, in several countries, ICUs have been unable to deliver enough beds and ventilators for patients with respiratory distress [1,5].
However, despite the numerous reports of critically ill patients in the literature [2,6], the clinical course, outcomes and interventions of patients admitted to the ICU are unclear. Owing to the differences in design, patient population, and geographies, there is a large variation among studies in the ICU admission rate (from 4.0% [7] to 32% [8]) and mortality rate (from 0.7% [9] to 52.4% [10]) in patients with COVID-19. Moreover, as patients with COVID-19 often have severe presentations and multiorgan failure, and require life-sustaining interventions for basic care (e.g. personal protective equipment and laboratory analysis), there is a need for highly skilled staff and more sophisticated and expensive interventions such as invasive mechanical ventilation, extracorporeal membrane oxygenation (ECMO), and renal replacement therapy (RRT) [2,6].
A more comprehensive knowledge of ICU utilization and outcomes could potentially help healthcare professionals and managers to estimate the need for ventilators, ICU beds, and dialysis monitors, and to manage more adequately their staffing patterns. These findings have significant implications for a better understanding of the epidemiology of COVID-19, and for better planning and organization of hospitals and ICUs to ensure better preparation and optimization of delivery of care under the pandemic circumstances.
In the present study we performed a systematic review of the current literature with the aim of describing the clinical course, interventions used and short-term outcomes of COVID-19 pneumonia requiring ICU admission.

Data sources and study selection
We conducted a systematic review of the literature according to the recommendations of the Meta-analysis of Observational Studies in Epidemiology (MOOSE) group [11] and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [12]. We searched MEDLINE, EMBASE and the Cochrane Library.
The most recent search was performed on 20th August 2020. The reference lists of retrieved articles and relevant review articles, as well as personal files, were manually searched. We considered the following criteria for study inclusion: (a) full-text prospective, retrospective or registry-based publications in patients admitted to the ICU for COVID-19, (b) studies including patients diagnosed with COVID-19 using a validated test, and (c) studies reporting an association between COVID-19 and at least one of the following outcomes: death at any time, length of stay in the ICU or in hospital, duration of mechanical ventilation (MV), and occurrence of acute respiratory distress syndrome (ARDS). Letters to the editor, individual case reports or reviews, and studies not reporting the number of confirmed cases were excluded.
Two investigators (RBS, JIFS) performed the study selection process, including the initial search for the identification of references, the selection of potentially relevant titles for review of abstracts and, among them, of those chosen for review of the fulllength reports. All selections were decided by consensus. This report was prospectively registered with the PROSPERO database of systematic reviews (CRD42020180850).

Data extraction and study quality assessment
Data extraction from the selected articles was independently performed by two authors (RBS, JIFS). The following data were recorded (when available): study characteristics (such as type of study, selection of patients, number of patients enrolled, publication date), patient characteristics (such as age, sex, patient setting), and outcomes (ARDS incidence, need for MV, vasopressor used, death in the ICU/hospital, and all patients length of hospital/ICU stay). We considered that the centre had an ICU according to the description of each author; data were not available to allow another classification or to allow further characterization. The ICNARC report described the ICU and high dependency units together in the same analysis [6].
To assess the methodological quality of the studies, we adapted the NewcastleeOttawa Quality Assessment Scale (NOS) [13] to better describe the risk of bias in our systematic review (Supplementary Material Table S1).

Analytical approach
We evaluated COVID-19 patient characteristics and main outcomes described.
We had especial interest in describing mortality, length of hospital stay, and interventions used (MV, non-invasive ventilation (NIV), RRT and use of vasopressors). For continuous variables, we described the mean and 95% confidence interval (CI) based on the reported data. Proportions were described with the numerator/ denominator and percentages. We used the SPSS v21 to analyse the data. Owing to the differences in design of the studies, we were not able to perform a meta-analysis.

Results
The literature search yielded 2927 studies. Of the 320 potentially relevant abstracts screened, 74 articles were available for detailed analysis. Finally, 32 articles that met the inclusion criteria were included in this systematic review. A flow diagram of the search and selection of the studies is depicted in Fig. 1.

Study characteristics
The characteristics of the 32 included studies are shown in Table 1. Twenty-eight studies [3e5,8e10,14e35] and five non-peerreviewed reports from national registries or research groups [2,6,36e38] were included. A total of 69 093 patients were admitted in the ICU and were evaluated. Most studies were performed in China, but they represent only 1.35% (932/69 093) of the ICU patients described [3,4,9,16e20,22e32]. Reports from national ICU registries and research databases included the largest number of patients in analysis (64 979 of ICU patients). The follow-up period of studies ranged from late December 2019 to 15th August 2020.

Quality assessment of studies
Seventeen cohort studies evaluated hospitalized patients and described patients who needed ICU admission (median of 122 patients, 95%CI 32e962) [9,16e23,25e28,30e32,34]. Nine cohort studies included only ICU patients (median of 155 patients, 95%CI 146e3713) [5,8,10,14,15,18,23,29,36]. Only one study described a 28-day mortality [31] and no studies described long-term outcomes after hospital discharge. Studies reported different results regarding symptoms, time to critical illness, clinical course, development of organ failure, intervention used, and short-term outcomes. The NOS score of each study is shown in the Supplementary Material Table S2.

Characteristics of patients admitted to the ICU
The design, sample size and outcomes in all the studies were highly variable. Fig. 2  Only two studies described the mortality in patients with ARDS in the ICU: 93% (50/59) [29] and 71% (26/35) [32]. Only three studies described the duration of MV, and the median was 8.4 (95%CI 1.6e13.7) days [2,6,34].

Discussion
This systematic review represents a synthesis of currently available data on the patients admitted to the ICU for COVID-19, with a focus on the main clinical outcomes, interventions used, and advanced life support measures. Our systematic review  identified 32 studies and reports. We described a significant number of patients (n ¼ 69 093) who required critical care. ARDS was present in 85% of patients admitted to the ICU [3,8e10,18,22,26,28,31]. The surge in patients with COVID-19 requiring hospitalization, ICU admission, and ventilatory support has represented an unparalleled challenge to physicians, nurses, hospital managers and healthcare systems. However, despite the rapid response of the medical community, the burden of COVID-19 on ICU facilities is unclear. Despite the lack of studies, this systematic review was able to provide relevant data on ICU utilization from peer-reviewed articles [4,5,8e10,14e23,25e29,31e34,36,38], three non-peerreviewed preprints [14,27,30] and also five large databases of scientific institutions and national registries of intensive care [2,6,35e37]. This review provides a unique international perspective on the interventions used and outcomes in patients with COVID-19 requiring ICU admission, thus increasing the current epidemiological knowledge and potentially providing useful information to help care for these patients.
Our study shows the high burden of COVID-19 on ICUs, which was demonstrated by the exceedingly high mortality and length of stay even when compared to other infectious diseases requiring ICU admission. The ICU mortality rate among patients with COVID-19 was 30.6%, which is relevant even when compared to the usually described mortality rates for community-acquired pneumonia (CAP) of about 16.6e18% [39,40] and for sepsis of 24.2e55.7% [41,42]. Moreover, when considering only mechanically ventilated patients, the mortality was exceptionally high (27 972/47 632, 59%, six studies) [6,21,28,31,33,36], especially in ARDS patients (up to 93%), which is more than the typical mortality rate from ARDS of about 35e45% [43,44]. We also described an elevated ICU length of stay for COVID-19 (8.0, 95%CI 5.1e11.0) as compared to that described in patients with severe CAP [39,45], representing a challenge in ICU bed management.
Our study found that almost half the patients admitted to the ICU needed invasive MV (58%), and a lower percentage (25.5%) required non-invasive ventilation. Studies in CAP described a much higher proportion of patients (up to 56%) using NIV in acute respiratory failure [45,46]. Indeed, the role of NIV in COVID-19 remains unclear. The uncertainty around the treatment of acute hypoxaemic respiratory failure with NIV [47] plus the purported risks of aerosol generation and delayed intubation have led to varying recommendations between authorities [7,48], potentially contributing to its limited use.
The use of ECMO as a salvage therapy for critically ill COVID-19 patients was limited and described in a small number of patients (272/11 494, 2.4%, 11 studies) [2,3,5,8,9,16,18,22,26,28,31]. Mortality in ECMO was described in only three studies and was very high (9/ 10, 90%) [3,28,31]. It remains unclear whether ECMO therapy is associated with improved outcomes. A recent study using data from the Extracorporeal Life Support Organization (ELSO) included 1035 patients with COVID-19 who received ECMO and also described a high mortality (380/968, 39%) and a significant percentage of patients (101/1035, 10%) discharged to a long-term acute-care centre [38]. Published studies from different countries describing the use of ECMO as rescue therapy in the 2009 H1N1 pandemic have reported lower mortality rates than that reported during the current COVID-19 pandemic (14e41%) [49e52].
This study has several limitations. First, owing to the urgency of publishing preliminary information on patients with COVID-19 during the current pandemic, studies have presented very heterogeneous data on clinical characteristics, interventions used, and outcomes of ICU patients. Significant differences in the design of the studies also contributed to the lack of specific and core clinical information in several reports. This limited our ability to pool and meta-analyse data on specific subgroups. In Supplementary Material Table S3 we have suggested a list of outcomes that should be assessed in future studies describing critically ill patients with COVID-19 [53,54]. Second, the sample sizes varied significantly, ranging from 20 patients in small cohort studies up to 64 979 patients in reports from national ICU registries. Third, the classification of ICU patients was performed according to the definition of each centre. Details regarding intensive care support were not described; hence, further stratification was not possible. This could have led to overestimation of the surge capacity. Fourth, the overlap of reported cases from the same centres may cause some bias; however, we believe that the large sample size and similarity of patients can minimize this effect. Fifth, only one study assessed the 28-day mortality, and no study reported long-term outcomes after hospital discharge [31]. Finally, owing to several aspectsdincluding the temporal and geographic development of the pandemicdavailable data from low-income countries are limited; they would be essentially the report from Brazil and the international report from ISARIC that included developing and developed countries [2,5,6,10,14,15,20,34e36].
The present study does have several strengths. As far as we are aware, this is the first systematic review to describe the interventions used and main clinical outcomes of COVID-19 patients admitted to the ICU. It describes a large number of ICU patients (n ¼ 69 093) in 37 countries over five continents. The addition of reports from national registries, although not peer-reviewed, adds relevant and insightful epidemiological data. Our main findings reflect a substantial use of ICU beds when a COVID-19 patient is hospitalized. It also shows that nearly half of ICU patients (57%) required mechanical ventilation [2,3,5,6,8e10,15e17,19,21,22,26e29,31e33,36] and had a high mortality (59%) [6,21,28,31,33,36].

Conclusions
This systematic review provides relevant data on ICU utilization of a high number of patients with COVID-19 during a time of scarce resources. Patients with COVID-19 admitted to the ICU have great need for invasive support, high mortality, and prolonged length of stay in the ICU.

Author contributions
RBS and JIFS were responsible for data collection, data input, study design, data analysis, and drafting of the manuscript. RBS was responsible for statistical analysis. RBS, PP, VSD, AK, and JIFS were responsible for critical analysis, manuscript revisions, and editorial assistance. All authors have read and approved the final manuscript.

Transparency declaration
The authors state that they have no competing interests. The study was performed with institutional departmental funding. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.