Impact of an Intermediate Respiratory Care Unit on Clinical Outcomes of COVID-19 Patients

Guillermo Suarez-Cuartin (  gsuarezc@bellvitgehospital.cat ) Hospital Universitari de Bellvitge https://orcid.org/0000-0003-2320-6047 Merce Gasa Bellvitge University Hospital: Hospital Universitari de Bellvitge Guadalupe Bermudo Bellvitge University Hospital: Hospital Universitari de Bellvitge Yolanda Ruiz-Albert Bellvitge University Hospital: Hospital Universitari de Bellvitge Marta Hernandez-Argudo Bellvitge University Hospital: Hospital Universitari de Bellvitge Alfredo Marin Bellvitge University Hospital: Hospital Universitari de Bellvitge Pere Trias-Sabria Bellvitge University Hospital: Hospital Universitari de Bellvitge Ana Cordoba Bellvitge University Hospital: Hospital Universitari de Bellvitge Albert Ariza Bellvitge University Hospital: Hospital Universitari de Bellvitge Joan Sabater Bellvitge University Hospital: Hospital Universitari de Bellvitge Nuria Romero Bellvitge University Hospital: Hospital Universitari de Bellvitge Cristina Subirana Bellvitge University Hospital: Hospital Universitari de Bellvitge Maria Molina-Molina Bellvitge University Hospital: Hospital Universitari de Bellvitge Salud Santos Bellvitge University Hospital: Hospital Universitari de Bellvitge

renal conditions are associated with worse clinical outcomes, while treatment with systemic corticosteroids may have a protective effect on mortality.

Background
Coronavirus disease 2019 (COVID-19) is a respiratory condition caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) (1). Patients with COVID-19 may become severely ill and require hospital admission, with estimated hospitalization rates of 1-18%, depending on age group (2). Current recommendations state that patients with COVID-19 related acute respiratory failure should be monitored, and support with high-ow nasal cannula (HFNC) oxygen therapy or non-invasive ventilation (NIV) should be considered when conventional oxygen therapy fails (3). In this regard, during the months of March and April of 2020, the COVID-19 pandemic conditioned a signi cant increase in healthcare burden across Europe, as 17-32% of admitted patients required critical care management (4)(5)(6)(7). The intensive care unit (ICU) beds and invasive mechanical ventilators achieved their limits of occupation, hence non-invasive supportive care was a valuable option for maintaining respiratory conditions. Therefore, a proper healthcare resource management was necessary to warrant an adequate patient care.
Intermediate respiratory care units (IMCU) are a useful resource for the management of complex patients that do not require admission to the ICU, invasive mechanical ventilation or invasive monitoring (8). IMCU can function as a space for management escalation and de-escalation between the general ward and the ICU, especially when patient monitoring is needed and/or when respiratory support with HFNC or NIV is required (8)(9)(10). Bene ts of IMCU include reducing ICU admission time and increasing ICU bed capacity, as well as lowering mortality and health care costs (8,10,11). Although it is well known the importance of ICU, the impact and speci c role of IMCU during the COVID-19 pandemic has not been properly assessed.
To this date, there have been more than 20 million reported cases worldwide, with over 730 thousand deaths (12). Mortality is variable among hospitalized patients with COVID-19 pneumonia. Studies from Chinese cohorts estimate a hospital mortality of 4-28% (4,5,13). Furthermore, a recent study from the United Kingdom showed an overall mortality of 26% in admitted patients (7). Most of these deaths were related to sepsis, respiratory failure, acute respiratory distress syndrome (ARDS) and heart failure (4). Moreover, mortality rates of patients in critical care are higher, ranging from 26-32% (7,14), including ICU and IMCU. Nevertheless, the speci c mortality of COVID-19 patients admitted to an IMCU has not been widely studied.
We aim to evaluate the impact of IMCU management on clinical outcomes of severely ill COVID-19 patients requiring monitoring and/or non-invasive respiratory support.

Study design
An observational and retrospective study was performed on consecutive patients admitted to the IMCU of a tertiary care hospital in Barcelona (Spain) throughout the months of March and April 2020. The nal date of follow-up was June 28, 2020. Study protocol was approved by the local ethics committee (Nº PR260/20). Inclusion criterion was admission to IMCU due to respiratory failure related to COVID-19 pneumonia requiring non-invasive monitoring and/or non-invasive respiratory support. Patients were diagnosed with a positive polymerase chain reaction for SARS-CoV2 from nasopharyngeal swab and the presence of patchy in ltrates on chest X-ray. According to local protocol, IMCU admission was limited to subjects with an oxygen saturation (SpO2) to inspired oxygen fraction (FiO2) ratio lower than 200 but not expected to require immediate support with invasive mechanical ventilation. Exclusion criteria were: recent admission to the ICU and respiratory failure due to any etiology other than COVID-19.

Data collection and analysis
Demographic, clinical, radiological and laboratory data were collected from electronic medical records for all patients at the time of IMCU admission. All participants were treated according to hospital protocols. Systemic corticosteroid therapy was divided into three categories depending on dose and administration route, as patients were treated before preliminary results from the RECOVERY trial (15): intravenous (IV) bolus of 1-2 mg/Kg/day methylprednisolone or its equivalent dexamethasone dose for 3 days, followed or not by oral prednisone starting from 0.5 mg/Kg/day, tapering the dose over 7 to 10 days. Treatment schemes were chosen depending on clinical and radiological severity, where more severe individuals received longer treatments. Patients were categorized depending on survival status and ICU transfer requirement during hospitalization. ICU admission criteria included cardiopulmonary arrest, sudden fall in level of consciousness, invasive ventilation requirement and shock. The decision of whether or not to transfer a patient to the ICU was always made by a multidisciplinary team including pulmonologists and intensive care physicians. For the survival analysis, clinical and laboratory features were studied using criteria for ARDS (16) and cut-off values identi ed in severe cases from previous studies (4,5,(17)(18)(19).

Statistical analysis
Frequency and percentages were used to present categorical data, and chi-squared test or Fisher's exact test were used to evaluate their differences. Continuous variables are expressed as mean and standard deviation (SD) for normally distributed variables or median and interquartile range (IQR) otherwise. ANOVA and Student's t test or their corresponding non-parametrical tests were used to evaluate their differences, when required. Kaplan-Meier curves were used for the survival analysis. In order to identify factors associated with mortality, a multivariable Cox proportional hazards analysis was performed including signi cant variables from univariate analysis. A p-value < 0.05 was considered statistically signi cant. Data were analyzed using R (software version 3.6.2).

Patient description
A total of 291 patients were admitted to the IMCU during the months of March and April of 2020 due to COVID-19 pneumonia. After excluding 38 patients that were previously treated in the ICU, 253 patients were nally included. Of them, 68% were male and median age was 65 years (IQR 18 years). The most frequent comorbidities were hypertension (50.2%), dyslipidemia (47.8%%) and diabetes mellitus (29.6%). Demographic and clinical characteristics of included patients at admission to IMCU are described in Table 1. A higher proportion of patients received home discharge in the IMCU group compared to those that required transfer to ICU (50.3% Vs 22.8%, respectively; p < 0.001). However, a similar proportion of subjects needed admission to socio-health centers or transfer to their regional hospital for convalescence. Six patients of the ICU group were still hospitalized, while none of the IMCU subjects were in the hospital at the end of follow-up. A comparison of clinical outcomes between groups is presented in Table 2. proportion of comorbidities such as dyslipidemia, chronic respiratory diseases and chronic kidney disease. Furthermore, these patients had higher blood leukocyte counts, serum lactate dehydrogenase (LDH), C-reactive protein and D-dimer, and lower blood lymphocyte counts on admission to the IMCU (Table 3).

Survival analysis
Kaplan-Meier survival analysis identi ed a signi cant higher mortality in patients of 65 years of age or older (Fig. 1). Also, signi cant differences in survival time were observed regarding chronic respiratory and renal conditions and corticosteroid treatment during hospitalization (Fig. 2).  Figure 3 shows the results for the multivariable Cox proportional hazards model.

Discussion
This is one of the rst and largest studies to assess the impact of IMCU during COVID-19 pandemic. The IMCU allows a secure environment for providing non-invasive respiratory support and patient monitoring, leading to positive patient outcomes and improving healthcare resource management.
Patient characteristics and clinical presentation of the disease are similar to what has been described in previous studies (7,(18)(19)(20) (15). Furthermore, a recent metaanalysis by the World Health Organization Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group concluded that the administration of systemic corticosteroids in critically-ill COVID-19 patients was associated with a lower 28-day mortality, compared to usual care or placebo (25).
Nevertheless, though the bene cial effect is clear in severe cases, the optimal dose and dose-reduction should be better evaluated for avoiding adverse events at the same time than achieving a proper lung recovery.
This study has several limitations, mainly related to the retrospective design of the analysis including a single center. The lack of a control group (non-IMCU hospital) does not allow to directly quantify the impact of IMCU in COVID-19 mortality or health-care burden. Also, our cohort included only severe patients, as we focused on the role of IMCU in patient management. This may limit the generalization of our results to less severe cases. Also, local treatment protocols changed during the inclusion period due to the pandemic situation and the scarce data on COVID-19, which may have in uenced the clinical outcomes of our study. However, the number of participants is higher than most previous studies, and our results agree with observations from different cohorts.
Conclusions IMCU allow to safely and effectively manage severe COVID-19 patients requiring non-invasive respiratory support and monitoring, therefore reducing ICU burden. Older age and chronic respiratory or renal conditions are associated with worse clinical outcomes while treatment with systemic corticosteroids may have a protective effect on mortality. acquisition and analysis. JS participated in data acquisition, analysis and interpretation of the results. NR participated in data acquisition and analysis. CS participated in data acquisition and analysis. MMM participated in study design, interpretation of data, and in the elaboration of the manuscript. SS participated in study design, interpretation of data and in the elaboration of the manuscript. All authors read and approved the nal manuscript.