This is a two-center retrospective cohort study that included critically ill patients with confirmed COVID-19 who were admitted to the ICU at two tertiary hospitals in Saudi Arabia between March 01, 2020, to January 31, 2021. COVID-19 diagnosis was confirmed according to reverse transcriptase-polymerase chain reaction (RT-PCR) obtained from nasopharyngeal or throat swabs. Patients were followed during ICU stay.
Patients who were 18 years of age or older and admitted to ICU with confirmed COVID-19 were eligible for inclusion. Patients were excluded if the ICU length of stay (LOS) was less than a day or labeled as "Do-Not-Resuscitate" code status within 24 hours of ICU admission. Eligible patients were classified into two groups based on the number of doses for tocilizumab during ICU stay. Multiple-dose of tocilizumab was defined as using two or more doses of tocilizumab during ICU stay.
This study was conducted in two tertiary governmental hospitals; King Abdulaziz Medical City, Riyadh, and King Abdulaziz University Hospital, Jeddah. The primary site for this study is King Abdulaziz Medical City (Riyadh). The study was approved by King Abdullah International Medical Research Center in February 2021 (Ref.# NRC21R/024/01).
Data gathered from the patients' electronic medical records included demographic data, comorbidities, vital signs and laboratory tests, severity scores (i.e., Acute Physiology and Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA) scores), Glasgow Coma Score (GCS). In addition, acute kidney injury (AKI), the need for mechanical ventilation (MV), and MV parameters (e.g., PaO2/FiO2 ratio, FiO2 requirement) within 24 hours of ICU admission were also collected (See additional file 1). Furthermore, renal profile, liver function tests (LFTs), coagulation profile (i.e., INR, aPTT, fibrinogen, D-dimer), and inflammatory markers (e.g., CRP, procalcitonin, serum iron) within 24 hours of ICU admission. Besides, the inflammatory markers as a follow-up during ICU stay were collected. Tocilizumab and systemic corticosteroid use were recorded for the eligible patients. Moreover, microbial isolates (i.e., bacteria and fungus) were identified in the blood, urine, wound, drainage, cerebrospinal fluid (CSF), and respiratory specimens. All patients were followed until they were discharged from the hospital or died during the in-hospital stay, whichever occurred first.
The study aims to compare the effectiveness and the safety of two tocilizumab dosing regimens. So, the primary outcome was the occurrence of in-hospital and 30-day ICU mortality compared between the single versus multiple tocilizumab doses administered to critically ill patients with COVID 19. The secondary outcomes were the hospital LOS, ICU LOS, MV duration, and ICU-related complication (s) during ICU stay (i.e., secondary infection, AKI, acute liver injury, respiratory failure requires MV, thrombosis/infarction).
- Secondary infection was identified through the blood, urine, wound, drainage, cerebrospinal fluid (CSF), and/or respiratory cultures. The bacterial or fungal growth considered significant if the growth is ≥ of 100,000 CFU/ml in sputum or endotracheal aspiration shows; bronchoalveolar lavage (BAL) shows growth ≥of 10,000 CFU of single organism/ml for protected specimen brushes (PSBs), and ≥100,000 CFU of single organism/ml for BAL fluid. Additionally, urinary cultures were considered significant if showing a growth of ≥100,000 CFU/ml of no more than two species of microorganisms . Cultures were excluded if the laboratory reported them as a "contaminant sample".
- Resistant organismswere defined as the non-susceptibility to at least three or more antimicrobial agents. Susceptibility of microorganisms created using documents and breakpoints based on Clinical Laboratory Standards Institute (CLSI) , 
- The International Classification of Diseases, Tenth Revision, Clinical Modification (ICD10-CM) codes were used to define Thrombosis/infarction during ICU stay (i.e., myocardial infarction (MI), ischemic stroke, pulmonary embolism, deep vein thrombosis) during ICU stay.
- Acute kidney injury (AKI) was defined based on the Acute Kidney Injury Network (AKIN) definition .
- Acute liver injury was defined as alanine aminotransferase (ALT) exceeding three times the upper limit of normal or double in patients with elevated baseline ALT during the hospital stay.
- Respiratory failure was identified either as hypoxemic respiratory failure (PaO2 < 60 mm Hg with a normal or low arterial carbon dioxide tension (PaCO2) or hypercapnic respiratory failure (PaCO2 > 50 mm Hg) that requires mechanical ventilation.
Categorical variables are presented as number (percentage), numerical variables (continuous variables) as mean and standard deviation (SD), or median and lower quartile (Q1) and upper quartile (Q3), as appropriate. The normality assumptions were assessed for all numerical variables using a statistical test (i.e., Shapiro–Wilk test) and graphical representation (i.e., histograms and Q-Q plots).
Baseline characteristics, baseline severity, and outcome variables were compared between the two groups. We compared categorical variables using the Chi-square or Fisher exact test. We compared the normally distributed continuous variables using student t-test and other non-normally distributed continuous variables with the Mann-Whitney U test.
Multivariable logistic and generalized linear regression were used to find out the relationship between the number of tocilizumab doses and the different outcomes considered in this study after adjusting for the for patient’s APACHE II score, systemic corticosteroids during ICU stay, CPK, lactic acid, and lymphocytes within 24 hours of ICU admission. The odds ratios (OR) and estimates with the 95% confidence intervals (CI) were reported for the associations. We assessed model fit using the Hosmer-Lemeshow goodness-of-fit test. No imputation was made for missing data as the cohort of patients in our study was not derived from random selection. We considered a P value of < 0.05 statistically significant, and we used SAS version 9.4 for all statistical analyses.