This was a retrospective, multi-center, non-interventional study of critically ill patients admitted to intensive care units (ICUs) with a confirmed diagnosis of COVID19 in Saudi Arabia. The diagnosis of COVID19 was confirmed by Reverse Transcriptase – Polymerase Chain Reaction (RT-PCR) on nasopharyngeal and/or throat swabs. All the patients who met our inclusion criteria during the study period (01/03/2020 – 31/12/2020) were included. COVID19 critically ill patients have been divided into two groups based on thiamine use as adjunctive therapy during ICU stay. Patients were followed during their hospital stay until discharge or in-hospital death, whichever occurred first. The study was approved by the Ministry of National Guard Health Affairs Institutional Review Board, Riyadh, Saudi Arabia (Study Number: RC20/589/R).
Patients were enrolled in the study if they were critically ill, aged 18 years or older, and admitted to ICU with positive PCR COVID-19. Patients were excluded if the ICU Length of stay (LOS) ˂1 day and/or labeled as "Do-Not-Resuscitate" status within 24 hours of ICU admission.
This study was conducted in two large, tertiary governmental hospitals; King Abdulaziz Medical City, Riyadh, and King Abdulaziz University Hospital, Jeddah. The ICUs admits medical, surgical, trauma, burn, and transplant patients and operates as a closed unit with 24/7 onsite coverage by critical care board-certified intensivists 8. The distributions of total enrolled patients were 77 % and 23 % in KAMC-CR and KAUH, respectively. The primary site for this multicenter study was King Abdulaziz Medical City (Riyadh).
We collected the following information, demographic data (See additional file 1), thiamine use, Acute Physiology And Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA) and Nutrition Risk in Critically ill (NUTRIC) scores, comorbidities, vital signs, laboratory tests, the needs for mechanical ventilation (MV) and MV parameters (e.g., PaO2/FiO2 ratio, FiO2 requirement) and inflammatory markers (CRP, procalcitonin) within 24 hours of ICU admission. ICU complication (s) during ICU stay (e.g., thrombosis, Acute Kidney Injury (AKI)) were recorded for eligible patients. Additionally, ICU length of stay (LOS), hospital LOS, mechanical ventilation (MV) duration, and ICU mortality were collected and followed. Patients were followed during ICU LOS until ICU discharge after improving, or in-hospital death, whichever occurred first.
The primary endpoints were to determine the association between using thiamine as adjunctive therapy with in-hospital mortality and 30-day ICU mortality in critically ill patients with COVID 19 (i.e., ICU mortality, ICU LOS). The secondary endpoints include MV duration, length of stay, evaluation of complication (s) during ICU stay (i.e., acute kidney injury (AKI), liver injury, thrombosis during ICU stay).
- The acute kidney injury (AKI) was defined using AKIN definition 29.
- Thrombosis/infraction was defined using ICD10-CM code (i.e., Myocardial infarction (MI), ischemic stroke, pulmonary embolism, deep vein thrombosis) 30.
- Respiratory failure was defined as either 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 invasive mechanical ventilation.
- Liver injury, defined as alanine aminotransferase (ALT), exceeds three times the upper limit of normal or double in patients with elevated baseline ALT.
Data management and Statistical analysis
Categorical variables were reported using numbers and percentages, whereas continuous variables reported using mean with standard deviation (SD) or median with interquartile range (IQR) when appropriate. The normality assumptions were assessed for all numerical variables using a statistical test (i.e., Shapiro–Wilk test) and also using graphical representation (i.e., histograms and Q-Q plots). We compared categorical variables using the chi-square or Fisher exact test, normally distributed numerical variables with the t-test, and other quantitative variables with the Mann-Whitney U test. Baseline characteristics, baseline severity, and outcome variables were compared between the two treatment groups. Multivariate logistic regression and generalized linear regression were used to determine the relationship between thiamine use and different outcomes considered in this study.
On the other hand, we assessed model fit using the Hosmer-Lemeshow goodness-of-fit test. Generalized linear regression was also used to determine the relationship between study outcome and the different study parameters considered in this study. The odds ratios (OR) and estimates with the 95% confidence intervals (CI) were reported for the associations. No imputation was made for missing data as the cohort of patients in our study was not derived from random selection.
Propensity scores were used to match patients who received thiamine to patients receiving no thiamine using a Propensity score matching Procedure (Proc PS match) (SAS, Cary, NC). A greedy nearest neighbor matching method was used in which one non-thiamine (control) is matched with each patient in the thiamine (treated) group. This eventually produces the smallest within-pair difference among all available pairs with treated patients. These patients are matched only if the difference in the logits of the propensity scores for pairs of patients from the two groups is less than or equal to 0.5 times the pooled estimate of the standard deviation. We considered a P value of < 0.05 statistically significant and used SAS version 9.4 for all statistical analyses.