This was a two-center, retrospective study of prospectively collected data of all consecutive critically ill COVID-19 patients who were admitted to the ICU from 01 March 2020 until 31-December 2020. We aimed to enroll as many patients as possible, with no predefined sample size. COVID-19 was confirmed using a reverse transcriptase-polymerase chain reaction (RT-PCR) obtained from nasopharyngeal or throat swabs. The study was approved by King Abdullah International Medical Research Center (KAIMRC)-Institutional Review Board, Riyadh, Saudi Arabia (Study Number: RC20/589/R).
Patients aged ≥ 18 years and were admitted to ICU for more > 24 hours with a confirmed COVID-19 were eligible for inclusion. Patients were excluded if were placed as "Do-Not-Resuscitate" code status within 24 hours of ICU admission. Enrolled patients were classified into two groups based on the administration of zinc sulfate use as adjunctive therapy during ICU stay. Patients who received zinc sulfate 220 mg (50 mg of elemental zinc) enterally tablets as new initiation in the ICU or prior to ICU admission and continued during ICU stay were included in the active group. Patients were followed during their hospital stay, until discharge or in-hospital death, whichever occurred first.
This study was conducted in two large, tertiary governmental hospitals; King Abdulaziz Medical City (KAMC), Riyadh, and King Abdulaziz University Hospital (KAUH), Jeddah. The ICUs admit medical, surgical, trauma, burn, and transplant patients and operate as a closed unit with 24/7 onsite coverage by critical care board-certified intensivists. The distributions of total enrolled patients were 77 % and 23 % in KAMC-CR and KAUH, respectively. The primary site for this study was KAMC, Riyadh.
Patients’ demographic data, comorbidities, vital signs, and laboratory tests were extracted from electronic medical records. The following labs were gathered renal profile, liver function tests (LFTs), coagulation profile (i.e., INR, aPTT, fibrinogen), inflammatory markers (C-reactive protein (CRP), procalcitonin) within 24 hours of ICU admission, and the "worst" values of inflammatory markers during ICU stay (maximum or minimum, depending on the parameter). The severity baseline scores (i.e., Acute Physiology And Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA), and Nutrition Risk in Critically ill (NUTRIC)) were calculated for each patient. In addition, we collected the Glasgow Coma Score (GCS), fluid balance status, the needs for mechanical ventilation (MV), and MV parameters (e.g., PaO2/FiO2 ratio, FiO2 requirement) within 24 hours of ICU admission.
Aim of study and Outcomes
This study aims to evaluate the efficacy and safety of zinc sulfate as adjunctive therapy in critically ill patients with COVID-19.The primary outcomes were the 30-day and in-hospital mortality in critically ill patients who received zinc sulfate as adjunctive therapy. The secondary outcomes include ICU LOS, hospital LOS, mechanical ventilation (MV) duration, and evaluation of complications during ICU stay, including acute kidney injury (AKI), liver injury, a respiratory failure that requires MV, and thrombosis/infraction during ICU stay.
Acute kidney injury (AKI) was defined using the Acute Kidney Injury Network (AKIN) definition .
Thrombosis/infraction was defined using ICD10-CM code (i.e. Myocardial infarction (MI), ischemic stroke, pulmonary embolism, deep vein thrombosis)
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 is defined as alanine aminotransferase (ALT) exceeding 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. We compared categorical variables using the Chi-square or Fisher exact test. Continuous variables were compared using numerical the student-t test (for the normally distributed variables) or other quantitative variables with the Mann-Whitney U test (for the non-normally distributed variables). The normality assumptions were assessed for all numerical variables using statistical tests (i.e., Shapiro–Wilk test) and graphical representation (i.e., histograms and Q-Q plots).
Propensity score matching procedure (Proc PS match) (SAS, Cary, NC) was used to match patients who received zinc sulfate (active group) to patients who did not (control group) based on baseline severity scores (i.e., APACHE II, SOFA score, NUTRIC scores), systemic use of corticosteroids and study centers. A greedy nearest neighbor matching method was used in which one patient who received zinc sulfate (active) group matched with one patient who did not (control), which eventually produced the smallest within-pair difference among all available pairs with treated patients. Patients were matched only if the difference in the logits of the propensity scores for pairs of patients from the two groups was less than or equal to 0.5 times the pooled estimate of the standard deviation.
Model fit assessed using the Hosmer-Lemeshow goodness-of-fit test. Multivariable Cox proportional hazards regression analyses were performed for the 30-day and in-hospital mortality. Additionally, Kaplan-Meier (KM) plots were generated for these outcomes. Multivariable regression analysis and negative binomial regression were used for the other outcomes considered in this study. The odds ratios (OR), hazard ratio (HR), or estimates with the 95% confidence intervals (CI) were reported as appropriate. 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 used SAS version 9.4 for all statistical analyses.