Evaluation of Zinc Sulfate as an Adjunctive Therapy in COVID-19 Critically ill Patients

A Two Center Propensity-Score Matched Study

Khalid Al Sulaiman; Ohoud Aljuhani; Abdulrahman I. Al Shaya; Abdullah Kharbosh; Raed Kensara; Alhomaidi Al Guwairy; Aisha Alharbi; Rahmah Algarni; Shmeylan Al Harbi; Ramesh Vishwakarma; Ghazwa B. Korayem


Crit Care. 2021;25(363) 

In This Article


Study Design

This was a two-center, retrospective study of all critically ill patients with COVID-19 who were admitted to the Intensive Care Unit (ICU) from March 1, 2020 until March 31, 2021. We aimed to enroll as many patients as possible, with no predefined sample size. The 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: NRC21R/287/07).


Patients aged ≥ 18 years and admitted to ICU for more than 24 h with a confirmed COVID-19 were eligible for inclusion. Patients were excluded if they died within 24 h of ICU admission, labeled as "Do-Not-Resuscitate" within 24 h of ICU admission, or received zinc before ICU admission (Figure 1). Enrolled patients were classified into two groups based on the administration of zinc sulfate as adjunctive therapy during ICU stay. Patients who received new initiation of zinc sulfate during ICU stay were included in the active group. The decision on whether to use zinc sulfate with a daily dose of 220 mg (50 mg of elemental zinc) enteral tablets for patients was solely based on physician clinical judgment. Patients were followed during their hospital stay, until discharge or in-hospital death, whichever occurred first.

Figure 1.

Inclusion/exclusion criteria


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 and clinical pharmacists. The primary site for this study was King Abdulaziz Medical City.

Data Collection

Each patients' data were collected and managed using Research Electronic Data Capture (REDCap®) software hosted by King Abdullah International Medical Research Center (KAIMRC). Patient's demographic data, comorbidities, vital signs, and laboratory tests were extracted from electronic medical records. The laboratory tests included the renal profile (Estimated glomerular filtration rate (eGFR), AKI status), liver profile (Aspartate transaminase (AST), Alanine transaminase (ALT), and total bilirubin), coagulation profile (international normalized ratio (INR), activated Partial Thromboplastin Time (aPTT)), and albumin levels within 24 h of ICU admission. In addition, surrogate biomarkers of the COVID-19-associated inflammation (ferritin, D-dimer, fibrinogen and C-reactive protein (CRP)) were collected and reported with their baseline and peak values during the ICU stay.[30] Peak levels were defined to be the highest level of the surrogate marker checked at any time during their ICU length of stay. The aim of investigating these biomarkers was to establish a reasonable correlation between zinc administration and disease progression that might be captured via an increase in the inflammatory surrogate markers. The selected biomarkers have been associated with poor outcomes in COVID-19 patients.[4,30] 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 using the MDCalc website for each patient.[20] In addition, we collected the needs for mechanical ventilation (MV), and MV parameters (e.g., PaO2/FiO2 ratio, FiO2 requirement) within 24 h of ICU admission. Lastly, tocilizumab and corticosteroids use within 24 h and the concomitant use of nephrotoxic medications (i.e. Vancomycin IV, Gentamicin IV, Amikacin IV, Colistin IV, Furosemide, Sulfamethoxazole/trimethoprim and Contrast,) during ICU stay were recorded for the eligible patients.

Aim of Study and Outcomes

This study aimed to evaluate the efficacy and safety of zinc sulfate as adjunctive therapy in critically ill patients with COVID-19. The primary endpoint was the 30-day mortality in critically ill patients who received zinc sulfate as adjunctive therapy. The secondary endpoint included the in-hospital mortality, ICU length of stay (LOS), hospital LOS, ventilator free days (VFDs), and evaluation of complications during ICU stay after zinc initiation, including acute kidney injury (AKI), liver injury, and thrombosis/infraction during ICU stay.


  • The 30-day mortality was defined as the in-hospital death occurring for any cause within 30 days of the admission date during the hospital stay.

  • Ventilator-free days (VFDs) at 30 days were calculated as the following: if the patients die within 30 days of MV, the VFDs = 0, VFDs = 30-days after MV initiation (if the patient survived and was successfully liberated from MV), and VFDs = 0 if the patient is on MV for > 30 days.

  • Acute kidney injury (AKI) was defined using the Acute Kidney Injury Network (AKIN) definition.[21]

  • Thrombosis/infraction was defined using the International Statistical Classification of Diseases (ICD) 10-CM code (i.e., Myocardial infarction (MI), ischemic stroke, pulmonary embolism, deep vein thrombosis)[22]

  • 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 were 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 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). Model fit assessed using the Hosmer–Lemeshow goodness-of-fit test.

Propensity score matching procedure (Proc PS match) (SAS, Cary, NC) was used to match patients who newly received zinc sulfate (active group) to patients who did not (control group) based on patient's APACHE II score, acute kidney injury, and systemic use of corticosteroids within 24 h of ICU admission. A greedy nearest neighbor matching method was used in which one patient who newly 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.

Multivariable Cox proportional hazards regression analysis 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 as appropriate for the other outcomes considered in this study. Regression analysis was done by consider PS score as one of the covariates in the model. 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 analysis.