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


A total of 756 eligible critically ill patients with COVID-19 were admitted to the ICU during the study period in the two study centers. Zinc sulfate 220 mg (50 mg of elemental zinc) enteral tablets once daily was newly initiated in the ICU to 90 patients, whereas 666 patients did not receive zinc as adjunctive therapy. We matched 164 patients using propensity score (1:1) according to the selected criteria. A total of 38 patients (46.3%) have received zinc sulfate within 24 h of ICU admission. The median (Q1, Q3) duration of zinc sulfate was 11 days (6, 15).

Study Population

Before PS matching, most of the patients in both arms were men (70.9%), and the average age was 60.8 ± 14.6 years in the whole cohort. The most common comorbidities were diabetes mellitus (60.1%), followed by hypertension (56.8%), and dyslipidemia (20.8%) (Additional file 1: Table e1). Moreover, there was a significant difference in the baseline characteristics between the two groups before PS. The baseline severity scores (i.e., APACHE II and SOFA scores), the nutritional status based on the NUTRIC score stratification, total WBCs, procalcitonin levels, AKI status, and INR were higher in the control group. Conversely, patients in the zinc group have a higher eGFR baseline and received more pharmacological deep vein thrombosis prophylaxis. However, after using PS matching based on the selected criteria, most of the baseline characteristics and comorbidities were balanced between the two groups except for lactic acid baseline, which was significantly higher in the control group. Moreover, the tocilizumab, corticosteroids use within 24 h of ICU admission, and the concomitant use of nephrotoxic medications during ICU stay were similar between the groups (Additional file 1: Table e1).

30-Day and In-hospital Mortality

In crude analysis, 19 patients (23.2%) died within 30 days among the zinc group, compared with 31 patients (38.8%) in the control group (P = 0.03). At multivariable Cox proportional hazards regression analyses, the 30-day mortality was lower in patients who received zinc sulfate (HR 0.52 CI 0.29, 0.92; p = 0.03). On the other hand, the in-hospital mortality was similar between the two groups (HR 0.64 CI 0.37, 1.10; p = 0.11) (Table 1). The overall survival probabilities using Kaplan–Meier (KM) plots were not statistically different during hospital stay among patients who received zinc after propensity score-matched (P = 0.0979) (Figure 2).

Figure 2.

Overall survival plot during hospital stay after PS matching comparing patient who received zinc as adjunctive therapy (82 patients) versus control group (82 patients)

Ventilator Free Days (VFDs) and Length of Stay (LOS)

Patients who received zinc have a longer median of VFDs than patients who did not (twenty versus zero days; P = 0.02). However, it was not statistically significant in the regression analysis (Beta coefficient 0.33 CI − 0.21, 0.87; p = 0.22). There were no statistically significant differences in ICU and hospital LOS between the two groups after using PS matching (Table 1).

Complications During ICU Stay

The acute kidney injury occurred in 10 patients who received zinc, compared with 25 patients in the control group (15.4% vs. 31.3%; P = 0.02). However, in the logistic regression analysis, it did not reach the statistical significance (OR (95%CI) 0.46 (0.19, 1.06), p = 0.07). The concomitant use of nephrotoxic medications was assessed and not statistically significant before and after PS matching between the two groups. Moreover, among the zinc group, only two patients (2.5%) have an acute liver injury versus seven patients (8.8%) in the control group. However, it was not statistically significant (OR (95%CI) 0.24 (0.05, 1.26), p = 0.09). No significant differences were observed in thrombosis/infraction (OR (95%CI) 0.46 (0.11, 1.98), p = 0.29) or respiratory failure requiring MV (OR (95%CI) 0.98 (0.31, 3.14), p = 0.98) (Table 2).

Follow-up Inflammatory Surrogate Markers

Comparing the effect of zinc on the COVID-19 inflammatory markers, patients who received zinc as new initiation in the ICU stay have a lower d-dimer (Beta coefficient &*minus; 0.80 CI &*minus; 1.28, &*minus; 0.32; p = < 0.001) and fibrinogen levels (Beta coefficient &*minus; 0.99 CI &*minus; 1.51, &*minus; 0.48; p = 0.0002) as a follow-up surrogate marker than the control group as shown in Table 3.