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


In this two-center, retrospective, propensity score matching study, zinc use as adjunctive therapy was associated with significantly lower 30-day mortality in critically ill patients with COVID-19; but the in-hospital mortality did not reach to a statistically significant difference. The overall survival probabilities were not statistically different during hospital stay between the two groups after propensity score. In addition, there was no significant difference in the MV duration, ICU and hospital LOS between the patients who used zinc and those who did not. Instead, patients who received zinc had lower odds of developing AKI; however. this finding did not reach statistical significance.

We have observed survival benefits with zinc supplementation within 30 days of hospital stay in critically ill COVID-19 patients. A retrospective study have shown that using zinc in combination with hydroxychloroquine and azithromycin in hospitalized patients with COVID-19 reduces mortality, ICU admission, and MV needs than patients who did not receive zinc.[23] However, a subgroup analysis in the same study of severely ill patients with COVID-19 found that zinc was not associated with a significant reduction in terms of in-hospital mortality.[23] A recent meta-analysis compared the outcomes of hospitalized patients receiving zinc supplementation with standard care.[24] This meta-analysis concluded that zinc supplementation did not have any beneficial impact on hospital mortality in COVID-19 patients.[24] It is noteworthy that the included studies in the meta-analysis were not critically ill patients, where the disease severity and low pre-admission nutritional status could justify the survival benefit observed in our analysis.

The pre-admission nutritional status is an important indicator for disease severity and might impact the COVID-19 patient's survival. A higher risk of mortality and longer stay in hospital was reported in critically ill COVID-19 patients with higher Nutritional Risk Screening (NRS) 2002.[25] We assessed our patients' nutritional status using the NUTRIC score, which was not significantly different among the groups after propensity score matching. It worth to mention, that Saudi population has a low intake of some micronutrients (such as zinc and selenium) which might have an impact on the preadmission nutritional status and the disease progression.[26] In agreement with our explanation, a recent study has evaluated the impact of preadmission zinc levels in non-critically ill COVID-19 patients and showed that patients with hypozincemia have a higher hospitalization rate due to respiratory complications within ten days.[27] Thus, the impact of hypozincemia on the disease progression and the clinical outcomes still worth further investigation in critically ill COVID-19 patients.

Several reports showed that elevated inflammatory surrogate markers such as d-dimer and fibrinogen levels had been linked with a higher mortality rate in critically ill COVID-19 patients.[4,28,30] Zinc effect on COVID-19 surrogate markers was not well studied. In our study, patients who received zinc supplementation had lower follow-up d-dimer and fibrinogen levels during their stay. This may play a role in COVID-19 disease progression, which might be translated to the mortality benefit seen in our study.

There were no statistically significant differences in the ICU LOS and hospital LOS between the two groups after using PS matching. Our results are consistent with previous retrospective studies and randomized controlled trials (RCTs) showing that the concomitant use of zinc with hydroxychloroquine did not affect the ICU LOS, hospital LOS, or duration of MV.[5,22] A systematic review of four RCTs conducted in non-COVID-19 critically ill patients found that zinc supplementation was not associated with significant differences in the duration of MV, ICU LOS, and hospital stay.[18] It is worth mentioning that most of these studies included patients with mild, and moderate COVID-19 but not critically ill patients.[5,22]

In terms of the complications during ICU stay, zinc use was associated with a lower odd of acute kidney injury; however, did not reach statistical significance. We included the AKI status within 24 h of ICU admission in PS analysis; additionally, the concomitant use of nephrotoxic medications was assessed and it was not statistically significant after PS matching between the two groups. The exact mechanism and explanation for the reduced AKI risk observed in our cohort are unknown; zinc was thought to reduce renal injury incidence via its antioxidant effect in pre-clinical studies.[25] The zinc renal protective effect and the precise impact of zinc supplementation on renal function in critically ill COVID-19 patients are worth further investigation.

Currently, the available evidence about the use of zinc in critically ill COVID-19 patients is limited. Many of the previous reports investigated zinc use in either non-COVID-19 or non-critically ill patients. As we are writing this manuscript, there is an ongoing double-blinded RCT study investigating the use of high-dose zinc in critically ill patients with SARS-COV2.[29] Compared to the published data, our study is one of the few studies that assessed the use of zinc in critically ill patients with COVID-19 with a propensity-score-matched group of patients.

Nonetheless, this study still has several limitations, such as the observational nature, small sample size, and the possibility of residual confounding may remain despite using propensity score matching. Additionally, our findings might be limited due to the administration of zinc via the enteral route, which might reduce the absorption in critically ill patients due to gastrointestinal ischemia and impaired intestinal flora. Even though zinc levels are challenging to measure accurately, this level might be valuable in determining the amount of zinc absorbed. The unavailability of zinc levels in this study might also limit our results. Furthermore, there was no defined treatment regimen, and the choice to initiate zinc was left to the discretion of the clinician. Given these limitations, the study's findings should not be used to guide clinical practice but to support the need for future RCTs to investigate the potential impact of zinc supplementation in critically ill patients with COVID-19.