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

Disclosures

Crit Care. 2021;25(363)

Conclusion

The use of zinc sulfate as adjunctive therapy in critically ill patients with COVID-19 may have survival benefits. Additionally, zinc use may have a protective effect on the kidneys. Further randomized clinical and interventional studies are needed to confirm our findings.

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Abbreviations
ICUs: Intensive care units; COVID-19: Coronavirus disease; MV: Mechanical ventilation; LOS: Length of Stay; APACHE II: Acute Physiology and Chronic Health Evaluation II; SOFA: Sequential Organ Failure Assessment; NUTRIC: Nutrition Risk in Critically ill; Q1, Q3: 1St interquartile and 3rd interquartile; eGFR: Glomerular filtration rate; AKI: Acute Kidney Injury; MV: Mechanical Ventilation; INR: International normalized ratio; aPTT: Activated partial thromboplastin time; C-RP: C-reactive protein; CPK: Creatine phosphokinase; PaO₂/FiO₂: Arterial oxygen tension/fraction of inspired oxygen

Acknowledgements
We would like to acknowledge all of the investigators in the Saudi critical care pharmacy research (SCAPE) platform who participated in this project. Additionally, we thank Dr. Hakeam A. Hakeam for his support during the study execution.

Funding
None.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from corresponding author on reasonable request.

Declarations
Ethics approval and consent to participate
The study was approved in November 19th, 2020 by King Abdullah International Medical Research Center Institutional Review Board, Riyadh, Saudi Arabia (Reference No: RC20/589/R). Participants' confidentiality was strictly observed throughout the study using the anonymous unique serial number for each subject and restricting data only to the investigators. Informed consent was not required due to the research's method as per the policy of the governmental and local research center.

Consent for publication
Not applicable.

Crit Care. 2021;25(363) © 2021 BioMed Central, Ltd.
Copyright to this article is held by the author(s), licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original citation.

Table 1. Regression analysis for the outcomes after PS matching
	Outcomes			Hazard ratio (HR) (95%CI)	P-value$
	Control	Zinc	P-value^^	Hazard ratio (HR) (95%CI)	P-value$
In-hospital mortality, n (%)^§	32 (40.0)	23 (28.4)	0.12	0.64 (0.37, 1.10)	0.11
30-day mortality, n (%)^§	31 (38.8)	19 (23.2)	0.03	0.52 (0.29, 0.92)	0.03
			P-value^	beta coefficient (estimates) (95%CI)	P-value$*
Ventilator free days, Median (Q1, Q3)^§	0.0 (0.00, 26.00)	20.0 (0.00, 28.00)	0.02	0.33 (− 0.21, 0.87)	0.22
ICU Length of Stay (Days), Median (Q1, Q3)^&	8.0 (5.00, 15.00)	10.0 (6.00, 15.00)	0.28	0.10 (− 0.16, 0.36)	0.46
Hospital Length of Stay (Days), Median (Q1, Q3)^&	16.0 (10.00, 28.00)	17.0 (12.00, 29.00)	0.61	0.03 (− 0.21, 0.27)	0.79

^§Denominator of the percentage is the total number of patients
^&Denominator is patients who survived
^^Chi-square test is used to calculate the P-value
^Wilcoxon rank sum test is used to calculate the P-value
^$Cox proportional hazards regression analysis is used to calculate hazard ratio (HR) and p-value
^$*Generalized linear model is used to calculate beta coefficient (estimates) and p-value

Table 2. Regression analysis for ICU complication (s) after PS matching
Outcomes	Crude analysis		P-value^^	Odds Ratio (OR) (95%CI)	P-value*^
Outcomes	Control	Zinc	P-value^^	Odds Ratio (OR) (95%CI)	P-value*^
Acute kidney injury, n (%)^§	25 ( 31.3)	10 ( 15.4)	0.02^^	0.46 (0.19, 1.06)	0.07
Liver injury, n (%)^§	7 ( 8.8)	2 ( 2.5)	0.08**	0.24 (0.05, 1.26)	0.09
Thrombosis/infraction, n (%)^§	7 ( 8.8)	3 ( 3.8)	0.19**	0.46 (0.11, 1.98)	0.29
Respiratory failure requiring MV, n (%)^$*	9/26 (34.6)	9/27 (33.3)	0.92^^	0.98 (0.31, 3.14)	0.98

^§After zinc initiation
^$*Denominator of the percentage is non-mechanically ventilated patients with 24 h of ICU admission
^^Chi-square/**Fisher Exact test is used to calculate the P-value
*^Multivariable logistic regression analysis is used to calculate Odds ratio and p-value

Table 3. COVID-19 Inflammatory surrogate markers: peak levels follow-up
	Surrogate markers*		P-value^	Beta coefficient (estimates) (95%CI)	P-value$*
	Control	Zinc	P-value^	Beta coefficient (estimates) (95%CI)	P-value$*
Ferritin level (ug/l), Median (Q1, Q3)^§	891.9 (350.0, 2476.0)	941.1 (511.0, 2344.0)	0.69	0.21 (− 0.18, 0.60)	0.29
D-dimer level (mg/l), Mean (SD)^§	15.0 (36.8)	6.7 (9.2)	0.75	− 0.80 (− 1.28, − 0.32)	0.001
Fibrinogen Level (gm/l), Median (Q1, Q3)^§	5.5 (3.39, 7.18)	4.8 (3.95, 6.65)	0.31	− 0.99 (− 1.51, − 0.48)	0.0002
C-reactive protein (mg/l), Mean (SD)^§	184.2 (148.1)	174.0 (124.3)	0.92	− 0.05 (− 0.36, 0.27)	0.77

^§Denominator is the total number of patients
^Wilcoxon rank sum test is used to calculate the P-value
^$*Generalized linear model is used to calculate estimates and p-value
*All levels represent peak levels for each one of the biomarkers