Zinc for Metabolic Resuscitation in Critical Illness

Did you know that zinc is the second-most abundant trace metal in the human body? A quick reminder that iron comes in first place. Zinc is an essential component of protein structure and function. It enables gene transcription and is a “catalytic component of approximately 2000 enzymes” (Read, et al). Could we use zinc for metabolic resuscitation?

In the pre-covid days, inflammatory cytokines were something only the nerds spoke about. Today, it is common knowledge as we at checking interleukin levels routinely in our ICUs. Did you know that zinc modulates the production of inflammatory cytokines (Alker)? It is also “crucial for the functioning of virtually all immune cells” (Alker).

By no means is this meant to suggest that supplementing zinc to our critically ill patients would result in a mortality benefit in a double-blind, placebo-controlled, multi-center, randomized study. Nor do I feel that it will independently decrease length of stay, decreased time on vasopressors, nor decrease time on mechanical ventilation. The purpose of this is to familiarize you with a rationale as to why we should consider zinc supplementation to hospitalized patients with infections, whether viral or bacterial. This is not medical advice.

There is still much to learn regarding zinc metabolism and homeostasis. I recommend you read the citations as the complexity of the topic dives into biochemical seas that I do not have the ability to dive into. Please see the citations below. Many of them are open-access and free.

How much zinc do you need per day?

Males need up to 9.5mg per day. Women need up to 7mg per day. (Duncan) If one wants to look at dosages for using zinc in metabolic resuscitation, this is a good starting point. There’s no evidence about what dose to use, by the way.

Should we perform lab testing to see who is zinc deficient?

A low zinc concentration in plasma is not diagnostic. Hypoalbuminemia and systemic inflammatory responses create erroneous interpretations of zinc levels. One should to check c-reactive protein (CRP) levels to ensure there’s no inflammatory response to create this false positive. (Duncan) If we are going to be administering zinc to our acutely ill patients, checking a zinc level based on this is pointless.

It is postulated that a low zinc concentration during acute illness may even be a physiologic function. One of the ideas behind this is that, like iron, pathogens at times require the essential elements and the body attempts to hide them. (Alker) Zinc redistributes in the body during inflammatory illnesses and those mechanisms are not yet fully understood (Alker). The primary organ to where zinc is redistributed to includes the liver (Hoeger).

Who develops zinc deficiency?

One needs to consider certain factors that create a zinc deficiency. One needs to consume a sufficient amount, reuptake and storage needs to function well, and you can’t excrete too much.

Zinc deficiency frequently occurs in elderly patients. It also occurs in patients with cardiovascular disease, chronic pulmonary disease, diabetes mellitus, alcoholism, hepatitis C, HIV, cirrhosis and inflammatory bowel disease. Don’t forget about the patients who are s/p gastric bypass surgery. Vegans/vegetarians should supplement their diets with additional zinc. The global prevalence of zinc deficiency is estimated to be between 17-20%.

Did you know that the diuretic, hydrochlorothiazide, creates an increased urinary excretion of zinc? This can cause zinc deficiency. The same is seen with ACE-inhibitors and ARBs. (Derwand).

Does Zinc help the antiviral response?

Zinc is an essential micronutrient, with strictly regulated systemic and intracellular concentrations, and it is physiologically necessary for an effective antiviral response. Read, et al. has a table with human clinical studies using zinc as an antiviral therapy. This includes viruses such as herpes, rhinovirus, the common cold, HIV, and chronic hepatitis C, amongst others. Benefits of these include reduced duration and severity of symptoms. This is one of the reasons why some say that zinc can help with COVID in the ambulatory setting.

Does Zinc help with bacterial infections?

Alker, et al. postulated about zinc and sepsis. There is a paucity of adult human trials looking at zinc in sepsis. For the aforementioned reasons of decreased zinc concentrations in acute illnesses, it is challenging to diagnose beforehand who is zinc deficient and who isn’t. Trying to diagnose your patient while in the hospital is pointless. Animal studies have shown a benefit but no human trials have looked at this. To be able to conduct such a trial, we would have to either try to diagnose zinc deficiency beforehand (good luck with that) or empirically provide it to an experimental arm of patients.

In a study on surgical patients in whom baseline zinc levels were checked on admission, those with lower zinc levels did not do as well. They were associated with a higher susceptibility to a recurrent sepsis episode. In addition to that, they had a higher number of organ dysfunctions. To make things worse, they had an increased in-hospital mortality at day 28 and 90 (Hoeger). They are not recommending administering zinc to people who are septic, though, as this can essentially become nutrition for the bacteria.

Adverse Effects: Too much of a good thing.

If consumed or provided in excess, you can have a zinc-induced copper deficiency. This is due to copper malabsorption.

Case reports showing copper deficiency due to zinc ingestion all reflect doses greater than 100mg per day. (Duncan)

If a patient is being prescribed zinc for more than 3 months, copper levels should be checked.

How would zinc administration affect in our patients in the hospital? We don’t know. Would supplementing zinc become pathogen food? Animal models do not suggest that.

Wrapping up Zinc for Metabolic Resuscitation

Seems as if the downsides are limited and a potential upside exists. I’d be lying to you if I said the evidence is clear cut. Documents from the Eastern Virginia Medical School in Norfolk, VA recommend 50-75mg of elemental zinc per day in COVID patients. Click here for a link to that protocol. Is this a cure for anything? I don’t think so.

To those purists looking for a randomized controlled trial, it doesn’t exist. And if it did, I can’t imagine the sample size necessary to show an endpoint that’s considered meaningful. I’d like to think about the tools used for metabolic resuscitation to be like the clubs used in golf. I’m not a golfer, by the way. Sure, a putter will get you out of the bunker, but a sand wedge will get you out easier. Or so they say.

If you want to learn more about metabolic resuscitation click here.

Check out this blog post on my podcast and YouTube video.

Zinc for Metabolic Resuscitation: Citations

Read SA, Obeid S, Ahlenstiel C, Ahlenstiel G. The Role of Zinc in Antiviral Immunity. Adv Nutr. 2019;10(4):696-710. doi:10.1093/advances/nmz013
Link to Article

Derwand R, Scholz M. Does zinc supplementation enhance the clinical efficacy of chloroquine/hydroxychloroquine to win today’s battle against COVID-19? [published online ahead of print, 2020 May 6]. Med Hypotheses. 2020;142:109815. doi:10.1016/j.mehy.2020.109815
Link to Article

Duncan A, Yacoubian C, Watson N, Morrison I. The risk of copper deficiency in patients prescribed zinc supplements. J Clin Pathol. 2015;68(9):723-725. doi:10.1136/jclinpath-2014-202837
Link to Abstract

Alker W, Haase H. Zinc and Sepsis. Nutrients. 2018;10(8):976. Published 2018 Jul 27. doi:10.3390/nu10080976
Link to Article

Hoeger J, Simon TP, Beeker T, Marx G, Haase H, Schuerholz T. Persistent low serum zinc is associated with recurrent sepsis in critically ill patients – A pilot study. PLoS One. 2017;12(5):e0176069. Published 2017 May 4. doi:10.1371/journal.pone.0176069
Link to Article


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