I'm very happy to be here today to share my thoughts with you on the implications of zinc in critical illness. My interest in zinc goes back for several years, but in this presentation, I'm going to summarize for you zinc physiology and metabolism, highlight conditions where zinc deficiency may occur in critical illness, and I want to convince you that there is a limited role for megadoses of zinc in critical illness. Here is a slide way back from the mid-1970s. A 50-year-old trauma patient develops a high-output fistula from the mid-ilium. The fistula drainage is about one liter per day, and the nurses were discarding the fistula drainage without putting it back into the GI tract. Now, after two weeks of penitent nutrition, the patient developed unexplained glucose intolerance and a loss of hair. Those days, we did not have intravenous micronutrients, especially trace elements, and therefore, we used to just use fresh frozen plasma twice or three times a week, and a peculiar rash was noted on his face, nasolabial folds, and in the upper extremities. We know now this is typical of zinc deficiency, and then here's a middle-aged patient with a massive bile leak due to bile duct injury from gallbladder surgery, and developed a rash in the gluteal area and a rash in the extremities, typically known as acrodermatitis entropathica. The slide on the right actually shows the rash after two or three days after intravenous zinc was given, and the rash is slowly actually disappearing. Yet another patient was on adequate enteral feeding, but a loss of hair was noted, and we got a zinc level, and it was low. This resolved with zinc supplementation, and in this case, we found that the zinc deficiency was because of ferrous sulfate supplements that the patient was getting through the tube feeding, and the iron was preventing absorption of zinc, or at least making the zinc absorption suboptimal. A few terms will have to be clarified. We may have a suboptimal intake, in which case a complement of the extra micronutrients, in this case zinc, is needed, and that is enough to change the deficit to a state of repletion, but in many cases in critical illness, physicians are recommending using megadoses as supplements, so supplementation of a micronutrient is not the same as complementing the suboptimal oral intake. The zinc content of the human body is the highest of any trace element, except for iron, and if you compare iron's content in the body at 3 to 5 grams, the content of zinc is about approximately 2 grams, and the functions of zinc can be classified into three, structural, structural, as in the structure of proteins, catalytic, like in enzymes, and regulatory, as in signaling in endocrine systems. Zinc has got major roles in protein and carbohydrate metabolism, very important roles in the immune system, roles as an anti-inflammatory agent, and as an antioxidant. It is a component of 300 metalloenzymes. You will see many of those enzymes listed on the slide, and most of us are familiar with enzymes like superoxide dismutase, the scavenger enzyme, and angiotensin converting enzyme, or the ACE enzymes, and as you can see therefore zinc has ubiquitous functions in the body. It is mainly absorbed in the duodenum and jejunum, and zinc has a very efficient enterohepatic circulation. The absorbed zinc is excreted in the bile, more about this later. The GI losses are 2 to 4 milligrams per day, urinary losses are 0.5 milligrams per day. The daily recommended intake is about 8 to 15 milligrams per day, which is present in a liter and a half of most enteral formulas, but not all the 15 milligrams of zinc is absorbed from the GI tract. Whatever is a loss and whatever the body needs is what is absorbed. This slide clearly shows that in addition to various other micronutrients that are absorbed in the duodenum, zinc is one of the main micronutrients that are absorbed in the duodenum. The enteral zinc is absorbed or reabsorbed by enterocytes, reabsorbed from the bile for example, and it is stored in metallothioneine, and the interesting thing is that this zinc that is required is released to the albumin, and if it is required in the liver, it is used up for the enzymes in the liver, the rest is excreted, and some of it is excreted in the pancreatic secretions also in addition to bile. But if the enterocytes sense that the serum zinc levels are adequate, then absorption actually becomes limited. I was able to find a post-mortem study on about 200 individuals looking at the zinc content of bile, and the zinc content of bile is quite significant. If you assume a 500cc bile loss and you multiply it by 4, it is about 2,000 micrograms or 2 milligrams of zinc loss per day. In parental nutrition, we give only 2.5 to 4 milligrams of zinc, so if someone has a 2 liter bile loss, you can see how significant the loss of zinc could be from the body. And zinc deficiency occurs whenever there is excessive GI losses, protracted diarrhea, MSS, high output fistula, short bowel syndrome, pancreatic insufficiency, trauma, burns, alcoholism, and renal insufficiency. High dose steroids, probably because of proteolysis. HIV infections and malignancies are also conditions where zinc deficiency is known to occur. Zinc deficiency is known to occur after bariatric surgery, and it may occur in spite of oral supplements, more common in bypass procedures than restrictive procedures, such as gastric banding. And almost all fat-soluble vitamins and B vitamins are known to be deficient after bariatric surgery. But among the trace elements, iron, zinc, and copper deficiencies are known to occur after bariatric surgery. What about renal replacement therapy? It depends upon the effluent losses, and increased requirements for zinc are likely for patients of renal replacement therapy. Prolonged renal replacement therapy increases losses, and therefore, anytime a person is on hemodialysis, we need to monitor the levels at least every two weeks. And this was well described in a paper by Dr. Berger and colleagues in Current Opinion in Critical Care. But of course, there are no studies on outcomes because of zinc deficiency in renal failure. What about zinc loss in peritoneal dialysis? This is a study that I actually did many years ago and showed very clearly that zinc and selenium are not lost in peritoneal dialysis. Therefore, if there is zinc deficiency in a patient on peritoneal dialysis, it is because of inadequate intake or decreased absorption rather than zinc loss in the peritoneal dialysis itself. So when do we measure zinc levels? Whenever you have gastrointestinal losses, which exceed the normal losses, bile losses, and possibly chile losses. So there's a paucity of information on the zinc content of chile. Increasing skin losses and burns is a very typical example where zinc loss occurs through the skin. Long-term parenteral nutrition is another condition where we have to measure zinc levels. Renal replacement therapy, chronic pancreatic insufficiency, and short gut syndrome. Now, these recommendations will be published very soon, or it could be published too by the time this presentation is available. But Dr. Pirroni and colleagues have written these very nice guidelines from the European Society for Parenteral and Enteral Nutrition about micronutrients and critical illness. These are the recommendations in those new guidelines. The features of zinc deficiency are numerous. The skin rash we talked about earlier, poor wound healing and loss of hair. The poor wound healing is especially problematic in burns and in trauma. The altered taste sensation, dysgeusia, and altered smell perception, dysosmia, are very peculiar to zinc deficiency. It's also very peculiar that these are actually seen in COVID deficiency or COVID infection. But as of today, we don't have any clear evidence to show that in COVID dysgeusia and dysosmia are because of zinc deficiency. Zinc deficiency occurs in protracted diarrhea. And the diarrhea causes zinc deficiency. And the zinc deficiency accentuates the diarrhea. So it is an endless cycle. Zinc deficiency results in glucose intolerance. We need zinc for the function of insulin. Hyperglycemia. You notice a decreased work capacity of muscles and the detrimental effect on respiratory function. And hepatic function also worsens when you have concomitant zinc deficiency. There are effects of zinc on inflammation, too. Zinc levels decrease rapidly with acute phase response and in perioperative period and in patients with respiratory failure. So you'll find that in most critically ill patients, zinc levels decrease rapidly because of the acute phase response. The zinc levels correlates with increased levels of interleukin 6 and TNS, TNF alpha. So when do we monitor trace element status? Not only zinc, but all trace element factors status. Serum levels of trace elements are not routinely measured in short term nutrition therapy because tests are not available easily and the results are not always available immediately when they are more useful for us to change the care of the patient. Special collection apparatus and tubes must be trace element free. Now, levels do not indicate deficiencies because they may represent redistribution, as I showed in the earlier slide. And the supplementation with zinc and other trace elements, too, may not increase the serum levels. Radioisotope studies in humans is well near impossible. And the serum levels after clotting are generally marginally higher than plasma levels in the case of zinc. So some labs use serum levels, other labs use plasma levels. They're almost the same, although serum levels are marginally higher. Even though there are limitations, getting serum levels is the best available tool. The serum levels represent only less than 0.1% of the total body zinc, but that is the best we have. Plasma zinc is the most widely used and the assessment has remained elusive for decades. But you must interpret the levels with caution because when you have a C-reactive protein that is greater than 20 and the albumin level is low, you'll find that the plasma zinc level is also low. So we really don't know the implications of a low zinc plasma level. So although not a perfect test, it is the best one available, as I have mentioned earlier. And when you want to monitor replacement of zinc, again, the plasma zinc is used. The dosage recommendations in enteral feeding is about 10 milligrams per day minimum. Most products contain about 15. In parenteral nutrition, it is 3 to 5. Additional amounts, either oral or via tubes or intravenously, in excessive GI losses or in burns, or when you clinically suspect zinc deficiency, those are the conditions where additional amounts are needed by whatever route. But the additional doses are used only for limited periods. And this, again, are the recommendations in the recent European Society for Parenteral and Enteral Nutrition. And the publication is pending. Now, here is a paper that came out just a few weeks, a few months ago, in which I was honored to be an author, where it was shown that the routine admission of micronutrients to parenteral nutrition, even though strongly recommended, is not always followed. Because of delays in initiating, the formulas may not be optimal. And there are specific clinical conditions where additional dosage of individual micronutrients may be needed. So we needed to sensitize clinicians regarding the role of micronutrients as an integral component of nutrition therapy. And this is true for zinc, too. So this paper was actually an international expert consensus opinion. And we made strong recommendations regarding accountability. Clinicians are accountable for good nutrition practice. And by clinicians, I mean physicians, dieticians, and pharmacists, mainly, when it comes to the nutrition care of patients. So not only all micronutrients, but pertinent to this talk, zinc must also be considered in all patients who are receiving any kind of artificial nutrition support. Here is a paper that came out in 2020, in which a meta-analysis was done using several studies that are available by Dr. Gudivada and associates. And the study was based on a systematic review with meta-analysis and trial sequential analysis and showed clearly that the evidence of benefit of antioxidant micronutrient supplementation in critically ill patients is questionable. And current evidence does not justify this practice. I was honored to be an author of a subsequent presentation using the same data on 37 randomized control trials and close to 5,000 patients. And here, a rather sophisticated statistical method was used, a Bayesian multiple treatment comparisons meta-analysis. In many studies on trace elements, multiple treatments were used. So it was very difficult to sift through the benefit or lack of benefit of an individual component. But in this study, with a very, very complex statistical analysis published in Clinical Nutrition Espen just a few weeks ago, showed clearly that there was no evidence to support antioxidant micronutrient supplementation over and above the recommended daily allowances or present in standard enteral or parental nutrition. And this was, of course, specific to critical care. Now, what about COVID? During the COVID crisis, a lot of clinicians were recommending zinc and a lot of misinformation on the web too. In general, if you look at the COVID guidelines by the National Institute of Health in the US and the Center for Disease Control, the CDC, clearly states that there is no evidence that routine zinc supplements in the general population affects infectivity or severity of COVID. There is no convincing reports correlating infectivity or morbidity or severity or mortality with the pre-morbid levels of zinc. And there is no evidence of benefit of additional supplementation in critically ill patients, again, specifically for COVID. So the panel clearly states that there is insufficient evidence for the COVID-19 treatment guidelines panel to recommend either for or against the use of zinc for the treatment of COVID-19. Some physician feels that the patient may be zinc deficient because of polypharmacy or because of the age or a poor diet, then it is okay to get it, especially enteral, not parental, of course, enteral. And the panel recommends against using zinc supplementation above the recommended daily allowance for the prevention of COVID-19, except as part of a clinical trial. So friends, I hope I have convinced you that mega doses of zinc are not needed in most cases of critical care. And I hope I have kindled your curiosity about this very, very important trace element, zinc. Thank you very much.

zinc

critical illness

zinc deficiency

metabolism

immune system