Selenium in Intravenous Nutrition

GASTROENTEROLOGY 2009;137:S61–S69

Selenium in Intravenous Nutrition ALAN SHENKIN Department of Clinical Chemistry, University of Liverpool, Liverpool, England

Selenium (Se) is an essential nutrient for human beings, with serious consequences resulting from clinical deficiency. It therefore should be provided intravenously to all patients who require parenteral nutrition (PN). Moreover, because the effects of suboptimal status are variable and unclear, this supplementation should be provided from the beginning of the course of PN. In most patients receiving PN at home or after surgery, 60 –100 mcg/day will meet their requirements. Patients who commence PN already depleted in selenium may require more. Critically ill patients or those with severe burns may have higher requirements. There is good evidence that up to 400 mcg/day is beneficial in burn patients, but the evidence is inconclusive regarding the benefit of high-dose selenium in severe sepsis. Where increased Se provision is used, or in long-term PN, selenium status should be monitored by measurement of plasma Se together with a measure of systemic inflammatory response syndrome, such as C-reactive protein. There are many research issues, including which biochemical measurements best reflect tissue function, especially immune function in seriously ill patients, the clinical consequences of suboptimal biochemical Se status, whether high-dose Se improves outcome in critically ill patients, and whether extra Se always should be given with extra intakes of other antioxidants.

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elenium (Se) is required for synthesis of selenocysteine, now known as amino acid 21. The presence of a specific transfer RNA for incorporation of selenocysteine into mammalian proteins confirms the essential role it plays.1 At least 25 selenoproteins exist in human tissues (Table 1). These fall into several classes, antioxidant enzymes (such as the glutathione peroxidases) and other putative antioxidant proteins (such as selenoprotein P and W), enzymes known to have other metabolic functions (eg, the iodothyronine deiodinases that regulate thyroid hormone metabolism and the thioredoxin reductases that regenerate reduced ascorbic acid), and many proteins for which the function is not yet known.2 Although influencing function in all tissues, potentially of special importance clinically are the beneficial effects of Se on immune function and on reducing the risk of viral pathogenesis.3,4 The wide range of biochemical and physiologic functions inevitably has led to a variety of presentations of selenium deficiency. The earliest of these to be recognized

was Keshan disease, a cardiomyopathy in selenium-poor parts of China, which was preventable by provision of oral selenium supplements.5 Since then there have been many case reports of Se deficiency during parenteral nutrition (PN), including fatal6,7 or reversible8 cardiomyopathy, skeletal muscle myopathy,9,10 abnormalities in nails11 and hair,12 and macrocytic anemia.12 An intriguing feature of these deficiency states is that only a small proportion of patients with very poor Se status develop clinical signs of deficiency, and it now is believed that some other agent or stressor is required to provoke symptoms.13 Selenium deficiency has been shown probably to cause mutation of benign Coxsackie virus to a virulent myocarditis-producing form.14 Most of the deficiency states in clinical practice occur in relatively short-term, severe Se deficiency. There is also growing interest in the potential role of Se in many chronic diseases, and whether optimizing Se status in populations with subclinical Se deficiency (ie, poor status but no clinical signs of Se deficiency) may reduce the risk of certain cancers, heart disease, reproductive problems, and cognitive decline.15 This clearly is relevant to the large number of patients receiving long-term home PN. Despite early optimism that selenium supplements may reduce the incidence especially of prostate cancer,16 the results of the recently published Selenium and Vitamin E Cancer Prevention Trial strongly suggest that selenium supplements, with or without added vitamin E, are ineffective in cancer prevention in an otherwise healthy population.17 Nonetheless, further research is needed.

Reliable Assessment of Deficiency or Toxicity A number of tests are available to assess Se status.

Assessment of Deficiency or Adequacy Plasma Se. Total plasma Se is the most widely used test of Se status. It reflects the amount of Se in plasma selenoproteins, the major components being selenoprotein P, which comprises more than 50% of the total, and extraAbbreviations used in this paper: FAO, Food and Agriculture Organization; GSHPx-3, extracellular glutathione peroxidase; ICU, intensive care unit; PN, parenteral nutrition; WHO, World Health Organization. © 2009 by the AGA Institute 0016-5085/09/$36.00 doi:10.1053/j.gastro.2009.07.071

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Table 1. Mammalian Selenoproteins and Their Functions Selenoprotein Glutathione peroxidases (GPXs) GPX1 GPX2 GPX3 GPX4 GPX6 Thioredoxin reductase (TRs)

TR1 TR2 TR3 Iodothyronine deiodinases Types D1 and D2 Types D1 and D3 Selenoprotein P Selenoprotein W Selenophosphate synthetase SPS2

15-kilodalton selenoprotein H, I, K, M, N, O, R, S, T, V

Proposed function Antioxidants, remove hydroperoxides Antioxidant in cell cytosol, selenium store? Antioxidant in gastrointestinal tract Antioxidant in extracellular space and plasma Membrane antioxidant, structural protein in sperm, apoptosis? GPX1 homologue? Multiple roles including dithioldisulphide oxoreductase Detoxifies peroxides, reduces thioredoxin (control of cell growth), maintains redox state of transcription factors Mainly cytosolic, ubiquitous Mitochondrial, ubiquitous Expressed by testes Production and regulation of active thyroid hormones Converts thyroxine (T4) to bioactive 3,5,3-tri-iodothyronine (T3) Converts thyroxine (T4) to bioinactive 3, 3, 5 reverse T3 Selenium-transport protein, antioxidant on endothelium Antioxidant in cardiac and skeletal muscle, and brain?

Synthesis of selenophosphate for selenocysteine and selenoprotein synthesis High levels in prostate Role largely unknown

Adapted from Beckett and Arthur2 and Rayman.3

cellular glutathione peroxidase (GSHPx-3). At a concentration less than 7 ␮g/dL (0.8 ␮mol/L), the plasma concentration correlates with the dietary Se intake. At a concentration greater than 7 ␮g/dL, the tissue concentration of selenoproteins tends to plateau, and it is concluded that Se requirements largely have been met.18 Plasma and indeed tissue measurements of Se need to be treated with some caution because organic Se in the form of selenomethionine may be incorporated nonspecifically into proteins in place of methionine, without reflecting a change in functional selenoproteins.19 In patients receiving inorganic Se as part of PN this would not be an issue. In interpreting plasma Se concentrations in patients, it is important to note that trauma or systemic inflammatory response syndrome causes an obligatory decrease in Se level, and resolution of this leads to an increase in Se.20,21 This seems likely to be owing to transcapillary escape and redistribution of selenoproteins, similar to

the effects of systemic inflammatory response syndrome on plasma albumin level.22 Hence, as with other trace elements, caution must be used in interpreting a single plasma Se result in a patient with ongoing acute illness. Greater accuracy of interpretation can be achieved by measuring plasma C-reactive protein levels at the same time, and monitoring sequential Se concentrations relative to changes in C-reactive protein level.23,24 Plasma glutathione peroxidase. Extracellular GSHPx-3 can be measured in plasma readily and accurately, and responds rapidly to changes in Se intake.25 It therefore correlates closely to plasma Se concentration, although contributing less than 20% to the total plasma Se.26 Red blood cell glutathione peroxidase. GSHPx-1 measurement has been found to correlate more with selenium intake over a longer period relating to the life span of the erythrocyte.25 It therefore reflects status over a longer term than plasma measurements. It is more difficult to measure accurately than plasma GSHPx-1. Selenoprotein P. Selenoprotein P is the major selenoprotein in plasma and is optimized more slowly than GSHPx. It is probably a good marker of adequacy of Se intake,27 but assays are not widely available so it is not used in clinical practice. Hair and nail selenium. Because of limitations in the reliability of sampling and complexity of analysis, measurements of Se in hair and nails are confined to use in a research setting.

Assessment of Toxicity Before its recognition as an essential element in nutrition, Se was noted for its toxic effects in areas of the world with high soil Se content.28 Although at physiologic concentrations Se has antioxidant activity, at very high concentrations it can function as a pro-oxidant and cause oxidative damage to cells and tissues.29 High blood or plasma Se concentration is helpful in assessing potential toxicity, but the lack of relationship with intake at high levels limits the accuracy of such measurements in assessing total exposure. Inorganic selenium (eg, selenite) is more likely to cause toxicity than organic forms (eg, selenomethionine). However, in patients with clinical signs of chronic toxicity (hair loss and brittle nails), plasma concentration is likely to be very high, about 10 times the upper limit of normal.30 If the plasma concentration is greater than 16 ␮g/dL (2 ␮mol/L) for a prolonged period as a result of high intake, this should be monitored and attenuated if possible. From studies in regions of selenosis, a no-observedadverse-effect-level of 800 ␮g/day was identified, including an uncertainty factor of 2 in the calculations leads to a tolerable upper intake level of 400 ␮g/day,18 which is the highest level of daily intake likely to pose no risk of adverse health effects.

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Requirement in Health and in PN Requirement in Health Establishing the dietary requirement for Se has been a controversial process, mainly because of the different approaches used, with the aim either of preventing clinical deficiency symptoms or of optimizing biochemical function.19 The minimum amount thought to be necessary for good health initially was set at 20 ␮g/day, this being the intake in adults in areas where Keshan disease does not occur in children.18 However, a more physiologic approach is to determine the amount necessary to optimize function of the various selenoproteins.18,19 A New Zealand study suggested that to optimize plasma GSHPx requires an average intake of 68 ␮g/day, and allowing for dietary variation this led to an upper estimated requirement of 90 ␮g/day.31 A similar Chinese study suggested 52 ␮g/day.32 Interpretation of these studies is complex,19 but taken overall the data from these studies led to the US recommendation of 55 ␮g/day.18 A more recent report from Australia and New Zealand recommends a dietary intake of 70 ␮g/day in men and 60 ␮g/day in women.33 There is uncertainty whether an intake that achieves 66% of maximal activity of plasma GSHPx, the approach taken by the World Health Organization (WHO)/Food and Agriculture Organization (FAO),34 is sufficient to achieve optimal health. These amounts more readily are achieved in the typical diet in many countries. However, there is a lack of logic in this approach if the objective is to optimize function.19 There is also the question of optimizing all other selenoproteins, but the current data suggest that an intake that achieves a plasma Se concentration of 8.0 –9.5 ␮g/dL (1.0 –1.2 ␮mol/L) will maximize the activities of most selenoproteins.19 It is clear that a wide range of dietary intakes can meet the requirements in different individuals and in different countries, possibly by adaptation to a low intake. Moreover, factors that increase oxidative stress such as smoking or high polyunsaturated fat intake will increase Se requirement. Most dietary selenium is in the form of selenomethionine and selenocysteine, about 90% of which is absorbed. Inorganic Se as selenite or selenate is absorbed more variably, to levels of 50%–90%.19 The form most widely used in PN is selenite, which readily can be incorporated directly into selenocysteine. Although selenomethionine also can be used intravenously,35 it first may be incorporated nonspecifically into other tissue or plasma proteins, and needs to be converted to selenocysteine before selenoproteins can be synthesized. Excess selenium in the diet largely is excreted via the kidney.18

Requirement in PN Defining the requirement in PN is a complex task. First, as noted earlier, there is substantial individual vari-

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ation in requirements for Se in health,4 so supply in PN must at least meet the dietary Reference Nutrient Intake, which as summarized earlier is probably in the range of 55–70 ␮g/day. Some patients may have basal requirements similar to an oral diet in health if they are well and on home PN. However, many will have an increased requirement if they have ongoing or intercurrent disease or are postsurgical because of the increased metabolic and antioxidant needs. Some seriously ill patients will have a very much higher requirement, both to meet the demands of oxidative stress and to replace increased losses. Definitive dose-ranging studies in these different conditions have not been undertaken, and intakes usually have been selected on a theoretical basis, and then assessed by monitoring the status of patients to determine if supply is adequate.

Home PN Most of the studies to evaluate Se requirements during PN have been in patients receiving long-term PN at home because this is the group in which biochemical and clinical evidence of Se deficiency largely has been observed. A summary of studies is given in Table 2. Taken overall the following conclusions can be reached. An intake of 30 –50 ␮g/day meets the ongoing requirements of some patients, probably those with basal requirements, but it is inadequate to correct Se depletion.36,37 An intake of 63 ␮g/day is adequate for the majority of home patients, but about 15% have a higher requirement than this.38 An intake of 85 ␮g/day seems to be sufficient to maintain tissue concentrations in most patients, although some may have even higher requirements.39 There is substantial variability in requirements, possibly related to the ongoing disease process. It also should be noted that not all patients in these studies received the supplements every day; therefore, the average daily intravenous (IV) intake was somewhat less. On the other hand, most patients had some oral intake, although absorption from the oral diet is uncertain. It therefore can be concluded that the IV requirement for most patients on home PN is in the range of 60 –100 ␮g/day, although some patients may require more if they are depleted on commencing home PN.

Patients Postsurgery There have been few reports of Se status during typical postsurgery PN. Two reports suggested that 32 ␮g/day was adequate to maintain Se status over short PN feeding periods,40,41 and more variable amounts prevented the decrease in Se usually found after surgery.42,43 Such patients are likely to have requirements higher than basal, to meet the increased oxidative stress of hypermetabolism. They also may have increased losses via fistulae or aspirates. It can be concluded that requirements are at

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Table 2. Studies on Selenium Supplementation in Home PN Study Lane et

al,58

1987

Number of patients 7

Malone et al,36 1989

14

Mansell et al,37 1989

11

Rannem et al,59 1993

9

Forbes and Forbes,38 1997

32

Reimund et al,60 2000

22

Howard et al,39 2007

8

Intake Se ␮g/d 80 followed by 160

Duration of Intravenous Nutrition

Results

Notes

1 month each level

Plasma Se increased but not Short-term study normalized 32 3–13 mo 8/14 low plasma Se at end of study period 40 13–280 d Maintained but did not correct Se status 200 followed by 100 4 and 8 mo Plasma Se level higher than Given as bolus healthy controls IV injection 63 64 mo (range, 1–175 mo) 5/32 low plasma Se at end of study 43, women; 66, men 18 mo (range, 1–132 mo) Plasma Se below reference Range, 20–120 in many patients ␮g/day 85 14 y (range, 2–21 y) Normal tissue content of Se in heart and liver, some low results in skeletal muscle and kidney

least as high as those on home PN (60 –100 ␮g/day), with some having a greater requirement.

Critically Ill Patients: Burns, Sepsis, and Trauma Patients in intensive care, especially if septic, may have substantially increased requirements as a result of markedly increased oxidative stress and losses through drains, dialysis, or through the wound. Patients with severe burns require about 210 ␮g/day to maintain balance44 and to compensate for the increased losses through the wound provision of 315–380 ␮g/day IV to such patients has been shown to reduce nosocomial pneumonia45 and to increase skin trace element content and improve outcome.46 After bone marrow transplant, patients received 120 ␮g/day with satisfactory biochemical response.47 Patients with sepsis in intensive care may benefit clinically from 9 days of high selenium intake (535, 285, and 155 ␮g/day for successive 3-day periods).48 A more recent multicenter study from the same group found that 1000 ␮g/day for 14 days improved outcome in the most severely ill patients in the intensive care unit (ICU).49 Other studies have not confirmed these results,29,50 and although these data are encouraging, further studies of high-dose selenium in the most severely ill patients are required.51 It can be concluded that such patients should minimally receive a typical PN intake (60 –100 ␮g/day), but it would seem safe to give up to 400 ␮g/day (the upper limit for selenium) for 2–3 weeks in severe burns and the most critically ill septic patients.52,53

Age and Selenium Requirements There appears to be little effect of age on Se requirements in health, and the Dietary Reference Intake is the same from adolescence until old age.18 For infants and children, adequate intakes/recommended dietary in-

takes for selenium in the oral diet have been set at 2.1–2.2 ␮g/kg/day (in the United States), at 12–15 ␮g/day (in Australia), and at 6 –10 ␮g/day (FAO/WHO) for those aged 0 –12 months; and within a range of 20 – 40 ␮g/day (in the United States), at 25–50 ␮g/day (in Australia), and at 17–32 ␮g/day (FAO/WHO) for those aged 1–13 years.18,54,55 The FAO/WHO recommendations are lower because they are based on 66% of maximal GSHPx activity. The report by Greene et al56 is consistent with the earlier-described recommendations, recommending an IV intake of 2 ␮g/kg/day, for preterm and term infants, and also for children. This was based on the normal oral intake of a breast-fed infant of approximately 2.5 ␮g/kg/ day, together with the expected absorption of about 80%. This is also in keeping with the approximate accretion rate of selenium of 1 ␮g/kg/day in preterm infants.57

Summary Recommendations Summary recommendations are as follows: first, selenium should be provided IV to all patients who require PN. Second, because the effects of suboptimal status are variable and unclear, this supplementation should be provided from the beginning of the course of PN. Third, for patients receiving PN at home or after surgery, 60 –100 ␮g/day will meet requirements in most patients. Patients who commence PN already depleted in selenium may require more. Selenium should be infused slowly over the course of the infusion of the other PN solutions. Fourth, critically ill septic patients or those with severe burns may have higher requirements. There is good evidence that up to 400 ␮g/day is beneficial in burn patients, but the evidence is inconclusive regarding the benefit of high-dose selenium in severe sepsis. Fifth, where increased Se provision is used, or in long-term PN, selenium status should be monitored by measurement of plasma Se together with a measure of systemic inflam-

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matory response syndrome, such as C-reactive protein. Sixth, key research issues include the following: which biochemical measurements best reflect tissue function, especially immune function in seriously ill patients, what are the clinical consequences of suboptimal biochemical Se status, does high-dose Se improve outcome in critically ill patients, and should extra Se always be given with extra intakes of other antioxidants?

Question and Answer Session DR HOWARD: Alan, you have told us that you think that the oral dose is around 50 –75 ␮g/day and the parenteral dose perhaps is 60 –100 ␮g/day. I want to just clarify what I think could explain this difference. We’re infusing sodium selenite and this has to go to the liver and attach itself to cysteine to become metabolically effective. All of us know that with parenteral nutrition, we are infusing into the systemic rather than the portal circulation so the first pass to the liver is only 50% to 75% of the dose. Twenty-five percent is seen immediately by the kidneys. So don’t you think it’s rational at least that the parenteral dose needs to be 25%–30% more? DR SHENKIN: I think that’s a very reasonable suggestion. I’ve not actually heard it expressed in exactly that way before, but certainly you’re right that a substantial amount of infused selenium is lost in the urine. That is the main route of selenium excretion and, therefore; it is entirely probable that giving selenium systemically, a proportion will end up immediately in the urine. DR SHULMAN: The importance of peroxidants in pediatric liver disease has been mentioned earlier. There’s some recent case reports suggesting that antioxidants like cysteine could potentially reverse cholestasis in children. The question I have is in the adult trials with selenium, is there any evidence of an impact on liver function? DR SHENKIN: I don’t think so. I don’t think these trials have shown any improvement in liver function. In my final recommendation I did not give the recommended doses for selenium in small children, which are 2 mcg/kg/day. There’s good evidence that this dose maintains selenium status in small children. I’ve not heard of any specific selenium benefit to pediatric liver function. DR BUCHMAN: Alan, if we measure whole-blood selenium versus serum versus plasma, are we measuring just the immediate intake or selenium stores? Is there a role for the measurement of a selenium enzyme, like glutathione peroxidase for example? DR SHENKIN: If you measure plasma selenium, you’re measuring primarily selenoprotein P, a bit of glutathione peroxidase and about 20 other small proteins which are floating around in plasma. In serum and plasma the concentrations of selenium are the same. Whole-blood selenium contains a much higher proportion of glutathione peroxidase from red cells, and hence

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it will reflect to a greater extent the selenium intake over the past 3-4 months. DR BUCHMAN: Is there a role for measurement of glutathione peroxidase as a functional test of selenium or is measuring plasma or serum selenium sufficient? DR SHENKIN: That is one of the big questions. Almost certainly there is a role for measuring plasma glutathione peroxidase because it is a functional marker. The body has made glutathione peroxidase, so it’s done something with the selenium. Part of the difficulty with the very high doses of selenium such as 1000 mcg/day which are sometimes given is we’ve no idea where the selenium is going. We know that all you need is about 50 mcg/day to make selenoproteins so what is the extra doing? Plasma glutathione peroxidase is regarded as the best available functional marker. But some workers have looked at thioredoxin reductase, for example, and at the deiodinase enzymes. And you can evaluate antioxidant activity by looking at excretion or production of MDA, seeing how effective the antioxidant pathway is with particular doses of selenium. Thus, I think there are a number of functional activities which can be looked at, but few studies have looked at them together and compared them to see which is best in a particular situation. DR BERGER: In patients who are acutely ill and have low plasma albumin, for example, burn patients, we’re feeding them enterally and we give doses of selenium of around 500 mcg as a very slow infusion. We have done studies giving the selenium fast or slow and demonstrated higher or lower urinary selenium excretion. So the rate of delivery is an important issue when you’re giving selenium in large doses. DR JEEJEEBHOY: I’m a little confused because it seems to me your data shows the only situation in critical illness where selenium is beneficial is as a cocktail for burn patients. That is the only case where statistical benefit has been demonstrated. DR SHENKIN: The most recent German study was giving only selenium in very high doses and in the subgroup analysis there was a significant benefit. DR JEEJEEBHOY: But that was a subgroup, which is really not kosher in terms of clinical trials. DR SHENKIN: I’m just trying to be fair. DR JEEJEEBHOY: But on the other hand the trials using the antioxidant cocktail in burn patients did show consistent benefit. DR SHENKIN: That is correct. To me, it makes much more sense that if you’re giving high doses of any nutrient, then you have to ensure that it’s proportional to many of the other nutrients, so you’re not causing a nutrient imbalance. But that’s theoretical and there is a pointer from the German study, even if we say it is not absolutely clean. There is enough information to suggest this study should be repeated with selenium alone. DR JEEJEEBHOY: There’s a study in Crohn’s disease patients with diarrhea, showing increased selenium

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losses. Do you think we should adjust for that in such patients? DR SHENKIN: Nobody has done the balance studies that you’ve done for zinc and copper so assessing the amount you might give extra for severe diarrhea or severe bowel losses is not known at this stage. DR SHIKE: You need relatively low levels of selenium to saturate glutathione peroxidase. Only if we assume that selenium has other major functions beyond the activity of the glutathione peroxidase, can we justify raising it to high levels. In the absence of a clear physiological basis and in the presence of non-kosher data (I am an expert on kosher as you know), how can one justify a recommendation to treat this sick patient with this amount of selenium. We are now frequently crossing the border between nutrition and pharmacologic action, all of a sudden, practically every nutrient cures cancer, will bring patients back from sepsis, will prevent the inflammatory response. I think in the nutrition field we have to be somewhat modest and careful. It’s mindboggling that you do a subgroup analysis after you didn’t get the result you wanted, and then you get something that helps your hypothesis! This is not how it should be done and I think we have to be very reluctant about making recommendations based on studies like this. DR SHENKIN: I’m not making that recommendation. I’m just the messenger. But I think it’s important to distinguish 2 different situations. Firstly, if you take Mette Berger’s burn patients, she has shown clearly that these patients lose large amounts of selenium through the wound over a 1- to 2-week period, and she’s calculated the amount of selenium which needs to be given back to prevent these patients becoming selenium deficient from a nutritional point of view. First she gave about 350 mcg/day. It didn’t appear to be quite enough and she upped it to 500 mcg/day. There’s logic behind this approach and she’s demonstrated that patients do better when their selenium is restored. The patients also receive high intakes of zinc, copper, and vitamin E. So I think burns are one group where these high intakes can be justified. However, I am 100% behind you when we look at the critically ill patients in the ICU. These patients have a low plasma selenium largely because of redistribution, because of the acute phase response, and movement of selenoproteins out of the plasma. I think it’s fine to suggest giving 100 mcg/day to this patient. Maybe give a bit more if they have large losses from fistulae or from dialysis, but I can’t see going above 400 mcg/day. That is the dose which is regarded as being the safe upper limit, although conceivably higher doses might be safe in the short term. So if you’re an absolute enthusiast, who feels that you really want to give a lot of selenium, then 400 mcg or somewhere in that order for 2 to 3 weeks may be acceptable because it is within the limits of safety and unlikely to do harm. That is where the value of 400 mcg

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has come about from. It is my recommendation for patients who are not burn patients but are in the ICU. Any higher recommendation must await the results of future studies. DR BIESALSKI: In regard to establishing higher requirements, I think it would make sense to look at the activity of the manganese SOD and copper SOD because they are up-regulated and overexpressed in oxidative stress. Interestingly, copper SOD appears in alveoli fluid and there is no catalase present, so you may need the higher doses of selenium and up-regulation of the GPx system to deal with the hydrogen peroxide and lipid peroxides formed by the Mn SOD in extreme oxidative stress. I think it would be possible to assess the concentration of manganese and the activity of the Mn SOD under critically ill conditions. This could tell us whether there is a need for higher selenium or not. Also, you have polymorphisms, widely distributed, in about 5%–7% in the European population, with an extremely high Mn SOD. I do not know if there are any studies that have looked at manganese and selenium in the critically ill. DR SHENKIN: I don’t think so, not that I’m aware of. But I think you make an important point. It gets back to the point which Moshe was making, that there are maybe some biochemical pathways out there that we don’t really know about. As I’ve mentioned already, there are other selenoproteins for which we do not know the function, so there’s a lot of work to be done to clarify which of these proteins is important and for which functions. DR HARDY: In the critically ill, if you look at the meta-analyses that Daren Heyland and most recently Alison Avenell in Scotland have done, it’s only selenium, not the antioxidant cocktails, that show an improved survival. We and others have shown that in countries like Uruguay and New Zealand where the general population has a low selenium status, compared for example to the United States, then if these people land up in intensive care, they immediately show a 20%–30% reduction in plasma selenium. In our opinion it is important to correct that deficit. There is still debate about what the optimum dose is, but I think it’s important to bring the level of selenium up in a few days. In our experience a positive effect depends on giving a bolus within the first few hours followed by a continuous infusion over a couple of weeks. Just continuous infusion is not effective. I’d be interested in Dr Forceville’s comments on this issue. DR SHENKIN: I broadly agree with you. There are differences in the protocols that have been used but I think we’re still left with the recognition that we do not know whether correcting the plasma concentration is beneficial. If I were to say to you, “this same patient in intensive care has got a serum iron of 2 ␮mol/L, and since the normal range for serum iron is 15– 40 ␮mol/L, let’s give this patient extra iron to get his iron back to normal,” you’d say “don’t be crazy.” The plasma iron has

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fallen because it’s a protective mechanism. The fact is we do not know if selenium has been moved from the plasma into the interstitial fluid, or it’s been moved from the plasma into the liver, or into other organs where it’s needed at this time. And we do not know the beneficial effects of this movement, and whether more selenium is needed to enhance them. DR FORCEVILLE: I will make 3 comments. Our studies look only at blood levels. We observed the decrease in blood selenium in septic shock. We know very little about what’s happening in the tissues. Septic shock is 2 events. The first event is the acute dysfunctioning of the endothelium, and selenoprotein P was shown by Burk in Philadelphia to bind to the endothelium. This may have a protective function. The second event is immunodepression. Mette Berger has shown that a multi-antioxidant formula can improve these immune defects. Finally, our interest is in giving selenite, not selenium. Selenite has been shown by Stedman at National Institutes of Health to block NF-␬B from binding to DNA. We have developed a sheep peritonitis model and shown that improved survival depends on achieving a high level of selenite in the first 24 hours. We think this is more a pharmocotherapy effect and not related to selenium trace element effect. Obviously, there is a potential for selenite toxicity but this is short-lived. Selenite acts like an oxidant while selenium is an antioxidant. DR SHENKIN: Dr Forceville and I largely agree, I think the important thing is there may be other mechanisms, such as the effects of selenoprotein P on vascular endothelium. That is an important possible mechanism which ought to be explored further. I think also that animal models might help because studies in intensive care are so difficult. Using a sheep model, for example, where you get rid of most of the other variables, might actually be very helpful and I look forward to seeing the results of Dr Forceville. DR LIPMAN: As a patient, if I wind up in the ICU I want to walk out on my feet rather than be taken out on a stretcher feet first and taken down to the morgue, also I’d like to walk out with a reasonable cost. What I’d like to know is that the interventions that are being done to me, on me, hopefully for me, have clinical efficacy and outcome benefit. It struck me listening to every presentation today, how much we are talking about surrogate end points, either plasma levels, or what is the appropriate level of selenium, or about various enzyme markers. Perhaps some of the final thoughts for today could be about the clinical outcome and clinical benefits rather than laboratory levels. Being in this field for many, many years and being described as one of the curmudgeons of the field of nutritional support, I remember that nitrogen balance was going to save us, and parenteral nutrition was going to save the world ,and then hypocaloric feeding, and then glutamine, and then RNA, and then om-

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ega-3 fatty acids, and now we’re into antioxidants. And we keep saying the same thing with a different subject matter. DR HOWARD: So, Alan, are there hard clinical end points that would get him out on his feet? DR SHENKIN: No, I think it was probably the first comment I made this morning, which said exactly the same thing, and I agree entirely with what you said, Dr Lipman. I’m a clinical biochemist. I spent my life running a clinical biochemistry laboratory and being involved in our hospital’s clinical nutrition team. And although there is a role for laboratory tests, I’ve spent most of my working life trying to stop people doing unnecessary tests on patients who are receiving nutritional support because laboratory tests are only as good as your ability to interpret them. And if you can’t interpret them, then there is no point in doing them. What we do need to know is which tissue functions can the laboratory help you to identify. Immune function, we keep coming back to markers of immune function. I think the immunologists have failed us completely, by not giving us tests of immune function, which tell us something about a patient’s progress and a patient’s ability to withstand an infectious challenge. And we need tests of muscle function. Khursh did this years ago but sadly it never took off as a clinical marker providing a way of assessing muscle strength. Brain function, surely there are ways of assessing brain function and how nutrition improves it. Function is the way forward, we have to find ways to look at this. There are lots of different organ systems, where it should be possible to quantify, investigate, and relate changes in function to provision of micronutrients, without necessarily going to a lot of cost of performing unnecessary laboratory tests. So I will be delighted when the monitoring protocols for patients on PN tell us about specific organ functions. DR HOWARD: Shall we let the last word come out of Dr Jeejeebhoy? DR JEEJEEBHOY: Well, I totally understand Dr Lipman saying that he’s one of those that believes the only test that’s valid is the one which looks at mortality. But this can be reductio ad absurdum, let’s take, for example, iron, we know that if you don’t give iron, people will get anemic, and if we wait long enough, the anemia will kill the patient. So we shouldn’t try to prove that, doing a control clinical trial in which we give no iron until the patient dies of anemia. We recognize there are certain situations in which the levels and the maintenance of levels is life giving. The same applies with zinc, it’s been shown in a group of patients very clearly that when zinc is not provided patients get an acquired form of acrodermatitis enteropathica, a very dangerous disease which people die from. And now we know that we have to give a certain amount of zinc, so the balance data does make sense in that situation. I think the same applies, for example, to Dr Berger’s studies because there’s a real

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relationship between actual losses from a huge denuded surface and the need for giving more nutrients, and clearly there is a difference in outcome. So I think it’s an ethical issue, taking diseases which we know occur and can be life-threatening and recognizing how to improve outcome. We need laboratory tests. Trials have to be adjusted according to what we think are physiological requirements and tempered by what we know of disease.

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Received May 12, 2009. Accepted July 29, 2009. Reprint requests Address requests for reprints to: Alan Shenkin, MD, Department of Clinical Chemistry, University of Liverpool, Liverpool, England L69 3GA. e-mail: [email protected]. Conflicts of interest The author discloses no conflicts.