Volume 21, Issue 1, Pages 44-48 (February 2010)

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ABSTRACT

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Trace elements

Summary

Trace elements are essential micronutrients. They are at present seldom considered in the routine management of critical care patients but are immensely important for redox balance and antioxidant function as well as the prevention of clinical deficiency states. Intensive care patients are at risk of both overt and sub-clinical trace element deficiencies and studies show that supplementing critically ill patients with trace elements may offer them a mortality benefit. This article reviews those trace elements relevant to critical care and the research that has been performed on them to date.

See Commentary, page 49.

Keywords: Trace elements, Critical care, Antioxidants, Nutrition

Article Outline

• Summary

• 1. What are trace elements?

• 2. Why are they important for normal health?

• 3. How much do we normally need?

• 4. What are normal levels?

• 4.1. Monitoring guidelines

• 5. What happens in critical illness?

• 5.1. Deficiency

• 5.2. Toxicity

• 6. What are the consequences of deficiency or toxicity?

• 6.1. Selenium

• 6.2. Copper

• 6.3. Zinc

• 6.4. Chromium

• 6.5. Molybdenum

• 6.6. Iodine

• 6.7. Cobalt

• 6.8. Manganese

• 7. Is there any evidence supporting pharmaconutrition in critical care?

• 8. Are there any administration guidelines for critical care?

• 9. Conclusions

• Appendix A.1.

• Appendix A.2.

• References

• Copyright

1. What are trace elements?

Trace elements are dietary minerals required in minute quantities for normal physiological function. They are mostly structural components of enzymes or cofactors whose roles include the prevention of nutritional deficiencies, immune functions, regulation of gene expression, antioxidant defence, and prevention of chronic diseases. They are generally defined as each constituting less than 0.01% of body mass and collectively comprise<1% of total body mass. These essential micronutrients are absorbed from the gastro-intestinal tract and stored in the liver and include: chromium, cobalt, copper, fluorine, iodine, iron, manganese, molybdenum, selenium and zinc (see Table 1).

Table 1.

Trace elements.


Trace Element	Essential to man	Risk of deficiency in critical care and with long-term TPN	Risk of toxicity with organ dysfunction and with long-term TPN	Interest in supra-physiological dosing in critical care
Arsenic (As)	?
Bromine (Br)	??
Cadmium (Cd)	??
Chromium (Cr)	✓	✓	✓
Cobalt (Co)	✓
Copper (Cu)	✓	✓	✓	✓
Fluorine (F)	✓
Iodine (I)	✓
Iron (Fe)	✓		✓
Lead (Pb)	??
Lithium (Li)	?
Manganese (Mn)	✓		✓
Molybdenum (Mo)	✓	✓
Nickel (Ni)	?
Selenium (Se)	✓	✓		✓
Silicon (Si)	?
Tin (Sn)	??
Vanadium (V)	?
Zinc (Zn)	✓	✓		✓

Table 2.

Reference Nutrient Intake (RNI).


Trace element		selenium	copper	zinc	chromium	molybdenum	iodine	manganese
ASPEN: JPEN6	Enteral	55mcg	0.9mg	11mg	30mcg	45mcg	150mcg	2.3mg
ASPEN: JPEN6	Parenteral	20–60mcg	0.3–0.5mg	2.5–5mg	10–15mcg	not routinely added	not well defined	60–100mcg
FSA/COMA7		60–75mcg	1.2mg	5.5–9.5mg	25mcg	not set	0.07–0.14mg	Not set
WHO8		40mcg	Not set	4.2–14mg	Not set	0.1–0.3mg	150mcg	Not set
US9		40–55mcg	0.7–0.9mg	12–15mg	25–35mcg	34–45mcg	150mcg	1.8–2.3mg

2. Why are they important for normal health?

Specific micronutrient deficiencies cause reproducible structural or biochemical deficits corrected by supplementation of the relevant element. However, overt nutritional deficiencies are rare in developed countries, even in the context of critical care.

The Food Standards Agency UK Dietary Survey 2003 found the intake of some trace elements (iron, copper, iodine) were well below the RNI (Reference Nutrient Intake) for a number of demographic groups and when compared with the population survey from 1986/7 there had been a significant reduction in consumption of copper, iodine and zinc from foods.1 Studies have also demonstrated that the EU population is selenium deficient, with an insufficient estimated daily intake and reduced plasma levels.2, 3, 4, 5

Case reports indicate that overt trace element deficiencies occur due to malabsorption syndromes, poor diet (e.g. alcoholics), long-term TPN administration, or genetic predisposition (e.g. inborn errors of metabolism). The UK general population is at risk from sub-clinical trace element deficiencies, especially the elderly, those institutionalised and patients with chronic health problems; it is particularly common in, and relevant to, critical care and maybe masked by co-existing disease.

3. How much do we normally need?

The Reference Nutrient Intake (RNI) for a number of trace elements are presented in Table 2.

4. What are normal levels?

The measurement of trace elements is complicated and interpretation of results should be done in conjunction with consideration of the clinical, nutritional and other biochemical information available. Trace element assays are susceptible to contamination and there are uncertainties in selecting the component to measure; laboratory tests lack sensitivity and specificity and there is often a long turnaround time (approximately 1 week). Measuring enzyme function maybe a more clinically useful tool for some trace elements in critical care as blood levels of trace elements vary with the acute phase reaction due to redistribution, changes in protein binding, as well as utilisation. Trace elements can be measured from whole blood or serum, urine, and a variety of tissues. Reference ranges will to some extent depend on the specific laboratory (Table 3).

Table 3.

Trace element reference ranges.10


Trace Element	Serum level	Measurement method	Other	Acute phase response
Selenium	0.9–2μmol/l	Atomic absorption spectrometry	Whole blood glutathione peroxidase 20-70U/g Hb	Levels fall
Copper	10–22μmol/l	Inductively coupled plasma/emission spectrometry	Caeruloplasmin 0.2–0.6g/l	Levels rise
Zinc	12–18μmol/l	Inductively coupled plasma/emission spectrometry	–	Levels fall
Chromium	–	Graphite furnace/atomic absorption spectrometry	Urine<6nmol/mmol creatinine. Improvement in glucose tolerance test after supplementation	–
Manganese	–	Graphite furnace/atomic absorption spectrometry	Whole blood 70–280nmol/l	–

4.1. Monitoring guidelines

Trace element requirements in critical illness are unknown. The National Institute for Clinical Excellence (NICE) recommend measuring selenium levels if there is a risk of depletion and subsequent testing depending on that result. Baseline copper and zinc levels are also recommended followed by levels every 2–4 weeks, as deficiency is common especially when there are increased losses. NICE also recommend manganese levels to be measured every 3–6 months in patients on home TPN due to the risk of toxicity.11 Sequential testing with the results reviewed in conjunction with inflammatory markers (e.g. CRP) will be most meaningful on the ICU and will prevent extremes of provision.

5. What happens in critical illness?

In practical terms for critical care the trace elements can be divided into 3 groups:

1.Risk of nutritional deficiency with critical illness and/or long-term TPN e.g. selenium, chromium, copper, zinc, molybdenum.

2.Risk of toxicity with TPN e.g. manganese (especially in liver disease).

3.No identified concerns e.g. iodine - neither deficiency nor toxicity reported.

5.1. Deficiency

Critical illness is a hypermetabolic state and trace element requirements are increased especially for use in redox reactions. Patients are at risk of deficiency for a number of additional reasons:

•Reduced trace element status on admission to critical care due to the background deficiency of our general population, chronic illness, alcohol abuse, and the elderly.

•Increased losses especially through burns, trauma and haemo- or peritoneal dialysis; studies on trace element kinetics in haemofiltration have demonstrated significant losses of selenium and copper, and losses to a lesser extent of chromium, manganese and zinc.12, 13, 14 Gut losses also occur through gastric aspiration, diarrhoea and fistulae and critical illness per se is associated with increased urinary losses of zinc, copper and iron and this maybe influenced by drug choice and preparation.15

•Reduced provision due to an inability to receive adequate calorific intake (poor enteral absorption, drug therapy, surgery and procedures requiring starvation periods) and inadequate prescriptions.

○Enteral: Most enteral feeds in common usage in the UK16 adequately provide the majority of essential trace elements if the feed is able to be given at sufficient calorific rates (Appendix A.1). The bioavailability of trace elements from feed is influenced by other feed-related factors e.g. the presence of fibre reduces zinc absorption.

○Parenteral: Although there are Total Parenteral Nutrition (TPN) formulations available which contain added trace elements the majority of formulations used “off the shelf” in current clinical practise16 do not and require the prescription and addition of specific preparations (e.g. Additrace® or Decan®) (Appendix A.2). There are clearly problems with this process as trace element deficiencies have been reported in patients on long-term TPN identifying a failure of care. This is unacceptable and clinicians must recognise the potential for acquiring a clinical deficiency and supplement trace elements before one occurs.

5.2. Toxicity

•Manganese and copper can both be toxic in liver dysfunction. This is a particular problem with manganese and TPN-associated cholestasis. Specific trace element deficiencies should be supplemented individually to prevent over-supplementation of manganese, chromium and iron with use of combination preparations.17

•Other problems reported are secondary to the competitive interactions of trace elements and include case reports of excessive zinc supplementation causing a clinical copper deficiency presenting with anaemia and neutropaenia.18

6. What are the consequences of deficiency or toxicity?

6.1. Selenium

Selenium has structural and enzymatic roles. It is predominantly incorporated into selenoproteins which are vital for normal health and reproduction. It is necessary for immunocompetence; antioxidant function; testosterone metabolism; sperm structure hence motility; and thyroid hormone metabolism. Overt selenium deficiency may cause a cardiomyopathy (Keshan disease) or an osteoarthropathy (Kashin-Bek disease), as well as skeletal muscle myopathy. Sub-clinical deficiency predisposes to cardiovascular disease, mood disorders and cancer, as well as impacting on immune and antioxidant function. Selenium toxicity is similar to arsenic poisoning and causes abdominal pain, nausea and vomiting, irritability, parasthesia, and hyper-reflexia; it may lead to shock, ARDS (Acute Respiratory Distress Syndrome) and death.

6.2. Copper

Copper is an essential component of many enzymes (e.g. superoxide dismutase (SOD), cytochrome oxidase) and a co-enzyme. It is required for free radical detoxification, the synthesis of haem, wound healing, antioxidant defences, immune function, and collagen synthesis. Large amounts of copper are stored in the liver so deficiency is rare except in long-term TPN and malnourishment. Copper deficiency results in haematological deficiencies: anaemia, neutropaenia, and thrombocytopaenia, osteopaenia with bone and joint abnormalities, psychomotor retardation, and skin depigmentation. Copper intake should be reduced in liver failure and cholestasis as it is mainly excreted in bile and may accumulate leading to toxicity. Copper toxicity presents as a haemolytic anaemia, gastroenteritis, and Wilson's disease with Kayser-Fleisher rings, hepatitis, cirrhosis, personality and behavioural changes, and cognitive impairment.

6.3. Zinc

Zinc is a component of over 200 enzymes important for immune function and with catalytic and structural roles. It is necessary for wound healing, regeneration of new cells, and acid-base balance as a component of carbonic anhydrase. Zinc deficiency results in poor wound healing, reduced work capacity of respiratory muscles, immune dysfunction, anorexia, diarrhoea, hair loss, dermatitis (acrodermatitis enteropathica), and depression. Zinc toxicity from chronic over-supplementation causes a sideroblastic anaemia.

6.4. Chromium

Chromium is involved in glucose metabolism and insulin activity. Chromium deficiency presents in a similar manner to type II diabetes with impaired glucose tolerance, neuropathy, elevated plasma fatty acids and atherosclerosis; it has only been reported in patients receiving long-term parenteral nutrition. Chromium is mainly excreted via the kidneys and therefore should not be supplemented in patients with renal failure. Chromium toxicity is an industrial disease in welders causing a contact dermatitis; fume inhalation results in lung diseases including malignancy.

6.5. Molybdenum

Molybdenum is a cofactor for various enzymes involved in hydroxylation reactions, including aldehyde oxidase, xanthine oxidase/dehydrogenase and sulphite oxidase. Molybdenum deficiency may occur in long-term TPN administration if molybdenum is not supplemented. There is no well-described deficiency syndrome although seizures and psychiatric phenomena may occur. Molybdenum toxicity causes a physiological copper deficiency. Respiratory symptoms may occur by fume inhalation.

6.6. Iodine

Iodine is essential for normal thyroid gland function and is thereby required for normal metabolism, growth and development. Deficiency results in goitre and hypothyroidism.

6.7. Cobalt

The only known function of cobalt is as the metal component of vitamin B12, hence deficiency of cobalt is revealed as vitamin B12 deficiency.

6.8. Manganese

Manganese is needed for carbohydrate metabolism and has an antioxidant role as a component of mitochondrial SOD. Manganese requirements are very low and deficiency is rare even in patients fed on long-term TPN. Toxicity has been described particularly in patients with liver disease, but also from cholestasis associated with long-term TPN, causing psychiatric disorders and Parkinsonian features. Products with a low manganese content should be available for all critical care patients and manganese-free TPN prescribed for liver patients.17

7. Is there any evidence supporting pharmaconutrition in critical care?

Following demonstration of the reduction in trace element levels, and in view of their antioxidant functions, a number of groups have looked at supplementing critical care patients with trace elements in conjunction with other antioxidants including glutamine, N-acetyl cysteine and vitamins (Table 4). The studies have included heterogeneous groups of patients and have mainly studied small numbers. Trace element doses range from provision of the RNI to supra-physiological dosing. In general, there appears to be benefit from supplementation, demonstrated by improvements in laboratory analysis of markers of antioxidant function, improvements in scoring systems, reduction in infection rates and possibly reduced mortality. On meta-analysis high dose selenium supplementation looks most likely to offer a mortality benefit19, 20 and zinc supplementation is associated with a non-significant reduction in mortality.21

Table 4.

Characteristics of trace element supplementation studies.


Trial	Critical Illness	No. of Patients	Micronutrients	End point
Kuklinski 199124	Pancreatitis	17	Selenium	Mortality
Young 199625	Head injury	68	Zinc	Neurological outcome Mortality
Zimmerman 199726	SIRS	40	Selenium	Mortality
Berger 199827	Burns	20	Selenium, Copper, Zinc	Infection Length of Stay
Angstwurm 199928	Sepsis/SIRS	42	Selenium	Blood antioxidant status Mortality
Porter 199929	Trauma	18	Selenium	Infection Length of Stay
Berger 200130, 31	Trauma	32	Selenium, Copper, Zinc	Blood antioxidant status Thyroid hormone metabolism
Berger 200432	Burns	21	Selenium, Copper, Zinc	Blood antioxidant status Skin protein turnover
Berger 2006*33	Burns	41	Selenium, Copper, Zinc	Blood antioxidant function Infections (pneumonia)
Mishra 200734	Sepsis/SIRS	40	Selenium	SOFA score, Mortality Antioxidant function
Angstwurm 200735	Sepsis/SIRS	249	Selenium	Mortality
Forceville 200736	Septic shock	60	Selenium	Time to vasopressor withdrawal Mortality
Berger 200837	Cardiac surgery, major trauma, SAH	200	Selenium, Zinc,	Organ dysfunction
Beale 200838	Sepsis	55	Selenium, Zinc	Organ dysfunction (SOFA)

*Combination of Berger 199827 and Berger 200432 papers.

The Canadian meta-analysis of combined vitamins and trace elements (selenium, copper and zinc) demonstrated a reduced mortality and the group suggested their use should be considered in critically ill patients. Differing regimens were used in this heterogeneous population and the optimal composition and dosing is unknown. There were no concerns re feasibility or cost. Two studies are in progress and may provide more conclusive evidence regarding supplementation.22, 23

8. Are there any administration guidelines for critical care?

Nutrition societies provide general guidance on trace element requirements (Table 2). In practical terms trace elements should ideally be given separately to avoid interactions and slowly to minimise losses through increased excretion.4 Clarification is required as doses and route of administration in the studies vary widely: selenium 100–1000mcg, zinc 10–40mcg, copper 1.3–3.75mcg.

9. Conclusions

Routine supplementation of trace elements is important and at a minimum should provide recommended daily allowances and correct deficiencies. It should occur with every prescription of enteral and parenteral nutrition as a basic standard of care for every patient. Micronutrients should be given from the first day of artificial nutritional support and subgroups at particular risk of deficiency should be identified. Whether meeting normal requirements is sufficient or pharmacological manipulation is more beneficial is unknown, and more conclusive evidence is required before pharmaconutritional therapy can be recommended as a routine.

Appendix A.1.

Trace element content of enteral feeds commonly used in critical care.


Trace element	Selenium		Copper		Zinc		Chromium		Molybdenum		Iodine		Manganese
Feed	mcg/100ml	daily intake	mg/100ml	daily intake	mg/100ml	daily intake	mcg/100ml	daily intake	mcg/100ml	daily intake	mcg/100ml	daily intake	mg/100ml	daily intake
Nutrison Standard	5.7	85.5	0.18	2.7	1.2	18	6.7	100	10	150	13	195	0.33	4.95
Nutrition Multifibre	5.7	85.5	0.18	2.7	1.2	18	6.7	100	10	150	13	195	0.33	4.95
Fresubin Original	6.7	100.5	0.13	2	1.2	18	6.7	100	10	150	13.3	200	0.27	4
Jevity	5.4	82.5	0.2	3	2.3	34	12	180	15	225	15	225	0.5	5.7
Osmolite 1cal	3.8	57	0.15	2.3	1.7	26	9.3	140	12	175	11.6	175	0.38	5.7
Nepro	7.4	74	0.21	2.1	2.6	26	12.5	125	7.9	79	16	160	0.21	2.1

(Daily intake based on 1500ml except Nepro 1000ml).

Appendix A.2.

Trace element content of parenteral feed supplements.


Trace element	Selenium	Copper	Zinc	Chromium	Molybdenum	Iodine	Manganese	Other
Feed μmol/l
Nutracel 400			80 (5mg)				10 (550mcg)
Nutracel 800			40 (2.5mg)				5 (275mcg)
NuTRIflex Lipid peri/plus/special			24/24/32 (1.5/1.5/2mg)
Supplementary preparations μmol/amp
Additrace® 10ml ampoule	0.4 (32mcg)	20 (1.2g)	100 (6.5mg)	0.2 (10mcg)	0.2 (19mcg)	1 (127mcg)	5 (275mcg)	Fe, F
Decan® 40ml ampoule	0.89 (70mcg)	7.55 (0.5g)	153 (10mg)	0.29 (15mcg)	0.26 (25mcg)	0.01 (1.2mcg)	3.64 (200mcg)	Fe, F, Co

Ref British National Formulary and “Prescribing Adult Intravenous Nutrition” Peter David Austin, Mike Stroud. Pub. Pharmaceutical Press, 2007 Appendix 3 table A3.2.

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Intensive Care Consultant, King's College Hospital, Denmark Hill, London, SE5 9RS, United Kingdom

Corresponding author.

PII: S0953-7112(09)00114-8

doi:10.1016/j.cacc.2009.08.004

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