Micronutrient Function, Status and Disposition in Critical Illness

Abstract

Vitamins and trace elements are collectively vital to physiologic function. Each micronutrient is unique and complementary to others, with some interdependency in intermediary metabolism. Micronutrients play a significant role in critical illness from preventing deficits to modulating immune function and oxidative stress and regulating gene expression. The inflammatory response alters the disposition of micronutrients, which has implications for laboratory parameter interpretation and nutritional regimen intervention.

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Introduction

Acutely ill patients, particularly when managed in a critical care unit, often require nutrition therapy to maintain or improve their metabolic status. This can take the form of enteral or parenteral nutrition when a diet cannot be tolerated or is impractical. A vital component of these therapeutic regimens is the micronutrient content, which is no less important than protein and calories to patient outcome. Micronutrients include the vitamins and minerals, the latter including electrolytes and trace elements. An appreciation of the physiologic roles played by these micronutrients is required to reasonably guide clinical assessment and therapeutic use in the critical care unit. This chapter will review the function of each key vitamin and trace element (Table 1) as well as their assessment and disposition in critically ill patients.

Table 1 Key micronutrients in the critically ill patient

Applications to Critical or Intensive Care

Micronutrient-specific dosing standards based on available evidence serve as the benchmark to guide dietary intake (Boullata 2013a). These are intended for otherwise healthy individuals consuming an oral diet. An example of this is the Dietary Reference Intakes that include Recommended Dietary Allowances or Adequate Intake levels in North America, and in the UK Dietary Reference Values include Reference Nutrient Intakes or Safe Intakes, while in Australia and New Zealand the Nutrient Reference Values serve the same purpose. Unfortunately, establishing micronutrient dosing requirements for the critically ill is very difficult, complicated in part by the great heterogeneity of those with acute illnesses. Performing the requisite micronutrient balance studies or depletion-repletion trials is full of challenges (ethical, technical, and physiologic). In the critically ill, immune activation/inflammation influences nutrient status, and micronutrients in turn are vital to modulating inflammation and immune function (Cordova et al. 2011). Vitamins and minerals are physiologically important in regulating metabolism through roles as coenzymes and cofactors and in free radical scavenging, intracellular signaling, and gene expression (Boullata 2013a). Further applications are described in later sections of this chapter.

The Micronutrients

Vitamins are low-molecular-weight organic compounds required for normal growth, development, and maintenance. What the vitamins have in common is that they cannot be synthesized, or at least not at an adequate rate, in human tissues. These compounds are effective in small amounts and, although not furnishing energy or serving as structural building units, are essential for transformation of energy and for regulation of metabolism. If any one of these compounds is lacking in the diet, then biochemical adaptations translate into changes in tissue/organ structure/function that can result in clinical manifestations known as deficiency diseases (Boullata 2013a). As vitamins differ in chemical composition and function, it has been convenient to classify them by physicochemical properties into two groups – fat-soluble and water-soluble compounds. They could just as easily be classified by other properties (e.g., chemical stability, postabsorptive transport, therapeutic index, tissue distribution, excretory routes). Vitamins A, D, E, and K fall into the fat-soluble group, since they can be extracted with fat solvents and are found in the fat fractions of tissues. The water-soluble vitamins include ascorbic acid and the B group of vitamins, consisting of nearly a dozen well-defined compounds. Of note, body stores of vitamins may be large (vitamin A, vitamin B₁₂) or small (vitamin K, thiamine) regardless of solubility group. The absorption of most vitamins is transporter mediated (Said 2011; Reboul and Borel 2011). The influence of the stress response on these transport mechanisms is not yet known.

The trace elements, or microminerals, are inorganic nutrients found in small quantities in the body (Table 2) but are no less vital to human metabolism and function, with daily intake requirements in the milligram or microgram range (Reilly 2004; Boullata 2013a; Boullata 2013b). The special role played by trace elements derives from properties consigned through the periodic table of elements. With brief reference to the periodic table, the metallic characteristics of elements decrease as valence electron numbers increase (i.e., from left to right), while metallic characteristics increase with the number of electron shells (i.e., down each period) (Reilly 2004). As such selenium is often referred to as a metalloid rather than a metal. All other trace elements under discussion are considered transition metals, having their valence electrons in more than one shell and can therefore exhibit a variety of oxidation states. These elements are of no biologic value in their insoluble metallic state. Instead they participate as indispensable cofactors of enzymes (i.e., metalloenzymes) or bound to other soluble organic compounds that each carry out complex biologic processes with considerable specificity and selectivity (Reilly 2004). The different chemical properties of each trace element in terms of redox potential, acid-base features, and structural or ligand coordination properties allow for their diverse physiologic roles. Although these elements exist in several oxidation states, only one or two are compatible with a biological environment (Boullata 2013b). Variable binding to different organic ligands is the means for effecting element transport and function while minimizing toxicity prior to excretion.

Table 2 Concentrations of select minerals in the human body

Micronutrient Metabolic Function

Broadly speaking, the micronutrients are valuable in the prevention of deficiency, maintaining immune function, sustaining inflammatory and oxidative balance, regulating gene expression, and other metabolic needs especially important to an acutely ill patient (Erdman et al. 2012; Ross et al. 2014). Although outright deficiencies are not common, less severe deficits can still impair biochemical processes that impact physiologic function. Poor micronutrient status prior to critical illness can rapidly compromise the patient with acute disease or injury particularly as micronutrient demands increase (Berger and Chioléro 2003).

Vitamins

Vitamin A is essential for cell growth and differentiation, as well as vision, immunity, and reproduction. Its role in the visual process is established best. Vitamin A alcohol is named retinol, while the aldehyde form is named retinal by virtue of its specific function in the visual process. Target tissues other than the eye use retinoic acid which regulates cell differentiation and tissue repair. Vitamin A also plays a regulatory role in immune cells and participates in maintaining epithelial membrane integrity. Normal structures may be substituted by stratified keratinizing epithelium in the eyes, paraocular glands, and respiratory, alimentary, and genitourinary tracts under the stresses of a deficiency. In severe deficiency the affected epithelial and connective tissue may become the site of infection because of the cells’ reduced resistance to microbial invasion. Plasma vitamin A is predominantly in the form of retinol with <5 % as retinyl esters and remains constant across a wide range of hepatic vitamin concentrations. Vitamin A and its metabolites serve as ligands for extracellular (RBP) and intracellular (CRABP, CRBP) binding proteins and membrane (Stra6) and intracellular (RAR, RXR) receptors important for its transport and effect.

Vitamin D classically represents the compounds effective in preventing rickets/promoting calcification of bony structures. Vitamin D is also involved in maintaining immunity, neural function, and pancreatic function. After absorption or cutaneous synthesis, vitamin D is converted, primarily in the liver, to 25(OH)-vitamin D, the predominant form in the circulation where it serves as the biomarker for vitamin D status and the storage form bound to DBP. The most important function for 25(OH)-vitamin D is as a precursor of 1,25(OH)₂-vitamin D (calcitriol). This hormone is produced and secreted under tight regulation in the kidney for general (endocrine) use and at specific tissues for local (autocrine, paracrine) use. Numerous vitamin D metabolites are formed subsequently. Through the action of active metabolites on cellular targets via VDRs, the vitamin aids in calcium homeostasis, from the intestinal tract and parathyroid gland to the kidneys and bone. A variety of nonskeletal effects at local tissues (e.g., pancreas, macrophage/monocyte, vascular smooth muscle) are also VDR responsive via hundreds of genes with VDREs. Many individuals have some degree of vitamin D deficit that has been associated with infection, inflammatory disease, and neurologic disorders. Deficits of vitamin D have been reported in critically ill patients as an outcome predictor (Braun et al. 2012).

Vitamin E designates the group of compounds with significant antioxidant and peroxyl (ROO•) free radical scavenger activity. The various forms (α-, β-, γ-, δ-) of tocopherol and tocotrienol are not interchangeable for human needs; only α-tocopherol meets vitamin E requirements. Although there is no discrimination of vitamin E form during absorption, the liver preferentially transfers α-tocopherol to VLDL via αTTP. Nonspecific binding to lipoproteins provides for α-tocopherol transport. Its most critical function occurs in membranes of organelles and cells including the lung epithelial tissue where it reacts with free radicals generated from oxidative deterioration of such substances as polyunsaturated fat. By forming the tocopheroxyl radical, vitamin E prevents membrane lipid autoxidation. The vitamin E radical then reacts with vitamin C to return vitamin E back to its reduced form. With oxidative stress there is a greater turnover of vitamin E reflected in lower plasma levels, more rapid in the presence of poor vitamin C or selenium status. α-Tocopherol may also regulate gene expression, participate in nucleic acid metabolism, and be involved in tissue healing.

Vitamin K refers to a group of napthoquinone compounds with similar antihemorrhagic bioactivity. The primary activity that makes the vitamin essential is its role in posttranslational γ-carboxylation of glutamic acid residues on specific proteins involved in coagulation and bone metabolism. Vitamin K is necessary to activate several clotting factors produced in the liver. Other vitamin K-dependent proteins, including osteocalcin and matrix Gla protein, exist in bones. Undercarboxylated osteocalcin can be used as an indicator of vitamin K status. Vitamin E and vitamin K both undergo ω-hydroxylation and β-oxidation. The body pool of phylloquinone is small with a rapid turnover.

Vitamin C (ascorbic acid) is necessary for the prevention of the classic deficiency disease scurvy. Its property as a reducing agent (electron donor) supports its many functions: a cofactor for 14 enzymes (oxygenases/hydroxylases) with roles in collagen synthesis and hypoxia-inducible factor, nonenzymatic function as an antioxidant in both intra- and extracellular environments, and a role in gene expression. Both intestinal absorption and renal tubular reabsorption are saturable so that in healthy individuals circulating concentrations are tightly maintained at ~70–80 μmol/L with a body pool of ~1,500 mg. By virtue of not being protein bound in the circulation, vitamin C distributes throughout the extracellular fluid space but is then concentrated to varying degrees in tissues by SVCTs. Trace amounts of the oxidized form (dehydroascorbic acid) are transported by GLUTs. Vasomotor instability, capillary fragility, neuropathies, and mental depression among other findings may occur with subclinical vitamin C deficits. Higher turnover in critical illness may explain lower concentrations in these patients. Vitamin C requirements are higher following trauma, during infections, and during periods of vigorous physical activity but still not exceeding 200 mg a day.

The so-called B complex vitamins are differentiated into at least 11 separate and distinct chemical entities most of which are required in nutrition. Although no natural source contains all the B vitamins in the proportions that are needed, multiple B-vitamin deficiencies often coexist. Diseases in which there is increased metabolism and stress can increase the need for more of these vitamins.

Biotin is essential as a cofactor for several carboxylases critical in intermediary metabolism and for histone biotinylation. It functions in carbon dioxide fixation reactions transferring a carboxyl group to acceptor molecules. Biotin requires transporters to cross cell membranes (e.g., using SMVT at the apical/brush border membrane of intestine and proximal tubule). Inactive metabolites are excreted in urine. Although synthesized endogenously, exogenous choline plays an important role both as a structural component of tissues and in methylation reactions. Besides its vital function as a precursor of acetylcholine, choline is an important contributor of methyl groups for S-adenosylmethionine in its role as a methyl donor. Some of the hepatic dysfunction associated with parenteral nutrition is related to choline deficits. Pancreatic and renal function may be similarly affected by choline deficiency. Folic acid in its reduced folate coenzyme forms is essential for one-carbon metabolism critical for nucleotide synthesis, amino acid metabolism, and methylation reactions including those regulating gene expression. The fully reduced form of this vitamin group is the 5,6,7,8-tetrahydrofolate (THF) involved in the one-carbon transfers. Although folic acid has greater oral bioavailability than dietary folates, once taken up by cells the vitamin is reduced by DHFR and retained as a polyglutamate. Intestinal absorption occurs by the proton-coupled folate transporter. The major circulating form of the vitamin is 5-methyl-THF, although poor efficiency of folic acid conversion results in unmetabolised folic acid in the circulation (Patanwala et al. 2014). Other mechanisms for transporting folic acid across membranes include cell surface folate receptors, multidrug resistance-associated protein 3, and the reduced folate carrier. Folate metabolism requires riboflavin, niacin, choline, pantothenic acid, and vitamins B₆ and B₁₂. Niacin refers to both nicotinic acid and nicotinamide which is essential for the function of the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). These coenzymes take part in numerous redox reactions, as well as other pyridine nucleotide-dependent reactions. For example, these nucleotides are critical in glycolysis, the Krebs cycle, electron transport chain, and β-oxidation. NAD also serves as a substrate for the sirtuins (deacetylases) and plays a role in mono- and poly-ADP-ribosylation of numerous proteins important to cell signaling and genomic stability. Ribosylation via poly(ADP-ribose) polymerase (PARP) is involved in NFκB signaling, inflammation, and sepsis. Niacin is absorbed via intestinal epithelial cell carriers. Depending on niacin status, the liver may store it as NAD, release into the circulation for peripheral availability (e.g., RBCs), or convert to end products (N-methylnicotinamide, nicotinuric acid) for urinary excretion. Pantothenic acid is a key component of coenzyme A (CoA), which is involved in many vital reactions transferring a two-carbon compound (the acetyl group) in intermediary metabolism. CoA is involved in the release of energy from carbohydrate, in the degradation and metabolism of fatty acids, and in the synthesis of such compounds as steroid hormones, porphyrins, and acetylcholine. Intestinal absorption of pantothenic acid by a saturable active transporter directly competes with biotin which may also occur at other epithelial cells. Erythrocytes rapidly concentrate and then transport pantothenic acid in the circulation. Tissue stores are mostly in the form of CoA. Vitamin B ₆ refers to pyridoxal, pyridoxamine, and pyridoxine which differ in the C4 substituent of the pyridine ring. Each can be phosphorylated at C5′ with pyridoxal 5′-phosphate (PLP) and pyridoxamine-5′-phosphate, the active coenzyme forms involved in amino acid biotransformation reactions (e.g., decarboxylation, transamination). The coenzymes also function in over 100 enzymes in carbohydrate, fat, and one-carbon metabolism, as well as neurotransmitter synthesis. Vitamin B₆ absorption involves a saturable carrier-mediated pathway as well as passive diffusion. Dephosphorylation is required for membrane transport, while post-transport phosphorylation assures cellular retention for activity. Plasma PLP concentration correlates with tissue levels and reflects vitamin B₆ status. Pyridoxic acid, the major end product of vitamin B₆ catabolism, is excreted renally. Vitamin B₆ metabolism depends on niacin, riboflavin, and zinc at various steps. Riboflavin is a component of the essential coenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) responsible for a wide variety of reactions in intermediary metabolism and the metabolism of other vitamins (e.g., folate, niacin, pyridoxine). FMN and FAD function in numerous 1- or 2-electron oxidation-reduction reactions under the influence of thyroid hormone. A large number of flavoprotein enzymes have been identified, each of which is specific for a given substrate, some containing metallic constituents (e.g., Cu, Fe, Mo). Absorption is aided by the riboflavin transporters (RFT1, RFT2). Carrier-mediated processes are involved in riboflavin distribution to tissues. The net renal excretion of riboflavin and its metabolites includes the ability to regulate secretion/reabsorption. Excretion is enhanced with trauma and metabolic stress. Thiamine is an essential cofactor for enzymatic (e.g., transketolase, pyruvate dehydrogenase, α-ketoglutarate dehydrogenase) reactions in normal carbohydrate, amino acid, and nucleic acid metabolism. Thiamine pyrophosphate (i.e., diphosphate) serves as the prosthetic group for these enzyme systems. Distinct functions attributed to thiamine triphosphate are being actively investigated. Thiamine absorption is active in jejunum and ileum via THTR1 and passive at high gut concentrations. Given minimal body stores (~30 mg) and high turnover with urinary excretion of thiamine and its metabolites, patients require a daily source of the vitamin to avoid beriberi and encephalopathy. Vitamin B ₁₂ (cobalamin) is essential to the function of three classes of enzymes responsible for intramolecular rearrangements critical to cytosolic and mitochondrial pathways involved in protein, carbohydrate, and fat metabolism, as well as – together with folic acid – in the anabolism of deoxyribonucleic acid. The vitamin is essential for the normal functioning of all cells but particularly for cells of the bone marrow, the nervous system, and the alimentary tract. The corrin ring structure with a central cobalt atom is attached to a nucleotide and to a prosthetic group (methyl in the cytoplasm involved in the methionine cycle, deoxyadenosyl in the mitochondria for propionyl-CoA metabolism). The vitamin requires cobalt in a monovalent state for its active form. The complex absorption of dietary cobalamin, dependent on intrinsic factor and its uptake system, may give way to inefficient passive absorption at high supplemental intake. Vitamin B₁₂ carriers include the transcobalamins. Serum methylmalonic acid rises in vitamin B₁₂ deficiency.

Trace Elements

Chromium exists in several oxidation states with the stable trivalent form biologically active. Its bioactivity comes from incorporation into a low-molecular-weight organic molecule (chromodulin) which improves tissue insulin sensitivity through amplification of protein tyrosine kinase activity. Chromium is transported bound to transferrin (and albumin) in the plasma and competes with iron for binding sites. The main excretory route is through the urine; however, some chromium is excreted in the feces through bile and small intestinal losses. Urinary losses increase with metabolic stress, trauma, and ascorbic acid deficits. Chromium deficits induce glucose intolerance, and glucose intolerance can further drive urinary chromium losses. Chromium supplementation is not beneficial to glucose tolerance in nutrient-replete patients. Administration is best reduced or discontinued in patients with renal dysfunction.

Copper is incorporated into numerous proteins (cuproproteins) including enzymes (e.g., oxidases, ferroxidases), binding proteins (e.g., metallothionein, transcuprein), transporters (e.g., CTR1), and low-molecular-weight ligands (e.g., amino acids, peptides). While enzymatic functions involve single-electron transfer reactions, the nonenzymatic functions of copper include gas transport, neurohormone homeostasis, and gene expression. Copper functions in the absorption and utilization of iron, electron transport, connective tissue metabolism, immune function, phospholipid formation, purine metabolism, and development of the nervous system. Plasma ceruloplasmin (a ferroxidase) accounts for 60–95 % of circulating copper, with the remainder bound as Cu²⁺ to albumin and amino acids. Ceruloplasmin delivers copper directly to tissues, with each molecule of this transport protein containing six copper atoms. Copper requires both transporters and chaperones for tissue/cellular distribution. Copper is reduced, dissociated from ceruloplasmin, and released to the cells; CTR1 and DMT1 transfer copper into cells. Then specific protein chaperones distribute the copper to specific intracellular targets. Although most copper is excreted through bile, small amounts may be eliminated via urine and sweat. Serum copper and ceruloplasmin levels are low only in severe deficiency. The most common defects observed in copper deficiency are anemia, leukopenia, and poor inflammatory response. Ceruloplasmin is an acute-phase protein and is therefore increased in inflammation. As a result, the plasma copper level increases with acute infections and in critically ill patients.

Iron is the most abundant trace element in the body (Table 2). It exists in several oxidation states, with ferrous (Fe²⁺) and ferric (Fe³⁺) the most clinically relevant. These allow iron to play a catalytic role in vital physiologic redox reactions. There are four groups of metalloproteins involved with iron function: nonenzymatic ferroproteins (e.g., hemoglobin, myoglobin) that account for most of the body’s iron content, heme enzymes involved in electron transfer or oxidase activity (e.g., cytochrome c oxidase, myeloperoxidase), iron-sulfur electron transfer compounds in energy (e.g., succinate dehydrogenase), and cofactor roles in enzymes (e.g., tyrosine hydroxylase). In contrast to most of the other trace elements, iron can be stored (e.g., as ferritin) for future metabolic needs, while excessive absorption is limited by a regulatory protein (i.e., hepcidin). The complex chain of transport proteins (e.g., DMT1, ferroportin, transferrin) carrying iron to functional sites serves to limit free iron and its reactive species. Iron metabolism and its complex regulation continue to unfold.

Manganese is incorporated into numerous proteins including the metalloenzymes arginase, glutamine synthetase, and superoxide dismutase-2. This mineral is also required for the production of endogenous steroids. Manganese is absorbed from the small intestine in part through DMT1 and then is transported in the circulation bound to transferrin, albumin, and a macroglobulin. At least 60–80 % of manganese is found in erythrocytes as Mn²⁺ so that a whole blood level measure of manganese is the best currently available biomarker. Some manganese is oxidized to Mn³⁺, then both forms are taken up by the tissues, possibly competing with iron and zinc for DMT1 and ZIP, respectively (Ross et al. 2014). Manganese is excreted in the bile and through the intestinal wall. At high manganese intakes, the element also is excreted in the pancreatic juice while urinary excretion is minimal. Although manganese deficiency has not been well recognized in humans, excessive exposure to this trace element can result in neurologic dysfunction which continues to be underrecognized.

Molybdenum is required as a cofactor in a pterin nucleus – forming the molybdopterin cofactor – for the activity of sulfite oxidase, aldehyde oxidase, and xanthine dehydrogenase. At its physiologic oxidation states, it has affinity for oxides and sulfides. The mineral is readily absorbed as molybdate (MoO₄²⁻) but may be attenuated by sulfate anion inhibition. It is transported in loose association with erythrocytes, with highest concentrations found in the liver, kidney, and bone. Deficiency can impair the ability to handle sulfur – including that from methionine.

Selenium is a vital component of the amino acid selenocysteine. As part of selenocysteine in its selenol form (R-Se-H), the selenium is largely ionized at physiologic pH making it highly reactive. In this form it plays a critical role in at least 25 selenoproteins, some of which are enzymes: antioxidant (e.g., GPx), endocrine (e.g., iodothyronine deiodinases), or redox signaling (e.g., thioredoxin reductases). Additionally, non-selenocysteine selenium-containing proteins also exist (e.g., Se-binding proteins). Selenoprotein P (SePP) is synthesized hepatically with the incorporation of ten selenocysteine residues per molecule, which can then bind to and protect endothelial cells from oxidative damage, while GPx isoenzymes play major antioxidant roles in cellular compartments and in the interstitium. SePP contributes more than half of the circulating selenium followed by GPx-3 at almost 20 %. These plasma biomarkers are reasonable reflections of selenium adequacy and function maximally at plasma selenium levels above ~1.8 μmol/L. Unlike other minerals, absorption of selenium is not under homeostatic regulation. Selenium is excreted primarily through the kidneys often in methylated forms, but metabolites can be lost in gastrointestinal secretions and expired air. Plasma selenium concentrations are significantly lower in critically ill patients, correlated strongly with disease severity, and are associated with morbidity and mortality even in patients receiving some selenium.

Zinc is found intracellularly in most tissues usually tightly bound to proteins. Zinc exists in hundreds of metalloproteins which play parts in cellular signaling, the stress response, immune function, protein synthesis, wound healing, and glucose control. Zinc’s physiologic roles are catalytic (i.e., enzymes), structural (e.g., zinc fingers), and regulatory (e.g., cell signaling, gene expression) in character. Although chemical properties allow zinc to have strong binding, it is the rapid ligand exchange that gives the mineral biochemical function. The divalent state predominates in physiologic systems, and its coordination geometry allows its vital structural role in gene regulation. Zinc-finger regions on specific proteins allow transcription factors and nuclear receptors to recognize binding domains. Although circulating zinc binds to most plasma proteins, it is bound most loosely to albumin which may be important for transport to and from tissues. The exchangeable zinc pool which includes plasma, liver and pancreas, accounts for ~10% of total body zinc. Large stores of zinc may be found in the skeletal muscle, bone, and liver, with smaller stores found in the skin, pancreas, kidney, and prostate. Whereas iron is found in distinct compartments for specific roles, zinc is much more ubiquitous across subcellular compartments. To maintain these distributions, numerous zinc transporters exist: the ZnT family of transporters removes zinc from the cytoplasm, and the ZIP transporters increase cytoplasmic zinc concentrations. The genes for these transporters can be upregulated or downregulated in response to zinc status. The principal route of excretion is via the feces, with zinc losses from the alimentary tract usually exceeding renal losses, although the latter may increase with tissue catabolism seen in critical illness. Amino acid infusions and hyperglycemia may also increase urinary zinc losses through proximal tubule secretion. Critically ill patients often have low serum zinc concentrations. The reduction of serum zinc correlates with disease severity, with greater declines seen in septic patients.

Micronutrient Status and Assessment in Critical Illness

General

Completing a nutrition assessment based on available data leads clinicians to an appropriate care plan for any patient. The critically ill patient adds further complexity given the inflammatory response and its ability to alter carrier protein synthesis and micronutrient disposition. These patients are often hypermetabolic and hypercatabolic early in their presentation and depend on enteral and/or parenteral nutrition. As a result, micronutrient status can vary in critical illness (Table 3), with blood concentrations of some nutrients significantly reduced. These lower concentrations can occur in some patients receiving nutrition regimens containing conventional amounts of micronutrients (Luo et al. 2008). Micronutrient deficits contribute to the dysregulation of cellular function and microcirculation that manifests as hyperinflammation, immunosuppression, or both in the critically ill (Weitzel et al. 2009). Subclinical deficiency is more prevalent than classic clinical deficiencies but may still have outcome implications. Biomarkers are readily available to guide assessment (Tables 4 and 5) with reference values dependent on laboratory, specific assay methodology, and sample limits of detection. The laboratory should participate in external quality assurance programs when available for the micronutrients assayed. However, even with good measures, assessing an individual’s micronutrient status can be challenging for a number of reasons. It is difficult to quantify the influence of multiple factors (e.g., poor premorbid nutrient status, acute fluid losses, post-resuscitation hemodilution, carrier protein suppression, vascular permeability, tissue sequestration, increased use, or increased losses) on the circulating levels of each micronutrient.

Table 3 Micronutrient status in critically ill patients

Table 4 Vitamin biomarkers

Table 5 Trace mineral biomarkers

Given the complexity of micronutrient kinetics among numerous compartments or “pools,” reported blood values are not always adequate indicators of total body status. The circulating concentrations are indirect reflections, at a single point in time, that correlate poorly with the target tissue levels; they only represent the transient flux between compartments. A measure of each nutrient’s function would be a more direct reflection of its status, but appropriate tests are few. In acute illness, the concentrations of albumin decrease, but ceruloplasmin and ferritin increase which also influences lab interpretation. The inflammatory response can alter distribution of micronutrients by altering vascular permeability or transporter activity. This may be considered adaptive if redistributed to tissues with greater needs (e.g., selenium), but not if low hepatic protein synthesis impairs transport to those peripheral tissues (e.g., retinol). The metabolic needs of the cell, rather than just extracellular availability of the micronutrient, likely control plasma membrane transporters. Losses through cutaneous wounds and externalized drains can be significant routes of micronutrient loss. Specific interventions (e.g., renal replacement therapies [RRT]) may increase the risk for micronutrient deficits.

The circulating reductions may indeed be transient, for example, following elective surgery, but more enduring in severely ill patients. In fact, the magnitude of the inflammatory response – based on C-reactive protein (CRP) – best predicts the degree of reduction in plasma levels of several vitamins (e.g., retinol, pyridoxine) and minerals (e.g., selenium, zinc) (Duncan et al. 2012). Whether the altered circulating micronutrient concentrations are beneficial (i.e., supporting increased requirements in interstitial fluid or tissues, sheltering or excreting nutrients that may benefit pathogens) continues to be explored. Clinical assessment of micronutrient levels is best performed with a concurrent marker of systemic inflammation (i.e., CRP). It remains too early to know whether there are differences in micronutrient assessment limitations between acute critical illness and prolonged acute critical illness or chronic critical illness.

Vitamins

That significant decreases in blood concentrations of vitamins occur during the acute-phase response in otherwise healthy individuals has been long recognized (Louw et al. 1992). Low concentrations of vitamins A and D occur at moderate CRP values (10–20 mg/L), while deficits of ascorbic acid and pyridoxine occur at lower CRP levels (5–10 mg/L). Although most changes are transient, the most consistent reductions were in plasma retinol, α-tocopherol, pyridoxine, and leukocyte vitamin C, which fell below normal ranges, but less consistency is seen in serum and erythrocyte folate, serum vitamin B₁₂, other B-vitamin markers, and plasma vitamin C. An evaluation of α-tocopherol levels requires normalization for serum lipid concentrations (Traber 2014). Vitamin deficit severity is associated with disease severity. The negative correlation with circulating concentrations of ascorbic acid, α-tocopherol, and several carotenoids possibly reflects the oxidative stress/lipid peroxidation in these patients (Oldham and Bowen 1998). Therefore, low vitamin C levels most likely reflect increased utilization rather than redistribution or excretion. RRT may induce measureable losses of ascorbic acid in the ultrafiltrate (Story et al. 1999). Accelerated thiamine turnover is also likely in acute illness. Hyperhomocysteinemia may occur in nearly half of critically ill surgical patients and is significantly associated with plasma and erythrocyte PLP, but not with serum folate and cobalamin (Hou et al. 2012). During the inflammatory response, there is reduced synthesis and plasma concentration of RBP and hence plasma retinol. Septic patients may experience higher urinary losses of vitamin A (Berger and Chioléro 2003). Several reports have described widespread vitamin D insufficiency and deficiency in critically ill patients (Nair and Venkatesh 2012). The lower 25(OH)-vitamin D concentration may be a function of lower DBP seen in critical illness. Measures of binding protein or free concentrations may provide a better picture of vitamin status (Quraishi and Camargo, 2012).

Trace Elements

The metabolic response to injury includes changes in trace element distribution, utilization, and excretion. Consequently, the circulating trace element levels may be rapidly reduced in critical illness. For example, a significant decrease occurs in blood levels of copper, selenium, and zinc in patients undergoing surgery (Stoppe et al. 2011). The magnitude of reduction is associated with organ failure during the critical care unit stay (Stoppe et al. 2011; Cander et al. 2011). Acute hepatic dysfunction may itself further influence trace element redistribution and excretion (Hoet et al. 2012).

The serum chromium concentration is not a good reflection of tissue content because it does not readily equilibrate with tissue stores. RRT may induce measureable losses of chromium, copper, selenium, and zinc (Story et al. 1999; Klein et al. 2002; Berger et al. 2004). Copper levels are the least associated with CRP values in part keeping with the increased ceruloplasmin levels. Cellular inflammation increases CTR1 mRNA, and a cell’s CTR1 levels increase in response to cellular copper deprivation with a greater proportion of this high-affinity transporter in the plasma membrane compared with that in the cytoplasm (Hasan and Lutsenko 2012). This process of translocation is influenced by insulin, which in turn influences insulin signaling, all suggesting a complex regulatory system that goes far beyond changes in circulating copper. The implications for the trafficking of cytosolic chaperones to copper efflux systems seem to support incorporation into ceruloplasmin during hypoxia. Given the increases in serum ceruloplasmin with the inflammatory response, this may increase availability of copper for cells of the immune system. Manganese concentrations are typically elevated in critically ill patients, a result in part of contaminants found in intravenous products. Circulating deficits of selenium occur at modestly elevated CRP (5–10 mg/L). The reduced plasma selenium concentrations in acute illness reflect redistribution of selenoproteins to the tissues and increased losses. Endothelial dysfunction associated with septic shock may require cellular SePP uptake for protective function. The low plasma selenium concentration and GPx activity in critically ill patients are associated with the degree of inflammation and poor outcome (Sakr et al. 2007; Manzanares et al. 2009). Selenium reductions may independently predict subsequent organ dysfunction (Stoppe et al. 2011). Urinary losses of selenium are correlated with urinary nitrogen losses – a marker of catabolism and injury severity. The selenium balance can rapidly become negative in the absence of supplementation (Berger et al. 2004; Story et al. 1999). Trauma patients with multiple drains lose selenium and zinc (Berger and Chioléro 2003). Hypozincemia is most prominent once CRP exceeds 20 mg/L. Worse serum zinc values are seen in septic patients in the face of elevated cytokines and increased transporter gene expression, suggesting further intracellular zinc transport with infection (Besecker et al. 2011). Zinc is redistributed from the vascular compartment, muscle, and skin to tissues with rapid cell proliferation and intense acute-phase protein synthesis. The increased tissue zinc uptake, especially by the liver, is attributed to interleukin-6 induction of metallothionein and zinc transporter expression. The intracellular shift of zinc may help to meet the needs of signaling pathways for immune responses and related metabolism (Ross et al. 2014). Increased urinary zinc excretion also takes place.

Blood loss from injury and phlebotomy contributes to anemia as does the severe inflammatory state of critical illness which suppresses erythropoiesis (Sihler and Napolitano 2008). This anemia is not necessarily related to body deficits of iron, although serum iron is low within days of admission even as ferritin levels are elevated (Rodriguez et al. 2001). Abnormally low serum iron with an elevated ferritin is the typical profile in critically ill patients due to the inflammatory response. This functional iron deficiency correlates with inflammatory status but does not rule out true iron deficits (Muñoz et al. 2005). The inflammatory state increases the production of hepcidin which results in iron sequestration in cells, a protective effect for the patient if intracellular oxidative stress is not increased (Sihler and Napolitano 2008; Lasocki et al. 2011; Andrews 2015). It is difficult to decipher whether a patient with anemia or inflammation is iron deficient or not. Both soluble transferrin receptor and hepcidin may indicate deficits of iron in the presence of critical illness and could serve as better biomarkers of iron status (Lasocki et al. 2011). Urinary losses of iron may be seen when EDTA-containing medications are infused (Higgins et al. 2000).

Pharmacologic Aspects of Micronutrients

In the face of increased metabolism, inflammation, and stress, the need for micronutrients may increase. Exogenous (non-dietary) micronutrient preparations serve a number of potential roles in the critically ill (e.g., to maintain nutrient status, to replete true deficits, to “correct” serum concentrations, or to improve biochemical or functional markers). Without qualification, low circulating levels of micronutrients cannot be interpreted as always requiring supplementation. Ideally, micronutrients are only used pharmacologically when evidence supports their administration in the critically ill. The primary goal of any micronutrient supplementation is to improve patient outcome rather than correcting an abnormal circulating micronutrient value. As such, intervention trials with kinetic characterization are required to determine the value of supplementation. The models that describe the disposition of nutrients, particularly trace elements, are much more complex than for drugs (Wastney et al. 2011). However, given the interdependence among the micronutrients, supplementation of an isolated nutrient may increase the need for another (e.g., thiamine in subclinical beriberi increases the need for riboflavin). Therefore, there is some justification for multivitamin/mineral therapy when deficits are suspected.

Micronutrients may be administered enterally or parenterally. The chemical forms and salts of micronutrients found in dietary supplement, enteral formula, or parenteral nutrition preparations will determine their bioavailability and participation in physiologic processes. Once considered equivalent, there are distinct differences in properties of vitamin D₂ (ergocalciferol) and vitamin D₃ (cholecalciferol) at pharmacologic doses. Organic forms of selenium (e.g., selenocysteine) have considerably better bioavailability and more efficient distribution and storage than inorganic forms (e.g., selenite salts). Sulfate salts of the minerals are often the most soluble and amenable to oral bioavailability, whereas the oxide salts are poorly soluble in the gastrointestinal tract with limited bioavailability. In the case of zinc, the sulfate salt is advantageous for clinical use, while for aluminum the oxide salt is welcome given the limited bioavailability afforded to this potential toxin.

With enteral administration, passive diffusion becomes operative at pharmacologic doses. This may overcome limitations of absorption when using a feeding tube bypasses sites of active absorption. Regulation of oral/enteral micronutrient supplements differs between countries. For example, in the USA many products are regulated as “dietary supplements,” although some may be regulated as “medical foods” which both imply less oversight compared with other enteral/parenteral nutrient products regulated as drugs.

For patients unable to consume an oral diet or enteral nutrition, injectable micronutrient products are available, either in fixed-dose multivitamin or multielement combinations or as individual nutrient preparations. Individual trace element products offer the advantage of individualizing doses. These products should be diluted in parenteral nutrient admixtures or other appropriate parenteral fluid before administration. However, the fixed-dose combination products do not meet all patient needs (Vanek et al. 2012). Additionally, there is no individual choline or cholecalciferol product available, and the amount of vitamin D in fixed-dose combination products is inadequate. Uniform international dosing standards have been proposed but require better appreciation of the requirements for critically ill patients (Vanek et al. 2012).

The intravenous route allows full bioavailability of micronutrients when concerned by compromised absorption or splanchnic first-pass effect. However, the intravenous route also circumvents the homeostatic control over excessive micronutrient exposure – especially a concern for those with a narrow therapeutic index or tightly regulated at the point of gastrointestinal absorption. Infusions are more likely to be tolerated compared with rapid bolus injection. High doses that exceed the physiologic capacity to distribute and store the micronutrient result in free (unbound) amounts available for interaction and prompt excretion when renal mechanisms are overwhelmed. Selenium may be one exception to bolus injection with the first dose (Boullata 2013b). Besides accelerating losses, rapid parenteral administration of micronutrients also exposes the kidneys and liver to high concentrations on first pass and may cause cell damage.

The dose and timing of micronutrient repletion or supplementation may be critical to any beneficial role in outcome while avoiding toxicity or exacerbating the inflammatory response. The availability of the vitamins in pure form several decades ago promoted the transition from the use of international units to microgram/milligram in appropriately expressing dosing amounts. Unfortunately, this transition is not yet universal. When using minerals therapeutically (enterally or parenterally), dosing is based on the elemental portion of the salt rather than the total amount of salt to minimize risk for error (e.g., mg of zinc rather than mg of zinc sulfate, mmol (or mEq) of magnesium rather than g of magnesium sulfate). Excessive doses should be avoided. In fact, in the patient with cholestasis, there is concern over excessive amounts of copper, which can cause cirrhosis, renal failure, and neurologic disorders. The known adverse effects of chronic exposure to micronutrients are difficult to extrapolate to acute pharmacologic use in the critically ill. Physiologic binding of micronutrients varies and can result in some competition for common binding sites that may alter transport, storage, excretion, and function, especially with trace elements setting the stage for interactions of clinical relevance. At pharmacologic doses, zinc inhibits copper absorption resulting in deficits. However, administration of zinc in excess of metabolic needs is associated with impaired neutrophil and lymphocyte function, indicative of the narrow therapeutic index for this mineral. The intrinsic contamination of some parenteral products with trace elements should also be taken into consideration.

Summary Points

• Micronutrients are no less important than macronutrients to patients’ metabolic status and outcome.

• The vitamins and trace elements each play key metabolic roles in normal physiology from the subcellular to multisystem level.

• Vitamins and trace elements are vital for the critically ill patient in preventing deficiencies, maintaining immune function, sustaining redox balance, and regulating gene expression.

• Important changes can occur in the circulating concentrations of individual vitamins and trace elements but must be interpreted with great caution in the face of the acute-phase response.

• Assess functional biomarkers of micronutrient status when available, because illness severity has an influence on micronutrient disposition.

• Results of well-designed intervention trials, supported by adequate kinetic information, help to guide when micronutrient supplementation will positively influence patient outcome.