بسم الله الرحمن الرحيم

By Dr Noha M. Elsharnouby

Lecturer of Anesthesia and

intensive care and pain

management Ain Shams university

That nutrition and health are intimately

linked has been known since ancient

times. It is now essential to realize the

vital importance of micronutrients to

health and that several micronutrients

have antioxidant roles.

What is the evidence in ICU?Early enteral feeding is best Hyperglycaemia/overfeeding are badNutritional deficit causes worse outcomeEN causes aspiration and VAP, while PN

cause infection EN and PN can be used to achieve goalsProtocols improve delivery of feedingSome nutrients show promising results

Anti-oxidantsNormal state: reduction > oxidation Acute stress: injury/sepsis causes acute

dysregulation: ROS/RNOS formed Mitochondria are both sources and targetsObservational studies: anti-oxidant capacity

inversely correlated with disease severity due to depletion during oxidative stress

Reactive Oxygen Species O-, NO-

Positive actions:Bactericidal Regulation of

vascular tone Cell signalling

But mostly detrimental:Cell injury (ischaemia

/reperfusion) DNA, Lipids, ProteinsOrgan dysfunction Lungs, Heart, Kidney Liver, Blood, Brain

Exacerbation of cell and tissue

injury

Inflammatory mediators

ROS/RNOS

Healing/repair/defence

MicroneutrientPresent in the body in amounts less than

50 ug per gram of body tissues. Essential nutrients for an optimal

functioning of organs and tissues, including the immune system and the heart.

In hypermetabolic patients in the ICU the trace element requirements may be far greater.

Nine trace elements are required by humans in small amounts : iron, iodine, fluorine, zinc, chromium, selenium, manganese, molybdenum, and copper.

All trace minerals are toxic at high levels, and some (arsenic, nickel, and chromium) have been implicated in carcinogenesis.

Except for deficiencies of iron, zinc, and iodine, mineral deficiencies do not often develop spontaneously in adults on ordinary diets; however, infants are more vulnerable because of their rapid growth and variation in intake.

SeleniumHumans and animals require selenium for the function of a number of selenium-dependent enzymes, also known as selenoproteins.

Seleinum function involves selenoproteins, glutathione peroxi dases, thioredoxin, and iodothyronine deiodinases (thyroid hormone deiodinases).

• Nutrient interactions:Selenium appears to support the activity of

vitamin E (a-tocopherol) in limiting the oxidation of lipids.

Thioredoxin reductase also maintains the antioxidant function of vitamin C by catalyzing its regeneration.

Selenium deficiency may exacerbate the effects of iodine deficiency.

Deficiency:Muscular weakness, muscle wasting, and

cardiomyopathy down-regulation of the nuclear transcription

factor kB,

• Disease PreventionImmune function stimulation:

expression of cell signaling molecules called cytokines, which orchestrate the immune response, selenium deficiency is associated with impairment of both cell-mediated immunity and B-cell function.

Viral infection prevention

• Disease Prevention

Cancer: increasing the levels of selenium metabolites that inhibit tumor cell growth.

Cardiovascular diseases: decrease the risk of cardiovascular diseases by decreasing lipid peroxidation and influencing the metabolism of prostaglandins.

• Toxicity high doses can be toxic. Acute and fatal toxicities have occurred with accidental

or suicidal ingestion of gram quantities of selenium. Chronic selenium toxicity (selenosis) may occur with

smaller doses of selenium over long periods of time.symptoms of selenosis are hair and nail brittleness

and loss, gastrointestinal disturbances, skin rashes, a garlic breath odor, fatigue, irritability, and nervous system abnormalities.

The Food and Nutrition Board (FNB) recently set the tolerable upper level (UL) for selenium at 400 mcg/day in adults based on the prevention chronic selenium toxicity.

• Drug Interactions• At present the anticonvulsant medication,

valproic acid, has been found to decrease plasma selenium levels.

•The Recommended Dietary Allowance (RDA) (55 mcg/day)

MOLYBDENUMfunction as a cofactor for three enzymes. Sulfite oxidase catalyzes the transformation of

sulfite to sulfate, a reaction that is necessary for the metabolism of sulfur-containing amino acids, such as cysteine. crucial for human health.

Xanthine oxidase catalyzes the breakdown of nucleotides (precursors to DNA and RNA) to form uric acid, which contributes to the antioxidant capacity of the blood.

Xanthine oxidase and aldehyde oxidase also play a role in the metabolism of drugs and toxins.

Deficiencyhas never been observed in healthy people. The only documented case of acquired molybdenum

deficiency occurred in a patient with Crohn's disease on long-term TPN without molybdenum added.

The patient developed rapid heart and respiratory rates, headache, night blindness, and ultimately became comatose.

The symptoms disappeared when the administration of amino acid solutions was discontinued.

Molybdenum supplementation (160 mcg/day) reversed the amino acid intolerance and improved his clinical condition.

The Recommended Dietary Allowance (RDA)

(45 mcg/day for adults) is sufficient to prevent deficiency. And the tolerable upper intake level (UL) of 2,000 mcg/day which should be safe for adults.

ZINC

Zinc plays important roles in growth and development, the immune response, neurological function, and reproduction.

On the cellular level, the function of zinc can be divided into three categories: 1) catalytic, 2) structural, and 3) regulatory.

Catalytic role: Nearly 100 different enzymes depend on zinc

for their ability to catalyze vital chemical reactions.

Structural role: Zinc plays an important role in the structure of

proteins and cell membranes. A finger-like structure, known as a zinc finger motif, stabilizes the structure of a number of proteins.

Loss of zinc from biological membranes increases their susceptibility to oxidative damage and impairs their function.

•Regulatory role:

•Regulate gene expression by acting as transcription factors (binding to DNA and influencing the transcription of specific genes).

•A role in cell signaling and has been found to influence hormone release and nerve impulse transmission.

•A role in apoptosis , a critical cellular regulatory process with implications for growth and development, as well as a number of chronic diseases.

Nutrient Interactions:Copper: interfere with copper bioavailabilityIron: Supplemental but not dietary levels of

iron may decrease zinc absorption. Calcium: Calcium in combination with phytic

acid reduces zinc absorption, and folic acid: Folate: the bioavailability of dietary folate is

increased by the action of a zinc-dependent enzyme.

Prevention of Diseases

Impaired growth and development: zinc availability affects cell signaling

systems that coordinate the response to the growth-regulating hormone, insulin-like growth factor-1 (IGF-1)

Impaired immune system function: Increased susceptibility to infectious

disease in children and elderly ( vulnerable to mild zinc

deficiency)

Drug InteractionsCertain antibiotics: as tetracyclines and

quinolones, may decrease absorption of the antibiotic

The therapeutic use of metal chelating (binding) agents like: penicillamine (as in Wilson's disease) has resulted in severe zinc deficiency.

Anticonvulsant drugs, especially sodium valproate, may also precipitate zinc deficiency.

Prolonged use of diuretics may increase urinary zinc excretion

The Recommended Dietary Allowance (RDA)The RDA for zinc (8 mg/day for adult women

and 11 mg/day for adult men)

FLOURIDE (FLOURINE)occurs naturally in the Earth's crust, water,

and food as the negatively charged ion, fluoride (F-).

About 95% of the total body fluoride is

found in bones and teeth.

fluoride is not generally considered an essential mineral element because humans do not require it for growth or to sustain life.

• Nutrient Interactions: Calcium and magnesium form insoluble complexes

with fluoride and significantly decreasing fluoride absorption

DeficiencyAn increased risk of dental caries for individuals of all ages.

The Adequate Intake (AI): 0.05 mg/kg of body weight most effectively without

causing the unwanted side effect of tooth enamel mottling known as dental fluorosis.

Disease PreventionPrevention of Dental caries , and osteoporosis.

Drug InteractionsCalcium supplements, as well as calcium and aluminum containing ant acids, can decrease the absorption of fluoride.

It is best to take these products 2 hours before or after fluoride supplements

CHROMIUMThe two most common forms of chromium are

trivalent chromium (III) and hexa valent chromium (VI)

Recent research suggests that a low-molecular-weight chromium-binding substance (LMWCr) may enhance the response of the insulin receptor to insulin. The ability of the LMWCr to activate the insulin receptor is dependent on its chromium content.

Nutrient Interactions:Iron, Vitamin C, and Carbohydrates

Deficiency:

Chromium deficiency was reported in patients on long-term intravenous feeding who did not receive supplemental chromium in their intravenous solutions.

These patients developed evidence of abnormal glucose utilization and increased insulin require ments that responded to chromium supple mentation.

chromium insufficiency has been hypothesized to be a contributing factor to the development of Type 2 diabetes.

The Adequate Intake (AI): from 20 -30 mcg\day.

Disease PreventionImpaired glucose tolerance and type 2 (non-

insulin dependent) diabetes.

Cardiovascular diseases: Impaired glucose tolerance and type 2 diabetes

are associated with adverse changes in lipid profiles and increased risk of cardiovascular diseases.

Increases muscle mass: Claims that chromium supplementation

increases lean body mass and decreases body fat are based on the relationship between chromium and insulin action.

MANGANESE The derivation of its name from the Greek word for magic Manganese (Mn) plays an important role in a

number of physiologic processes as a constituent of some enzymes and as an activator of other enzymes

Antioxidant function: • Manganese super oxide dismutase (MnSOD) is the

principal antioxidant enzyme of mitochondria. • MnSOD catalyzes the conversion of super oxide

radicals to hydrogen peroxide, which can be reduced to water by other antioxidant enzymes.

Metabolism: A number of manganese-activated

enzymes play important roles in the metabolism of carbohydrates, amino acids, and cholesterol. Pyruvate carboxylase, and phospho

enolpyruvate carboxykinase (PEPCK), manganese-activated enzymes, play critical roles in gluconeogenesis.

Arginase, other manganese-containing enzyme, is required by the liver for the urea cycle

• Bone development: Manganese is the preferred cofactor of

enzymes called glycosyl transferases, which are required for the synthesis of proteoglycans that are needed for the formation of healthy cartilage and bone.

Wound healing: manganese is required for the activation

of prolidase, an enzyme that functions to provide the amino acid, proline, for collagen formation in human skin cells.

Nutrient Interactions: iron, magnesium and calcium.

Drug Interactions:Magnesium-containing antacids and laxatives and the antibiotic medication, tetracycline, may decrease the absorption of manganese .

The adequate intake (AI) 2.3 mg/day for adult men and 1.8 mg/day

for adult women.

IRONIn humans, iron is an essential component of

hundreds of proteins and enzymes.Oxygen transport and storage: Hemoglobin and

myoglobinElectron transport and energy metabolism:

Cytochromes are heme-containing compounds that are critical to cellular energy production and therefore life, through their roles in mito chondrial electron transport.

Nonheme iron-containing enzymes, such as NADH dehydro genase and succinate dehydrogenase, are also critical to energy metabolism.

Antioxidant and beneficial pro-oxidant functions: Catalase and peroxidases are heme-containing enzymes that protect cells against the accumulation of hydrogen peroxide, a potentially damaging reactive oxygen species.

DNA synthesis: Ribonucleotide reductase is an iron-dependent

enzyme that is required for DNA synthesis. Regulation of intracellular iron: Iron response elements are short sequences of

nucleotides found in the messenger RNA (mRNA) that codes for key proteins in the regulation of iron storage and metabolism.

Oxygen sensing: Under hypoxic conditions transcription

factors, known as hypoxia inducible factors (HIF), bind to response elements in genes that encode various proteins involved in compensatory responses to hypoxia and increase their synthesis.

Recent research indicates that an iron-dependent prolyl hydroxylase enzyme plays a critical role in regulating HIF and consequently, physiologic responses to hypoxia.

• Nutrient Interactions:

Vitamin A: deficiency may exacerbate iron deficiency anemia.

Copper: Adequate copper nutritional status appears to be necessary for normal iron metabolism and red blood cell formation.

Zinc: iron supplements can inhibit the absorption of zinc.

calcium: decrease the absorption of iron.

Disease PreventionImpaired intellectual development in childrenLead toxicity: Iron deficiency may increase the risk of lead poisoning

in children.Pregnancy complications: severe anemia in pregnant women are associated with

adverse pregnancy outcomes.Impaired immune function: Iron is required by most infectious agents, as well as

by the infected host in order to mount an effective immune response, including the differentiation and proliferation of T lymphocytes and the generation of reactive oxygen species (ROS), which are used for killing pathogens.

Adverse Effects:

At therapeutic levels for iron deficiency, iron supplements may cause: gastro intestinal irritation nausea, and vomiting diarrhea, or constipation. Stools will often appear darker in color

Drug Interactions:Medications that decrease stomach acidity, such as

antacids, histamine (H2) receptor antagonists, and proton pump inhibitors may impair iron absorption.

Decreased absorption and efficacy of the

medication: levodopa, levothyroxine, methyl dopa, penicillamine, quinolones, tetracyclines, and bisphosphonates.

Cholestyramine resin interferes with iron absorption.

The Linus Pauling Institute RecommendationA multivitamin/multimineral supplement

containing 100% of the daily value (DV) for iron provides 18 mg of elemental iron.

COPPERAn essential trace element.The ability of copper to easily accept and donate electrons explains its important role in oxidation-reduction (redox) reactions and the scavenging of free radicals.

Copper is a critical functional component of a number of essential enzymes, known as cuproenzymes.

• Energy production: The copper-dependent enzyme, cytochrome c

oxidase, plays a critical role in cellular energy production. By catalyzing the reduction of molecular oxygen (O2) to water (H2O).

• Connective tissue formation: Another cupro enzyme, lysyl oxidase, is

required for the cross-linking of collagen and elastin, which are essential for the formation of strong and flexible connective tissue.

Iron metabolism: Two copper-containing enzymes, ceruloplasmin

(ferroxidase I) and ferroxidase II have the capacity to oxidize ferrous iron (Fe2+) to ferric iron (Fe3+).

Central nervous system: A number of reactions essential to normal function of the

brain and nervous system are catalyzed by cupro enzymes

Neurotransmitter synthesis, metabolism and the formation and maintenance of myelin:

The myelin sheath is made of phospholipids whose synthesis depends on cytochrome c oxidase activity.

Melanin formation: The cuproenzyme, tyrosinase, is required for the formation

of the pigment melanin.

• Antioxidant Functions: Superoxide dismutase: functions as an antioxidant by catalyzing the conversion of

superoxide radicals to hydrogen peroxide, which can subsequently be reduced to water by other antioxidant enzymes.

Ceruloplasmin: Free copper and iron ions are powerful catalysts of free radical damage.

By binding copper, ceruloplasmin prevents free copper ions from catalyzing oxidative damage.

The ferroxidase activity of ceruloplasmin (oxidation of ferrous iron) facilitates iron loading onto its transport protein, transferrin, and may prevent free ferrous ions (Fe2+) from participating in harmful free radical generating reactions.

Regulation of gene expression:

Copper-dependent transcription factors regulate transcription of specific genes.

Deficiency:Clinically evident or frank copper

deficiency is relatively uncommon.Anemia that is unresponsive to iron

therapy but corrected by copper supplementation.

Abnormal neutropenia and increased susceptibility to infection.

Less common features of copper deficiency may include loss of pigmentation, neurological symptoms, and impaired growth

• Disease Prevention Cardiovascular diseases: Increased serum copper levels have been

associated with increased cardiovascular disease risk .

Immune system function: Development and maintenance of immune

system function, but the exact mechanism of its action is not yet known.

Osteoporosis: lysyl oxidase, is required for cross-linking of collagen, a key element in the organic matrix of bone.

• The Adequate Intake (AI): The RDA for copper 900 mcg/day for adults

IODINEIodine, a non-metallic trace element. Iodine is an essential component of the

thyroid hormones, T3 and T4 and is therefore, essential for normal thyroid function

Deficiency: Thyroid enlargement (goiter)

Disease Prevention: Radiation-induced thyroid cancer.

Disease Treatment: Fibrocystic breast condition.

Nutrient Interactions:Selenium deficiency can exacerbate the effects of iodine deficiency.

Acute Toxicity:Is rare and usually occurs only with doses of many grams.

Symptoms of acute iodine poisoning include burning of the mouth, throat, and stomach, fever, nausea, vomiting, diarrhea, a weak pulse, and coma.

Drug Interactions:Amiodarone contains high levels of iodine and

may affect thyroid function. Medications used to treat hyperthyroidism,

such as propylthiuracil (PTU) and methimazole may increase the risk of hypothyroidism.

Lithium in combination with pharmacologic doses of potassium iodide may result in hypothyroidism.

Pharmacologic doses of potassium iodide may decrease the anticoagulant effect of warfarin .

The Adequate Intake (AI): Given the importance of sufficient iodine during

prenatal development and infancy, pregnant and breastfeeding women should consider taking a supplement providing 150 mcg of iodine/day.

OPTIMIZATION OF INTAKE OF TRACE ELEMENTS

Prevention of deficiency states cannot be regarded as the only end point in terms of provision of micro nutrients. Some measure of functional benefit would appear to be most valuable, as improved immune function and improved antioxidant .

Laboratory tests are of relatively little value with regards to assigning optimal levels of intake.

Most of the laboratory tests are affected by illness, either by the acute-phase reaction with changes in carrier proteins, or by altering the distribution of the trace elements themselves.

SUGGESTED PROVISION OF MICRONUTRIENTS IN CRITICALLY-ILL PATIENTS

Ideally, most critically-ill patients will meet their micronutrient requirements by the enteral route.

In practice, intake of nutrients by the enteral route will be limited and hence intravenous supply should be considered.

Berger & Shenkin have suggested provision of approximately 10 mg Zn, 1·3 mg Cu, chromium 20-35 mcg and 100 mg Se in the intensive care patient.

This level of provision rising to 40 mg Zn, 3·75 mg Cu and 375 mg Se in burn patients.

FACTORS AFFECTING THE MICRONUTRIENT STATUS OF A SEVERLY-INJURED PATIENT

• 1) The status on admission as those consuming excess alcohol, or the elderly.• 2) Increased requirements to meet metabolic demandsdue to hypercatabolism which is associated with severe illness

3) Increased losses Severely-ill patients , blood loss, those who

require haemodialysis or peritoneal dialysis, or who develop complications of surgery leading to gastric aspirate or intestinal fistula losses, will all lose trace elements.

4) Reduced provisionDue to the delay in the full nutrition regimen whilst stabilization the patient condition, so that the prescribed amounts are not provided in each 24 h period.

CONSEQUENCES OF IMPAIRED MICRONUTRIENT STATUS

• Subclinical Deficiency• Initially there is depletion of stores and of tissue

content, with attempts to compensate either by increased absorption from the gut or by reduced excretion.

This stage is followed by a period of reduced intracellular concentration, leading to some impairment of biochemical functions. This stage in turn may lead on to a period of non-specific functional defects where there may be identifiable problems in metabolism, immune function, certain types of cognitive function, or in fatigue and work capacity.

Clinical Deficiency StatesSevere micronutrient deficiency leads to deficiency states, with specific structural or functional changes which are reversible on provision of the individual micronutrient.

The main effects of subclinical deficiency are:

(a) an altered balance of reactive oxygen species and antioxidants

leading to oxidative damage of polyunsaturated fatty acids and nucleic acids, with increased production of pro-inflammatory cytokines;

(b) impaired immune function with increased likelihood of infectious complications.

CONCLUSIONIt is often very difficult to correlate the

biochemistry of a dietary deficiency with clinical symptoms because trace elements have multiple roles in metabolism.

The development of biomarkers to measure oxidative stress means that more reliable and precise estimates of oxidative stress may be made.

Any Questions ?

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