بسم الله الرحمن الرحيم

1. بسم الله الرحمن الرحيم

2. Microneutrients By Dr Noha M. Elsharnouby Lecturer of Anesthesia and intensive care and pain management Ain Shams university

3. 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.

4. What is the evidence in ICU? • Early enteral feeding is best • Hyperglycaemia/overfeeding are bad • Nutritional deficit causes worse outcome • EN causes aspiration and VAP, while PN cause infection • EN and PN can be used to achieve goals • Protocols improve delivery of feeding • Some nutrients show promising results

5. Anti-oxidants • Normal state: reduction > oxidation • Acute stress: injury/sepsis causes acute dysregulation: ROS/RNOS formed • Mitochondria are both sources and targets • Observational studies: anti-oxidant capacity inversely correlated with disease severity due to depletion during oxidative stress

6. Reactive Oxygen Species O-, NO- Positive actions: • Bactericidal • Regulation of vascular tone • Cell signalling But mostly detrimental: Cell injury (ischaemia /reperfusion) • DNA, Lipids, Proteins Organ dysfunction • Lungs, Heart, Kidney Liver, Blood, Brain

7. ACUTE INSULT Inflammatory mediators ROS/RNOS Exacerbation of cell and tissue injury Healing/repair/defence

8. Microneutrient • Present 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.

9. 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.

10. Selenium • Humans and animals require selenium for the function of a number of selenium-dependent enzymes, also known as selenoproteins. • Seleinumfunction involves selenoproteins, glutathione peroxi­dases, thioredoxin, and iodothyroninedeiodinases (thyroid hormone deiodinases).

11. Nutrient interactions: • Selenium appears to support the activity of vitamin E (a-tocopherol) in limiting the oxidation of lipids. • Thioredoxinreductase 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,

12. Disease Prevention • Immune 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

13. 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.

14. 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 hairandnail 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.

15. 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)

16. MOLYBDENUM • function as a cofactor for three enzymes. • Sulfite oxidasecatalyzes 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. • Xanthineoxidasecatalyzes the breakdown of nucleotides (precursors to DNA and RNA) to form uric acid, which contributes to the antioxidant capacity of the blood. • Xanthineoxidase and aldehydeoxidasealso play a role in the metabolism of drugs and toxins.

17. Deficiency • has 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.

18. 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.

19. 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.

20. 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.

21. 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.

22. Nutrient Interactions: • Copper: interfere with copper bioavailability • Iron: 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.

23. 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)

24. Drug Interactions • Certain 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 diureticsmay increase urinary zinc excretion

25. The Recommended Dietary Allowance (RDA) • The RDA for zinc (8 mg/day for adult women and 11 mg/day for adult men)

26. 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.

27. 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 weightmost effectively without causing the unwanted side effect of tooth enamel mottling known as dental fluorosis. • Disease PreventionPrevention of Dental caries , and osteoporosis.

28. Drug Interactions • Calcium supplements, as well as calcium and aluminum containing ant­acids, can decrease the absorption of fluoride. • It is best to take these products 2 hours before or after fluoride supplements

29. CHROMIUM • The two most common forms of chromium are trivalent chromium (III) and hexa­valent 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

30. 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 require­ments that responded to chromium supple­mentation. • 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.

31. Disease Prevention • Impaired 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.

32. 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 super­oxide dismutase (MnSOD) is the principal antioxidant enzyme of mitochondria. • MnSOD catalyzes the conversion of super­oxide radicals to hydrogen peroxide, which can be reduced to water by other antioxidant enzymes.

33. Metabolism: • A number of manganese-activated enzymes play important roles in the metabolism of carbohydrates, amino acids, and cholesterol. • Pyruvatecarboxylase, and phospho­enolpyruvatecarboxykinase (PEPCK), manganese-activated enzymes, play critical roles in gluconeogenesis. • Arginase, other manganese-containing enzyme, is required by the liver for the urea cycle

34. Bone development: Manganese is the preferred cofactor of enzymes called glycosyl­transferases, 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.

35. 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.

36. IRON • In humans, iron is an essential component of hundreds of proteins and enzymes. • Oxygen transport and storage: Hemoglobin and myoglobin • Electron transport and energy metabolism: Cytochromes are heme-containing compounds that are critical to cellular energy production and therefore life, through their roles in mito­chondrial electron transport. • Nonheme iron-containing enzymes, such as NADH dehydro­genase and succinatedehydrogenase, are also critical to energy metabolism.

37. 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: Ribonucleotidereductase 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.

38. 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 prolylhydroxylase enzyme plays a critical role in regulating HIF and consequently, physiologic responses to hypoxia.

39. 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.

40. Disease Prevention • Impaired intellectual development in children • Lead 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.

41. Adverse Effects: • At therapeutic levels for iron deficiency, iron supplements may cause: • gastro­intestinal irritation • nausea, and vomiting • diarrhea, or constipation. • Stools will often appear darker in color

42. 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, methyl­dopa, penicillamine, quinolones, tetracyclines, and bisphosphonates. • Cholestyramine resin interferes with iron absorption.

43. The Linus Pauling Institute Recommendation • A multivitamin/multimineral supplement containing 100% of the daily value (DV) for iron provides 18 mg of elemental iron.

44. COPPER • An 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.

45. Energy production: The copper-dependent enzyme, cytochromecoxidase, plays a critical role in cellular energy production. By catalyzing the reduction of molecular oxygen (O2) to water (H2O). • Connective tissue formation: Another cupro­enzyme, lysyloxidase, is required for the cross-linking of collagen and elastin, which are essential for the formation of strong and flexible connective tissue.

46. 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 cupro­enzymes • 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.

47. 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.

48. Regulation of gene expression: • Copper-dependent transcription factors regulate transcription of specific genes.

49. 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

50. 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: lysyloxidase, 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