parenteral nutrition are there problems with current doses...

"Are There Problems with Current Doses of Micronutrients?"

Gil Hardy PhD FRSCProfessor of Pharmaceutical and

Clinical Nutrition

New ZealandNew Zealand

Parenteral Nutrition

“No you can’t be a Beatle with that tie”

Liverpool

• Prof Sherwood Jones• Dr Mike Peaston

Whiston HospitalLiverpool

“The Practitioner 1966”

“intravenous feeding is routinely instituted if either oral or tube feeding is contraindicated”

Early HPN Patient – Dr Stan Dudrick1970s

5050+ + componentscomponentsinto a singleinto a single bagbag

All-In-One (AIO) PN Admixtures

First UK HPN patient

at St MarksLondon

1977

Fat Friends?

Thin Friends 1980

Fat Friends 2005

Support GroupSupport Group:

Patients On Intravenous and Naso Gastric Nutrition Therapy

‘Supporting all patients on enteral and parenteral nutrition’

Contact and mutual support for people receiving artificial nutrition in the

community

www.pinnt.co.uk

email: pinnt@dial.pipex.com

Registered Charity 327878

The ‘Champagne Effect’

Are we Flogging a Dead Horse?

Multilayer Bags Oxygen Impermeable

Minimise Vitamin Degradation

Eliminate Air Bubbles

No Champagne Effect

Micronutrients

Vit D Vit C Vit E Biotin

9 Trace Elements

13 Vitamins

Vitamins in Parenteral Nutrition

* FNB – Food and Nutrition Board oral RDA

*

Fat Soluble

Water Soluble

Cernevit®

Identical to

MVI-12®

Not your ordinary nutrients!Vitamins are catalysts for metabolic processes driven by enzymesMany enzymes contain Trace Elements as key componentsMany micronutrients are powerful AntioxidantsMicronutrients are critical and life-saving

“Micro in content: Mega in importance”

Micronutrient - Synergisms

ROOH, ROH Tocopheryl Ascorbate GSSG NADPHFree radicals

Vit E Vit C

ROO-, RO- Tocopherol Dehydro- GSH NADP Ascorbate

GPx (Se) Vit B12

Free Radicals Antioxidants Energy

Too Little:problems of inadequate micronutrients

Impaired Function• ↓Wound Healing • ↓Immunity • ↑Free Radicals

↓Antioxidant Activity

Too Little:problems of inadequate micronutrients

Clinical DeficiencyScurvy, osteomalacia, retinal problems

Thiamine in PN

B1 participates as co-enzyme in oxidative decarboxylation reactions

essential in PN for glucose metabolism body stores very limited

paediatric fatalities due tothiamine deficiency

death due to lactic acidosis,subsequent heart failure

Water-soluble Vitamins B group, Biotin, C, K, Folic acid Not stored by the bodyMust be taken on a regular basis, just as in a regular oral dietExcess excreted in the urine (“renal threshold”)If given too rapidly, renal threshold is exceeded and vitamins lost in urine Unstable in air and sunlight

Vitamins A, D, E

Soluble in body fatStored by the bodyCan overdose (hypervitaminosis A)Overdoses can be toxicCare with storage and administrationVitamin A lost on bag and set surfacesLosses if exposed to sunlight

Vitamin DNature Clinical Practice Gastroenterology & Hepatology (2006) 3, 689-699

• 80 nmol/liter of 25(OH)D

• 3-100 ng/ml of 25(OH)D

• 400 IU/day (DeLuca ASPEN 2009)

• 1600-1800 IU/day (Jacobs 2009)

Vitamin D: Optimal Concentrations

Time in sunshine to achieve dietary equivalent of 1000 IU of vitamin D per day (Jacobs 2009)

25% exposure Webb et al. skin types (1-6):

2 hours, 25 min3 hours, 45 min1 hour, 8 minSkin Type 52 hours, 5 min1 hour, 19 min28 minutesSkin Type 2

January 20

25 minutes17 minutes15 minutesSkin Type 511 minutes7 minutes7 minutesSkin Type 2

July 20

NYC: Partly cloudy at

noon

NYC: Full sunshine at

noon

Tucson: Full sunshine at

noon

Date, Skin Type

Skin type 2: Caucasian, blond or red hair, freckles, fair skin, blue or green eyesVery sensitive to UV; usually burns easily; tans with difficulty, fair skin toneSkin type 5: Middle Eastern, Latin, Light African American, IndianMinimally sensitive to UV; rarely burns, tans easily, olive or dark skin tone

The Answer?

Elements

Mn, Zn, Cu, Fe, Se

Co-enzymes, structural, metabolic

Traces usually obtained from food

HPNers rely almost entirely on

PN regimen

Trace

Too Little or Too Much• Diarrhoea

– Zinc↓ Copper↓• Cholestasis

– Manganese↑• Renal insufficiency

– Aluminium↑• Blood loss

– Iron↓

Hair LossIron↓ Zinc↓ Selenium↕ Biotin↓

• role: Mn S.O.D, pyruvate carboxylaseAntioxidant protection Energy metabolismNo PN deficiency (unless induced)

• dosageAdults: [150-800 μg/d (3-15 μmol/d) AMA][275μg/d AuSPEN 1999 ] 60 - 100 μg/d ASPEN 2004

Recommend: 55μg/day (1 μmol/d) ESPEN 2006Infants : 1 μg/kg/d -1.5 μg/kg/d (max 50μg/d)

Manganese (Mn)

Hardy, Manzanares, Menendez Nutrition 2009Hardy ASPEN Workshop 2009

WARNING: brain accumulation - cholestasis

Manganese in Long Term HPN Patients (Case Reports)

• 25y male HPN 5yrs and 57y male HPN 10yrs• MTE additive: Zn, Cu, Cr, Se, Mn (500mcg/day)

• Plasma Mn: 59.9 and 42.0 nmol/l (normal :5.5-18.2 nmol/l)

• MRI showed Mn deposition in globus pallidus• 9 mo after withdrawal of Mn = MRI normal

• 54 Peds (760g- 65.2kg)• Received 20mcg/kg Cu and 5mcg/kg Mn per day• 15 Cu: 21 Mn: 7 Cu & Mn: 20 had cholestasis• Determine Cu and Mn levels monthly

Mcmillan et al NCP 2008:23;161

Stevens et al NCP 2008:23;197

“opinion is now weighted in favour of excluding opinion is now weighted in favour of excluding MnMn from routine PN regimensfrom routine PN regimens””

• Numerous incidents of PN-associated Mn toxicity and/or hypermanganesemia

• Over 50% of HPN patients may have elevated Mn levels leading to hypermanganesemia– Cerebral, hepatic complications

• No reports of Mn Deficiency

• Mn contamination in additives

• Post mortem data confirm accumulation of Mn(Howard and Shenkin 2007)

COCNMC 2008

Hypermanganesemia

Selenium

Incorporated into Selenoproteins (25+)

• Glutathione Peroxidase (GPx) contains 4 atoms Selenium

• important Antioxidant - removes lipid peroxides

• anti-inflammatory – down regulates NFkB

• Essential for Male Fertility (XY) and Reproduction

• GPx protects developing sperm

Only trace element specified in Genetic Codei.e. Selenocysteine (21st Amino Acid)

“The Se-XY Nutraceutical”

Factors affecting micro-nutrient stability in PN

• Amino Acid buffering• Fat Emulsion source• Electrolytes and

Antioxidants• Concentrations of

nutrients and pH• Sequence of Mixing

*Oxygen * Light * Heat 0

20

40

60

80

100

0 7 14 21 28 60 90 120 150 180

-2 C 4 C 25 C

Time/Days

% T

hiam

ine

% V

itam

in C

Allwood & Hardy Clin Nutr 1992

Trace Elements vs Vitamins in PN

Vitamin C oxidation is catalysedby copper ions or seleniteVitamin C losses 48 hours after mixing

Selenite interacts with Vitamin C at low pHFerric iron may destabilise lipid-PNAdditives must be kept apart until

immediately before administrationAdverse influences of air and light

Protect all PN from Light!

DosageRecommendations

• Zinc: 1-3mg/d adults• 12mg/L g.i losses, diarrhea

• Copper: 0.3mg/d adults• 0.4-0.5mg/d diarrhea• 20mcg/kg/d peds

• Chromium: 10-15mcg/d adults• 0.14-0.2mcg/kg/d peds

• Selenium: 60-100mcg/d adults• 2-2.5mcg/kg/d peds

• Iron: 1mg/d adult males• 1.5mg/d adult females• 500mcg/d peds

• Iodine: 70-150mcg/d adults• 1mcg/kg/d peds

Gastroenterology 2009

DosageRecommendations

• Vitamin C: 100-200mg/d adults• 20-100mg/d peds

• Vitamin D: 30-100 ng/ml 25OH D• 400 IU/d

• Vitamin K: 150mcg/d adults• 2.5-5mg/week• 10mcg/d peds

• Choline: 1-2g/d adults• Carnitine 2-5mg/d adults

• Biotin: 60-69mcg/d adults

• Vitamin B12: 6-50mcg/d adults

Gastroenterology 2009

Daniells & Hardy COCNMC 2010

Manzanares & Hardy COCNMC 2010

More is not always better !

More is not always better !

Chromium >3mg ↑ joint degeneration, immune problemsCopper > 5mg ↑ behavioural problems, infections, anemiaIron ↑ vomiting, diarrhoea, hyperglycemiaManganese ↑ neuro symptomsSelenium > 750 mcg/d ↓ Deiodination, ↑ hair + nail discolorationZinc > 50 mcg/d ↓ immunity Vitamin C > 1 g/d ↑ oxalosis, acute RFVitamin E > 150 mg/d ↑ mortality Some Tocopherols ↑ toxic (tocotrienols)

Conclusion• Long Term HPNers may have increased

micronutrient requirements.

• Micro supplements can:– improve antioxidant capacity– enhance the immune response – reduce infection rates

• CARE:– A Trace is Good. More is not always Better– Make All Additions Aseptically: Protect from Light– Monitor regularly

• RESEARCH

Micronutrients: Future Research

• Better data on deficiency syndromes• Optimum requirements in IF• Synergy between micronutrients• Efficacy of supra-physiological doses• Better Analytical methods• Stability and compatibility issues

Do you have other problems/questions?

Do you have other problems/questions?

Thanks to PN-DU

A Troop of A Troop of PendoosPendoos

contactpndu@gmail.com

Here’s to the Next 25 Years !!!