Vitamins & Trace elements –What is evidence based?

Micronutrients in clinical nutrition How much evidence is required?

Pr. Mette M BergerAdult Intensive Care & Burns CentreCHUV – Lausanne - Switzerland

Paleolithic nutrition revisitedEstimated daily paleolithic intake vs. actual

Eaton SB et al, Europ J Clin Nutr, 51: 207, 1997

Paleolithic RDA Current USEnergy (kcal) 3000 2200-2900 1750-2000Fiber (g) 104 20-30 10-20Riboflavin (mg) 6.5 1.3-1.7 1.3-2.1Folate 0.36 0.2 0.15-0.2Thiamin 3.9 1.1-1.5 1.1-1.8Ascorbate 604 60 77-109 Carotene (RE) 2870 800-1000 1170Tocopherol 32.8 8-10 7-10Iron 87.4 10-15 10-11Calcium 1960 800-1200 750Zinc 43.4 12-15 10-15

MICRONUTRIMENTS et IMMUNITÉ CELLULAIRE

ZnB6

thymuline

thymulineactive

thymus

ZnB6

Vit A

synthèse IL-2, IL-3

maturation des LT

lymphocyte T

Zn

polynucléaires

macrophages

IL - 1

chimiotactismephagocytosebactéricidie

ZnSeCuB9

Vit C

action mitogéniquedirecte

ZnSeB6B9

Vit AVit EJF Zazzo

Malnutrition and InfectionAlternative model - Beck MA 1999

MalnutritionMicronutrient deficiency

Oxidative stress

Immunity virus virulenceSusceptibility to pathogens

(viral, bacteria, fungi)

Infections

Micronutrients – in clinical nutrition- in clinical settings?

Micronutrients = integral part of nutritionProportionality between macro-and micro-nutrientsAnswer 1 – Evidence Level A

Micronutrients = pharmacologic agentsaiming at AOX reinforcementAnswer 1 – Evidence Level A

Decline of serum/plasma levels over the years.Evidence that European intakes of selenium are falling

Selenium - Time to act Rayman, BMJ 314: 387, 1997

The argument for ⇑ selenium intakeRayman MP, Proc Nutrition Society 61: 203 2002

Recent mean levels of serum or plasma Se in Europe compared with (---), bottom tertile in Nutritional Prevention of Cancer (NPC) trial of Clark et al. (1996); (·····), level required for optimal plasma GPx activity

Status in Critical illnessOxidative stressTrace elements

Plasma redox status relates to severity in critically ill patients

Alonso de Vega J et al, CCM 28:1812, 2000

APACHE III scores and plasma redox status (r2 = 0.56; p < .001) as defined by the ratio total antioxidant capacity (mM) /lipoperoxides (uM)

APACHE III scores and plasma myeloperoxidase concentrations (r2 = 058; p < .001)

73 patients at admission to a mixed ICU: 8 deaths

Reactive oxygen species production in the critically ill

Infection, acute illnessSurgery (major thoracic, abdominal)Trauma, burn

Local +systemic response

SIRS

ICU ttt- mech vent

- cvvh- drugs

Secondary organ failure:

gut, liver, kidney, lung,

Brain …

ShockReperfusion

injury

TE status challenges in critically illBorderline/actual deficiency: frequentCausesAcute phase response stress

redistribution to liver, spleendepletion of vascular compartment

Losses ⇐ condition (exudates, drains, urines, digestive losses)

Losses ⇐ treatment (CVVH, ..)⇑ requirements (hypermetabolism, oxidative stress)Low intakes (EN < 2000 kcal, poor absorption, no IV supplements)

Antioxidants status in the critically illSelenium in plasma

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

µmol/L

ICU ICU SIRS SIRS Sepsis Trauma D2 Burns D2n = 175 134 42 94 40 43 45

Ref Hawker F. Angstwurm Forceville 98 Berger 96 Berger 92-98

Se pl

asma

leve

ls

Negative balances – the causes in critically illBerger, NCP 21:438, 2006

Pre-admission deficit

Trace elements in burns : Balance studyZinc losses

Berger et al, Burns 1992, 18:373

n = 10TBSA 33 %

0

50

100

150

200

Zn (m

g)

0 1 2 3 4 5 6 7Days post-injury

Cutaneous exsudate

Aspirations

Feces

Urine

TE in TraumaSe Balances (without supplements)

Berger MM et al, J Trauma, 40:103, 1996

n = 11x ± sd

-100

-75

-50

-25

0

25

µg /

24h

0 1 2 3 4 5 6 7Days post-injury

Berger et al 1994

Selenium

Micronutrient losses during CVVHBerger MM et al, Amer J Clin Nutr, 410, 2004

Plasma Cu, Se, Zn, and thiamine in effluents from patients with acute renal failure under CRRT with either Na-bicarbonate (Bic group; Full) or Na- lactate (Lac group;

)

Redox balance during critical illness

ProOX enzyme activity(NADPH oxidase, xanthine oxidase, mitochondrialrespiratory chain)NO, O2, H2O2, ONOO, HOCL

AOX enzyme activity(GSHPx, SOD, catalase)GSH SH functionsFAD, NADPAntioxidants

Oxidative stressICU patients ⇑ ⇑ ⇑

⇓ ⇓ ⇓

AOX defences

AntioxidantDefinition

Any substance that significantly delays or inhibits oxidation of a substrate, when present at low

concentrations compared to those of that substrate

Halliwell B & Gutteridge JMC, 1989

Antioxydants endogènesd’origine nutritionnelle

Eléments traces Cuivre (pro-)ManganèseSéléniumZinc

Vitamines Vitamine CVitamine ERétinol (A)Vitamine Q10

Can oxidative damage be ttt nutritionally?Berger MM Clin Nutr, 2005

NutritionalAOX intakeAOX defence

Qua

ntity

Oxidative damage

Normalrange

Time (minutes → years)

Injury – Acute disease

1

2

Evidences in the critically illFrequent pre-illness precarious conditionIncreased metabolic requirementsNegative micronutrient balances are frequent in the ICU due to

losses of biological intakes and hypocaloric feeding

Oxidative stress +++AOX Micronutrients are depleted

What should we do?

PRCT TE supplementation trial in major burns- Outcome

Berger et al, Am J Clin Nutr, 1998, 68:365

Group Placebo Group TEn = 10 n = 10

Death 0 1Infections 3.0 ± 1.0 * 1.9 ± 0.8 *LOS 66 ± 31 54 ± 27LICU/ BSA 0.6 ± 0.3 0.4 ± 0.2LBU / BSA 0.9 ± 0.3 * 0.6 ± 0.2 *LOS / BSA 1.5 ± 0.8 1.1 ± 0.7* p < 0.02, BU = Burns Unit

TE supplements in burns3 consecutive trials – Se doses

Berger & Chiolero, Crit Care & Shock, 2002, 2:91

0.00

0.50

1.00

1.50µmol/L

0 5 10 15 20 25Days

Selenium

Trial2Trial 1Trial 3Placebo

Se dose1: 0.6 µmol

2: 2.93 µmol

3: 4.8 µmol

Burns : Tissue Se, Zn & GSH…Berger et al, Amer J Clin Nutr, 2007

p < 0.01

p < 0.02

Trace element (Cu,Se,Zn) substitution in Burns - Nosocomial pneumoniaBerger et al, 2006, Crit Care e-pub

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

3 8 13 18 23 28 Days

ETP

65% reductionof pneumonia

risk

Aggregation of 2 consecutiveRandomizedtrials

Log Rank p=0.0014Wilcoxon p=0.0019

Antioxidants in critically illSelenium replacement in severe SIRS patients

Angstwurm et al, Crit Care Med, 27: 1807, 1999

42 patientsAge 59 / 54 yrsF/M 8/13 5/16Apache II:

19 / 17

Day 0: nsDay 3: p < .001Day 7: p < .001Day 14: p < .013

AOX Trace elements reduce mortality in ICU patients - Selenium

Heyland et al, Intensive Care Med, 31:321, 2005

199119961997

RR 0.52 – 95% confidence intervals 0.28-0.94, p = 0.04Trials with positive impact used TE (Se and Zn)Vitamins alone: no impact

Selenium in ICU SIRS-sepsis patients – PRCTAngstwurm et al- CCM 35:118,2007

249 patients - severe sepsis or septic shock: 1000 mcg Se or placebo daily for 2 weeks after a loading doseKaplan -Meier survivalcurves in patients by intention to treatanalysis. Differencebetween groups by log rank test.

The estimated mean survival time was 19.7 days in Se1 patients (bold line) versus 16.4 days in the Se0 group (dotted line) (p = 0.0476).

AOX trial – 200 ICU patients: trauma-cardiacSe-Zn, Vit E, Vit C, Vit B1Berger et al in preparation

0.00.10.20.30.40.50.60.70.80.91.0

Prob

abili

ty o

f hsp

ital s

tay

0 10 20 30 40 50 60 70 80 90 100 120 140Total LOS (days)

Prob>Chi2

Log Rank p=0.248Wilcoxon p=0.180

Pro

abilit

y of

hos

pita

l sta

y

0.00.10.20.30.40.50.60.70.80.91.0

0 10 20 30 40 50 60 70 80 90 100 110 120Total LOS (days)

Log-Rank p=0.0177Wilcoxon p=0.0039

PlaceboAOX

Pro

abilit

y of

hos

pita

l sta

y

0.00.10.20.30.40.50.60.70.80.91.0

0 10 20 30 40 50 60 70 80 90 100 110 1200.00.10.20.30.40.50.60.70.80.91.0

0.00.10.20.30.40.50.60.70.80.91.0

0 10 20 30 40 50 60 70 80 90 100 110 1200 10 20 30 40 50 60 70 80 90 100 110 120Total LOS (days)

Log-Rank p=0.0177Wilcoxon p=0.0039

PlaceboAOXPlaceboAOX

All 200:

Kaplan-Meyer analysis of length of hospital stay in all 200 and trauma surviving patients –trend (p=0.18) to shorter stay in supplemented patients – significant in trauma

Supplementation

Enteral or I.V.or both?

Intestinal absorption of micronutrientsTrace elements Absorption Body pool

Fe 5-15% 3-5 gZn 10-30% 3 gCu 20-50% 150 mgSe 80-90% 9 mgMn 1.3%M, 3.6%F 2.5 mgCr III 0.4-2.5% < 1 mg

Vitaminsthiamine - B1 90%A 70-90%K 80-100%

Influence of fluid resuscitation on visceral edema

Kinsky MP et al, J Trauma, 49: 844 2000Tissue water content for colon, ileum, kidney, liver, pancreas, and skeletal muscle. Mean ± SEM from 9 to 12 animals per group. Asterisk indicates p < 0.05, HSD (7.5% NaCl/6% dextran70) versus LR; [psi], p < 0.05, HSD vs nonburned skin; [delta], p < 0.05, LR vsnonburned skin.

0

50

100

150µg/L

Se-1 Se+1 Se+3 Se+5

Selenium

Mean

14

13

12

11

10

9

8

7

6

5

4

3

2

1

0

1

2

µmol/l

Cr-1 Cr+1 Cr+3 Cr+5

Chromium

0

5

10

15

20

Preop Op +1 +3 +5

Time (days)

Zinc

Patients

0

50

100

150µg/L

Se-1 Se+1 Se+3 Se+5

Selenium

Mean

14

13

12

11

10

9

8

7

6

5

4

3

2

1

0

50

100

150µg/L

Se-1 Se+1 Se+3 Se+5

Selenium

Mean

14

13

12

11

10

9

8

7

6

5

4

3

2

1

0

1

2

µmol/l

Cr-1 Cr+1 Cr+3 Cr+5

Chromium

0

1

2

µmol/l

Cr-1 Cr+1 Cr+3 Cr+5

Chromium

0

5

10

15

20

Preop Op +1 +3 +5

Time (days)

Zinc

0

5

10

15

20

Preop Op +1 +3 +5

Time (days)

Zinc

Patients

N = 14Age 65 yrs - Weight 70 kg4 days of SupplementationEarly EN with:Chromium 400 ugSelenium 300 ugZinc 20 mg

Safety and intestinal tolerance

of high-dose enteral AOX and

glutamine peptides after upper

gastrointestinalsurgery

Schroeder et alEur J Clin Nutr (2005,

59:307)

0

20

40

60

AT-1 AT+1 AT+3 AT+5

α-tocopherol

Mean

14

13

12

11

10

9

8

7

6

5

4

3

2

1

0

25

50

75µmol/l

AA-1 AA+1 AA+3 AA+5

Ascorbic acid

0

0.2

0.4

0.6

Preop Op +1 +3 +5

Time (days)

ß-carotene

Patients

0

20

40

60

AT-1 AT+1 AT+3 AT+5

α-tocopherol

Mean

14

13

12

11

10

9

8

7

6

5

4

3

2

1

0

20

40

60

AT-1 AT+1 AT+3 AT+5

α-tocopherol

Mean

14

13

12

11

10

9

8

7

6

5

4

3

2

1

0

25

50

75µmol/l

AA-1 AA+1 AA+3 AA+5

Ascorbic acid

0

0.2

0.4

0.6

Preop Op +1 +3 +5

Time (days)

ß-carotene

Patients

0

25

50

75µmol/l

AA-1 AA+1 AA+3 AA+5

Ascorbic acid

0

25

50

75µmol/l

AA-1 AA+1 AA+3 AA+5

Ascorbic acid

0

0.2

0.4

0.6

Preop Op +1 +3 +5

Time (days)

ß-carotene

Patients

0

0.2

0.4

0.6

Preop Op +1 +3 +5

Time (days)

ß-carotene

0

0.2

0.4

0.6

Preop Op +1 +3 +5

Time (days)

ß-carotene

Patients

Safety and intestinal tolerance

of high-dose enteral AOX and

glutamine peptides after upper

gastrointestinalsurgery

Schroeder et alEur J Clin Nutr (2005,

59:307)

Micronutrients: alone or in combination?

ROO-, RO-

ROOH, ROHGSSG

2 GSH

NADPH

NADP+

Ascorbate

Dehydro-Ascorbate

Tocopheryl-

Tocopherol

Glutamic acid+Cysteine+Glycine

α-ceto-glutarate → Glutamate → Glutamine ↔

Selenium +Cysteine+.. ↓GSH-peroxydase

Dihydrolipoic acid

Lipoic acid

ROO-, RO-

ROOH, ROHGSSG

2 GSH

NADPH

NADP+

Ascorbate

Dehydro-Ascorbate

Tocopheryl-

Tocopherol

Glutamic acid+Cysteine+Glycine

α-ceto-glutarate → Glutamate → Glutamine ↔α-ceto-glutarate → Glutamate → Glutamine ↔

Selenium +Cysteine+.. ↓GSH-peroxydase

Selenium +Cysteine+.. ↓GSH-peroxydase

Dihydrolipoic acid

Lipoic acidDihydrolipoic acid

Lipoic acid

Berger & Chiolero CCM 2007

PRCT AOX trial in critically ill surgical patientsNathens AB et al, Ann Surg, 236: 814, 2002

Patient characteristics (mean SD)n = 575 / 770 Placebo (294) AOX (301)Age 39 ± 15 38 ± 15Trauma 268 (91%) 274 (91%)ISS 20 ± 11 19 ± 10APACHE II 14 ± 6 14 ± 6Shock 93 (31%) 78 (26%)LICU 6.4 5.3MOF 18 (6.1%) 8 (2.7%)Mortality hospital 9 (3.1%) 5 (1.7%)

PRCT AOX trial in critically ill surgical patientsRisk of pulmonary morbidity (ARDS or pneumonia)Nathens AB et al, Ann Surg, 236: 814, 2002

Trend to lower likelihood of pulmonary morbidity (p = 0.2)Solid: placebo; ---: AOX

301 patients on AOX supplement294 patients on standard care

Effect of micronutrient supplements on quality of life and ventricular function in elderly CHF patientsWitte K et al, Europ Heart J, 2005, 26:2238Long term (9 months) micronut supplements (Ca,

Mg, Zn, Cu, Se, VitA, B1, riboflavine, B6, folate, B12, vit C, E, D, coenz Q10) vs placebo

30 patients aged 75 yearsLVEF < 35%Results: patients well matched, 2 deathsLV volumes in micronut (-13.1% vs –3.8% in P)LVEF in micronut by 5.3% (no change in P): p <

0.05QoL in micronut by 9.5 (-1.1 in placebo)

Quality of life score (% maximum) for patients taking placebo (unfilled circles) or micronutrient supplementation (filled circles)

Change in left ventricular end-diastolic volume with placebo and micronutrient supplementation

Effect of micronutrient supplements on quality of life and ventricular function in elderly CHF patientsWitte K et al, Europ Heart J, 2005, 26:2238

Micronutrients in clinical nutrition?How much evidence? Conclusion

Nutrition includes Micronutrients Hypermetabolic patients have requirements of all of them - no further evidence is required

Intakes should with other nutrientsCritically ill have an altered micronutrient status, with a depletion of the circulating compartment

acute phase responselosses

Losses should be SubstitutedTiming: immediately ♣

Micronutrients in ICU patientsConclusions

Oxidative stress is present in in most acute ICU patients

Micronutrients and particularly Se are essential AOX activity can be restored by supplements

Large supplements => better clinical outcome = enough arguments for early intervention

Supplementation is rationalTiming: early therapeutic window

Micronutrients in clinical nutrition?How much evidence? Conclusion

Route: bioavailability - IV only certain Open questions:Which Combinations of micronutrients?

TE: Selenium, ZincVitamins: C, EGlutamine, glutathione, omega-3

Doses? Avoid prooxidation

Trauma, burn & septic ICU patients should receive additional supplementsMinimal combination: Se, Zn, B1

♣

SeleniumA lunatic element3rd millenium: “ THE “ antioxidant