ESPEN Congress Florence 2008

The long-term ICU patient

Micronutrient requirements of the long-term ICU

patient

Mette M. Berger (Switzerland)

Micronutrient requirements of the long-term ICU patient

Mette M. Berger Dpt of Intensive Care Medicine & Burns

CHUV – Lausanne - Switzerland

25

« Long-term » ICU patient

ICU treatment > 7 days? > 14 days ?

Persistent organ failure

What about the gut?

Organ failure by SOFA score

Cardio / resp / renal / liver (bili) / hemato / neuro

What about the gut?

Essential MicronutrientsTrace elements (10) Vitamins (13)

Cu Copper A Retinol

Se Selenium D Cholecalciferol

Zn Zinc E Alpha-tocopherol

Fe Iron K Phyloquinone

Mn Manganese B1 Thiamin

Mo Molybdenum B2 Riboflavin

Cr Chromium B3 Niacin(PP)

F Fluoride B5 Pantothenic acid

I Iodide B6 Pyridoxine

Co Cobalt B8 Biotine(H)

B9 Folic acid

B12 Cobalamin

+ 4 Ni, Si, Sn, V C Ascorbic acid

Micronutrients FunctionsNutrition + Prevention of deficiencies: Anabolism enzyme cofactors of carbohydrate,

lipid and protein metabolism

Immunity Humoral: immunoglobulin production

Cellular: macrophages, neutrophil, lymphocytes

Regulation Gene expression

AOX defence Confine free radicals in defined spaces and [ ]

Modulation of the extension of acute diseases

Prevention of chronic diseases

The argument for selenium intake in EuropeRayman MP, Proceedings of the 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

Monitoring micronutrients – why ?

Some pathologies are associated with altered

absorption (pernicious anaemia, bariatric surgery,

inflammatory bowel diseases, celiac disease)

Some conditions losses: inflammatory bowel

disease, fistulae, burns, haemorrhage

Some of our therapies directly deplete the

patients of hydrosoluble micronutrients such as

renal replacement therapies, drains

Status is unpredictable Hyper- & Hypo- both deleterious

Chronic conditions – bariatric surgeryInflammatory bowel diseasesFluid resuscitation

Absorption issues

Nutritional follow up after gastric bypassGasteyer et Giusti, Rev Med Suisse, 2:844, 2006

0

20

40

60

80

100

3 6 12 18 24

Time after bypass (months)

% substitutionMicronutrient

Bariatric surgery

Impact of fluid resuscitation on visceral edemaKinsky MP et al, J Trauma, 49: 844 2000

Tissue 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% dextran

70) versus LR; [psi], p < 0.05,

HSD vs nonburned skin;

[delta], p < 0.05, LR vs

nonburned skin.

The ICU patient

Impact on micronutrient status

Oxidative stress

Inflammation

Organ failure

Trace elementsAcute phase response

Shenkin, Nutrition 11:100, 1995

0

5

10

15

20

25

µm

ol /

L

-16 -8 0 8 16 24 32 40 48

Time (hours)

Incision

Cu

Fe

Zn

Oxidative stress and metallothionein expression - liver of rats with severe thermal injury Ding et al Burns, 28:215, 2002

Effects of severe thermal injury on the zinc concentrations both in the serum

and in the liver. mean±sem, n=5. *P<0.001, **P<0.01 and # P<0.05 vs. the

corresponding normal control

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

Trace elements in burns : Balance study Copper losses

Berger et al, Burns 1992, 18:373

n = 10TBSA 33 %

0

5

10

15

20

25

30

35

Cu

(m

g)

0 1 2 3 4 5 6 7

Days post-injury

Cutaneous exsudate

Aspirations

Feces

Urine

Se balances after major trauma Berger MM et al, J Trauma, 40:103, 1996

-100

-75

-50

-25

0

25

µg

/ 2

4h

0 1 2 3 4 5 6 7

Days post-injury

Selenium

n = 11x ± sd

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; )

Trace Elements RequirementsChanging paradigms

Controversies regarding how to establish recommended intakes

Making universal recommendations among the different ecologic, anthropologic, and geographic settings appears futile

Lower than normal body stores may be adaptiveGaps in our knowledge regarding the bases of

nutrient requirementsTE are inorganic: potential for accumulation (Cu,

Fe, Mn) and toxicityScientists must produce new evidences

Solomons & Ruz, 1998

New integrative concept Dietary Reference Intakes (DRI)

Set of 4 reference values:

Estimated Average Requirements (EAR)

Recommended Dietary Allowances (RDA)

Adequate Intakes (AI)

Tolerable Upper Intake Levels (UL)

Antioxidants - Synergisms

ROOH, ROH Tocopheryl Ascorbate GSSG NADPHradical

Vitamin E Vitamin C

ROO-, RO

- Tocopherol Dehydro- GSH NADP Ascorbate

Malnutrition and InfectionAlternative model - Beck MA 1999

Malnutrition

Micronutrient deficiency

Immunity virus virulence Susceptibility to pathogens

(viral, bacteria, fungi)

Infections

Oxidative stress

Critically ill

Requirements

Supplementation Trials

Micronutrient supplementation – AimsBerger & Shenkin, Curr Opin Clin NutMC,

9:711,2006

Nutritional effect (intermediate metabolism)

Substituting for losses = restore normal status

and enzyme activity

Providing supranormal status = pharmacological

AOX action

Decrease and shorten the inflammatory response

Can oxidative damage be treated nutritionally?

Berger MM Clin Nutr, 2005

Nutritional

AOX intake

AOX defence

Qu

an

tity

Oxidative

damage

Normal

range

Time (minutes years)

Injury – Acute disease

1

2

Trace element in Burns – Plasma TE, GSHPx

Berger et al, 2006, submitted

Higher plasma Se &

Gshpx

concentrations in

TE group

from day 5.

Antioxidants TE in major burnsMDA with trace element

supplementsBerger & Chiolero, Burns, 21: 507, 1995

Design: PCT

11 patients

(5 / 6)

BSA 42 / 43 %

- control: ø

- TE: Cu,Se,Zn

Urine:

24 hr collection

p < 0.030

50

100

150

200

1 2 3 4 5 6 7 10 15 20 Days

MDA (µmol/24hr)

Group C

Group TE

PRCT TE supplementation trial in major burns- Outcome

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

Group Placebo Group TE

n = 10 n = 10

Death 0 1

Infections 3.0 ± 1.0 * 1.9 ± 0.8 *

LOS 66 ± 31 54 ± 27

LICU/ BSA 0.6 ± 0.3 0.4 ± 0.2

LBU / 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

Trace element in Burns – Tissue Se, Zn & GSH…Berger et al, 2006, submitted

p < 0.01

p < 0.02

Time to first

Nosocomial

Pneumonia

N = 41

Burns 45% BSA

p=0.002 by

stratified

Log rank test

Trace element in burns – Nosocomial pneumoniaBerger et al, Critical Care 2006 in press

Selenium in ICU SIRS-sepsis patients – PRCTAngstwurm et al- CCM 2006 in press

249 patients in severe sepsis or septic shock: 1000 mcg Se or placebo daily for 2 weeks after a loading dose

Kaplan -Meier survival curves in patients by intention to treat analysis. Difference between 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).

EN enriched with carotenoids normalizes the carotenoid status and oxidative stress in long-

term enterally fed patientsVaisman N et al, Clin Nutr 2006, 25:897

PRCT : 2 x 25 patients: Mean serum carotenoid levels (ng/ml)

and CI; low dose carotenoid mixture (3 mg/1500 kcal: Nutrison® Nutricia)

EN enriched with carotenoids normalizes the carotenoid status and oxidative stress in long-

term enterally fed patientsVaisman N et al, Clin Nutr 2006, 25:897

NFkB and MDA evolution

More is not always better !

Vitamins: lack of a salutary effect consistently for various doses (Vit E 50-800 IU) of vitamins in diverse populations Vivekananthan DP et al Lancet.

2003;361:2017

High-dosage vit. E supplements may increase all-cause mortality Miller RD et al Ann Intern Med, 2005 142:37

Specific forms of tocopherol in excess may be toxic (tocotrienols). Warrants strategic investment into the lesser known forms of vitamin ESen et al, Life Sci, 2006;78(18):2088

Dose response curveB

iolo

gic

ca

l activity

A+B+C deficieny, D suboptimal, E optimal, G toxicity, H lethal

Effect of excessive micronutrient intakes

Chromium >3mg Spinal / joint degeneration,

immunity problems

Copper > 5mg behavioural problems, vascular

defects, infections, anemia, Wilson’s d

Iron vomiting, diarrhoea, metabolic acidosis,

hyperglycemia

Manganese neuro: extrapyramidal symptoms

Selenium > 750 mcg/d Deiodination, hair + nail discoloration

Zinc > 50 mcg/d immunity

Vitamin C > 1 g/d oxalosis, acute RF

Vitamin E > 150 mg/d mortality

Micronutrients - Why monitor?

Status is unpredictable

Absorption uncertain with bowel oedema

Hypo-status deleterious

–Deficiency associated with altered immune and

AOX defences

Hyper-status deleterious too: toxicity

You can do something about the status

Targets can be defined for some micronutrients:

plasma levels/activities

Helps defining length of supplementation

Micronutrient monitoring - plasma– which ones? – when? – interpretation?

Trace elements

Selenium burns, TPN, CVVH

Zinc burns, trauma, TPN

Iron /ferritin anemia

Copper bariatric surg, burns

Chromium insulin R+++ TPN

Manganese home TPN

Vitamins - chronic

B6 macrocytic anemia

B12 macrocytic anemia, neuro

Vitamins - acute

B1 lactic acidoses, cardiac failure

neuro, CVVH

> 5 days, and repeat one a weekalong with prealbumin, CRP

Value < 10% < ref range= deficiency

Micronutrient requirements of the long-term ICU patient

Conclusions

Oxidative stress present in most acute conditions and persist with long stay

Critically ill have an altered micronutrient status, with

of circulating levels acute phase response losses

Several micronutrients (Se, Zn, carotenoids, vit C, vit E) are essential for AOX defence which can be restored by supplements

Monitoring weekly: burns, supplemented, long stays