Raul V. Destura MDInternal Medicine-Infectious Diseases

Director, Institute of Molecular Biology and Biotechnology,

National Institutes of Health

Convenor, Study Group on Enteric Diseases in the Philippines

The Interaction of Malnutrition and Infection Micronutrients and Infectious Disease Resistance

Broadening Focus on Human Pathogens and Resistance Focus on HIV

Immunonutrition and Sepsis

Newer Paradigms on the Research Horizon

Critical Care Nutrition (Canada)

NCBI Resource: Pub Med

Protein-energy malnutrition is usually measured in

terms of body size

Indicators in children Stunting: low height-for-age Underweight: low weight-for-age Wasting or acute malnutrition: low weight-for-height

Indicators in adults Low body mass index (BMI)

in its mild and moderate forms is not always recognized

often referred to as “hidden hunger”

Most commonly reported micronutrient deficiencies in both adults and children are

• iron

• vitamin A

• iodine deficiency

Micronutrient malnutrition

Deficiencies in other vitamins and minerals that

are vital for the body’s normal functions and for the

work of the immune system are not commonly

measured, but they occur frequently in populations

with high infectious disease burden

monotonous, poor quality diets

diets characterized by limited consumption of animal products and seasonal or periodic food insecurity

Infections affect nutritional status by reducing dietary intake and nutrient absorption, and by increasing the utilization and excretion of protein and micronutrients as the body responds to invading pathogens.

Anorexia, fever, and catabolism of muscle tissue frequently accompany

the acute phase response

Even mild infectious diseases influence nutritional status

Almost any nutrient deficiency, if sufficiently severe, will impair resistance to disease.

Infections also result in the release of pro-oxidant cytokines and other reactive oxygen species.

The relationship between HIV and nutrition is complicated by the fact that the virus directly attacks and destroys the cells of the immune system.

The vicious cycle of micronutrient deficiencies and HIV pathogenesis: Nutritional deficiencies affect immune functions that

may influence viral expression and replication, further affecting HIV disease

HIV affects the production of hormones which are involved in the metabolism of carbohydrates, proteins and fats

As adjuvant to the mitigation of Infections Vitamin A Supplementation

Extensive research and meta-analysis largely confirms:

Survival Advantage and reduction in morbidity for complicated Measles

(Hussey GD & Klein M, 1990; Coutsoudis A., et. al., 1991; HuimingY, et. al., 2005)

Zinc Supplementation + ORS Reduces the duration and severity of episodes and has been

officially recommended by WHO (WHO 2004)

In the prevention of Infections

Vitamin A Supplementation Prevents infectious disease complications among small premature

infantsDarlow BA., et al. Cochrane Review. 2002

Zinc Supplementation Reduces risks of infection and re-infection of Enteric Pathogens

Roy Sk., et al., 1999; Baqui AH, et al., 2002

Vitamin D Increasing promise for prophylactic application in epidemic viral

diseases such as Influenza and diverse microbial infections Tremyzaygues L., et al., 2006; Canell JJ., et al., 2006

Parasitic Infections

HIV

Malnutrition, protozoa and multicellular parasites

Classic scenario – depleting nutritional stores caused by intestinal hookworms

Vitamin A deficiency – filarial nematodes which have evolved elaborated retinoid receptor systems to access the vitamin A of their hosts

Sani BP & Comley JC., 1985

Human Immunodeficiency Syndrome Discovered in 1981

We are seeing a rising epidemic in the Philippines particularly among young urban professionals working in unique environments like the call centers

South African political cartoon, April 2005

The Vicious Cycle of Malnutrition and HIV is well recognized

Insufficient dietary intake

Malabsorption, diarrhea

Altered metabolism and

nutrient storage

Increased HIV

replication

Hastened disease

progression

Increased morbidity

Increased oxidative

stress

Immune suppression

Nutritional

deficiencies

Source: Semba and Tang, 1999

Increased energy requirements 10% increase during asymptomatic infection 20-30% increase during secondary infections 50-100% increase for children (WHO, 2003)

Reductions in dietary intake Due to appetite loss, depression, oral sores Food insecurity/loss of livelihoods

Nutrient malabsorption and loss HIV-infection of GI cells

Diarrhea-related losses

Metabolic changes Cytokine-related changes affect appetite Impaired transport, storage, utilization of some nutrients (e.g. protein) Increased utilization of antioxidant vitamins and enzymes, resulting in oxidative stress

– may increase viral replication

Photo: M McCrary

Micronutrients and host defence and resistance to infections in humans

Antioxidant capacity Immune system Resistance to infections

A ↑ ↑↑↑ ↑↑↑ / ↓

B ↑ ↑

C ↑↑↑ ↑

E ↑↑↑ ↑↑

Iron ↓ ↑ ↑/↓

Zinc ↑↑↑ ↑↑↑ ↑↑↑

Selenium ↑↑↑ ↑ ↑

↑: increase, ↓: decrease, number of arrows indicate relative importance, arrows in both directions indicate conflicting findings

Vitamin A Iron Zinc Multiple MN supplements

Perinatal and Child Outcomes- Mother-to-child transmission (MTCT)- Other birth outcomes (BW, SGA, prematurity)- Child morbidity, growth, and mortality- Child immunologic status

Adult Outcomes- Immunological and virological progression

- Clinical disease progression and mortality

Studies on micronutrients and HIV have measured a range of outcomes

Lack of adequate biomarkers of MN status, especially in presence of acute phase response

Underlying nutritional status, diet intake infrequently measured yet may affect relationships

• Sometimes causes conflicting results• Makes it difficult to compare across studies

Potential confounding (SES/poverty) & HIV-related reporting bias for dietary intakes when measured

Early observational studies showed an inverse dose-response relationship between maternal serum retinol and HIV viral load (Kenya) and MTCT of HIV-1 (Malawi)

Semba, Lancet 1994;343:1593

Serum retinol mmol/L

MALAWI

Nduati, J Infect Dis 1995;172:1461

KENYA

As a result, several RCT were designed to look at the impact of Vitamin A supplementation on MTCT and related outcomes

Country Recruitme

nt

N Study intervention (placebo controlled) Co-interventions (to all)

Micronutrien

t

Daily Postpartum Iron/folate

(mother)

Vitamin A

South

Africa

28-32 wk 728 Vitamin A 5.000 IU + 30 mg -carotene 200.000 IU 60/5 mg/day

Malawi 18-28 wk 697 Vitamin A 10.000 IU 30/0.4 mg/day 100.000 IU at 6 weeks

(mother)

Tanzania

Zimbabwe

14-27 wk

1-4 d

1075

4495

Vitamin A

Multivitamins

Vitamin A

5.000 IU + 30 mg -carotene

Vitamins B, C and E

200.000 IU

Continued

400,000 IU

(Mother)

50,000 IU

(Baby)

120/5 mg/day 100.000 IU at 6, 12, 18

months (infant)

Coutsoudis et al – South Africa - Study intervention and iron/folate given from recruitment until delivery.

Kumwenda et al. – Malawi . Study intervention and iron/folate given from recruitment until delivery.

Fawzi et al. – Tanzania - Two-by-two factorial design, i.e. two placebo-controlled interventions. Study intervention and iron/folate given from recruitment and

throughout and several years after lactation. Multivitamins included 20 mg thiamin, 20 mg riboflavin, 25 mg vitamin B6, 50 mg vitamin B12, 100 mg niacin, 0.8

mg folate, 500 mg vitamin C, and 30 mg vitamin E.

Humphrey et al – Zimbabwe – Two by two factorial design that included > 9500 HIV negative mothers also. Mothers, babies randomized to single dose VA

or placebo

Adapted from Table by Friis, 2005

South Africa (Coutsoudis et al, 1999; Kennedy-Oji et al, 2002)

Lower risk of pre-term deliveries

No overall effect on MTCT Improved maternal PP weight

retention

Malawi (Kumwenda et al, 2002)

Higher BW & weight & length at 6 w,

Lower PNT 6 w-24 mo (2.8% vs. 7.7%; p=0.04)

Lower anemia at 6 w

Tanzania (Fawzi et al, 2000; 2002; Baylin et al, 2005)

Improved infant serum retinol, reduced VAD

No effect on birth outcomes No effect on PNT, mortality Total MTCT significantly higher

by 24 months (34.2% v 25.4%;p=0.009)

Zimbabwe (Humphrey et al, 2006)

If IP infected infants, VAS reduced mortality (by 28%; p = 0.01)

No effect on PNT 2-fold increased risk of death

in infants alive, PCR negative at 6 w

Positive impact of VAS on morbidity and growth of hospitalized children (HIV+/HIV-) – Tanzania Villamor et al. Pediatrics 2002

Positive impact of VAS on morbidity of HIV+ children – South Africa – Coutsoudis et al, 1995

No effect of VAS on vaginal shedding of HIV, plasma HIV levels, immune status in women – Kenya – Baeten et al, 2002

Suggestive effect of maternal VAS on risk of maternal HIV acquisition – Zimbabwe

Variable Adj. HR 95% CI p

Maternal VAS (vs. placebo)

1.09 (0.85, 1.38) 0.51

Age (y) 0.94 (0.92, 0.97) 0.001

Parity > 1 1.44 (1.07 – 1.93) 0.02

Serum retinol

< 70 mmol/L

10.43 (3.00-36.28) 0.001

Hb <70 g/L 2.68 (1.18-6.07) 0.02

Models adjusted for marital status*sexual activity & occupation

Incidence of new infections: 3.4% per year (95% CI: 3.0-3.8%)

VAS tended to be protective against incidence in women with low Se Retinol

Adj. HR = 0.29 (95% CI 0.03 - 2.60; P=0.26)

Anemia of chronic disease (ACD) Hb, Reticulocytes, Serum Fe, Transferrin, % Fe saturation,

normal or serum ferritin, low serum EPO, normal or Fe stores in bone marrow

Nutrient deficiencies (Fe, folate, B12)

Hookworm, malaria

Malignancies

Opportunistic infections of bone marrow

ART use (ZDV), other OI drugs suppress RBC production

51.9

68.964.7

78.481.778.9

0

25

50

75

100

Mali Cote d'Ivoire Burkina Faso

% l

ow

hem

og

lob

in

HIV+

HIV-

Sources: Mali (Diallo et al, 2003); CI (Ramon et al, 1999); BF (Meda et al, 1999)

… and is associated with higher maternal mortality, LBW, pre-maturity, MTCT (next slides)

Taha et al Bull WHO, 2006- Malawi – predictors of death by 24 months post-delivery

Adj HR 95% CI

BF status (yes/no) 0.35 0.12-1.03

Age (< 25 y) 0.71 0.35-1.46

Viral load(Log 10)

3.84 2.06-7.16

Hb (g/L) 0.80 0.68-0.93

BMI 0.82 0.75-1.00

Maternal Hb at delivery(g/L)

Adj. OR – IP (n=3375)

Adj. HR – PN(n=2870)

<70

70<90

90<110

>=110

2.40 (1.16-4.97; p=0.02)

1.53 (0.99-2.37; p=0.05)

1.25 (0.93-1.69; p=0.15)

1.00

2.66 (1.06-6.68; p=0.04)

1.02 (0.54-1.96; p=0.94)

1.03 (0.67-1.59; p=0.88)

1.00

Both models adjusted for maternal B/L plasma viral load, CD4 cell count

IP model: gestational age, duration of membrane rupture, infant birth weight

PN model: maternal age, MUAC, early feeding pattern, death during F/U

Neither VAS nor infant sex were significant predictors of IP, PN transmission

A few studies suggest that supplemental iron given to HIV+ may cause increased iron stores in bone marrow and other tissues, oxidative stress, faster HIV disease progression, and subsequent increased mortality (Friis et al., 2003; Boelart et al., 1996).

Associated with haptoglobin 2-2, a specific type of this heme-binding protein (Friis et al., 2003; Gordeuk et al., 2001; Delanghe et

al., 1998).

P=0.31 for test of difference in decline of VL between groups; no effect of Fe supplementation after controlling for baseline VL, hookworm infection

Early observational studies showed increased mortality (shorter survival) in HIV+ adults with higher zinc intakes

Additional concerns that Zn supplementation may induce HIV replication

HIV-Tat protein and HIV nucleocapsid protein NCp7, which play a role in viral replication, are strongly zinc dependent

96 HIV+ infants randomized to daily Zn sulfate (10 mg/d) vs. placebo in Durban, SA

Block randomization stratified by age (6-23 m, 24-41, 42-60 mo) Hypothesis: Zn will decrease plasma viral log (VL) by 0.5 log

HIV RNA, CD4, CD4 %, measured at baseline, 3 wks, 3 mo, 6 mo post-intervention (NO EFFECT)

Morbidity, growth, survival measured (BENEFIT-morbidity) - next slide

Author’s conclusion: “Zinc supplementation is safe and beneficial and 10 mg/day should be part of the nutritional package for HIV+ children”

Zinc Placebo

P*Routine All Routine All

# of visits 360 407 370 447

% watery diarrhea 6.7 7.4 10.5 14.5 0.001

% pneumonia 10.8 14.0 12.7 18.6 0.07

% URI 39.2 40.3 44.6 45.2 0.1

% ear infection 10.8 11.3 14.1 14.5 0.2

% tuberculosis 8.3 14.9 7.3 6.5 0.1

*Chi-square test comparing proportion of all visits with diagnosis

400 HIV+ women randomized to daily Zn (30 mg Zn sulfate) or placebo from 12-27 wks gestation to 6 wks post partum (fizzy tablet)

All received MV supplement (BCE), ferrous sulfate (400 mg=120 mg ferrous Fe), folate (5 mg) daily, prophylactic chloroquine, sd NVP

No effect of Zn on pregnancy duration (p=0.99), BW (p=0.96), BL (p=0.87), change in CD4 (p=0.97), CD4:CD8 (p=0.23)

Zn associated with non-significant increase in fetal, peri-natal & neonatal mortality & MTCT - next 2 slides

Zn associated with lower PP HB recovery (p=0.03), change in RBC count (p<0.01), packed cell volume (p=0.01), also associated with increased risk of wasting in HIV+ women (Villamor et al, 2006)

Non-significant adverse effect of maternal Zinc supplements on fetal and early postpartum infant survival

Outcome No. at

Risk

Zinc

n (%)

Placebo

n (%)

Relative risk (95%

CI)6

p-value

Abortion 397 5 (2.5) 3 (1.5) 1.68 (0.17, 40.3) 0.50

Stillbirth 397 13 (6.6) 10 (5.0) 1.31 (0.44, 4.55) 0.53

Fetal death1 397 18 (9.1) 13 (6.5) 1.39 (0.58, 3.86) 0.36

Perinatal death 397 28 (14.1) 20 (10.1) 1.41 (0.73, 2.96) 0.22

Neonatal death 397 10 (5.5) 7 (3.8) 1.44 (0.38, 7.04) 0.47

1 Includes stillbirths and abortions

Slide by W Fawzi; From Fawzi et al, 2004

Maternal Zinc supplements (25 mg/d) given in addition to vitamins BCE from 12-27 wks gestation through 6 wks post-delivery are associated with non-significant increases in MTCT in HIV+

Tanzanian mothers -2

Villamor et al, EJCN, 2006

Vit A

Beta

carotene Vit D

Vit E

Vit C

Vit B1

Vit B2Niacin

Vit B6

Vit B12Vit KFolic

Acid

Folacin Pantothenic

Acid

Iron Zinc

CopperSelenium

Iodine

Magnesium

Manganese Chromium

Cystine

Which combination/dose of micronutrients is the most effective and safe?

A Tomkins slide

Vit A

Beta

carotene Vit D

Vit E

Vit C

Vit B1

Vit B2Niacin

Vit B6

Vit B12Vit KFolic

Acid

Folacin Pantothenic

Acid

Iron Zinc

CopperSelenium

Iodine

Magnesium

Manganese Chromium

Cystine

Micronutrient formulation in Thai study (yellow)

A Tomkins slide

0.53

0.37

0.26

0

0.3

0.6

Overall CD4 <200 CD4 < 100

Adju

sted M

orta

lity

Ris

k(P=0.10)

(P=0.05)

(P=0.03)

There was no effect on HIV viral load, genital shedding

Vit A

Beta

carotene Vit D

Vit E

Vit C

Vit B1

Vit B2Niacin

Vit B6

Vit B12Vit KFolic

Acid

Folacin Pantothenic

Acid

Iron Zinc

CopperSelenium

Iodine

Magnesium

Manganese Chromium

Cystine

Micronutrient Formulation in Tanzania Trial

Relative Risk 95% CI P-value

AIDS related death

0.73 0.51-0.04 0.09

Progression to stage 4

0.50 0.28-0.90 0.02

Progression to stage 3

0.72 0.58-0.90 0.003

>= 2 stage increases

0.66 0.52-0.84 <0.001

Fawzi et al, NEJM, 2004

Mean diff in viral load = -0.18 log – or est. 30% increase in survival time

Relative Risk 95% CI P-value

Thrush 0.47 0.30-0.73 <0.001

Oral ulcers 0.44 0.28-0.68 <0.001

Dysentery 0.66 0.45-0.95 0.03

ARI 0.79 0.66-0.96 0.02

Fawzi et al, NEJM, 2004

Other protective effects – gingival erythema, angular chelitis, nausea and vomiting, difficulty swallowing, painful mouth, fatigue, rash

28 30 32 34 36 38 40

59

60

61

62

63

MV

NO MV

Weight (kg)

Week of Gestation

238 g/wk

185 g/wk

Fetal Death

Low Birthweight (<2500g)

Preterm Birth (<37 weeks)

Small for Gestational Age

Severe Preterm Birth (<34 weeks)

0 0.5 1.0 1.5 2.0

Slide from W Fawzi Relative Risk

….and prevented MTCT by most vulnerable mothersFawzi et al, AIDS, 2002

0.99

0.37

1.01

0.48

1.03

0.51

1.07

0.27

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

Relative Risk

P=0.03P=0.06 P=0.06

P=0.04

Reduced morbidity and hospitalizations in adults ( B, C, E - Fawzi et al, 2004; Se -Burbano et al, 2003)

Increased survival in adults (Fawzi et al, 2004; Jiamton et al, 2003)

Improved immune recovery in adults on HAART (Kaiser et al, 2006; Odunukwe, 2006)

Increased weight gain in HIV+ pregnant women (Villamor et al, 2002)

Reduced morbidity and improved growth in HIV+ children (Vitamin A – Coutsoudis et al, 1995; BCE – Villamor et al, 2002; 2005; Zinc – Bobat et al, 2005)

Improved birth outcomes and infant immune status (Fawzi et al, 1998; 2003; Friis et al, 2004)

Reduced MTCT in nutritionally and immunologically vulnerable (Fawzi et al, 2002)

“There is no conclusive evidence at present to show that MN supplementation effectively reduces morbidity and mortality among HIV-infected adults. It is reasonable to support the current WHO recommendations to promote and support adequate dietary intake of MN at RDA levels wherever possible. There is evidence of benefit of VA supplementation in children. The long-term clinical benefits, adverse effects, and optimal formulation of MN supplements require further investigation.” (Irlam et al, The Cochrane

Collaboration, 2005)

> 1 RDA may be needed to correct nutritional deficiencies

But there is concern that high doses of some nutrients may cause adverse outcomes.

Current MN requirements are similar for PLWHA until more data available (WHO 2003)

“Adequate intake is best met through an adequate diet. “ However, in settings where these intakes and status cannot be achieved, multiple micronutrient supplements may be needed in pregnancy and lactation. Pending additional information, micronutrient intakes at the RDA level are recommended for HIV-infected women during pregnancy and lactation.”

Vitamin A supplementation Clear evidence of benefit for HIV+ children No evidence of benefit for HIV+ mothers, with possible exception of

those who are severely deficient, and harm not ruled out

Zinc supplementation Evidence of benefit for HIV+ children No evidence of benefit for HIV+ adults (possible harm if not

deficient; same re: Se)

Iron supplementation Limited data Same recommendations as for HIV-negative pregnant women and

treatment of anemia

Insult

• infection• trauma• I/R• hypoxemic/hypotensive

Activation ofPMN’s

= oxidative stress

Death

organ = failure

Pathophysiology of Critical Illness (1)

mitochondrial dysfunction

Role ofGIT

Key nutrient deficiencies(e.g. glutamine, selenium)

activation of coagulation

generation of OFR (ROS + RNOS)

endothelial dysfunction

elaboration of cytokines, NO, and other mediators

cellular = energeticfailure

Microcirculatory Dysfunction

Metabolic Effects of Arginine

enteral / parenteralsupply

L-Arginine L-CitrullineL-Ornithine

Polyamine Synthesis

• Putrescine• Spermidine• Spermine

Hormone release

• GH• IGF• Insulin• Glucagon• Prolactin• catecholamines

Urea

Nitrogenous compounds

• Nitric oxide• Nitrite• Nitrate

Suchner Brit J Nutrition 2001

Mitaka Shock 2003;19: 305

Underlying PathophysiologyRole of Nitric Oxide

cNOS

cNOS + iNOS

Har

mfu

l

Arginine / NO

availability

Optimal NO-Balance

- Hemodynamic instability

- Immune Suppression

- Cytotoxicity

- Organe dysfunction

- Microcirculation

- Immune augmentation

Suchner Brit J Nutrition 2001

Randomized, double

blind, placebo-controlled

Beagles

Parenteral L-arginine (+

NAC) vs placebo

Canine model of E. coli peritonitis

Kalil Crit Care Med 2006;34:2719

Arginine administration

associated with:Plasma arginine

NO products

And worse shock,

worse organ injury

Increased mortality!

Kalil Crit Care Med 2006;34:2719

No effect of NAC

3 RCTs

3 different products

All describing excess

mortality in patients with infection

0

2

4

6

8

10

12

14

16

mortality

Arginine

Control

1) Bower Crit Care Med 1995;23:436

2) Dent, Crit Care Med 2003;30:A17

3) Bertolini Intesive Care Med 2003;29:834

Copyright ©2007 The American Society for Nutrition

Mechanisms by which fatty acids can affect immune cell function

Wanten, G. J. et al. Am J Clin Nutr 2007;85:1171-1184

NFκB Binding

CytokinesIL-8

TNF-α

PGE1

mRNA

CytokinesIL-8

TNF-α

PGE1

mRNA

NFκB Binding

T.T. Pluess1, D. Hayoz2, M.M. Berger1, L. Tappy3, J.P. Revelly1, B. Michaeli1, Y.A. Carpentier4 and R.L. Chioléro1

21 patients with sepsis requiring TPN

Randomized to recieve PN with an n-3 or n-6 lipid emulsion for 5 days

Dose: 350 ml og s 10% n-3 lipid emulsion (Omegevan)

Am J Respir Crit Care Med 2003; 167: 1321

TPN with N-3 vs n-6 FAs in severe sepsis. Monocyte membrane FA composition: arachidonic, EPA, DHA

Mayer K, Am J Respir Crit Care med 2003; 167: 1321

TPN with N-3 vs n-6 FAs in severe sepsis. Ex vivo monocyte cytokine release in response to LPS

Mayer AJRCCM 2003; 167: 1321

47 Patients with severe acute pancreatitis

Randomized, double blind study of PN

N-3 lipid emulsion (omegaven 10%) vs. Soybean emulsion with TPNx 5days

Dose of fish oils: 0.15-0.20 g/kg/d

Patients comparable at baseline

Control group mortality 10%; no deaths in FO group

Wang JPEN 2008;32:236

Put figure 2 and 3

Wang JPEN 2008;32:236

RCT of 146 critically ill

patients with ALI and BAL+

for WBCs

Double-blinded; ITT

Experimental: Oxepa®

Control: high fat diet

Groups well matched at

baseline

Gadek Crit Care Med 1999;27:1409

After 3-4 days

• Reduction in AA and increase in EPA in lung and alveolar macrophage

• Decrease in neutrophils recovered in BAL fluid

• Improved oxygenation

RCT of 146 critically ill

patients with ALI and BAL+

for WBCs

Double-blinded; ITT

Experimental: Oxepa®

Control: high fat diet

Groups well matched at

baseline

0

5

10

15

20

25

Vent

Days

ICU

Days

ICU

Deaths

Oxepa

control

Gadek Crit Care Med 1999;27:1409

P=0.03 P=0.17P=0.02

www.criticalcarenutrition.com

Potential Beneficial Effects of Glutamine

Fuel for

Enterocytes

Fuel for

Lymphocytes

Nuclotide

Synthesis

Maintenance of

Intestinal

Mucosal Barrier

Maintenance of

Lymphocyte

Function

Preservation

of TCA Function

Decreased FreeRadical availability (Anti-inflammatory action)

Glutathione

Synthesis

GLN

pool

GlutamineTherapy

Enhanced Heat

Shock Protein

Anti-cataboliceffect

Preservation of Muscle mass

Reduced

Translocation

Enteric Bacteria

or Endotoxins

Reduction of

Infectious

complications

Inflammatory Cytokine

Attenuation

NF- B

?

Preserved CellularEnergetics-ATP content

GLN

Pool

Critical Illness

Enhancedinsulinsensitivity

Effect of Glutamine:A Systematic Review of the Literature

www.criticalcarenutrition.com

Infectious Complications

Effect of Glutamine:A Systematic Review of the Literature

www.criticalcarenutrition.com

Mortality

Pharmaconutrients Impact Outcomes!

www.criticalcarenutrition.com

1 10 1000.1.01

Glutamine

Antioxidants

Fish/Borage OilsPlus AOX

Effect on Mortality

Arginine

Death

Metabolic

Shutdown

Survivors

•↓mt DNA

•↓ ATP, ADP,

NADPH

•↓ Resp chain

activity

•Ultra structural

changes

↓ mitochondrial

activityProlonged

inflammationNO

Endocrine

effects

cytokine

effect

Genetic down

regulation

Tissue

hypoxia

• preserved ATP

•Recovery of mt DNA

•Regeneration of mito

proteins

Hypoxia Accelerates Nitric Oxide Inhibition of Complex 1 Activity

Nitration of Complex 1 in Macrophages activated with LPS and IFN

21% O2 1% O2

Frost Am J Physio Regul Interg Comp Physio 2005;288:394

mitochondria

Cell

Respiratorychain

nucleus

nDNA mtDNA

Mitochondrial Damage

ROS

RNS

LPS exposure leads to GSH depletion and oxidation of mtDNA within 6-24 hours

Levy Shock 2004;21:110 Suliman CV research 2004;279

Potentially Irreversible by 48 hours

mtDna/nDNA Ratio by Day 28 Survival

0 5 10 15 20 250.0

0.5

1.0

1.5

2.0

Alive Individuals

Expired Individuals

Alive Reg line

Expired Reg Line

P=0.04

Day

mtD

na

/nD

NA

Ra

tio

Heyland JPEN 2007;31:109

Effect of Antioxidants on Mitochondrial Function

Heyland JPEN 2007;31:109

Single center RCT double-blinded

ITT analysis

40 patients with severe sepsis Mean APACHE II 18

Primary endpoint: need for RRT

standard nutrition plus 474 ug x 3 days, 316 ug x 3 days; 31.6 ug thereafter vs 31.6 ug/day in control

Mishra Clinical Nutrition 2007;26:41-50

Increased selenium levels

Increased GSH-Px activity

No difference in

• RRT (5 vs 7 patients)

• mortality (44% vs 50%)

• Other clinical outcomes

Mishra Clinical Nutrition 2007;26:41-50

*p=<0.006

* *

Effect on SOFA scores

•

0

50

100

150

200

250

0 1 2 3 4 5

Cardiac

Trauma

SAH

CRP levels daily in the Control groups

Significant reduction with AOX in Cardiac and Trauma but not SAH

Berger Crit Care 2008

RCT

200 patients

IV supplements for 5 days after admission (Se 270 mcg, Zn 30 mg, Vit C 1.1 g, Vit B1 100 mg) with a double loading dose on days 1 and 2 (AOX group), or placebo.

No affect on clinical outcomes

Nathens Ann Surg 2002;236:814

Surgical ICU patients, mostly trauma

770 randomized; 595 analysed

alpha-tocopherol 1,000 IU (20 mL) q8h per naso- or orogastric tube and 1,000 mg ascorbic acid IV q8h or placebo

Tendency to less pulmonary morbidity and shorter duration of vent days

Multicenter RCT in Germany double-blinded

non-ITT analysis

249 patients with severe sepsis

standard nutrition plus 1000 ug bolus followed by 1000 ug/day or placebo x14 days

0

10

20

30

40

50

60

70

80

90

100

28 day Mortality

Selenium

Placebo

Greater treatment effect observed in those

patients with:

•supra normal levels vs normal levels of selenium

•Higher APACHE III

•More than 3 organ failures Crit Care Med 2007;135:1

p=0.11

Effect of Combined Antioxidant Strategies in the Critically Ill

Effect on Mortality

www.criticalcarenutrition.com

Inflammation/oxidative stress

Mitochondrial dysfunction

Organ dysfunction

Antioxidants

Antioxidants

Antioxidants

INTESTINAL EPITHELIUM

SIRS

Bacteria

DISTAL ORGAN

INJURY

(Lung, Kidneys)

via thoracic duct

Underlying Pathophysiologyof Critical Illness (3)

Characteristics : Time dependentCorrelation to disease severity

Consequences: Risk of infectionRisk of MOFS

• Maintenance of gut barrier function

• Increased secretion of mucus, bile, IgA

• Maintenance of peristalsis and blood flow

•Attenuates the stress response

Alverdy (CCM 2003;31:598)

www.criticalcarenutrition.com

www.criticalcarenutrition.com

The Keshan’s disease story

Progressive fatal pulmonary disease

Associated with low selenium levels

Murine model of pulmonary infections using benign mouse coxackie virus Same virus turned virulent when selenium deficient mice were

inoculated

THIS OBSERVATION POINST TOWARDS A NEW DEPARTURE IN NUTRITION:INFECTION INTERACTIONS – WHERE THE MICRONUTRIENT STATUS OF THE HOST COULD DETERMINE THE VIRULENCE OF PATHOGENS ACROSS A WHOLE SOCIETY