1

Iyan DarmawanMedical Department PT Otsuka Indonesiaemail: iyan@ho.otsuka.co.id

Iyan DarmawanMedical Department PT Otsuka Indonesiaemail: iyan@ho.otsuka.co.id

2

Malnutrisi Trauma

ImunSistem

Operasi Antibiotik

Nutrisi

Obat Rawat Intensif

Dukungan Imunologis pada Operasi dan Sakit Kritis

Dukungan Imunologis pada Operasi dan Sakit Kritis

3

• Intestinal Mucosal barrier

• Fuel for Immune cells

• Modulasi respon radang

Mekanisme ImunonutrisiMekanisme Imunonutrisi

4

• Intestinal Mucosal barrier

Mekanisme ImunonutrisiMekanisme Imunonutrisi

5

• Intestinal Mucosal barrier

• Fuel for Immune cells

• Modulasi respon radang

Mekanisme ImunonutrisiMekanisme Imunonutrisi

9

InflammatoryResponses

+

-

Severe Systemic Inflammatory Response

Severe Systemic Immunosuppression

TraumaSepsisBedah mayor

Well-regulated Responseby Immunonutrition

Early MOF

InfectionLate MOF

Modulasi Respon Radang oleh Immunonutrisi

Modulasi Respon Radang oleh Immunonutrisi

10

-3 fatty acidsArginine

Taurine

NucleotidesVitamins A, C, E

Greater effects

Lesser effects

Zinc

Glutamine

Immunonutrients

11

Dengan dosis serendah 800-1200 kcalsudah terlihat efek immune-enhancing

kcal

Immune-enhancingproperty:

demam (-) atauLeukositosis (-)/

NEOMUNE Standard

12

Dengan dosis serendah 800-1200 kcalsudah terlihat efek immune-enhancing

kcal

Immune-enhancingproperty:

demam (-) atauLeukositosis (-)/

NEOMUNE Standard

Neomune+

Standard

13

GLUTAMINE

14

GlutamineGlutamine

15

Bahan bakar untuk enterosit dan sel imun

Precursor untuk nucleotide & glutathione

Substrat untuk gluconeogenesis & ureagenesis

Asam amino bebas terbanyak dalam plasma,

Pada kondisi normal tidak esensial

Conditionally essential selama catabolic state

Sintesis utama di otot rangka

otot rangka, dan seluruh tubuh

GlutamineGlutamine

16

Pemecahanotot

Glutamine

Alanine Glucose

Acute phase proteinUrea

Glutamine dibutuhkan lebih pada stress

Glutamine dibutuhkan lebih pada stress

17

Gln UptakeAla Uptake

Protein Synthesis

Release

Protein SynthesisGln Uptake

Integrity

Gln UptakeAla UptakeGluconeogenesisProtein Synthesis

Protein Synthesis

Whole BodyProtein Turnover

Protein Breakdown

Gln

Immune function

LactatePyruvate

Efek Suplementasi GlutamineEfek Suplementasi Glutamine

18

Glutamine

PMNs MacrophagesLymphocytes

Efek terhadap sel-sel imunologi

19

TNF, IL-1, IL-2, IL-10, Interferon

Host Defense Organ Injury

Stress

PMNs MacrophagesLymphocytes

Glutamine

Immune Cells

Stress and Cytokines

20

Control diet Gln diet

Pasien

Pneumonia

Bactremia

Sepsis

31 29

14 513 28 1

ISS>20 First 15 days morbidity

Houdijk APJ et al:Lancet 352:772, 1998

* p< 0.02=

(45%)(42%)(26%)

(17%)

(7%)

(3%)

*

*

*

Penurunan komplikasi infeksi dengan nutrisi enteral yg diperkaya glutamine

pada pasien multitrauma

Penurunan komplikasi infeksi dengan nutrisi enteral yg diperkaya glutamine

pada pasien multitrauma

21

ARGININEARGININE

22

1. Memacu sekresi hormonPituitary-GH, Prolactin

Pancreas-Insulin, Glucagon, Somatostatin

2. Sintesis protein inti sel

3. Zat antara siklus urea

4. Prekursor Glutamine

5. Prekursor Nitric Oxide

1. Protein Breakdown

2. Fungsi imun

3. Penyembuhan luka

4. Pertumbuhan tumor

Nitrogen Retention

Efek-efek ArginineEfek-efek Arginine

23

Arginine

PMNs MacrophagesLymphocytes

Efek Arginine terhadap fungsi sel imunEfek Arginine terhadap fungsi sel imun

24

Arginine

Ornithine

Glutamine Proline PolyamineImmuno-enhancing Wound healing

ProteinEnergy metabolism

arginase

Trauma diikuti oleh penurunan kadar arginine plasma

Penjelasan:Laju destruksi oleh arginase dalam sel-selimun meningkat 10-kali lipat

Trauma dan ArginineTrauma dan Arginine

25

NO ONOO OH

L-Arginine O 2-

- .(Nitric Oxide) (Peroxynitrite)

Nitric Oxide synthase

Vasodilatation Tissue Injury Bactericidalactivity

Arginine dan NO

26

Growth Hormone

Liver

IGF-1

Tissues

Anabolic Effect

Immune System

Immunostimulatory Effect

Prolactin

Arginine

Arginine memacu imunitas via sekresi hormon hipofisisArginine memacu imunitas via sekresi hormon hipofisis

27

Brittenden J et al:Surgery 115:205,1994

Patients with breast cancer (n=24)

Arginine 30g/day for 3 days orally

Lymphocyte mitogenesis

Natural killer cell cytotoxity

Lymphokine-activated killer cell cytotoxity

L-arginine merangsang pertahanan hospes pada pasien kanker payudaraL-arginine merangsang pertahanan

hospes pada pasien kanker payudara

280 95 190 380 760 1250 3040

0

0.5

1.0

1.5

2.0

Supplemental Arginine (mol)

Labeled Staph.aureus Normal human PMNs

Flow cytometry

Repeated measures ANOVA

p<0.001

Moffat FL Jr et al: J Cell Physiol 168:26,1996

Ph

ago

cyto

sis

(to

tal

flu

ore

sce

nce

)Efek terhadap fagositosis bakteri

oleh sel PMNEfek terhadap fagositosis bakteri

oleh sel PMN

31

FISH OIL

32

Fish oilFish oil

33

Omega-3-fatty acidsOmega-3-fatty acids• fish oilfish oil

• immune function, booster neutrophil immune function, booster neutrophil activity,activity,

• distribution of lymphocyte throughout the distribution of lymphocyte throughout the bodybody

• reducing the body’s inflammatory reducing the body’s inflammatory response to trauma [ level of CRP, IL-6, response to trauma [ level of CRP, IL-6, leukotriene B4, PAF]leukotriene B4, PAF]

34

Linoleic acid (18:2 w6) -Linolenic acid (13:3 W3)

Arachidonic acid(20:4 w6)

PG2 Series

LT4 Series

PG3 Series

LT5 Series

PG1 Series

-6 Fatty Acid -3 Fatty Acids

dihomo-γ-linoleic acid (20:3 w6) Eicosapentaenoic acid (20:5 w3)(EPA)

Docosahexaenoic acid (22:6 w3)(DHA)

Eicosapentaenoic acid (20:5 w3)(EPA)

Eicosanoid Synthesis from Polyunsaturated Fatty Acids

Eicosanoid Synthesis from Polyunsaturated Fatty Acids

35

Anti-inflamatorik ~ immunosupresif

-3 Fatty Acids

MISUNDERSTANDINGMISUNDERSTANDING

36

Alexander JW, Saito H et al:Ann Surg204:1986

Metabolic Rate

Cell-mediated Immunity

Serum Opsonic Activity

-3 Fatty Acids (Fish Oil) in a Burn Model

37

Optimum dietary ratio for -6:-3 fattyacids in critically ill patients?

In western countries, the ratio > 10

Ratio < 5 ( around 2 ) would be desirable.

In Japan, the ratio 12:3 = 4:1

Ratio of -6 to -3 PUFAsRatio of -6 to -3 PUFAs

38

Glutamine 10-15

Arginine 12-15

-3 fatty acids 1.5-2.0

Standard DietsDiets

Immune

3-6

1.5-2.5

0-0.1

(g/1000 cal)

(g/1000 cal)

(g/1000 cal)

Kandungan nutrientKandungan nutrient

39

Mortality

Treatment Effect

(Treat/Ctrl)1.05 NS

Infection rate 0.60 0.005

Length of stay

(Treat/Ctrl)

-2.9 days (Treat-Ctrl) 0.0002

ICU stay -1.4 days (Treat-Ctrl) NS

Ventilators days -2.6 days (Treat-Ctrl) 0.04

12 trials:Impact 10, Immune-Aid 2 1,482 patientsBeale RJ et al:Crit Care Med 1999;27:2799

Summary of Meta-analysis ofImmunonutritive Enteral DietsSummary of Meta-analysis ofImmunonutritive Enteral Diets

40

Effect of Immunonutrition on Infectious Complications

Daly et al 1992Daly et al 1995

Braga et al 1996Schilling et al 1996Gianotti et al 1997

Senkal et al 1997Braga et al 1999

Senkal et al 1999Snydemanl et al 1999

Critically III PatientsBrown et al 1994Moone et al 1994

Kudsk et al 1996Bower et al 1995

Ross Products Division

Engel et al 1997of Abbott Laboratories, 1996

Mendez et al 1997Rodrigo and Garcia 1997

Galban et al 2000

Pooled Risk Ratio

0.005 0.01 0.05 0.1 0.5 1 5 10 50 100

Risk Ratio (95% Confidence Interval)

18 trials

Heyland DK et al:JAMA 286:944, 2001

Immunonutrition

Favors

Elective Surgical PatientsStandard DietFavors

Impact

41

Effect of Immunonutrition on Length of Hospital Stay

Daly et al 1992Daly et al 1995

Braga et al 1996Schilling et al 1996Gianotti et al 1997

Senkal et al 1997Braga et al 1999

Senkal et al 1999Snydemanl et al 1999

Cerra et al 1990Moone et al 1994

Kudsk et al 1996Bower et al 1995

Ross Products Divisionof Abbott Laboratories, 1996

Mendez et al 1997

Atkinson et al 1998Weimann et al 1998

-4 -3 -2 -1 0 1 2 3Effect Size (95% Confidence Interval)

Heyland DK et al:JAMA 286:944, 2001

Critically III Patients

Pooled Risk Ratio

17 trialsImmunonutrition

Favors

Elective Surgical PatientsStandars Diet

FavorsImpact

42

Questions for Immunonutrition Therapy in Surgical Stress

What types of surgical stress ?

What types of nutritional status ?

When to begin ?

What is optimal dosing ?

What is optimal length of treatment ?

What is expected outcome ?

43

Indications of Immunonutrition

GI Surgery

Trauma

Burns

Critically Ill ?

Sepsis ?

44

Control IMN P

Mortality 32%Mortality (APACHEII=10-15)

Bactremia

>1 nosocomial infection

Length of stay (days)

Ventilator days

28%

22%

20%

17

12

19%

4 %

8 %

6 %

18

12

.05

.02

.01

.01

.41

.90181 patients Infection source: mainly pneumoniaAPACHE II >10

Calban C et al Crit Care Med 2000; 28:643

Effects of IMN in SepticICU Patients

Effects of IMN in SepticICU Patients

45

Immune-enhancing enteral nutrition resulted in asignificant reduction in the mortality rate andinfection rate in septic patients admitted to the ICU.

These reductions were greater for patients withless severe illness.

Calban C et al Crit Care Med 2000; 28:643

It is recommended that trials of immunonutrition bestratified by high-risk and low-risk patients toprospectively determine the benefits ofimmunonutrition for ICU patients, as a function ofillness severity.

Effects of IMN in Septic ICU PatientsEffects of IMN in Septic ICU Patients

46

Timing of Administration

47

TIMINGTIMING

EARLYEARLY( ( < 24 HOURS of ADMISSION, post-op.day 1< 24 HOURS of ADMISSION, post-op.day 1))

Napolitano.L.M, Bochiccio.G, Enteral feeding of critically ill.; Current Opinion in Critical Care 2000;6:136-142

Lower incidence of infections (RR:0.45 ; 95%CI,0.30-0.66 p=.00006), Lower incidence of infections (RR:0.45 ; 95%CI,0.30-0.66 p=.00006), Reduced LOS(hospital) (mean red.of 2.2 days,95%CI 0.81-3.63days Reduced LOS(hospital) (mean red.of 2.2 days,95%CI 0.81-3.63days p=.004), no significant diff.in mortality.p=.004), no significant diff.in mortality.Marik.P.E, Zaloga.P.G; Early enteral nutrition in acutely ill patients: A systematic review; Critical Care Medicine 2001;29:2264-2270

IMN, is associated with a significant reduction in the risk of IMN, is associated with a significant reduction in the risk of developing infectious complications and reduces the overall hospital developing infectious complications and reduces the overall hospital staystay

Suplementation of enteral diet with arginine,RNA, and omega-3-FA in Suplementation of enteral diet with arginine,RNA, and omega-3-FA in the early post.op. time period improves post.op. immunologic the early post.op. time period improves post.op. immunologic responses and helps to overcome more rapidly the immunologic responses and helps to overcome more rapidly the immunologic depression after surgical traumadepression after surgical trauma..

Kemen.M Senkel.M, Critical Care Medicine;1995;23:652-659Kemen.M Senkel.M, Critical Care Medicine;1995;23:652-659

48

50

40

30

20

10

0

1 4 8

* p<0.05

**

% P

hago

cyto

sis

Control

60

50

40

30

-8 -1

** IEF

% P

hago

cyto

sis

1 4 8

* p<0.01

OP

Braga M et al: Arch Surg 1996;131:1257Braga M et al:Eur J Surg 1996;162:105

Postop dayPre-op

Monocyte Phagocytosis

Enteral feeding

OP

Enteral feeding

Pre-op Postop day

Orally 1 L/d

Neutrophil Phagocytosis

Immune Effects of Early Enteral NutritionImmune Effects of Early Enteral Nutrition

49

Optimal Dose Given

50

DOSINGDOSING

??Glutamine 0.1-0.3 g/kg/oral(enteral)Glutamine 0.1-0.3 g/kg/oral(enteral)

Arginine Arginine up to 30 g/day up to 30 g/day

51

Dose-Response Effect of ImmunonutrientsIn GI Surgery

Post-Op IntakeEffects

Heslin MJ et al () 30% of goal

60% of goal

Ann Surg 1997;226:567

Daly JM et alAnn Surg 1995;221:327

(+)

Schlling J et al (+) 70% of goal Nutrition 1996;12:423

95% of goal Gianotti L et alArch Surg 1997;132:1222

(+)

52

Mean IntakeEffects

17 ml/kg/day**

Atkinson et alCrit care Med 1998;26:1164

(+)

Galban et al (+) Crit Care Med 2000;28:643

Diagnostic Category

Critically ill

19 ml/kg/daySepsis

**>2.5 L within 72 hrs of ICU admission

Bower et al (+) Crit Care Med 1995;23:43618 ml/kg/day*Sepsis

* 821 mL/day at least 7 days

Dose-Response Effect of ImmunonutrientsIn Critically Ill and Sepsis

Dose-Response Effect of ImmunonutrientsIn Critically Ill and Sepsis

53NPC 200 kcal/sachet; Protein 12,5 g/sachet

NeomuneNeomune

1 sachet 5 sachetArginine 2,5 g 12,5 gGlutamine 1,25 g 6,25 gFish oil 1,11 g 5,55 gCasein 12,5 g 62,5 gCarbohydrate 47,5 g 237,5 gVitamins Minerals

54

Impact Immun-Aid

Protein (% Calories)

Free Glutamine(g/l)

Free Arginine (g/l)

Fat (% Calories)

-3 fatty acids (g/l)

22 32

0 9.0

14.0 15.4

BCAA (g/l) 9.6 29.0

25 20

1.68 1.1

Neo-Mune

14.1

10.6

1.8

25

26

8.75

Nucleotides (g/l) 1.25 01.0

Immunonutrient FormulationImmunonutrient Formulation

55

Goal: 8 –10 sachets/day Full dose

5 Sachets/ day ( ~ 60% of goal) as supplement is sufficient given orally

Recommended DosageRecommended Dosage

56

NPC : 1500-1800 Kcal Protein 60-90 g

Neomune 5 sachet 1000 62,5

+ diet oral atau

1L KAENMG3 + 400 1L PanAmin G 200 27

Pasien kgPasien kg

57