Neomune Pelni

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Iyan Darmawan Medical Department PT Otsuka Indonesia email: iyan@ho.otsuka.co.id1

Dukungan Imunologis pada Operasi dan Sakit Kritis

Malnutrisi

Trauma

is SOperasi

m te

Im

unNutrisi2

Obat Antibiotik

Rawat Intensif

Mekanisme Imunonutrisi

Intestinal Mucosal barrier Fuel for Immune cells Modulasi respon radang

3

Mekanisme Imunonutrisi

Intestinal Mucosal barrier

4

Mekanisme Imunonutrisi

Intestinal Mucosal barrier Fuel for Immune cells Modulasi respon radang

5

Terminology OR (Odds Ratio)No of patients in the treatment group who experienced event/ No who did not No of patients in the control group who experienced event/ No who did not

RR (Relative Risk)No of patients in the treatment group who experienced event/ No of all patients No of patients in the control group who experienced event/ No of all patients

6

Meta-analysis Critically Ill/Surgical Patients MortalityAuthor Heys Beale Heyland Mortality* 1.77 (OR) 1.05 (RR) 1.10 (RR) 95% CI 1.00-3.12 0.78-1.41 0.93-1.31

OR = Odds Ratio; RR = Relative Risk CI= Confidence Interval * OR or RR < 1 favors immunonutrition7

Effect of Immunonutrition on Infectious ComplicationsFavors ImmunonutritionElective Surgical PatientsDaly et al 1992 Daly et al 1995 Braga et al 1996 Schilling et al 1996 Gianotti et al 1997 Senkal et al 1997 Braga et al 1999 Senkal et al 1999 Snydemanl et al 1999

Favors Standard Diet

18 trials Impact

Critically III PatientsBrown et al 1994 Moone et al 1994 Bower et al 1995 Kudsk et al 1996 Ross Products Division of Abbott Laboratories, 1996 Engel et al 1997 Mendez et al 1997 Rodrigo and Garcia 1997 Galban et al 2000

Heyland DK et al:JAMA 286:944, 2001

Pooled Risk Ratio0.005 0.01 0.05 0.1 0.5 1 5 10 50 100

8

Risk Ratio (95% Confidence Interval)

Modulasi Respon Radang oleh ImmunonutrisiSevere Systemic Inflammatory Response Early MOF Well-regulated Response by Immunonutrition Trauma Sepsis Bedah mayor+Inflammatory Responses

-

Severe Systemic Immunosuppression

Infection 9 Late MOF

ImmunonutrientsGreater effectsGlutamine Arginine -3 fatty acids

Lesser effectsNucleotides Vitamins A, C, E Zinc Taurine

10

Dengan dosis serendah 800-1200 kcal sudah terlihat efek immune-enhancingkcal 2000 NEOMUNE Standard

1200 1000 800

Immune-enhancing property: demam (-) atau Leukositosis (-)/

11

Dengan dosis serendah 800-1200 kcal sudah terlihat efek immune-enhancingkcal 2000 Neomune+ NEOMUNE Standard Standard

1200 1000 800

Immune-enhancing property: demam (-) atau Leukositosis (-)/

12

GLUTAMIN E13

Glutamine

14

GlutamineAsam amino bebas terbanyak dalam plasma, otot rangka, dan seluruh tubuh Sintesis utama di otot rangka Substrat untuk gluconeogenesis & ureagenesis Precursor untuk nucleotide & glutathione Bahan bakar untuk enterosit dan sel imun Pada kondisi normal tidak esensial Conditionally essential selama catabolic state15

Glutamine dibutuhkan lebih pada stressPemecahan otot

GlutamineAlanine Glucose Acute phase protein Urea16

Efek Suplementasi Glutamine

GlnProtein Synthesis Lactate Pyruvate Release Immune function Gln Uptake Ala Uptake Protein SynthesisGluconeogenesis

Gln Uptake Protein Synthesis Integrity

Gln Uptake Ala Uptake Whole Body Protein Turnover Protein Synthesis Protein Breakdown

17

Efek terhadap sel-sel imunologi

Glutamine

Lymphocytes

Macrophages

PMNs18

Stress and Cytokines StressLymphocytes Macrophages PMNs

Immune Cells

GlutamineTNF, IL-1, IL-2, IL-10, Interferon

Host Defense

Organ Injury

19

Penurunan komplikasi infeksi dengan nutrisi enteral yg diperkaya glutamine pada pasien multitrauma

Control diet Gln diet Pasien Pneumonia Bactremia Sepsis

31 29 14 (45%) 5 (17%)* 13 (42%) 2 (7%) * 8 (26%) 1 (3%) *ISS>20 First 15 days morbidity * p< 0.02 =20 Houdijk APJ et al:Lancet 352:772, 1998

ARGININE

21

Efek-efek Arginine1. 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

22

Efek Arginine terhadap fungsi sel imun

Arginine

Lymphocytes

Macrophages

PMNs23

Trauma dan ArginineTrauma diikuti oleh penurunan kadar arginine plasma Penjelasan: Laju destruksi oleh arginase dalam sel-sel imun meningkat 10-kali lipat

Argininearginase Ornithine Glutamine Proline Polyamine Protein

Immuno-enhancing

Wound healing

24 Energy metabolism

Arginine dan NOL-ArginineNitric Oxide synthase O2

NO(Nitric Oxide) Vasodilatation

ONOO(Peroxynitrite) Tissue Injury

-

OH.Bactericidal activity

25

Arginine memacu imunitas via sekresi hormon hipofisis

Arginine Growth Hormone Prolactin Liver IGF-1 Tissues26 Anabolic Effect Immunostimulatory Effect

Immune System

L-arginine merangsang pertahanan hospes pada pasien kanker payudaraBrittenden 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 cytotoxity27

Efek terhadap fagositosis bakteri oleh sel PMN2.0Phagocytosis (total fluorescence)Moffat FL Jr et al: J Cell Physiol 168:26,1996 Repeated measures ANOVA p1 nosocomial infectionMortality Length of stay (days) Ventilator days181 patients APACHE II >10

IMN 19% 4% 8% 6% 18 12

P .05 .02 .01 .01 .41 .9044

17 12

Infection source: mainly pneumonia

Effects of IMN in Septic ICU PatientsImmune-enhancing enteral nutrition resulted in a significant reduction in the mortality rate and infection rate in septic patients admitted to the ICU. These reductions were greater for patients with less severe illness. It is recommended that trials of immunonutrition be stratified by high-risk and low-risk patients to prospectively determine the benefits of immunonutrition for ICU patients, as a function of illness severity.45

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

Timing of Administration

46

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

EARLY

IMN, is associated with a significant reduction in the risk of developing infectious complications and reduces the overall hospital stayNapolitano.L.M, Bochiccio.G, Enteral feeding of critically ill.; Current Opinion in Critical Care 2000;6:136-142

Suplementation of enteral diet with arginine,RNA, and omega-3-FA in the early post.op. time period improves post.op. immunologic responses and helps to overcome more rapidly the immunologic depression after surgical 47 trauma.

Immune Effects of Early Enteral NutritionMonocyte PhagocytosisEnteral feeding

Neutrophil PhagocytosisOrally 1 L/d Enteral feeding

50% Phagocytosis

40 30 20 10* p