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

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Dukungan Imunologis pada Operasi dan Sakit Kritis

Malnutrisi

Trauma

is S
Operasi

m te

Im

un
Nutrisi
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Obat Antibiotik

Rawat Intensif

Mekanisme Imunonutrisi

Intestinal Mucosal barrier Fuel for Immune cells Modulasi respon radang

Mekanisme Imunonutrisi

Intestinal Mucosal barrier

Mekanisme Imunonutrisi

Intestinal Mucosal barrier Fuel for Immune cells Modulasi respon radang

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

Meta-analysis Critically Ill/Surgical Patients Mortality

Author 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 immunonutrition
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Effect of Immunonutrition on Infectious Complications

Favors Immunonutrition
Elective Surgical Patients
Daly 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 Patients

Brown 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 Ratio

0.005 0.01 0.05 0.1 0.5 1 5 10 50 100

Risk Ratio (95% Confidence Interval)

Modulasi Respon Radang oleh Immunonutrisi

Severe Systemic Inflammatory Response Early MOF Well-regulated Response by Immunonutrition Trauma Sepsis Bedah mayor
+
Inflammatory Responses

Severe Systemic Immunosuppression

Infection 9 Late MOF

Immunonutrients
Greater effects
Glutamine Arginine -3 fatty acids

Lesser effects
Nucleotides Vitamins A, C, E Zinc Taurine

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Dengan dosis serendah 800-1200 kcal sudah terlihat efek immune-enhancing

kcal 2000 NEOMUNE Standard

1200 1000 800

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

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Dengan dosis serendah 800-1200 kcal sudah terlihat efek immune-enhancing

kcal 2000 Neomune+ NEOMUNE Standard Standard

1200 1000 800

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

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GLUTAMIN E
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Glutamine

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Glutamine
Asam 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 state
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Glutamine dibutuhkan lebih pada stress

Pemecahan otot

Glutamine
Alanine Glucose Acute phase protein Urea
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Efek Suplementasi Glutamine

Gln
Protein Synthesis Lactate Pyruvate Release Immune function Gln Uptake Ala Uptake Protein Synthesis
Gluconeogenesis

Gln Uptake Protein Synthesis Integrity

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

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Efek terhadap sel-sel imunologi

Glutamine

Lymphocytes

Macrophages

PMNs
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Stress and Cytokines Stress

Lymphocytes Macrophages PMNs

Immune Cells

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

Host Defense

Organ Injury

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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

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Efek-efek Arginine
1. Memacu sekresi hormon
Pituitary-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

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Efek Arginine terhadap fungsi sel imun

Arginine

Lymphocytes

Macrophages

PMNs
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Trauma dan Arginine

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

Arginine
arginase Ornithine Glutamine Proline Polyamine Protein

Immuno-enhancing

Wound healing

24 Energy metabolism

Arginine dan NO
L-Arginine
Nitric Oxide synthase O2

NO
(Nitric Oxide) Vasodilatation

ONOO
(Peroxynitrite) Tissue Injury

OH.
Bactericidal activity

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Arginine memacu imunitas via sekresi hormon hipofisis

Arginine Growth Hormone Prolactin Liver IGF-1 Tissues

26 Anabolic Effect Immunostimulatory Effect

Immune System

L-arginine merangsang pertahanan hospes pada pasien kanker payudara

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
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Efek terhadap fagositosis bakteri oleh sel PMN

2.0
Phagocytosis (total fluorescence)
Moffat FL Jr et al: J Cell Physiol 168:26,1996 Repeated measures ANOVA p<0.001

Normal human PMNs Labeled Staph.aureus Flow cytometry

1.5

1.0

0.5

95

190

380

760

1250

3040
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Supplemental Arginine ( mol)

Arginine Supplementation vs. Delayed Hypersensitivity Response

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DNFB Ear Thickness (% Change)
Postburn day 12

- Guinea Pig Burn Model -

40 30 20 10 0

* P<0.05 2% vs 0, 4%

2 4 0 1 Arginine (% of Total Energy Intake)

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Role of Arginine for Immune Function

An essential amino acid for immune function in stress. High dose supplementation may be immunodepressive.
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FISH OIL

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Fish oil

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Omega-3-fatty acids
fish oil
immune function, booster neutrophil activity, distribution of lymphocyte throughout the body reducing the bodys inflammatory response to trauma [ level of CRP, IL-6, leukotriene B4, PAF]
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Eicosanoid Synthesis from Polyunsaturated Fatty Acids

-6 Fatty Acid
Linoleic acid (18:2 w6)

-3 Fatty Acids
-Linolenic acid (13:3 W3)

PG1 Series

dihomo--linoleic acid (20:3 w6)

Eicosapentaenoic acid (20:5 w3) (EPA) Docosahexaenoic acid (22:6 w3) (DHA)

Arachidonic acid(20:4 w6)

PG2 Series

LT4 Series

PG3 Series

LT5 Series
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MISUNDERSTANDING
-3 Fatty Acids

Anti-inflamatorik

~ immunosupresif

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

Metabolic Rate Cell-mediated Immunity Serum Opsonic Activity

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

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Ratio of -6 to -3 PUFAs
In western countries, the ratio > 10 In Japan, the ratio 12:3 = 4:1 Ratio < 5 ( around 2 ) would be desirable. Optimum dietary ratio for -6: -3 fatty acids in critically ill patients?

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Kandungan nutrient
Standard Diets Glutamine
(g/1000 cal)

Immune Diets

3-6 1.5-2.5 0-0.1

10-15 12-15 1.5-2.0

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Arginine
(g/1000 cal)

-3 fatty acids
(g/1000 cal)

Summary of Meta-analysis of Immunonutritive Enteral Diets Treatment Effect

Mortality Infection rate Length of stay ICU stay 1.05 0.60
(Treat/Ctrl) NS (Treat/Ctrl) 0.005

-2.9 days (Treat-Ctrl) 0.0002 -1.4 days (Treat-Ctrl) NS

Ventilators days -2.6 days (Treat-Ctrl) 0.04

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

Effect of Immunonutrition on Infectious Complications

Favors Immunonutrition
Elective Surgical Patients
Daly 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 Patients

Brown 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 Ratio

0.005 0.01 0.05 0.1 0.5 1 5 10 50 100

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Risk Ratio (95% Confidence Interval)

Effect of Immunonutrition on Length of Hospital Stay

Elective Surgical Patients
Daly 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 Immunonutrition

Favors Standars Diet

17 trials Impact

Critically III Patients

Cerra et al 1990 Moone et al 1994 Bower et al 1995 Kudsk et al 1996 Ross Products Division of Abbott Laboratories, 1996 Mendez et al 1997 Weimann et al 1998 Atkinson et al 1998 Heyland DK et al:JAMA 286:944, 2001

Pooled Risk Ratio

-4 -3 -2 -1 0 1 2 Effect Size (95% Confidence Interval) 3 41

Questions for Immunonutrition Therapy in Surgical Stress

What types of surgical stress ? What types of nutritional status ? When to begin ? What is optimal length of treatment ? What is optimal dosing ? What is expected outcome ?
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Indications of Immunonutrition
GI Surgery Trauma Burns Sepsis ? Critically Ill ?
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Effects of IMN in Septic ICU Patients

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

Control 32% Mortality (APACHEII=10-15) 28% Bactremia 22% 20% >1 nosocomial infection
Mortality Length of stay (days) Ventilator days
181 patients APACHE II >10

IMN 19% 4% 8% 6% 18 12

P .05 .02 .01 .01 .41 .90

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17 12

Infection source: mainly pneumonia

Effects of IMN in Septic ICU Patients

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

Timing of Administration

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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 stay
Napolitano.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 Nutrition

Monocyte Phagocytosis
Enteral feeding

Neutrophil Phagocytosis
Orally 1 L/d Enteral feeding

50
% Phagocytosis

40 30 20 10
* p<0.05

% Phagocytosis

60

*
50 40

IEF

OP
30
* p<0.01

OP -8 -1
Pre-op

Control

Pre-op

Postop day
Braga M et al:Eur J Surg 1996;162:105

Postop day48

Braga M et al: Arch Surg 1996;131:1257

Optimal Dose Given

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DOSING

?
Glutamine 0.1-0.3 g/kg/oral(enteral) Arginine up to 30 g/day
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Dose-Response Effect of Immunonutrients In GI Surgery

Effects Post-Op Intake Heslin MJ et al
Ann Surg 1997;226:567

() (+) (+) (+)

30% of goal 60% of goal 70% of goal 95% of goal

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Daly JM et al
Nutrition 1996;12:423

Ann Surg 1995;221:327

Schlling J et al Gianotti L et al
Arch Surg 1997;132:1222

Dose-Response Effect of Immunonutrients In Critically Ill and Sepsis

Diagnostic Category Effects Mean Intake

Bower et al

Crit Care Med 1995;23:436

Sepsis

(+) 18 ml/kg/day*

Atkinson et al
Crit care Med 1998;26:1164

Critically ill (+) 17 ml/kg/day**

Galban et al

Crit Care Med 2000;28:643

Sepsis

(+) 19 ml/kg/day

* 821 mL/day at least 7 days **>2.5 L within 72 hrs of ICU admission 52

Neomune
1 sachet Arginine 2,5 g Glutamine 1,25 g Fish oil 1,11 g Casein 12,5 g Carbohydrate 47,5 g Vitamins Minerals 5 sachet 12,5 g 6,25 g 5,55 g 62,5 g 237,5 g

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

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Immunonutrient Formulation
Impact Immun-Aid Neo-Mune

Protein (% Calories) Free Glutamine(g/l) Free Arginine (g/l) BCAA (g/l)

22 0 14.0 9.6

32 9.0 15.4 29.0 20 1.1 1.0

25 10.6 14.1 8.75 26 1.8 0

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Fat (% Calories) 25 -3 fatty acids (g/l) 1.68 Nucleotides (g/l) 1.25

Recommended Dosage
Goal: 8 10 sachets/day Full dose

5 Sachets/ day ( ~ 60% of goal)

as supplement is sufficient given orally

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Pasien 60 kg
NPC : 1500-1800 Kcal Protein 60-90 g 1000 62,5

Neomune 5 sachet

+ diet oral atau

1L KAENMG3 + 1L PanAmin G 400 200 27
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