Immunonutrients in Surgical Patients

Benny Philippi

Introduction

1. Increased complexity of managing nutritional support in surgical patients (trauma, sepsis, critically ill)

2. Malnutrition is a common practice in these patients

3. Understanding normal nutrition & metabolic changes is essential for surgeon

MALNUTRITION: PARAMETERS RSUPN – C.M.

DIGESTIVE SURGERY DIVISION

BODY MASS INDEX (BMI):FEMALE : BMI 18,5 – 23,5 (NORMAL VALUE)MALE : BMI 22,5 – 25 (NORMAL VALUE)

ALBUMIN: 3 g%TOTAL LYMPHOCYTE COUNT SCORING: PROGNOSTIC NUTRITION INDEX

(PNI)

Malnutrition: Digestive Operative Cases 2003 (Overview: BMI Value)Patients

Colorectal 14 (46,4%)

Hepatobiliary 9 (30%)

Esofago Gastric 3 (10%)

Others 4 (13,4%)

30 Cases

• BMI– Female: 18

• Malnutrition 6 (20%)

– Male: 12• Malnutrition 11 (36%)

• Albumin: Hypoalbuminemia– Preoperative : 13%– Post Operative Day 1 : 70%

Fat Cell

Keton

Free fatty acid

Growth hormon cortisol

Thyroid hormon

NE/E

GlucoseGlucose

Glucagon

NE/N

Insulin

Thyroid hormon

cortisolcortisol

ADHNE / EACTHTSH

GH

Amino acid

METABOLIC RESPONSE TO OVERNIGHT FASTING

HepaticGluconeogenesis

Fat Cell

METABOLIC RESPONSE TO TRAUMA / ELECTIVE SURGERY

Keton

Free fatty acid

Growth hormon cortisol

Thyroid hormon

NE/E

GlucoseGlucose

Glucagon

NE/N

Insulin

Thyroid hormon

cortisolcortisol

ADH (post hypophisis)NE / E (symp n / adrenal med)ACTH TSH ant hypophisisGH

Amino acid

NeuroendocrineActivation

Fat Cell

METABOLIC RESPONSE TO SEPSIS

Keton

Free fatty acid

Growth hormon cortisol

Thyroid hormon

NE/E

GlucoseGlucose

Glucagon

NE/N

Insulin

Thyroid hormon

cortisol

cortisol

ADHNE / EACTHTSHGH

Amino acid

Cytokines

“Cytokine driven”

METABOLIC RESPONSE TO SEVERE INJURYINJURY / SURGERYY

Afferent neural activity Tissue hypoperfusion Neutrophils Macrophages

CENTRAL NERVOUS SYSTEM

Cytokiens Oxygen free radicals

Arachidonic acid matabolites

Hormonal activity Anorexia Immobility

Pyrexia

Afferent neural activity Direct tissue effects

Changes in cellular hydration and cellular energetics Protein catabolism

Capillary leak Organ dysfunction

THE GOAL IN SURGERY IS TO THE GOAL IN SURGERY IS TO KEEP CYTOKINES OUT OF THE KEEP CYTOKINES OUT OF THE

CIRCULATIONCIRCULATION

METABOLICMETABOLIC

CHANGESCHANGES

REEREE

INCREASESINCREASES

URINARYURINARY

NITROGENNITROGEN

EXCRETIONEXCRETION

Uncomplicated

Surgery

10% < 15 g/day

Severe Trauma 25 – 30%

(median survival 15 days)

15 – 20 g/day

( lean tissue lost 750 g/day)

Severe Burns 100 – 200%

(median survival

7 – 10 days)

30 -40 g/day

( lean tissue lost 1500 g/day)

Sepsis 50 – 80%

(median survival 10 days)

20 – 30 g/day

Cancer with PCM 20 – 30%

GENERAL GOAL AND PRINCIPLES

Macronutrients:

1. Total Calories: 25 kcal/kg BW, in general 1 ml of water/kcal (matching energy input with expenditure remains controversial)

2. Glucose: 30 – 70% of total calories/day (2 – 5 g glucose/kg BW/day)

3. Fat: 15 – 30% of total calories/day

4. Protein: 15 – 20% of the total calories/day (estimated 1.2 – 1.5 g/kg BW/day)

Micronutrients:

Potassium, Magnesium, Zinc, and Phosphate.

Route of Administration

Enteral route:

Preferred for NS, preserve gut integrity, barrier, immune functions, and reduce infection.

Early enteral nutrition (as soon as possible after resuscitation) is preferred.

ENTERAL NUTRITION

1. In the early years EN focused predominantly on delivering adequate calories and protein

2. As more was learned from altered metabolism (renal, hepatic, diabetic, organ dysfunction ) : New formulas emerged

Specialized formulation

IMMUNE ENHANCE FORMULA / IMMUNO-NUTRIENT

1. Contain spesific substrates aimed at cellular target

2. Intended to enhance immune cellularity and function minimized inflammation

3. Potential to alter outcomes : infections (morbidity)

HOW TO PRACTICE :1. Which specific patients subgroups will

benefit from “ These formula “ compared with standard formula

2. Therapeutic dose for that benefit ?

3. When should the intervention be initiated for that benefit and for how long ?

NUTRITION IN CLINICAL PRACTICE : EVIDENCE BASE

1. Critically ill patient / sepsis : These patients were extremely heterogenous “ Varied in results “

2. Elective surgical gastrointestinal cancer patients were more homogenous

Immunonutrients

• Greater effects– Glutamine– Arginine -3 Fatty Acids

• Lesser effects– Nucleotides– Vitamins A, C, E– Zinc– Taurine

Arginine:

• Conditionally essential AA (growth, illness, metabolic stress)

• Exogenous source of arginine appears necessary for optimal immune system functioning (T lymphocyte)

• Improve N – balance• “Modulate vascular flow patterns

via nitric oxide”

Glutamine:

• Conditionally essential AA:– stress conditions– fuel for rapidly replicating cells: immune

cells, GI mucosa cells

Product Neomune Impact Immun-Aid Oxepa

Manufacturer Otsuka Novartis B Braun Ross

Protein Source Caseinates, L-arginine; L-glutamine

Caseinates, L-arginine

Lactalbumin, L-arginine; L-

glutamine, L-valine, L-isoleucine

Caseinates

Fat Source MCT, fish oil, corn oil Palm kernel oil (MCT), fish oil, sunflower oil

MCT, Canola oil Canola oil, MCT, fish oil, Borage oil,

Lecithin

Carbohydrate Source Maltodextrin, fructose Hydrolized cornstarch

Maltodextrin, corn starch

Sucrose, Maltodextrin

% Protein (g/L)

% CHO (g/L)

% Fat (g/L)

25 (62.5)

50 (125)

25 (28)

22 (56)

53 (130)

25 (28)

32 (80)

48 (120)

20 (22)

16.7 (62.5)

28.1 (105.5)

55.2 (93.7)

Cal/mL 1.0 1.0 1.0 1.5

Free arginine (g/L) 12.5 12.5 14 0

Dietary Nucleotides (g/L)

0 1.2 1.0 0

-3 : -6 ratio

MCT : LCT ratio

1 : 2.52

50 : 50

1 : 1.47

27 : 63

1 : 2.18

50 : 50

1 : 2

25 : 75

Free Glutamine (g/L)

6.25 0 9 0

Beta Carotene

Carnitine & Taurine

Yes

Yes

Yes

No

Yes

No

Yes

Yes

Osmolality (mOsm/kg Water)

400 375 460 493

Meta-analysis of Immunonutrition Enteral Feeds in GI Surgical Patients

Heys, et al: Ann Surg 1999; 229: 467.

Immunonutrition Control

Mortality 6/246 (2%) 4/251 (2%)

Infection rate 32/243 (13%) * 61/244 (25%)

Length of stay - 2,4 days *

6 trials: 497 patients * significant

Infections: pneumonia, intra abdominal abcess, wound infection, bactremia

Effects of Perioperative Effects of Perioperative Imunonutrition inImunonutrition in

Malnourished Surgical PatientsMalnourished Surgical Patients

Postop-StandardDiet

(n=50)

Preop-IMNPostop-Standard diet

(n=50)

Preop-Postop IMN

(n=50)

Patients with majorcomplications

Patients with infectiouscomplications

Patients withcomplications, total No.

Mean LOS (days)

12

12

21

15.3

9

8

14

13.2**

6

5

9*

12.0#

*P=.02 VS the control group.**P=.01 VS the control group.

#P=.04 VS the preoperative group and P=.001 VS the control group.Weight loss>10%

Braga M et al: Arch Surg 2002;137:174

Effects of Preoperative Oral Effects of Preoperative Oral ImmunonutritionImmunonutrition

in Non-malnourished Patientsin Non-malnourished Patients

Patients with infectiouscomplications

Length of hospital stay(days)

1 1 2

31 14* 16*

36 30 28

49 36 34

14 12* 12*Body weight loss<10% Preop 5days oral impact 1 L/d* p<0.03

Gianotti L et al:Gastroenterol 2002;122:1763

Preop-IMN

(n=102)

Preop-Postop IMN

(n=101)

Conventional

(n=102)

Death

Patients with noninfectiouscomplications

Patients with anycomplication

Gastroesophageal, pancreatic and colorectal resections

When to Begin

Pre operative Peri operative Post operative

The Use of Immune-Enhancing Enteral Formula with L-arginine, L-glutamine, Omega-3 Fatty Acids for Post

Operative Digestive Cancer Patients: Report of 20 Cases

Benny Philippi

Daldiyono

Lanny C. Salim

Table 1. Inclusion and Exclusion Criteria

Inclusion Criteria:Weight loss 10% (from recent usual BW)post operative digestive malignancy patients, 18-65 years old, appropriate candidates to receive enteral nutrition for at least 7 days post operatively.

Exclusion Criteria:preoperative evidence of infection, hepatic and renal dysfunction,history of insulin-dependent diabetes mellitus, body weight > 130% of IBW, patients receiving immunosupressive agents or corticosteroids within 6 months

Objective

• To evaluate the nutritional and immunology effects and clinical outcome of immune-enhancing formula compared with standard hospital formula in post operative digestive cancer patients.

Patient’s Distribution

• Number of patients recruited: 27• Number of patients drop out: 7• Number of patients completed the trial: 20• Comparison: Male & Female = 9 (45%) : 11 (55%)• Age interval: 27 – 65 years (mean: 43.46 years)

Table 2. Diagnosis and procedures

Variable No Procedures

Ca Gaster 6 Gastric resection (2)

Total Gastrectomy (4) *

Hepatobilier 1 Biliodigestive

Ca Caecum 2 Hemicolectomy Dex

Ca Sigmoid 8 Sigmoid resection

Ca Rectum 3 LAR

Total 20

* One case wound infection

Table 3. Blood Analysis

Male Female

Pre - Op Post - Op Pre – Op Post - Op

Albumin (g/DL) 2,99 3,73 2,92 3,56

Pre albumin

(mg/dL)

13,06 21,98 15,53 22,87

Transferin

(mg/dL)

200,78 229 231 246,40

TLC 1031,11 2300 1272 1832

CD 4 474 847 297,11 568,33

CD 8 441,44 535,56 209.89 264,22

Understanding CD4 and CD8 cells

• CD4 cells and CD8 cells are types of immune system white blood cells:– CD4 cells (also called helper T-cells)

coordinate immune activity and direct other immune cells

– CD8 killer T cells attack cancerous cells and cells infected with viruses

– (CD8 suppressor T cells inhibit immune activity once an invader is conquered)

Table 4. Average Neomune® Intake

Mean Kcal/day 1041,36

Mean Protein g/day 64,96

Mean Days to start Neomune®

0.93

500

1.000

1.500

2.000

2.500

pre 1.388,3 977,9

post 2.100,0 1721,4

ca gastric ca colon

* =p<0.05 ; Normal Value > 1000 cells/μL

*

*

Immunologic Status: TLC

250,0

500,0

750,0

1.000,0

pre 643,0 271,9

post 848,3 597,6

ca gastric ca colon

* =p<0.05

*

*

Immunologic Status: cd 4

200

300

400

500

600

700

pre 636,0 212,6

post 553,0 311,4

ca gastric ca colon

ns=p>0.05

Immunologic Status: cd 8

10

15

20

25

pre 14,28 12,65

post 22,53 18,38

ca gastric ca colon

* = p<0.05; Normal Value: 16 – 40 mg/dL

*

Catabolic Status: Pre albumin

150

200

250

300

pre 221,3 184,9

post 255,2 192,1

ca gastric ca colon

* = p<0.05; Normal Value: 200 – 360 mg/dL

*

Catabolic Status: Transferrin

2,5

3,0

3,5

4,0

pre 3,22 2,84

post 3,82 3,53

ca gastric ca colon

* = p<0.05; Normal value: 3.5 – 5 g/dL

**

Albumin

1,000

1,200

1,400

1,600

1,800

2,000

pre 1,158

post 1,812

tlc

*=p<0.05

*

Immunologic Status: TLC

300.0

400.0

500.0

600.0

700.0

800.0

pre 385.6

post 707.7

cd4

*=p<0.05

*

Immunologic Status: cd 4

100.0

200.0

300.0

400.0

pre 325.7

post 399.9

cd8

ns=p>0.05

Immunologic Status: cd 8

10.00

15.00

20.00

25.00

pre 14.36

post 22.45

prealbumin

*

*=p<0.05

Catabolic Status: Pre Albumin

200.0

210.0

220.0

230.0

240.0

pre 216.7

post 238.2

transferin

ns=p>0.05

Catabolic Status: Transferrin

2.5

3.0

3.5

4.0

pre 2.95

post 3.64

albumin

*=p<0.05

*Albumin

Recommendations US Summit on Immune-enhancing enteral therapy 2001; benefits from

immunonutrition include:

1. Patients undergoing major elective gastrointestinal (GI) surgery, especially malnourished patients

2. Patients with blunt and penetrating torso trauma

3. Malnourished patients undergoing surgery for head and neck cancer

4. Patients with severe head injury5. Burn patients6. Ventilator – dependent non septic patients at

risk for infection

Practical Strategies

• Adequate IEF Nutrition content (glutamine, arginine, ω-3 Fatty Acid) and volume (arginine > 12 g/L)

• Duration of giving IEF > 3 days ( 5 – 10 days)

• Nasogastric feeding (every 4 – 6 hours,gastric residual 150 – 200 ml)

• Feeding goals: 25 kcal/kg BW, 800 ml.day

• NEO-MUNE Formula: 5 – 8 sachet/day

Thank You