Metabolic Response to Metabolic Response to InjuryInjury

Objectives

• Factors mediating the metabolic response• Consequences of the metabolic response• The differences between metabolic responses to

starvation and trauma• The effect of trauma on metabolic rate and

substrate utilization• Modifying the metabolic response

Mediating the Response

• The Acute Inflammatory Response

• Cellular activation

• Inflammatory mediators (TNF, IL1, etc)

• Paracrine Vs endocrine effects

Mediating the Response

• The Endothelium

• Selectins, Integrins, and ICAMs

• Nitric Oxide

• Tissue Factor

Mediating the Response

• Afferent Nerve Stimulation

• Sympathetic Nervous System

• Adrenal Gland Medulla

Mediating the Response

• The Endocrine System

• Pituitary Gland (GH, ACTH, ADP)

• Adrenal Gland (Cortisol, Aldosterone)

• Pancreatic (Glucagon, Insulin)

• Others (Renin, Angiotensin, Sex hormones, T4)

Consequences of the Response

• Limiting injury

• Initiation of repair processes

• Mobilization of substrates

• Prevention of infection

• Distant organ damage

Starvation & Injury

10

20

30

40

I II III IV V

Exogenous

Glycogen

Gluconeogenesis

GL

UC

OS

E U

TIL

IZE

D (

g/h

ora)

Ruderman NB. Annu Rev Med 1975;26:248

I II III IV V

GLUCOSEGLUCOSE GLUCOSEGLUCOSE, KETONES

GLUCOSE, KETONES

FUEL FOR BRAIN

LEGEND

Metabolic Response to Fasting

Starvation – Early Stage

Intestine

Muscle

Liver

Brain

Kidney

Gluconeogenesis

Ketogenesis

Ureagenesis

Glutamine

Alanine / PyruvateGlucose

Ketones

Urea

NH3

Ketones

Glycerol

AGLFat

Starvation – Late Stage

Intestine

Muscle

Liver

Brain

Kidney

Gluconeogenesis

Ketogenesis

Ureagenesis

Glutamine

Alanine / PyruvateGlucose

Ketones

Urea

NH3

Ketones

Glycerol

AGL

Fat

Metabolic Response to Starvation

Hormone

NorepinephrineNorepinephrineEpinephrineThyroid Hormone T4

Source

Sympathetic Nervous SystemAdrenal GlandAdrenal GlandThyroid Gland (changes to T3 peripherally)

Change in Secretion

Landberg L, et al. N Engl J Med 1978;298:1295.

Energy Expenditure in Starvation

Long CL et al. JPEN 1979;3:452-456

010 20 30 40

Partial Starvation

Days

Nitr

ogen

Exc

retio

n (g

/day

)12

8

44

Total Starvation

Normal Range

Metabolic Response to Trauma

Time

Ener

gy E

xpen

ditu

re

Ebb PhaseEbb

PhaseFlow

PhaseFlow

Phase

Cutherbertson DP, et al. Adv Clin Chem 1969;12:1-55

Metabolic Response to Trauma:Ebb Phase • Characterized by hypovolemic shock• Priority is to maintain life/homeostasis

Cardiac output Oxygen consumption Blood pressure Tissue perfusion Body temperature Metabolic rate

Cuthbertson DP, et al. Adv Clin Chem 1969;12:1-55Welborn MB. In: Rombeau JL, Rolandelli RH, eds. Enteral and Tube Feeding. 3rd ed. 1997

Metabolic Response to Trauma:Flow Phase Catecholamines Glucocorticoids Glucagon• Release of cytokines, lipid mediators• Acute phase protein production

Cuthbertson DP, et al. Adv Clin Chem 1969;12:1-55Welborn MB. In: Rombeau JL, Rolandelli RH, eds. Enteral and Tube Feeding. 3rd ed. 1997

Metabolic Response to Trauma

Fatty Deposits

Liver & Muscle (glycogen)

Muscle (amino acids)

Fatty Acids

Glucose

Amino Acids

Endocrine Response

Metabolic Changes after Trauma

Intestine

Muscle

Liver

Brain

Kidney

Gluconeogenesis

Ketogenesis

Ureagenesis

Glutamine

Alanine / PyruvateGlucose

Ketones

Urea

NH3

Ketones

Glycerol

AGL

Fat

Metabolic Response to Trauma

10 20 30 40

28

24

20

16

12

8

4

0

Nitro

gen

Excr

etio

n (g

/day

)

DaysLong CL, et al. JPEN 1979;3:452-456

Severity of Trauma: Effects on Nitrogen Losses and Metabolic Rate

Adapted from Long CL, et al. JPEN 1979;3:452-456

Basal Metabolic Rate

Cirugíamayor

Cirugíaelectiva

InfecciónSepsisgrave

Quemaduramoderada a grave

Nitr

ogen

Los

s in

Urin

e

MajorSurgery

ElectiveSurgery

Infection

SevereSepsis

Moderate to SevereBurn

Comparing Starvation and Trauma

Metabolic rate

Body fuels

Body protein

Urinary nitrogen

Weight loss

Starvation

conserved

conserved

slow

Trauma or Disease

wasted

wasted

rapid

The body adapts to starvation, but not in the presence of critical injury or disease.

Popp MB, et al. In: Fischer JF, ed. Surgical Nutrition. 1983.

Modifying the Response

• Medication (before or after injury)

• Nutritional status

• Severity of injury

• Temperature

• Anesthetic technique

Summary

• Injury (Trauma or Surgery) leads to a metabolic response

• Metabolic response to injury is an adaptive response

• Metabolic response could overwhelm the body and lead to increased morbidity and mortality

• We can modify the metabolic response before and sometimes after injury

Metabolic Response to Injury

Questions

Determining Calorie Requirements

• Indirect calorimetry• Harris-Benedict x stress factor x activity factor• 25-30 kcal/kg body weight/day

Metabolic Response to Starvation and Trauma: Nutritional Requirements

Example:

Energy requirements for patient with cancer in bed

= BEE x 1.10 x 1.2

ADA: Manual Of Clinical Dietetics. 5th ed. Chicago: American Dietetic Association; 1996Long CL, et al. JPEN 1979;3:452-456

InjuryMinor surgeryLong bone fractureCancerPeritonitis/sepsisSevere infection/multiple traumaMulti-organ failure syndromeBurns

Stress Factor1.00 – 1.101.15 – 1.301.10 – 1.301.10 – 1.301.20 – 1.401.20 – 1.401.20 – 2.00

ActivityConfined to bedOut of bed

Activity Factor1.21.3

Metabolic Response to Overfeeding

• Hyperglycemia• Hypertriglyceridemia• Hypercapnia• Fatty liver• Hypophosphatemia, hypomagnesemia, hypokalemia

Barton RG. Nutr Clin Pract 1994;9:127-139

Macronutrients during Stress

Carbohydrate

• At least 100 g/day needed to prevent ketosis• Carbohydrate intake during stress should be between

30%-40% of total calories• Glucose intake should not exceed

5 mg/kg/min

Barton RG. Nutr Clin Pract 1994;9:127-139 ASPEN Board of Directors. JPEN 2002; 26 Suppl 1:22SA

Macronutrientes during Stress

Fat

• Provide 20%-35% of total calories• Maximum recommendation for intravenous lipid

infusion: 1.0 -1.5 g/kg/day• Monitor triglyceride level to ensure adequate lipid

clearance

Barton RG. Nutr Clin Pract 1994;9:127-139ASPEN Board of Directors. JPEN 2002;26 Suppl 1:22SA

Macronutrients during Stress

Protein

• Requirements range from 1.2-2.0 g/kg/day during stress• Comprise 20%-30% of total calories during stress

Barton RG. Nutr Clin Pract 1994;9:127-139 ASPEN Board of Directors. JPEN 2002;26 Suppl 1:22SA

Determining Protein Requirements for Hospitalized Patients

Stress Level

Calorie:Nitrogen Ratio

Percent Potein / Total Calories

Protein / kg Body Weight

No Stress

> 150:1

< 15% protein

0.8 g/kg/day

Moderate Stress

150-100:1

15-20% protein

1.0-1.2 g/kg/day

1.5-2.0 g/kg/day

> 20% protein

< 100:1

Severe Stress

Role of Glutamine in Metabolic Stress• Considered “conditionally essential” for critical patients• Depleted after trauma• Provides fuel for the cells of the immune system and GI

tract• Helps maintain or restore intestinal mucosal integrity

Smith RJ, et al. JPEN 1990;14(4 Suppl):94S-99S; Pastores SM, et al. Nutrition 1994;10:385-391Calder PC. Clin Nutr 1994;13:2-8; Furst P. Eur J Clin Nutr 1994;48:607-616 Standen J, Bihari D. Curr Opin Clin Nutr Metab Care 2000;3:149-157

Role of Arginine in Metabolic Stress• Provides substrates to immune system• Increases nitrogen retention after metabolic stress• Improves wound healing in animal models• Stimulates secretion of growth hormone and is a precursor

for polyamines and nitric oxide• Not appropriate for septic or inflammatory patients.

Barbul A. JPEN 1986;10:227-238; Barbul A, et al. J Surg Res 1980;29:228-235

“ Giving arginine to a septic patient is like putting gasoline on an already burning fire.”

- B. Mizock, Medical Intensive Care Unit, Cook County Hospital, Chicago, IL

Key Vitamins and Minerals

Vitamin AVitamin CB VitaminsPyridoxineZinc

Vitamin EFolic Acid,Iron, B12

Wound healing and tissue repairCollagen synthesis, wound healingMetabolism, carbohydrate utilizationEssential for protein synthesisWound healing, immune function, protein synthesisAntioxidantRequired for synthesis and replacement of red blood cells