Metabolic Response to Injury

ObjectivesFactors mediating the metabolic responseConsequences of the metabolic responseThe differences between metabolic responses to starvation and traumaThe effect of trauma on metabolic rate and substrate utilizationModifying the metabolic response

Mediating the ResponseThe Acute Inflammatory ResponseCellular activationInflammatory mediators (TNF, IL1, etc)Paracrine Vs endocrine effects

Mediating the ResponseThe EndotheliumSelectins, Integrins, and ICAMsNitric OxideTissue Factor

Mediating the ResponseAfferent Nerve StimulationSympathetic Nervous SystemAdrenal Gland Medulla

Mediating the ResponseThe Endocrine SystemPituitary Gland (GH, ACTH, ADP)Adrenal Gland (Cortisol, Aldosterone)Pancreatic (Glucagon, Insulin)Others (Renin, Angiotensin, Sex hormones, T4)

Consequences of the ResponseLimiting injuryInitiation of repair processesMobilization of substratesPrevention of infectionDistant organ damage

Starvation & Injury

Metabolic Response to Fasting

10

20

30

40

I

II

III

IV

V

Exogenous

Glycogen

Gluconeogenesis

GLUCOSE UTILIZED (g/hora)

Ruderman NB. Annu Rev Med 1975;26:248

I

II

III

IV

V

GLUCOSE

GLUCOSE

GLUCOSE

GLUCOSE, KETONES

GLUCOSE, KETONES

FUEL FOR BRAIN

LEGEND

Starvation Early Stage Fat

Starvation Late Stage

Metabolic Response to Starvation Landberg L, et al. N Engl J Med 1978;298:1295.

Hormone NorepinephrineNorepinephrineEpinephrineThyroid Hormone T4SourceSympathetic Nervous SystemAdrenal GlandAdrenal GlandThyroid Gland (changes to T3 peripherally)Change in Secretion

Energy Expenditure in Starvation Long CL et al. JPEN 1979;3:452-456

Metabolic Response to TraumaCutherbertson DP, et al. Adv Clin Chem 1969;12:1-55

Metabolic Response to Trauma:Ebb Phase Characterized by hypovolemic shockPriority 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;12:1-55 Welborn MB. In: Rombeau JL, Rolandelli RH, eds. Enteral and Tube Feeding. 3rd ed. 1997

Metabolic Response to Trauma:Flow Phase Catecholamines Glucocorticoids GlucagonRelease of cytokines, lipid mediatorsAcute phase protein production

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

Metabolic Response to TraumaFatty DepositsLiver & Muscle (glycogen)Muscle (amino acids)Fatty Acids

Glucose

Amino AcidsEndocrine Response

Metabolic Changes after Trauma

Metabolic Response to Trauma 102030402824201612840Nitrogen Excretion (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

Comparing Starvation and Trauma 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.

Metabolic rateBody fuelsBody proteinUrinary nitrogenWeight lossStarvation

conservedconserved

slowTrauma or Disease

wastedwasted

rapid

Modifying the ResponseMedication (before or after injury)Nutritional statusSeverity of injuryTemperatureAnesthetic technique

SummaryInjury (Trauma or Surgery) leads to a metabolic responseMetabolic response to injury is an adaptive responseMetabolic response could overwhelm the body and lead to increased morbidity and mortalityWe can modify the metabolic response before and sometimes after injury

Metabolic Response to InjuryQuestions

Determining Calorie RequirementsIndirect calorimetryHarris-Benedict x stress factor x activity factor25-30 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 1.2ADA: 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 syndromeBurnsStress 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 bedActivity Factor1.21.3

Metabolic Response to OverfeedingHyperglycemiaHypertriglyceridemiaHypercapniaFatty liverHypophosphatemia, hypomagnesemia, hypokalemia

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

Macronutrients during StressCarbohydrateAt least 100 g/day needed to prevent ketosisCarbohydrate intake during stress should be between 30%-40% of total caloriesGlucose intake should not exceed 5 mg/kg/minBarton RG. Nutr Clin Pract 1994;9:127-139 ASPEN Board of Directors. JPEN 2002; 26 Suppl 1:22SA

Macronutrientes during StressFatProvide 20%-35% of total caloriesMaximum recommendation for intravenous lipid infusion: 1.0 -1.5 g/kg/dayMonitor 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 StressProteinRequirements range from 1.2-2.0 g/kg/day during stressComprise 20%-30% of total calories during stressBarton 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 LevelCalorie:Nitrogen RatioPercent Potein / Total CaloriesProtein / kg Body WeightNo Stress> 150:1< 15% protein0.8 g/kg/dayModerate Stress150-100:115-20% protein1.0-1.2 g/kg/day1.5-2.0 g/kg/day > 20% protein< 100:1 Severe Stress

Role of Glutamine in Metabolic StressConsidered conditionally essential for critical patientsDepleted after traumaProvides fuel for the cells of the immune system and GI tractHelps maintain or restore intestinal mucosal integrity

Smith RJ, et al. JPEN 1990;14(4 Suppl):94S-99S; Pastores SM, et al. Nutrition 1994;10:385-391 Calder 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 StressProvides substrates to immune systemIncreases nitrogen retention after metabolic stressImproves wound healing in animal modelsStimulates secretion of growth hormone and is a precursor for polyamines and nitric oxideNot appropriate for septic or inflammatory patients.

Barbul A. JPEN 1986;10:227-238; Barbul A, et al. J Surg Res 1980;29:228-235Giving 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, B12Wound 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

*Metabolism of substrates and micronutrients is altered by starvation and trauma. During periods of starvation, metabolic processes slow down to conserve energy and adapt to calorie deprivation. After trauma, the bodys hormonal situation changes, increasing the demand for energy, proteins, and micronutrients. If nutritional requirements are not recognized and met during starvation or trauma, there may be a loss of body mass, body protein, and impairment or loss of body functions.

*Lesson objectives are:Explain the differences between metabolic responses to starvation and trauma.Explain the effect of trauma on metabolic rate and substrate utilization.Determine calorie and protein requirements during metabolic stress.This session will also review macronutrients during metabolic stress, highlighting the role of conditionally-essential nutrients in specific situations.

*Lesson objectives are:Explain the differences between metabolic responses to starvation and trauma.Explain the effect of trauma on metabolic rate and substrate utilization.Determine calorie and protein requirements during metabolic stress.This session will also review macronutrients during metabolic stress, highlighting the role of conditionally-essential nutrients in specific situations.

*Lesson objectives are:Explain the differences between metabolic responses to starvation and trauma.Explain the effect of trauma on metabolic rate and substrate utilization.Determine calorie and protein requirements during metabolic stress.This session will also review macronutrients during metabolic stress, highlighting the role of conditionally-essential nutrients in specific situations.

*Lesson objectives are:Explain the differences between metabolic responses to starvation and trauma.Explain the effect of trauma on metabolic rate and substrate utilization.Determine calorie and protein requirements during metabolic stress.This session will also review macronutrients during metabolic stress, highlighting the role of conditionally-essential nutrients in specific situations.

*Lesson objectives are:Explain the differences between metabolic responses to starvation and trauma.Explain the effect of trauma on metabolic rate and substrate utilization.Determine calorie and protein requirements during metabolic stress.This session will also review macronutrients during metabolic stress, highlighting the role of conditionally-essential nutrients in specific situations.

*Lesson objectives are:Explain the differences between metabolic responses to starvation and trauma.Explain the effect of trauma on metabolic rate and substrate utilization.Determine calorie and protein requirements during metabolic stress.This session will also review macronutrients during metabolic stress, highlighting the role of conditionally-essential nutrients in specific situations.

*Lesson objectives are:Explain the differences between metabolic responses to starvation and trauma.Explain the effect of trauma on metabolic rate and substrate utilization.Determine calorie and protein requirements during metabolic stress.This session will also review macronutrients during metabolic stress, highlighting the role of conditionally-essential nutrients in specific situations.

*The metabolic response to fasting is an adaptation by the body to preserve protein by using alternative sources of energy.The carbohydrate deposits of the body last about 18 to 20 hours and new glucose is produced through gluconeogenesis of amino acids from the lean body mass.

Ruderman NB. Muscle amino acid metabolism and gluconeogenesis. Annu Rev Med 1975;26:248.*The initial response to fasting is mediated by a drop in serum insulin and an increase in glucagon. During this period energy is provided mainly by glucose from gluconeogenesis. However, lipolysis generates free fatty acids which are oxidized into ketones. *After several days, most of the body organs are using ketones (acetoacetic, propionate, and butyric acids) for energy and gluconeogenesis decreases to half of the early phase. Brain, red blood cells, and nerve tissue still rely partially on glucose for energy.

*Conservation of energy is one of the basic adaptive responses to calorie reduction; when food is in short supply, metabolic activity decreases to spare fuel.Adjustments in the energy requirements of the body in response to changes in caloric intake occur through the action of several hormones, primarily norepinephrine and thyroid hormone. Norepinephrine is produced by the sympathetic nervous system and the adrenal glands, located near the kidneys. Thyroid hormone T4 is produced by the thyroid gland, and is modified in the periphery to the active hormone T3. Both norepinephrine and T3 participate in the decrease in metabolic activity when calorie intake decreases.

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

*The two lines on this graph show another adaptive response to severely reduced calorie intake. Urinary nitrogen excretion gradually decreases, indicating conservation of body protein and demonstrating adaptation to starvation.

Long CL et al. JPEN 1979;3:452-456 *Trauma causes major alterations in energy and protein metabolism.The response to trauma can be divided into the ebb phase and the flow phase. The ebb phase occurs immediately after trauma and lasts from 24-48 hours followed by the flow phase. After this, comes the anabolism phase and finally, the fatty-replacement phase.

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

*The ebb phase is characterized by hypovolemic shock. Cardiac output, oxygen consumption and blood pressure all decrease, thereby reducing tissue perfusion. These mechanisms are usually associated with hemorrhage. Body temperature drops. The reduction in metabolic rate may be a protective mechanism during this period of hemodynamic instability.

Cuthbertson DP, et al. Adv Clin Chem 1969;12:1-55 Welborn MB. In: Rombeau JL, Rolandelli RH, eds. Enteral and Tube Feeding. 3rd ed. Philadelphia, PA: WB Saunders; 1997. *The ebb phase is characterized by hypovolemic shock. Cardiac output, oxygen consumption and blood pressure all decrease, thereby reducing tissue perfusion. These mechanisms are usually associated with hemorrhage. Body temperature drops. The reduction in metabolic rate may be a protective mechanism during this period of hemodynamic instability.

Cuthbertson DP, et al. Adv Clin Chem 1969;12:1-55 Welborn MB. In: Rombeau JL, Rolandelli RH, eds. Enteral and Tube Feeding. 3rd ed. Philadelphia, PA: WB Saunders; 1997. *Endocrine response in the form of increased catecholamines, glucocorticoids and glycogen, leads to mobilization of tissue energy reserves. These calorie sources include fatty acids and glycerol from lipid reserves, glucose from hepatic glycogen (muscle glycogen can only provide glucose for the involved muscle) and gluconeogenic precursors (eg, amino acids) from muscle.

*The response to trauma includes a breakdown of muscle tissue. This mechanism provides amino acids for gluconeogenesis and for synthesis of proteins involved in immunologic response and tissue repair. However, this process can lead to a loss of body mass, most notably body protein.Prolonged metabolic stress without provision of adequate calories and protein leads to impaired body functions and ultimately malnutrition.The remainder of this session deals with nutritional requirements during metabolic stress.

Moore EE, et al. J Am Coll Nutr 1991;10:633-648. *This slide illustrates nitrogen losses in relation to trauma. With respect to protein, the greater the trauma, the greater the effect on the nitrogen balance. Similar to metabolic rate, patients experience nitrogen losses according to the severity and duration of the trauma.The normal range is indicated by the shaded area. The amount of protein requirement relative to calories increases in patients with metabolic stress.

Long CL, et al. JPEN 1979;3:452-456. *This graph illustrates that severity of injury correlates to increasing urinary nitrogen loss and increasing energy needs. Elective surgery being least traumatic and the lowest nitrogen loss in urine, whereas burn results in an increase in basal metabolic rate and urinary loss of nitrogen.

Adapted from Long CL, et al. JPEN 1979;3:452-456. *The metabolic response to starvation can be contrasted to trauma or disease:Metabolic rate drops during starvation, while in trauma patients it rises in proportion to the trauma severity.Body fuels and body proteins are conserved during starvation, but are wasted during trauma.Urinary nitrogen values fall with inadequate protein and calorie intake, but increase in response to metabolic stress.Weight loss is slow in underfed patients but rapid in trauma patients.Changes in body composition with trauma usually occur two to three times faster than during starvation.

Popp MB, et al. In: Fischer JF, ed. Surgical Nutrition. Boston: Little, Brown and Company; 1983. *Lesson objectives are:Explain the differences between metabolic responses to starvation and trauma.Explain the effect of trauma on metabolic rate and substrate utilization.Determine calorie and protein requirements during metabolic stress.This session will also review macronutrients during metabolic stress, highlighting the role of conditionally-essential nutrients in specific situations.

*In summary, the body responds differently to starvation and trauma. Starvation is associated with a decreased metabolic rate, which allows the body to adapt to reduced intake. After trauma, metabolic changes are associated with increased nutritional requirements. If nutritional requirements are not met during trauma, loss of protein and body mass can produce significant impairment.

*Metabolism of substrates and micronutrients is altered by starvation and trauma. During periods of starvation, metabolic processes slow down to conserve energy and adapt to calorie deprivation. After trauma, the bodys hormonal situation changes, increasing the demand for energy, proteins, and micronutrients. If nutritional requirements are not recognized and met during starvation or trauma, there may be a loss of body mass, body protein, and impairment or loss of body functions.

*There are a wide variety of methods for estimating energy requirements. Common methods include indirect calorimetry and the Harris-Benedict Equation.Indirect calorimetry is based on calculating heat production by measuring oxygen consumed and carbon dioxide produced, through analysis of exhaled gas or use of pulmonary catheters.The Harris-Benedict Equation calculates basal energy requirements for healthy people, but has also been applied to sick patients through the use of correction factors for stress and activity.The simplest estimate of adequate energy intake for patients in metabolic stress is the rule of thumb of 25-30 kcal/kg body weight per day.

*When the Harris-Benedict Equation is used to calculate energy requirements, estimated basal energy expenditure is multiplied by a stress factor. As shown in this slide, the stress factor for a long bone fracture is 1.15-1.30, resulting in a metabolic rate increase of 15%-30%. Burns have a greater impact on energy requirements, increasing basal energy expenditure by 20%-100%.In addition, activity factor of 1.2 or 1.3 must be multiplied to determine the energy requirement.

ADA: Manual of Clinical Dietetics. 5th ed. Chicago: American Dietetic Association; 1996. Long CL, et al. JPEN 1979;3:452-456. *Trauma or critically ill patients should not be overfed. Alterations in serum glucose and lipid levels, development of fatty liver, and electrolyte shifts have been associated with overfeeding.

Barton RG. Nutr Clin Pract 1994;9:127-139. *Delivery of appropriate substrates or macronutients is essential. Patients require at least 100g of glucose per day during metabolic stress to prevent ketosis. During hypermetabolic stress, a carbohydrate level of 30%-40% of total calories is recommended. 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.*Dietary fat should provide between 20-35% of total calories. Maximum recommended infusion rate when administering intravenous lipids is 1.0-1.5 g/kg/day. Serum triglyceride levels in stressed patients should be monitored to ensure adequate lipid clearance.

Barton RG. Nutr Clin Pract 1994;9:127-139. ASPEN Board of Directors. JPEN 2002;26 Suppl 1:22SA*Protein requirements increase during metabolic stress and are estimated at between 1.2-2.0 g/kg/day, or approximately 20% to 30% of the total calorie intake during stress.Barton RG. Nutr Clin Pract 1994;9:127-139. ASPEN Board of Directors. JPEN 2002;26 Suppl 1:22SA*Calorie-to-nitrogen ratios can be used to prevent lean body mass from being utilized as a source of energy. Therefore, in the non-stressed patient, less protein is necessary to maintain muscle as compared to the severely stressed patient.

Nitrogen balance can be affected by the biological value of the protein as well as by growth, caloric balance, sepsis, surgery, activity (bed rest and lack of muscle use can promote nitrogen excretion), and by renal function.

*Glutamine is one of the few nutrients included in the category of conditionally-essential amino acids.Glutamine is the bodys most abundant amino acid and is involved in many physiological functions. Plasma glutamine levels decrease drastically following trauma.It has been hypothesized that this drop occurs because glutamine is a preferred substrate for cells of the gastrointestinal cells and white blood cells. Glutamine helps maintain or restore intestinal mucosal integrity.

Smith RJ, et al. JPEN 1990;14(4 Suppl):94S-99S.Pastores SM, et al. Nutrition 1994;10:385-390.Calder 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.*Arginine is also considered a conditionally essential amino acid. Barbul and colleagues showed that arginine supplements increased thymus weight in uninjured rats and decreased thymus involution from trauma.(Barbul A, et al. J Surg Res 1980;29:228-235)In studies on humans and animals, arginine supplements increased nitrogen retention and immune function and improved wound healing.Arginine plays other roles that are not well understood; for instance as a scretagogue (growth hormone), precursor for polyamines and nitric oxide. Therefore, one should avoid providing more than 2% of total calories as arginine.Because arginine is considered an immune-enhancing nutrient, it may not be appropriate to feed supplemental arginine to septic or inflammatory patients whose immune system is already stimulated and where addition of arginine supplementation may be detrimental.

Barbul A. JPEN 1986; 10: 227-238 It is worth noting that the studies on the use of arginine supplementation were done with patients in the early phase of stress.*Micronutrient, trace element, vitamin, and mineral requirements of metabolically stressed patients seem to be elevated above the levels for normal healthy people.There are no specific dosage guidelines for micronutrients and trace elements, but there are plausible theories supporting their increased intake.This slide lists some of these nutrients along with the rationale for their inclusion.