Subject: Surgery Topic: Metabolic and Inflammatory Response to Injury Lecturer: Dr. Raymundo Resurreccion Date of Lecture: Nov.

23, 2011 Transcriber: Aaron Villoso Pages: 17

Legend: SNS- Sympathetic nervous system; NER- Neuroendocrine response Extensive thermal injury- mother of all injury Factors Modifying the Response to Injury Severity of injury Nature of injury- better prognosis in stab wound than gunshot wound Infection Genetic factors Nutritional status- BMI normal range- 18.5-25; BMI 26-27 actually results to a better outcome in an ICU setting compared to those people in their normal BMI since those who are slightly overweight have more stores of energy in the form of fat. However Coexisting diseases Ambient temperature- should be maintained in a thermoneutral condition to avoid increase in metabolic needs Anesthesia & drugs Factors Mediating The Metabolic Response To Injury o Acute inflammatory response o o Inflammatory cells (macrophages, monocytes, neutrophils) Proinflammatory cytokines & other inflammatory mediators Multiple, interlinked cascades

Effects of hemorrhage + oxygen deficit, followed by neuro-endocrine response Cellular + humoral components- mediates inflammatory cascade

SY 2011-2012

o o o

Endothelial cell activation Adhesion of inflammatory cells (margination, clumping of platelets) Vasodilatation Increased permeability- allows diapedesis Afferent nerve stimulation Release of stress hormones- elicits the fight or flight response Bacterial infection & endotoxin

Humoral Response o o o o Complement Kinins-(opposite of vasoconstrictors) allow inc. prefusion in areas that require repair or need bacterial killing; allows PMNs to go to areas with bacteria and mediates bacterial killing Coagulation- limits blood loss Cytokine mediated: TNF, IL1, IL6, IL8, IFN

IL-6, IL-8 and TNF - proinflammatory cytokines IL-6 growth and differentiation of lymphocytes, activation of lymphocytes and acute phase protein response IL-8- chemoattractant IL-10- immunomodulator- regulates inflammatory cascade; inhibits immune function

TNF AND LPS BINDS WITH Toll like receptors- interaction of which allows intracellular signalling NFKB- normally inhibited by inhibitory NFKB subunit but once phosphorylated it will be allowed to enter the nuclues. Once in the nucleus allows transcription of inflammatory proteins Effects of Humoral Response o o Membrane damage- eg. acute respiratory distress syndrome Cellular damage- eg.Px with severe sepsis may eventually manifest Jaundice due to direct liver cell damage

o o o o o

Sludging- secondary to inc. endothelial permeability plasma escapes from the blood and therefore resulting in an increase viscosity which may eventually lead to formation of microthrombi and slowing down of perfusion. Leaky capillaries- hypovolemic shock Coagulopathy- DIC causing hypoperfusion Anaerobic metabolism- enhances inflammatory problems; due to hypoperfusion there will be accumulation of lactic acid Compromise of organ function Effects of Cellular Response o o o o o Membrane damage Coagulation Cellular damage Coagulopathy Organ compromise

Cellular Response o o o o o Cytokine mediated Leukocyte activation Endothelial activation Platelet activation Systemic inflammation

Mediators in SIRS/Sepsis MEDIATOR Interleukin-1 Prostaglandins Corticosteroids Glucagon Norepinephrine Growth, thyroid hormones Complement, anaphylatoxins Kinin system, serotonin histamine Oxygen free radicals Tumor necrosis factor Myocardial depressant factor Nitric oxide EFFECTS Fever, proteolysis Vasodilation Hypermetabolism Gluconeogenesis Hypermetabolism Acute catabolism Microcirculatory damage Vasodilation Membrane damage Tissue injury, shock Cardiac dysfunction Vasodilation, hypotension

Central Nervous System Regulation of Inflammation Afferent Signals to the Brain The central nervous system (CNS) plays a key role in orchestrating the inflammatory response. The CNS influences multiple organs through both neurohormonal and endocrine signals. Injury or infection signals are recognized by the CNS through afferent signal pathways (Fig. 2-2). The CNS may respond to peripheral inflammatory stimuli through both circulatory and neuronal pathways. Inflammatory mediators activate CNS receptors and establish phenotypic responses such as fever and anorexia. The vagus nerve has been described as highly influential in mediating afferent sensory input to the CNS.

Neuro-endocrine Response o o o o o o o Massive receptor stimulus Hypothalamopituitary axis Catecholamines Gluco + mineralo corticoids Glucagon ADH Insulin

Insulin is also increased however its effect is masked by the effects of the 4 remaining hormones. Glucagon, cortisol, Epi, NE promotes glucose mobilization and proteolysis ..net effect= from base line level there is an inc. in protein synthesis (insulin) but it is predominated by the proteolysis mediated by the 4 said hormones. Hormonal Response to Injury

Effects of catecholamines, cortisol and glucagon are CATABOLIC while insulin, HGH and testosterone are ANABOLIC

2 distinct periods of the post-traumatic responses Ebb phase Characterized by hypovolemic shock/ hemodynamic instability Goal is to maintain life/homeostasis Dec. cardiac output, dec. glucocorticoids, blood pressure, time perfusion, body temperature and metabolic rate: all of these are preservatory mechanisms Flow phase- period of compensation Redistribution of blood, direct resources to injured site Inc. catecholamines, glucocorticoids, glucagon and metabolic rate- hypermetabolism Shift to anabolic pathway

KETOADAPTATION: seen in starvation only fats are converted to energy first so that proteins are not depleted Lipolysis fats ketones release of energy

Metabolic Response to Injury Rapid glycogenolysis H2O + NaCl retention edema Glucose intolerance Gluconeogenesis Protein synthesis redirected to acute phase proteins + wound healing Muscle wasting Increased energy expenditure o Pain, anxiety, fever o Muscular effort-work of breathing, shivering Physiologic stress response: Catabolic phase o increased caloric needs, inadequate intake o gluconeogenesis wasting of endogenous protein stores, increased urinary nitrogen losses Hypermetabolic state increases demands less efficient use of nutrients for energy more nutrients used to meet the demands Negative energy balance is highly correlated to complications in critically ill patients

Effects of Surgical Trauma on Resting Energy Expenditure Hypermetabolic state increases demands less efficient use of nutrients for energy more nutrients used to meet the demands Negative energy balance is highly correlated to complications in critically ill patients

NOTE: In surgical patients, there is a marked increase in energy demands and change in nutrient utilization with 50% from fat, 30% from carbohydrates and 20% from protein *Glycogen stores do not last for more than 48 hrs, so during fasting of >48 hrs, energy comes from muscle protein and fat stores.

Metabolism after Injury (derived from the book) Injuries or infections induce unique neuroendocrine and immunologic responses that differentiate injury metabolism from that of unstressed fasting (Fig. 2-21). The magnitude of metabolic expenditure appears to be directly proportional to the severity of insult, with thermal injuries and severe infections having the highest energy demands (Fig. 2-22). The increase in energy expenditure is mediated in part by sympathetic activation and catecholamine release, which has been replicated by the administration of catecholamines to healthy human subjects. Lipid metabolism after injury is intentionally discussed 55 first, because this macronutrient becomes the primary source of energy during stressed states.

SHORT REVIEW ON BIOCHEM: Regeneration of lactate to glucose is through the cori cycle Ketones from - oxidation of fats are used by the kidney, heart and muscle Gluconeogenesis generates glucose from other sources: glycerol and amino acids

Long term starvation leads to protein preservation and decreased metabolic state The greater the stress, the more the patient becomes catabolic Major burns > sepsis > skeletal trauma > elective surgery

The decrease or return to normal is due to the institution of therapeutic regimen

Substrate Utilization in Surgery Protein Surgical trauma is accompanied by a negative nitrogen balance Nitrogen balance is more negative than during pure fasting

Explanation: The net changes in protein catabolism and synthesis correspond to the severity and duration of injury (Fig. 227). Elective operations and minor injuries result in lower protein synthesis and moderate protein breakdown. Severe trauma, burns, and sepsis are associated with increased protein catabolism. The rise in urinary nitrogen and negative nitrogen balance can be detected early after injury and peak by 7 days. This state of protein catabolism may persist for as long as 3 to 7 weeks. The patient's prior physical status and age appear to influence the degree of proteolysis after injury or sepsis. NOTE: Activation of the ubiquitin-proteosome system in muscle cells is one of the major pathways for protein degradation during acute injury. This response is accentuated by tissue hypoxia, acidosis, insulin resistance, and elevated glucocorticoid levels.

Protein turnover rates in trauma patients- more on proteolysis; it is wrong to assume that there is no protein synthesis during injury. It just so happen that proteolysis predominates protein synthesis Leucine flux (micromol/kg/min)

Role of gluatamine in metabolic stress Considered conditionally essential for critical patients Depleted after trauma Provides fuel for the cells of the immunse system and GI tract Helps maintain or restore intestinal mucosal integrity

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.

Sick patient past 24 hrs. As sepsis score gets higher, the individual becomes more sick, lower utilization of glucose such that the source of fuel becomes more inclined to fat oxidation, as shown by the second diagram above.

From Schwartz: The metabolic changes during sepsis differ from those observed after injury. The REE (Rest Energy Expenditure) rises 5080% above the norm, and urinary nitrogen excretion reaches 2030 g per day, predominantly due to profound muscle catabolism and impaired synthesis. Catabolism at this rate equates to a median survival of 10 days without nutritional input. The plasma glucose, amino acid, and FFA levels increase more than with trauma. Hepatic protein synthesis is stimulated, with both enhanced secretion of export protein and accumulation of structural protein. The RQ falls to 0.690.71, indicative of intense lipid oxidation. This unchecked lipolysis and gluconeogenesis continues despite supplementation with carbohydrate or fat, leading to the hyperglycemia and insulin resistance commonly observed in septic patients. Energy Utilization Marked increase in energy demands and change in nutrient utilization with 50% from fat, 30% from carbohydrates, and 20% from protein (in cases of injury) 60-70% caloric needs come from carbohydrates 1g = 4cal during stress goes down to 30% 25-30% comes from fats 1g= 9 cal during stress goes up to 50% ( even in high protein diet) 5-10% from proteins 1g= 4cal during stress goes up to 20%

Primary Considerations Malnutrition in neuro/surgical patients is common and they are at risk for: o Developing malnutrition o Progressing to a worse malnourished state Progressive weight loss leads to increased morbidity and early death Adequacy of intake is a major issue in the management of the surgical patient

Why is Nutrition Important? The goal of nutritional support in the surgical patient is to prevent or reverse the catabolic effects of disease or injury. From Schwartz: A fundamental goal of nutritional support is to meet the energy requirements for metabolic processes, core temperature maintenance, and tissue repair. Failure to provide adequate nonprotein energy sources will lead to consumption of lean tissue stores. The requirement for energy may be measured by indirect calorimetry and trends in serum markers (e.g., prealbumin level) and estimated from urinary nitrogen excretion, which is proportional to resting 60 energy expenditure. However, the use of indirect calorimetry, particularly in the critically ill patient, is labor intensive and often leads to overestimation of caloric requirements. Critical Illness + Poor Nutrition = Prolonged ventilator dependency- inability of the patient to breathe by their own Prolonged ICU stay Heightened susceptibility to nosocomial infections- MOF Increased mortality with mild/moderate or severe malnutrition

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*MOF- multiple organ failure; GALT- GIT assoc. lymphoid tissue; CARS- compensatory anti-inflammatory response syndrome/ BURNOUT PHASE (HYPERACTIVE/HYPERINFLAMMATORY-TISSUE DAMAGE EARLY MOF); SIRS- systemic inflammatory response syndrome Systemic inflammatory response syndrome (SIRS) is an inflammatory state affecting the whole body, frequently a response of the immune system to infection, but not necessarily so. Criteria for SIRS

>> SIRS can be diagnosed when two or more of these criteria are present. Immunesuppressionpatients develop CARS which renders them more susceptible to infection. Compensatory Anti-inflammtory response syndrome One major consequenceof CARS is the modification of the immune status that could favour the enhanced susceptibility of intensive care patients to nosocomial infections. It is characterized by the presence of the following: (derived from an article in PubMed) Cellular/molecular elements Lymphocyte dysfunction (ie, reduced proliferative and/or type 1 helper T-cell [Th1] cytokine production in response-defined antigens or specific T-cell stimuli) Lymphocyte Apoptosis Down-regulation of monocyte HLA receptors Monocyte deactivation (ie, reduced Th1/proinflammatory cytokine production in response stimuli) IL-10 production Transforming growth factor-beta production Prostaglandin E2 production Clinical elements Cutaneous anergy Hypothermia Leukopenia Susceptibility to infection Failure to clear infection

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Difference between SIRS and CARS The difference between the 2 was that while SIRS was a proinflammatory syndrome that seemed tasked with killing infectious organisms through activation of the immune system, CARS was a systemic deactivation of the immune system tasked with restoring homeostasis from an inflammatory state. Moreover, it has become apparent that CARS is not simply the cessation of SIRS, it can exist separately from SIRS. Bacterial translocationwhen bacteria are able to penetrate the splanchnic circulation Consequences of Malnutrition: Loss of lean body mass Poor wound healing, anastomotic breakdown Compromised immune defense Impaired organ function Increased mortality rates

Determining Calorie Requirements Harris-Benedict x stress factor x activity factor Baseline Energy Expenditure (BEE)- function if weight, height, age and sex Stress factor is what caused the patient to be at the hospital Short method: 25-30 kcal/kg body weight/day--- gives predictive value just like Harris-Benedict equation For underweight/ near IBW use actual body weight For obese patient- cant use actual body weight for it will only perpetuate overfeeding instead use ideal body weight and multiply it with 25-30 kcal/kg body weight/day Multiply by the ideal body weight for a particular height Indirect calorimetry- Gold standard Vs. direct, which is a direct measurement of heat produced Using up oxygen; measurement of oxygen consumed per unit time by catching expired breath

There are a wide variety of methods for estimating energy requirements. Common methods include indirect calorimetry and the Harris-Benedict Equation. Basal energy expenditure (BEE) may also be estimated using the Harris-Benedict equations:

where W = weight in kilograms; H = height in centimeters; and A = age in years. 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. Injury Minor surgery Long bone fracture Cancer Peritonitis/sepsis Severe infection/multiple trauma Stress Factor 1.00 1.10 1.15 1.30 1.10 1.30 1.10 1.30 1.20 1.40

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Multi-organ failure syndrome Burns

1.20 1.40 1.20 2.00

Activity Confined to bed Out of bed

Activity Factor 1.2 1.3

Example: Energy requirements for patient with cancer in bed = BEE x 1.10 x 1.2 NOTE: 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. Conditions Affecting Caloric Needs REE Change Fever (perC) Sepsis Trauma Burn Treatments Mech. ventilation -25 to -35% +10 to 15% +20 to 60% +20 to 50% +40 to 80%

Nutritional support

+20%

Agitation

+50 to 100%

Drugs Affecting Caloric Needs Drug Opiates Sedation Barbiturates REE Change -9% -20 to -55% -32%

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Muscle relaxants Catecholamines -blockers

-42% +32% -6 to -7%

Metabolic Response to Injury Risk of oxidative stress increased due to: o o o Hyperglycemia Increased glucose production in excess of need Associated with increased mortality & morbidity Systemic effects: increased risk of infection, impaired wound healing Better glucose control has been shown to improved clinical outcomes. Loss of substantial antioxidants via blood loss, burns, dialysis/CVVH delayed or interrupted nutrient supply (ischemia/reperfusion) medical interventions associated with highly increased formation of OFR (e.g. ventilator treatment)

Consequence of the Metabolic Response to Injury Increased energy expenditure: 35-40kcal/d Increased glucose & fat turnover Breakdown of adipose tissue as principal energy source Catabolism of skeletal muscle to provide amino acids for gluconeogenesis & hepatic synthesis of acute-phase proteins.

Weight Loss after Surgical Trauma Where? Muscle Fat

Why? Reduced food intake Increased energy expenditure Derangements in protein/fat metabolism

Unintentional weight loss (>10% in six months) Patient Population Major burns and trauma Spinal injury rehab Outpatient rehab Nursing home Incidence 80% 80% 20%-40% 25% plus

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Loss of Lean Mass Correlates with Degree of Mortality Complications Relative to Loss of Lean Body Mass* Lean Body Mass (% loss of total) 10 Complications (related to lost lean mass) Impaired immunity, increased infection 20 Decreased healing, weakness, infection 30 Too weak to sit, pressure sores, pneumonia, no healing 40 Death, usually from pneumonia 100 50 30 10 Associated Mortality (%)

Consequence of Continuing Injury Sodium & water retention in response to hypovolemia, aldosterone & ADH release edema Increased inflammatory response due to ischemia/ reperfusion injury to the gut Excessive production of pro-inflammatory cytokines such as IL-1, IL-6, TNF-organ injury

Trauma to Sepsis Immune compromise Devitalized tissue Catheter-related infections Hematomas abscesses Contamination Malnutrition Gut failure bacterial translocation

Local to Systemic Response:

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Biphasic Immuno-inflammatory Response:

ABOVE: Another representation of SIRS and CARS NOTE: NFkB activation elevated in sepsis and higher in non-survivors vs survivors Cytokine concentrations in patients with severe sepsis Cytokine TNF- (pg/ml) IL-1 (pg/ml) IL-6 (ng/ml) 0 0 Controls 0 Survivors 47.3 (7-320) 32.0 (24-270) 37.0 (15-56) Non-survivors 64.3 (7-360) 46.0 (24-290) 63.4 (39-76)

NOTE: Sepsis results in elaboration of inflammatory cytokines, most notably TNF-, IL-1, and IL-6. Alteration in hepatic protein synthesis towards production of acute-phase proteins is triggered by IL-6. Septic patients also develop an abnormal plasma amino acid pattern (increased levels of AAAs and decreased levels of BCAAs) similar to that of patients with liver failure. In contrast to simple starvation, protein conservation does not occur in sepsis. Terminal sepsis results in further increases in plasma amino acids and a fall in glucose concentration, as hepatic amino acid clearance declines and gluconeogenesis ceases.

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Mortality rate increases as the number of dysfuntional organs increases Strategies to Modify the Inflammatory Response Hypotensive / goal-directed resuscitation Timing of surgery Appropriate ventilation Normoglycemia Infectious precautions Normothermia Early enteral / parenteral feeding

Summary The initial insult leads to local and nonspecific systemic inflammation and to activation of a stress hormonal response to produce a hypermetabolic-catabolic state. Resulting hormonal, humoral and cellular responses may lead to further injury particularly to capillaries, basement membranes, organs. Nutritional requirements increase during trauma and energy deficit is common.

The degree of hypermetabolism and catabolism is dependent on both the degree of injury and the host response to injury. The increased use of protein for fuel rapidly depletes lean body mass.

The hormonally-induced metabolic response produces a change in nutrient utilization with 50% from fat, 30% from carbohydrates, and 20% from protein. Inadequate provision of calories and micronutrients during surgical stress leads to increased morbidity and mortality.

__________________________________END OF MY TRANSCRIPTION_____________________________________ MERRY CHRISTMAS AND HAPPY NEW YEAR BATCH 2014!!! Ilang months na lang and were done with 2 YEHEY!!! This is my last tranx for this year..keep on supporting Cor Christi. Thanks for supporting me and Christel during JFT Hi to my Med dance family, Cor Christi family, SUSETS, My micro and PD groupmate !! Happy Holidays
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