SYSTEMIC RESPONSE TO INJURY & METABOLIC SUPPORT

A review of Schwartzs Principles of SurgeryChapter 2

Muhammad Reza - M. Saidi

Introduction

Inflammatory response to injury

to restore tissue function Eradicate invading microorganisms

Local- limited duration, restores function Further

overwhelming inflammatory response Potential multi-organ failure Adversely impacts patient survival

SIRS

Central Nervous System Regulation of Inflammation

The CNS influences multiple organs through both neurohormonal and endocrine signals Neural parasympathetic vagal stimulation attenuates the inflammatory response via Ach release

Reduces HR, increases gut motility, dilates arterioles, constricts pupils, and decreases inflammation Reduces macrophage activation Reduces macrophage release of pro-inflammatory mediators (TNF-, IL-1, IL-18)

Hormonal Response to Injury

Hormone classifications
polypeptide (cytokine, insulin) amino acid (epinephrine, serotonin, or histamine) fatty acid (cortisol, leukotrienes)

Pathways
Receptor Kinases insulin Guanine nucleotide binding (G-protein) - prostaglandins Ligand Gated ion channels

Adrenocorticotropic Hormone

Synthesized anterior pituitary Regulated by circadian signals Pattern is dramatically altered in injured patients Elevation is proportional to injury severity Released by: pain, anxiety, vasopressin, angiotensin II, cholecystokinin, catecholamines, and pro-inflammatory cytokines ACTH signals increase glucocorticoid production

Glucocorticoids

Cortisol elevated following injury,

duration of elevation depends on severity of injury

Potentiates hyperglycemia

Hepatic gluconeogenesis Muscle and adipose tissue > induces insulin resistance Skeletal m.> protein degradation, lactate release Adipose -> reduces release of TG, FFA, glycerol Impair wound healing ; reduce TGF-, IGF-I

Macrophage Inhibitory Factor

Glucocorticoid antagonist produced by anterior pituitary & Tlymphocytes Reverses immunosuppressive effects of glucocorticoids

Growth Hormone

During stress -> protein synth, fat mobilization, and skeletal cartilage growth 2 to release of insulin-like growth factor (IGF1) Injury reduces IGF1 levels

Catecholamines

Severe injury activates the adrenergic system Norepi and Epi immed. increase 3-4 fold and remain elevated 24-48hrs after injury Epinephrine
hepatic glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis Decreases insulin Peripheral- lipolysis, insulin resistance in skeletal m. = stress induced hyperglycemia Reduces release of aldosterone Enhances leukocyte demargination and lymphocytosis

Aldosterone

Synthesized, stored, released from the adrenal zona glomerulosa Maintains intravascular volume
Conserves sodium Eliminates potassium and hydrogen ions Acts on the early distal convoluted tubules

Deficiency- hypotension, hyperkalemia Excess- edema, HTN, hypokalemia, metab alkalosis

Insulin

Stress inhibited release + peripheral insulin resistance = hyperglycemia Injury has 2 phases of insulin release
Within hours- release is suppressed Later- normal/xs insulin production with peripheral insulin resistance

Activated lymphocytes have insulin receptors -> enhanced Tcell proliferation and cytotoxicity Tight control of glucose levels esp. in diabetics significantly reduces mortality after injury

Acute Phase Proteins

Nonspecific markers Produced by hepatocytes Response to injury, infection, inflammation Induced by IL-6 C-reactive protein best reflects inflammation
No diurnal variation, not affected by feeding Affected only by preexisting hepatic failure

INFLAMMATORY MEDIATORS
Heat Shock Protein Reactive Oxygen Metabolites Eicosanoids Fatty Acid Metabolites Kallikrein-Kinin System Serotonin

Histamine Cytokines

Kallikrein-Kinin System

Bradykinins are potent vasodilators Stimulated by hypoxic and ischemic injury

Hemorrhage, sepsis, endotoxemia, tissue injury Magnitude proportional to severity of injury

Produced by kininogen degradation by kallikrein Kinins increase capillary permeability (edema), pain, inhibit gluconeogenesis, renal vasodilation, incr bronchoconstriction In clinical trials, bradykinin antagonists help reverse Gsepsis, but do not improve survival

Serotonin

Present in intestinal chromaffin cells & platelets Vasoconstriction, bronchoconstriction, platelet aggregation Myocardial chronotrope and ionotrope Unclear role in inflammation

Histamine

Stored in neurons, skin, gastric mucosa, mast cells, basophils, and platelets H1 bronchoconstriction, increases intestinal motility and myocardial contractility H2 inhibits histamine release H1/H2 hypotension, decreased venous return/peripheral blood pooling, increased capillary permeability, myocardial failure.

Tumor Necrosis Factor

Secreted from monocytes, macrophages, Tcells Responds early, T < 20min Potent evocation of cytokine cascade Induces muscle catabolism/cachexia, coagulation, PGE2, PAF, glucocorticoids, eicosanoids Circulating TNF receptors compete with cellular receptors and may act as a counter regulatory system to prevent excessive TNF- activity

Cytokines

Most potent mediators of inflammation Local- eradicate microorganisms, promote wound healing Overwhelming response- hemodynamic instability (septic shock) or metabolic derangements (muscle wasting) Uncontrolled- end-organ failure, death Self-regulatory production of anti-inflammatory cytokines, but inappropriate release may render the patient immunocompromised and susceptible to infection

Cell Signaling Pathways

G-protein receptors

Largest family of signaling receptors Adjacent effector protein activated receptor Second messengers cAMP or calcium Can result in gene transcription or activation of phospholipase C

Ligand Gated Ion Channels

When activated by a ligand, a rapid influx of ions cross the cell membrane. i.e. neurotransmitters

Cell Signaling Pathways

Tyrosine Kinases

When activated, receptors dimerize, phosphorylate, and recruit secondary signaling molecules Used in gene transcription and cell proliferation i.e. insulin, PGDF, IGF-1

Cell Signaling Pathways

Janus Kinase/Signal Transduction and Activator of Transcription (JAK-STAT)

IL-6, IL-10, IL-12, IL-13, IFN- Ligand binds to the receptor, receptor dimerizes, enzymatic activation via phosphorylation propagates through the JAK domain and recruits STAT to the cytosolic receptor portion. STAT dimerizes and translocates into the nucleus as a transcription factor Suppressors of cytokine signaling (SOCS) block JAK-STAT

Apotosis

Apoptosis - normal fcn of cellular disposal w/o activating the immune/inflammatory system 2 receptors
TNFR-1 : inflammation, apoptosis, circulatory shock TNFR-2 : no inflammation or shock

CD95 (Fas) receptor similar structure to TNFR-1

Initiates apoptosis

Cell Mediated Inflammation

Platelets

Source of eicosanoids and vasoactive mediators Clot is a chemoattractant for PMNs/monocytes Modulate PMN endothelium adherence Migration occurs within 3 hrs of injury

Mediated by serotonin, PAF, PGE2

Eosinophils

Migrate to parasitic infection and allergen challenge to release cytotoxic granules Reside in the GI, lung, and GU tissues Activated by IL-3, GM-CSF, IL-5, PAF, and anaphylatoxins C3a and C5a

Cell Mediated Inflammation

Lymphocytes

T-helpers produce IL-3, TNF-, GM-CSF

TH1: IFN-, IL-2, IL-12 TH2: IL-4, IL-5, IL-6, IL-9, IL-10, IL-13 Severe infection shift toward more TH2

Mast Cells

First responders to injury Produce histamine, cytokines, eicosanoids, proteases, chemokines, TNF- (stored in granules) Cause vasodilation, capillary leakage, and recruit immunocytes

Cell Mediated Inflammation

Monocytes

Downregulation of receptor TNFR is clinically and experimentally correlated with CHF, nonsurvival in sepsis Immune response : release of inflammatory mediator, phagocytosis of microbial pathogen
Modulate acute inflammation Induced by chemotactic mediators from site of injury Effects are adherence and promote cell migration into injured tissue Short half-lives time (4-10 hours

Neutrophils

Endothelium-Mediated Injury

Neutrophil-Endothelium Interaction Nitric Oxide Prostacyclin (PGI2) Endothelins Platelet activating factor Atrial Natriuretic peptides

Endothelium-Mediated Injury

Neutrophil-Endothelium Interaction
Increased vascular permeability facilitate oxygen delivery and immunocyte migration Accumulation of neutrophils at injury sites can cause cytotoxicity to vital organs Ischemia-reperfusion injury potentiates this response by releasing oxygen metabolites and lysosomal enz.

Nitric Oxide

Derived from endothelial surfaces responding to Ach, hypoxia, endotoxin, cellular injury, or shear stresses of circulating blood Known as endothelium-derived relaxing factor T = seconds Reduces microthrombosis, mediates protein synthesis in hepatocytes

Prostacyclin (PGI2)

Endothelium derived in response to shear stress and hypoxia Vasodilator Platelet deactivation (increases cAMP) Clinically used to reduce pulmonary hypertension (especially pediatric), increase cardiac output, increase splanchnic blood flow

Surgical Metabolism Metabolism During Fasting

Comparable to changes seen in acute injury Requires 25-40 kcal/kg/day of carbs, protein, fat Normal adult body contains 300-400g carbs (glycogen) 75-100g hepatic, 200-250g muscle (not available systemically due to deficiency of G6P)

Mass (kg) Energy (Kcal)

Water 49 0

Days Available
0

Protein

24,000
800 140,000 164,800

13
0.4 78 91.4

Glycogen 0.2 Fat Total 15 70.2

Metabolism During Fasting

A healthy 70kg adult will use 180 g /d of glucose to support obligate glycolytic cells (neurons, RBCs, PMNs, renal medulla, skeletal m.) Glucagon, Norepi, vasopressin, AngII promote utilization of glycogen stores Glucagon, Epi, and cortisol promote gluconeogenesis Precursors include lactate (sk.m., rbc, pmn), glycerol, and aa (ala, glutamine)

Metabolism of Simple Starvation

Lactate is not sufficient for glucose demands Protein must be degraded (75 g/d) for hepatic gluconeogenesis Proteolysis from decreased insulin and increased cortisol Elevated urinary nitrogen (7 -> 30 g/d)

Metabolism of Prolonged Starvation

Proteolysis is reduced to 20g/d and urinary nitrogen excretion stabilizes to 2-5g/d Organs (myocardium, brain, renal cortex, sk.m) adapt to ketone bodies in 2-24 days Kidneys utilize glutamine and glutamate in gluconeogenesis Adipose stores provide up to 40% calories (approx 160 g FFA and glycerol)

Stimulated by reduced insulin and increased glucagon and catecholamines

Metabolism Following Injury

Magnitude of expenditure is proportional to the severity of injury Changes in

Lipid Absorption Lipid Oxidation Carbohydrate metabolism

Lipid Absorption

Oxidation of 1g fat = 9 kcal energy Dietary lipids require pancreatic lipase and phospholipase to hydrolyze TG into FFA and monoglycerides within the duodenum After gut absorption, enterocytes resynthesize TG from monoglycerides + fatty acyl-CoA Long chain TG (>12 carbons) enter the circulation as chylomicrons. Shorter FA chains directly enter portal circulation and are transported via albumin Under stress, hepatocytes utilize FFA as fuel Systemically TG and chylomicrons are used from hydrolysis with lipoprotein lipase (suppressed by trauma and sepsis)

Fatty Acid Oxidation

FFA + acyl-CoA = LCT are transported across the mitochondrial inner membrane via the carnitine shuttle Medium-chain TG (MCT) 6-12 carbons long, freely cross the mitochondrial membrane Fatty acyl-CoA undergoes -oxidation to acetylCoA to enter TCA cycle for oxidation to ATP, CO2, and water Excess acetyl-CoA is used for ketogenesis

Carbohydrate Metabolism

Carbohydrates + pancreatic intestinal enzymes yield dimeric units (sucrase, lactase, maltase) Intestinal brush border disaccharidases break them into simple hexose units which are transported into the intestinal mucosa Glucose and galactose are absorbed via a sodium dependent active transport pump Fructose absorption via facilitated diffusion

Carbohydrate Metabolism

1g carbohydrate = 4 kcal energy IV/parenteral nutrition 3.4 kcal/g dextrose In surgical patients dextrose administration is to minimize muscle wasting Glucose can be utilized in a variety of pathways phosphorylation to G6P then glycogenesis or glycogenolysis, pyruvic acid pathway, or pentose shunt

Protein and Amino Acid Metabolism

Average adult protein intake 80-120 g/day

every 6 g protein yields 1 g nitrogen 1g protein = 4 kcal energy

Following injury, glucocorticoids increase urinary nitrogen excretion (>30g/d), peak at 7d, persist 3-7 wks

Nutrition in the Surgical Patient

Nutritional assessment to determine the severity of deficiencies/excess Wt loss, chronic illnesses, dietary habits, quality/quantity of food, social habits, meds Physical exam loss of muscle/adipose tissue, organ dysfunction Biochemical Cr excretion, albumin, prealbumin, total lymphocyte count, transferrin

Surgical Nutrition

Support the requirements for protein synthesis Nonprotein calorie : nitrogen ratio = 150:1 A lower rate of 80-100:1 may be beneficial in some critically ill or hypermetabolic patients Basal Energy Expenditure (BEE):
men = 66.47 + 13.75(W) + 5(H) 6.76(A) kcal/d women = 655.1 + 9.56(W) + 1.85(H) 4.68 (A) kcal/d W= wt in kg, H= Ht in cm, A= age in years

Enteral Feeding

Less expensive and risks than parenteral Reduced intestinal atrophy 44% reduction in infections over parenteral in the critically ill Healthy patients without malnutrition undergoing uncomplicated surgery can tolerate 10 d of maintenance IV fluids only before significant protein catabolism begins

Initiation of Enteral Feeding

Immediately after adequate fluid resuscitation (UOP) Not absolute prerequisites: presence of bowel sounds, passage of flatus or stool Gastric residuals of >200ml in 4-6 hrs or abdominal distention requires cessation/lowering the rate

Enteral Formulas

Low-residue isotonic

caloric density 1.0kcal/ml, 1500-1800 ml/day Provide carbs, protein, lytes, water, fat, water sol vitamins, calorie:Nitrogen of 150:1. No fiber bulk = minimum residue Standard for stable patients with an intact GI tract
Soluble and insoluble fiber (soy) Delay GI transit time and reduce diarrhea Not contraindicated in the critically ill

Isotonic with fiber

Enteral Formulas

Immune-Enhancing

Glutamine, argenine, omega-3 FA, nucleotides, beta-carotene. Benefits not consistent in trials Expensive
1.5-2 kcal/ml, higher osmolality (ok for intragastric feeding) for fluid restriction/inability to tolerate larger volumes

Calorie-Dense

High-Protein

Isotonic and nonisotonic available calorie:Nitrogen ratio of 80-120:1

Enteral Formulas

Elemental
Contain predigested nutrients, small peptides Limited complex carbs and fat (long/med chains) Easily absorbed, but limited long term use High osmolality = slow infusion or diluted Expensive

Renal-Failure
Lower fluid volume, K, phos, and Mg Essential aa, high calorie : nitrogen ratio, no vitamins

Enteral Formulas

Pulmonary-Failure
Fat content is increased to 50% of total calories Reduces CO2 production and ventilation burden

Hepatic-Failure
50% of aa are branched chains (Leu, Ile, Val) Potentially reverses encephalopathy Controversial, no clear benefits in trials

Enteral Access

Nasogastric Tube - requires intact mental status and laryngeal reflexes to reduce aspiration

Difficult to place, requires radiographic confirmation If required >30 d, convert to PEG Problems: clogging, kinking, inadvertent removal Impaired swallowing/obstruction, major facial trauma Contraindications: ascites, coagulophathy, gastric varices, gastric neoplasm, lack of suitable location Tubes can be use for 12-24 mos Requires endoscopic transillumination of abdominal wall and passage of catheter into an insufflated stomach Complications in 3% of cases: infection, peritonitis, aspiration/pneumonia, leaks, dislodgement, bowel perforation, enteric fistulas, bleeding

Percutaneous Endoscopic Gastrostomy

Percutaneous Endoscopic Gastrostomy-Jejunostomy

Feeding administered past the pylorus Cannot tolerate gastric feedings/signif aspiration Passes a catheter through an existing PEG past the pylorus into the duodenum Long term malfunction >50% due to retrograde tube migration into the stomach, kinking, clogging

Direct Percutaneous Endoscopic Jejunostomy

Same technique as PEG placement but requires an enteroscope/colonscope to reach the jejunum Less malfunction than PEG-J Kinking/clogging reduced by placing larger caliber catheters

Surgical Gastrostomy and Jejunostomy

With complex abdominal trauma/laparatomy there may be an opportunity for placement Contraindication: distal obstruction, severe intestinal wall edema, radiation enteritis, inflammatory bowel disease, ascites, severe immunodeficiency, bowel ischemia Adverse effects: abdominal/bowel distention, cramps, pneumotosis intestinalis, small bowel necrosis

Parenteral Nutrition

Continuous infusion of hyperosmolar carbs, proteins, fats and other nutrients through a catheter into the SVC Optimal > 100-150 kcal/g nitrogens Higher rates of infection compared to enteral Studies with parenteral nutrition and complete bowel rest results in increased stress hormone and inflammatory responses

Parenteral Nutrition Rationale

Seriously ill patients with malnutrition, sepsis or surgery/trauma when use of the GI tract for feeding is not possible
Short bowel syndrome after massive resection Prolonged paralytic ileus (>7 days) Severe intestinal malabsorption Functional GI disorders esophageal dyskinesia Etc.

Total Parenteral Nutrition

Central parenteral nutrition, aka TPN Requires access to a large diameter vein Dextrose content is high (15-25%)

Peripheral Parenteral Nutrition

Lower osmolality Reduced dextrose (5-10%) Protein (3%) Not appropriate for severe malnutrition due to need for larger volumes of some nutrients Shorter periods, < 2 wks

Parenteral Nutrition

Dextose 15-25% Amino acids 3-5% Vitamins (Vit K is not included) Lipid emulsions to prevent essential FA deficiency (10-15% of calories) Prepared by the pharmacy from commercially available kits If prolonged supplement trace minerals

Zinc (eczematous rash), copper (microcytic anemia), chromium (glucose intolerance)

Parenteral Nutrition

Insulin supplement to insure glucose tolerance IV fluids/electrolytes if high fluid losses Freq. monitor fluid status, vital signs, UOP, electrolytes, BUN, and LFTs. Glucose q6h

Complications

Hyperglycemia pt with impaired glc tolerance or high infusion rate

Tx- volume replacement, correct electrolytes, insulin Avoid by monitoring daily fluid balance, glc, & lytes

Overfeeding results in CO2 retention and respiratory insufficiency Hepatic steatosis Cholestasis and gallstones Hepatic abnormalities serum transaminase, alk phos and bilirubin Intestinal - atrophy from disuse, bacterial overgrowth, reduced lymphoid tissue and IgA production, impaired gut immunity

Special Formulations

Glutamine and Arginine

Glutamine nonessential aa, comprises 66% of free amino acids During stress glu is depleted and shunted as a fuel source to visceral organs and tumors Inconclusive data for benefits of increased supplementation Arginine nonessential aa, promotes net nitrogen retention and protein synthesis in the critically ill/injured. Benefits still under investigation.
Canola or fish oil. Displaces omega-6 FAs, theoretically reducing pro-inflammatory responses ? Increase cell proliferation, DNA synthesis, T Helper cell function

Omega-3 Fatty Acids

Nucleotides

References
The material in this presentation was directly adapted from: E. Lin, S. E. Calvano, and S. F. Lowry. Chapter 1. Systemic Response to Injury and Metabolic Support. In Schwartz's Principles of Surgery, 8th ed. F. C. Brunicardi, D. K. Andersen , T. R. Billiar, D. L. Dunn, J. G. Hunter, R. E. Pollock, eds. McGraw-Hill Professional, 2004.