schwart chp 1

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SYSTEMICRESPONSETO

INJURY

& METABOLIC

SUPPORT

A review of Schwartzs Principles of Surgery-Chapter 2

Muhammad Reza - M. Saidi


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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


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S I R S


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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)


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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


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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


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Glucocorticoids

Cortisol elevated following injury,

duration of elevation depends on severity of injury

Potentiates hyperglycemia

Hepatic gluconeogenesis

Muscle and adipose tissue > induces insulinresistance

Skeletal m.> protein degradation, lactate release

Adipose -> reduces release of TG, FFA, glycerol

Impair wound healing ; reduce TGF-, IGF-I


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Glucocorticoid antagonistproduced by anterior pituitary & T-lymphocytesReverses immunosuppressiveeffects of glucocorticoids

MacrophageInhibitory

Factor

During stress -> protein synth, fatmobilization, and skeletal

cartilage growth 2 to release of insulin-like

growth factor (IGF1)

Injury reduces IGF1 levels

GrowthHormone


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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 andl m hoc tosis


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Aldosterone

Synthesized, stored, released from the adrenal zonaglomerulosa

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


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Insulin

Stress inhibited release + peripheral insulinresistance = hyperglycemia

Injury has 2 phases of insulin releaseWithin 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 diabeticssignificantly reduces mortality after injury


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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 feedingAffected only by preexisting hepatic failure


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INFLAMMATORYMEDIATORS

Heat Shock Protein

Reactive Oxygen MetabolitesEicosanoids

Fatty Acid MetabolitesKallikrein-Kinin SystemSerotonin

HistamineCytokines


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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, incrbronchoconstriction

In clinical trials, bradykinin antagonists help reverse G-sepsis, but do not improve survival


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Serotonin

Present in intestinal chromaffin cells & platelets

Vasoconstriction, bronchoconstriction, plateletaggregation

Myocardial chronotrope and ionotrope

Unclear role in inflammation


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Histamine

Stored in neurons, skin, gastric mucosa, mastcells, basophils, and platelets

H1 bronchoconstriction, increases intestinalmotility and myocardial contractility

H2 inhibits histamine release

H1/H2 hypotension, decreased venousreturn/peripheral blood pooling, increasedcapillary permeability, myocardial failure.


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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 cellularreceptors and may act as a counter regulatorysystem to prevent excessive TNF-activity


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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 patientimmunocompromised and susceptible to infection


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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 ofphospholipase C

Ligand Gated Ion Channels

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


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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


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

IL-6, IL-10, IL-12, IL-13, IFN-

Ligand binds to the receptor, receptor dimerizes, enzymaticactivation via phosphorylation propagates through the JAKdomain 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


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Apotosis

Apoptosis - normal fcn of cellular disposal w/oactivating 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


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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


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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


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Mast Cells

First responders to injury

Produce histamine, cytokines, eicosanoids, proteases,

chemokines, TNF-(stored in granules) Cause vasodilation, capillary leakage, and recruit

immunocytes


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Monocytes

Downregulation of receptor TNFR is clinically andexperimentally correlated with CHF, nonsurvival in sepsis

Immune response : release of inflammatory mediator,phagocytosis of microbial pathogen

Neutrophils

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


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Endothelium-Mediated Injury

Neutrophil-Endothelium Interaction

Nitric Oxide

Prostacyclin (PGI2) Endothelins

Platelet activating factor

Atrial Natriuretic peptides


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Endothelium-Mediated Injury

Neutrophil-Endothelium Interaction

Increased vascular permeability facilitate oxygendelivery and immunocyte migration

Accumulation of neutrophils at injury sites can causecytotoxicity to vital organs

Ischemia-reperfusion injury potentiates this response

by releasing oxygen metabolites and lysosomal enz.


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Nitric Oxide

Derived from endothelial surfaces responding toAch, hypoxia, endotoxin, cellular injury, or shearstresses of circulating blood

Known as endothelium-derived relaxing factor

T = seconds

Reduces microthrombosis, mediates proteinsynthesis in hepatocytes


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Prostacyclin (PGI2)

Endothelium derived in response to shear stressand hypoxia

Vasodilator

Platelet deactivation (increases cAMP)

Clinically used to reduce pulmonaryhypertension (especially pediatric), increasecardiac output, increase splanchnic blood flow


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Surgical Metabolism

Metabolism During Fasting Comparable to changes seen

in acute injury

Requires 25-40 kcal/kg/dayof carbs, protein, fat

Normal adult body contains300-400g carbs (glycogen) 75-100g hepatic, 200-250gmuscle (not availablesystemically due to deficiencyof G6P)

Mass (kg) Energy(Kcal)

DaysAvailable

Water 49 0 0

Protein 6 24,000 13

Glycogen 0.2 800 0.4

Fat 15 140,000 78

Total 70.2 164,800 91.4


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Metabolism During Fasting

A healthy 70kg adult will use 180 g /d of glucoseto support obligate glycolytic cells (neurons,RBCs, PMNs, renal medulla, skeletal m.)

Glucagon, Norepi, vasopressin, AngII promoteutilization of glycogen stores

Glucagon, Epi, and cortisol promote

gluconeogenesis Precursors include lactate (sk.m., rbc, pmn),

glycerol, and aa (ala, glutamine)


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Metabolism of Simple Starvation

Lactate is not sufficient for glucose demands

Protein must be degraded (75 g/d) for hepaticgluconeogenesis

Proteolysis from decreased insulin and increasedcortisol

Elevated urinary nitrogen (7 -> 30 g/d)


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Metabolism of Prolonged Starvation

Proteolysis is reduced to 20g/d and urinary nitrogenexcretion stabilizes to 2-5g/d

Organs (myocardium, brain, renal cortex, sk.m) adaptto ketone bodies in 2-24 days

Kidneys utilize glutamine and glutamate ingluconeogenesis

Adipose stores provide up to 40% calories (approx 160

g FFA and glycerol) Stimulated by reduced insulin and increased glucagon and

catecholamines


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Metabolism Following Injury

Magnitude of expenditure is proportional to theseverity of injury

Changes in

Lipid Absorption

Lipid Oxidation

Carbohydrate metabolism


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Lipid Absorption

Oxidation of 1g fat = 9 kcal energy

Dietary lipids require pancreatic lipase and phospholipase tohydrolyze TG into FFA and monoglycerides within theduodenum

After gut absorption, enterocytes resynthesize TG frommonoglycerides + fatty acyl-CoA

Long chain TG (>12 carbons) enter the circulation aschylomicrons. Shorter FA chains directly enter portal circulationand are transported via albumin

Under stress, hepatocytes utilize FFA as fuel

Systemically TG and chylomicrons are used from hydrolysis withlipoprotein lipase (suppressed by trauma and sepsis)


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Fatty Acid Oxidation

FFA + acyl-CoA = LCT are transported acrossthe mitochondrial inner membrane via thecarnitine shuttle

Medium-chain TG (MCT) 6-12 carbons long,freely cross the mitochondrial membrane

Fatty acyl-CoA undergoes -oxidation to acetyl-

CoA to enter TCA cycle for oxidation to ATP,CO2, and water

Excess acetyl-CoA is used for ketogenesis


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Carbohydrate Metabolism

Carbohydrates + pancreatic intestinal enzymesyield dimeric units (sucrase, lactase, maltase)

Intestinal brush border disaccharidases breakthem into simple hexose units which aretransported into the intestinal mucosa

Glucose and galactose are absorbed via a sodium

dependent active transport pump

Fructose absorption via facilitated diffusion


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Carbohydrate Metabolism

1g carbohydrate = 4 kcal energy

IV/parenteral nutrition 3.4 kcal/g dextrose

In surgical patients dextrose administration is tominimize muscle wasting

Glucose can be utilized in a variety of pathwaysphosphorylation to G6P then glycogenesis orglycogenolysis, pyruvic acid pathway, or pentoseshunt


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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 increaseurinary nitrogen excretion (>30g/d), peak at 7d,persist 3-7 wks


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Nutrition in the Surgical Patient

Nutritional assessment to determine the severityof 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


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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/dwomen = 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


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Enteral Feeding

Less expensive and risks than parenteral

Reduced intestinal atrophy

44% reduction in infections over parenteral inthe critically ill

Healthy patients without malnutritionundergoing uncomplicated surgery can tolerate10 d of maintenance IV fluids only beforesignificant protein catabolism begins


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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 orabdominal distention requires

cessation/lowering the rate


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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

Isotonic with fiber

Soluble and insoluble fiber (soy)

Delay GI transit time and reduce diarrhea

Not contraindicated in the critically ill


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Enteral Formulas

Immune-Enhancing Glutamine, argenine, omega-3 FA, nucleotides, beta-carotene.

Benefits not consistent in trials

Expensive

Calorie-Dense 1.5-2 kcal/ml, higher osmolality (ok for intragastric feeding)

for fluid restriction/inability to tolerate larger volumes

High-Protein Isotonic and nonisotonic available

calorie:Nitrogen ratio of 80-120:1


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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


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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


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Enteral Access

Nasogastric Tube - requires intact mental status and laryngealreflexes to reduce aspiration Difficult to place, requires radiographic confirmation

If required >30 d, convert to PEG

Problems: clogging, kinking, inadvertent removal

Percutaneous Endoscopic Gastrostomy 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

P E d i


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Percutaneous Endoscopic

Gastrostomy-Jejunostomy

Feeding administered past the pylorus

Cannot tolerate gastric feedings/signif aspiration

Passes a catheter through an existing PEG pastthe pylorus into the duodenum

Long term malfunction >50% due to retrogradetube migration into the stomach, kinking,clogging

Di P E d i


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Direct Percutaneous Endoscopic

Jejunostomy

Same technique as PEG placement but requiresan enteroscope/colonscope to reach thejejunum

Less malfunction than PEG-J

Kinking/clogging reduced by placing largercaliber catheters

S i l G d


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Surgical Gastrostomy and

Jejunostomy

With complex abdominal trauma/laparatomythere may be an opportunity for placement

Contraindication: distal obstruction, severeintestinal wall edema, radiation enteritis,inflammatory bowel disease, ascites, severeimmunodeficiency, bowel ischemia

Adverse effects: abdominal/bowel distention,cramps, pneumotosis intestinalis, small bowelnecrosis


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Parenteral Nutrition

Continuous infusion of hyperosmolar carbs,proteins, fats and other nutrients through acatheter into the SVC

Optimal > 100-150 kcal/g nitrogens

Higher rates of infection compared to enteral

Studies with parenteral nutrition and completebowel rest results in increased stress hormoneand inflammatory responses


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Parenteral Nutrition Rationale

Seriously ill patients with malnutrition, sepsis orsurgery/trauma when use of the GI tract forfeeding is not possible

Short bowel syndrome after massive resection

Prolonged paralytic ileus (>7 days)

Severe intestinal malabsorption

Functional GI disorders esophageal dyskinesia Etc.


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Total Parenteral Nutrition

Central parenteral nutrition, aka TPN

Requires access to a large diameter vein

Dextrose content is high (15-25%)


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Peripheral Parenteral Nutrition

Lower osmolality

Reduced dextrose (5-10%)

Protein (3%)

Not appropriate for severe malnutrition due toneed for larger volumes of some nutrients

Shorter periods, < 2 wks


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Dextose 15-25%

Amino acids 3-5%

Vitamins (Vit K is not included)

Lipid emulsions to prevent essential FAdeficiency (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)


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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


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Complications

Hyperglycemiapt with impaired glc tolerance or high infusionrate Tx- volume replacement, correct electrolytes, insulin

Avoid by monitoring daily fluid balance, glc, & lytes

Overfeedingresults in CO2 retention and respiratoryinsufficiency

Hepatic steatosis

Cholestasis and gallstones

Hepatic abnormalities serum transaminase, alk phos andbilirubin

Intestinal - atrophy from disuse, bacterial overgrowth, reducedlymphoid tissue and IgA production, impaired gut immunity


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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 underinvestigation.

Omega-3 Fatty Acids Canola or fish oil. Displaces omega-6 FAs, theoretically reducing

pro-inflammatory responses

Nucleotides ? Increase cell proliferation, DNA synthesis, T Helper cell

function


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References

The material in this presentation was directlyadapted from:

E. Lin, S. E. Calvano, and S. F. Lowry. Chapter1. Systemic Response to Injury and MetabolicSupport. In Schwartz's Principles of Surgery, 8thed. F. C. Brunicardi, D. K. Andersen , T. R.Billiar, D. L. Dunn, J. G. Hunter, R. E. Pollock,eds. McGraw-Hill Professional, 2004.

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