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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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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
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Cell Signaling Pathways
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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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
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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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Cell Mediated Inflammation
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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Parenteral Nutrition
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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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
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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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