Body's Response to Injury

7/31/2019 Body's Response to Injury

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Systemic inflammation is a central featureof both sepsis and severe trauma*Sepsis: systemic inflammatory response to infection

This report reviews the autonomic, cellular andhormonal responses to injury

to be able to develop therapies to interveneduring sepsis or after a severe injury, an

understanding of the complex pathways thatregulate local and systemic inflammation isnecessary


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Immune System respond to and neutralize pathogenic

microorganisms; coordinate tissue repair

(+) injury orinfection

InflammatoryResponse

Cell signallingcell migration

mediator release


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MINOR HOST INSULT local inflammatoryresponse; transient and in most cases

beneficial

MAJOR HOST INSULT immune reactionscan become amplified; systemicinflammation and potentially detrimentalresponses


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SIRS

(+) Two or more of following criteria

T 38C or 36C

HR 90 beats/min

RR 20 breaths/min or PaCO2 32 mmHgor mechanical ventilation

WBC count 12,000/L or 4000/L or 10%band forms

Sepsis

Identifiable source of infection + SIRSSevere sepsis Sepsis + organ dysfunctionSeptic shock Sepsis + cardiovascular collapse


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1. Acute proinflammatory state

innate immune system recognize ligands

activation of cellular processes to restore tissuefunction and eradicate invading microorganisms

2. Anti-inflammatory or counter regulatory phase

Serves to modulate the proinflammatory phase prevent excessive proinflammatory activities


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Schematic representation of SIRS after injury:

Severe inflammationmay lead to:multiple organ failure(MOF) andearly death afterinjury

EXCESSIVE counter regulatory anti-inflammatory response(CARS) may induce prolonged immunosupressed state

Normal recovery requires a period of a systemic inflammationfollowed by return to homeostasis


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influences multiple organs

RECOGNIZE injury or infection signals

throughafferent signal pathways

When receptors are activated by

inflammatory mediators phenotypicresponses are produced through bothcirculatory and neuronal pathways


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Cholinergic Anti-Inflammatory Pathways

VAGUS NERVE

- ANTI-inflammatory pathways

efferent signals are transmittedthrough neurotransmitter

acetylcholine

Activate nicotinic acetylcholinereceptors on immune mediator

cells

INHIBITION ofcytokine activity

reduce injuryfrom diseaseprocesses


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HORMONES chemical signals that modulatethe function of target cells.

Categories:

polypeptides cytokines, glucagon, insulin

amino acids epinephrine, serotonin,histamine

fatty acids glucocorticoids,prostaglandins and leukotrienes


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Hormone Regulation

Hypothalamus Anterior PituitaryPosteriorPituitary

CRH TRH GHRH LHRH

ACTH Cortisol TSH T3, T4, GH Insulin-like

growth factor (IGF) Gonadotropins

Sex hormones

Prolactin Somatostatin Endorphins

Vasopressin Oxytocin


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Further mediator release

Protein synthesisthrough intracellularreceptor binding either directly by hormone or

through secondary signalling molecule

- example of intracellular receptor:

Glucocorticoid Receptor


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Activate receptor at zona fasciculata of the adrenalgland to mediate cortisol release

stimulated by:

Corticotropin-releasing hormone (CRH)

Pain, anxiety

Catecholamines and pro-inflammatory cytokines

Excessive ACTH stimulation leads toadrenocortical hypertrophy


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Cortisol

glucocorticoid steroid hormone

released by adrenal cortex in response toACTH

Increased during stress

chronically elevated in certain diseaseprocesses

Burn patients may exhibit elevation for 4 weeks


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metabolic hyperglycemia

skeletal muscles &

adipose tissues

Release of substrates for

gluconeogenesis

wound healing Delays wound healing

Immunosuppressive

T-cell and natural killer cellfunction

Inhibit leukocyte migration tosites of inflammation

Inhibit intracellular killing inmonocytes

Effects of Cortisol


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Counter regulatory mediator

reverses the immunosuppressive effects ofglucocorticoids

activity of immunocytes against pathogens


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Up-regulated by hypothalamic GH-releasinghormone (GHRH)

Down-regulated by somatostatin

Secondary effect: hepatic synthesis of IGF

Insulin-Like Growth Factors (IGF)

Circulates bound to IGF-binding proteins

Anabolic effects: glycogenesis, lipogenesis


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Role of GH during inflammation...

(+) Critical illness (+) GH resistance &

IGF

phagocytic activity of immunocytes

T-cell

Therefore:

GH administration in critically ill patientsmay be worsen inflammatory response


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Catecholamines

secreted by chromaffin cells of adrenal medulla

Common catecholamines:

Epinephrine

Norepinephrine

Dopamine

Potent vasoconstrictors

If (+) injury: levels 3-4x (may last 24-48 hrs)


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act on both alpha and beta receptors

Metabolic effects: mainly catabolic

Immunomodulatory effects: Mediated through beta2 receptors in

immunocytes increases leukocytedemargination

inhibit release of inflammatory cytokines

Catecholamines


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Pharmacologic Significance

Used to treat hypotension during septic shockbecause it cardiac output and subsequent incardiac O2 demand

Rx: Beta blockers: reduce cardiac stress


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Aldosterone

Mineralocorticoid Act on distal convoluted tubules to retain sodium and

eliminate potassium and hydrogen ions

Stimulants for release:

ACTH

blood volume

Hyperkalemia Aldosterone Aldosterone

Hypotension Hypertension

Hyperkalemia HypokalemiaMetabolic Alkalosis

Edema


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Insulin

Secreted by Islets of Langerhans of pancreas

Mediates overall anabolic state:

Reverses effects of hyperglycemia:

Glycosylation of immunoglobulins phagocytosis

Respiratory burst of monocytes

Therefore: hyperglycemia is associated with increased risk for

infection


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Either or in response to inflammatory stimuli

Increase = positive APP

Decrease = negative APP

C-reactive protein: most commonly used APPas marker of inflammation

* major stimulus: Interleukin-6

produced by liver therefore if (+) hepatic

insufficiency, APPs are unreliable marker ofinflammation


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Mediatorsof Inflammation


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exaggerated physiologic response whichinvolves a vascular and cellular response byphagocytic cells to infection or injury

*classic signs of injury/inflammation:

Pain (dolor) Swelling (tumor)

Heat (calor) Loss of Function (functiolaesa)

Redness (rubor)

Inflammation


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Cytokines

Protein signaling compounds

pro-inflammatory effects:

immunocyte proliferation eradication ofinvading microorganisms

promote wound healing


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Heat Shock Proteins (HSP)

intracellular proteins that are in times of stress

Fxns:

chaperones for ligands such as bacterial DNAand endotoxin

Presumed to protect cells from deleteriouseffects of traumatic stress

When released by damagedcells, they alert the immune

system of tissue damage


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Reactive Oxygen Species (ROS)

highly reactive small molecules due tounpaired outer orbit electrons

potent oxygen radicals:

Oxygen ions, superoxide anion, H202 Hydroxyl radicals

Effect: oxidize unsaturated FACell

membrane

Cellular damage(host or pathogenic cells)


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enzymes that protect cells from damaging effectsof ROS:

Superoxide dismutase:

superoxide H2O2 + O2 Catalase: H2O2 H2O + O2 Glutathione peroxidase reduce H2O2 by

transferring energy of reactive peroxides toglutathione

Endogenous Antioxidants


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Eicosanoids


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Physiologic roles of Eicosanoids

Leukotrienes Vasoconstriction Bronchospasm Capillary permeability

Thromboxanes Vasoconstriction Platelet aggregation

Prostacycline Vasodilation Inhibit platelet aggregation

Prostaglandin Vasodilation Potentiates edema


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Fatty Acid Metabolites

Dietary omega-3

and omega-6fatty acids s

are substratesfor eicosanoidproduction


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Kallikrein-Kinin System

Group of protein that contribute to inflammation,

BP control, coagulation and PAIN responses

Hageman factor, trypsin,

plasmin, factor XI

Prekallikrein kallikrein

HMWK from liver Bradykinin


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Kinins mediate several inflammatoryprocess:

Vasodilation

Increased capillary permeability

Tissue edema

Pain pathway activation

Degree of elevation associated to magnitude ofinjury and mortality

Kallikrein-Kinin System


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Serotonin

derived from tryptophan

released at sites of injury, primarily byplatelets

Inflammatory effects: vasocontriction, bronchoconstriction and platelet

aggregation

serotonin receptor blockade productionof TNF and interleukin-1


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Histamine

From decarboxylation of histidine

Histamine Receptors

H1 binding

VasodilationBronchoconstrictionintestinal motilitymyocardial contractility

H2 binding gastric acid secretion

H3 autoreceptor histamine release

H4 bindingeosinophil and mast cellchemotaxis


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Cytokine Responseto Injury


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Tumor Necrosis Factor (TNF)

Potent mediator of inflammatory response

Primarily synthesized by macrophages, monocytesand T cells

Brief half life of 20min Immunomodulatory roles:

coagulation activation

Macrophage phagocytosis

expression of adhesion molecules


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Interleukin -1

inflammatory sequence similar to that of TNF

Released in response to cytokines andforeign pathogens

Has 2 active subtypes: IL-1 and IL-1 It is an endogenous pyrogen

activate

prostaglandinactivity

hypothalamus

fever


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Interleukin -2

Pro-inflammatory:

T-cell proliferation and differentiation,

immunoglobulin production

Up-regulated by Interleukin-1 Short half life of < 10min

Blocking IL-2R induces immunosuppressive

effectspharmacologically used in organtransplant


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Interleukin-4

released by activated helper T cells

Pro-inflammatory effects:

stimulate differentiation and proliferation of T cells,

and B-cell activation produce predominantly IgG and IgE (allergic and

antihelmintic response)

anti-inflammatory effects on macrophage:

Attenuate macrophage response Increases macrophage susceptibility to anti-

inflammatory effects of glucocorticoids


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Interleukin-6

Released by macrophages

stimulated by endotoxins, TNF and IL-1

detectable in the circulation by 60 min

peak bet 4-6 hours can persists up to 10 days

Plasma level is proportional to the tissueinjury

Has counter regulatory effects inhibition ofTNF and IL-1


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Interleukin-8

potent chemoattractant for neutrophils levels are associated with disease severity

and end organ dysfunction during sepsis

Interleukin-10 Anti-inflammatory secretion of

proinflammatory cytokines

negative feedback regulator TNF and IL-1 IL-10

IL-10TNF


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Interleukin-12

Regulator of cell-mediated immunity Stimulates natural killer cell cytotoxicity and helper

T cell differentiation

Deficiencyphagocytosis in neutrophils

Inhibited by IL-10

Interleukin-13 Has net anti-inflammatory effect

same immunomodulatory effects as IL-4

Inhibits release of TNF, IL-1, IL-6 and IL-8

mediates neutropenia, monocytopenia, andleukopenia during septic shock


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Interleukin-15

regulator of cellular immunity Has immunomodulatory effects similar to

those of Interleukin-2

Potent inhibitor of lymphocyte apoptosis

Interleukin-18 Synthesized primarily by macrophages

Regulated by IL-18 binding protein (IL-18BP)

With IL-12 synergistically release IFN- fromT-cells


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Interferons

Type I interferons

IFN-, IFN-, IFN-

binds to common receptor, IFN- receptor

induce maturation of dendritic cells

Alpha and beta interferons cytotoxicity of naturalkiller cells

Have been studied as therapeutic agents in

hepatitis C and relapsing MS


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Type II Interferon:IFN- (gamma interferon)

Stimulates release of IL-12 and IL-18

Down-regulators: IL-4, IL-10 and glucocorticoids

Enhance macrophage phagocytosis and microbialkilling

levels is associated with increase susceptibilityto viral and bacterial pathogens

chemoattractants and adhesion molecules tosite of inflammation

G l t M h


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Granulocyte-Macrophage

Colony-Stimulating Factor (GM-CSF)

upregulates granulocyte and monocyte cells

Inhibits apoptosis of monocytes and neutrophils

cytotoxicity of monocytes GM-CSF block alveolar macrophage activity

As growth factor promote maturation andrecruitment of functional leukocytes

may also be effective in wound healing


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High Mobility Group Box-1

DNA transcription factor

facilitates binding of regulatory protein to DNA

Stimulants: endotoxin, TNF and gamma interferon

proinflammatory response release of TNF frommonocytes

Elevation is delayed: peak at 16 hours and remainelevated beyond 30 hrs

Other mediators such as TNF: peak at 1-2 hrsand becomes undetectable by 12 hrs


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Cellular Responseto Injury


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Gene Expression and Regulation

regulated at various stages:a. point of DNA transcription

b. mRNA transcription:

Splicing cleave mRNA and remove noncoding

regions

Cappingmodify the 5 ends of mRNA to inhibitbreakdown by exonucleases

Addition of polyadenylated tail adds noncoding

sequence to the mRNA increase half life oftranscript

c. Once out of the nucleus inactivated or translated toform proteins


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CELL-SIGNALING PATHWAYS:

G-Protein Receptors (GPR) transmembrane receptors

Binding results in conformational change and

activation of associated second messengers: cAMP can activate gene transcription

through signal transducers such as proteinkinase A

Calcium can activate phospholipase C


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receptors canrespond toadrenaline andserotonin

Upon ligand binding to the receptor (R), the G-protein(G) undergoes guanosine triphosphate to diphosphate

conversion, and in turn activates the effector (E)component

The Ecomponentsubsequentlyactivates 2ndmessengers


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Ligand-gated Ion Channels (LGIC)

transmembrane receptors that allow rapid influx of ions Nicotinic acetylcholine receptor prototypical LGIC

Ligandbinding

chemical signals convertedinto an electrical signal

change in cell membrane

potential

On activation of the channel

ion influx into the cell


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Receptor Tyrosine Kinases

cell signalling for several growth factors

On ligand binding,

RTKs dimerize

multipleautophosphorylation

steps to recruit andactivate signalling

molecules

Janus Kinase/Signal Transducer and


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Janus Kinase/Signal Transducer and

Activation of Transcription Signaling

JAKs tyrosine kinase receptor

rapid pathway from membrane to nucleus

Inhibited by:

phosphatase

the export of STATs from the nucleus

antagonistic proteins: suppressors of cytokine

signaling (SOCS)


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Suppressors of Cytokine Signaling

(SOCS) negative feedback down-regulate the

JAK/STAT pathway by binding with JAK and

thus compete with STAT Deficiency may render a cell hypersensitive

to certain stimuli such as inflammatorycytokines and growth hormones


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JAKs bind to cytokines anddimerize.

Activated JAKs recruit andphosphorylate STATmolecules

Activated STAT proteinsfurther dimerize

STAT complexestranslocate into themolecules and modulatethe transcription of targetgenes


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Mitogen-Activated Protein Kinases

Pathways mediated through MAPKcontribute to:

inflammatory signaling

regulation of cell proliferation and cell death Activated receptors:

Dephosphorylation of MAPK mediatorsinhibit their function


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sequential stages of mediatorphosphorylation

activation of downstream effectors

Ligandbinding

c-Jun N-terminalkinase (JNK)

Extracellularregulated protein

kinase (ERK)

p38 kinase

immunocytedevelopment

formstranscription

factor activatedprotein1


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Nuclear Factor B

central role in regulating gene products

Composed of 2 smaller polypeptides: p50 & p65

Resides in the cytosol in the resting state through

inhibitory binding of inhibitor of B (I-B) On release, NF- B travels to the nucleus and

promote gene expression


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Toll-like Receptors and CD14

pattern recognition receptors

activated by pathogen-associated molecularpatterns (PAMP)

Function as effectors of innate immunesystem

TLR4 recognize lipopolysaccharides (LPS)

TLR2 recognizes PAMP from gram-positivebacteria


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APOPTOSIS

Regulated cell death

organized mechanism for clearing senescent ordysfunctional cells without promoting an inflammatoryresponse

Necrosis disorganized sequence; can activateinflammatory response

regulatory factors:

Inhibitor of apoptosis proteins

Regulatory caspases (caspases 1, 8, and 10)

Caspases effectors of apoptotic signaling thatmediate organized breakdown of nuclear DNA


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a. Extrinsic Pathway activated through binding ofdeath receptors: Fas, TNFR

Leads to activation of Fas-associated death domain

protein (FADD) and subsequent activation ofcaspases

b. Intrinsic Pathway protein mediators influencesmitochondrial membrane permeability

Leads to release of mitochondrial Cytochrome C,which ultimately activates caspases, and thusinduce apoptosis

APOPTOSIS


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CELL-MEDIATED

INFLAMMATORYRESPONSE


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Platelets

Non-nucleated structures, but containsmitochondria

Derived from megakaryocytes

release inflammatory mediators at site of injury that

serve as principal chemoattractant Migration occurs within 3 hrs of injury, enhanced by

serotonin, platelet-activating factor, and PGE2

Thrombocytopenia is a hallmark of septic response

NSAIDS inhibit platelet function through theblockade of COX


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Lymphocytes and T-Cell Immunity

Lymphocytes are circulating immune cells

composed primarily of B cells, T cells andnatural killer cells

T-lymphocytes are mediators of adaptiveimmunity

arginine is essential for T-cell proliferation andreceptor function

Helper T-lymphocytes are broadly categorizedinto 2 groups:

T 2 cells


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TH1 cells

- cellular

immuneresponse

TH2 cells

- Humoralresponse

activation ofmonocytes,

B-lymphocytes,and cytotoxic

T-lymphocytes

Inhibited byIL-4 and Il-10

Glucocorticoid is apotent stimulant

activation ofeosinophils,mast cells, andB-lymphocyteIg4 and IgE

production

Inhibited byinterferon-


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Eosinophils

anti-parasitic and anti-helmintic

Found mostly in lung and GI tract

Activated by IL-3, IL-5, GM-CSF,

chemoattractants and platelet-activating factor

Activation can lead to release of toxic mediatorsincluding reactive oxygen species, histamine andperoxidase


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Mast Cells

role in anaphylactic response to allergens

Stimuli: allergen binding, infection and trauma

Action: produce histamine, cytokines,

eicosanoids, proteases and chemokines whichleads to

Vasodilation

capillary leakage

immunocyte recruitment


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Monocytes

Main effector cells of immune response can differentiate into:

Macrophages

Osteoclasts

Dendritic cells

Immune mechanisms:

Phagocytosis of microbial pathogens

Release of inflammatory mediators Clearance of apoptotic cells


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Neutrophils

Potent mediators of acute inflammation

Among the first responders to sites of inflammation

adherence to vascular endothelium is induced bychemotactic mediators from site of injury

transmigrate to injured tissue Short half life: 4-10 hours

Stimulants: TNF, IL-1, and microbial pathogens

Immune mechanisms:

Phagocytose

Release lytic enzymes

Generate large amounts of toxic ROS


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ENDOTHELIUM-MEDIATED INJURY


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Vascular Endothelium

critical function as barriers that regulate tissuemigration of circulating cells

Has anticoagulant properties

During sepsis, endothelial cell are differentially

modulated

decreasedproduction of

anticoagulantfactors

Procoagulant

shift

microthrombosis &

organ injury


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Neutrophil-Endothelium interaction

Neutrophils migrate through actions of:

vascular permeability

chemoattractants

SELECTINS adhesion factors that areelaborated on cell surfaces

endothelium increases surfaces expression ofP-selectin to mediate neutrophil rolling

After 2 hours, however, cell surface expressionfavors E-selectin expression


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L-selectin and P-selectin glycoprotein ligand-1(PSGL-1) are responsible for over 85% ofmonocyte-to-monocyte and monocyte-to-

endothelium adhesion activity and targetedimmunocyte migration

Effective rolling involves a significant degreeof functional overlap between individual

selectins

Neutrophil-Endothelium interaction

Sequence of selectin-mediated neutrophil


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Sequence of selectin mediated neutrophil

interaction after inflammatory stimulus

Capture (tethering) Initialrecognition leukocytesmarginate toward the endothelialsurface

Fast Rollling rapid L-selectinshedding from cell surfaces

Slow Rolling mediated by P-selectin

Arrest (firm adhesion) leadingto transmigration

Molecules that mediate leukocyte-endothelial adhesion,

categorized by family


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AdhesionMolecule

Action OriginInducers ofexpression

Target cells

SelectinsL-selectins Fast rolling Leukocytes Native

Endothelium,Plateleteosinophils

P-selectins Slow rollingPlatelets andendothelium

Thrombin,histamine,cytokine

Neutrophils,monocytes

E-selectin Very slow rolling Endothelium CytokinesNeutrophils,monocytes

lymphocytes

Immunoglobulins

ICAM-1Firm adhession/

transmigration

Endothelium,leukocytes, fibro-

blasts, epithelium

Cytokines

Leukocytes

ICAM-2 Firm adhessionEndothelium,

PlateletNative

VCAM-1Firm adhession/transmigration

EndotheliumCytokines monocytes

Lymphocytes

M l l th t di t l k t d th li l dh i


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Molecules that mediate leukocyte-endothelial adhesion,


AdhesionMolecule

Action Origin Inducers ofexpression

Target cells

PECAM-1Firm adhession/transmigration

Endothelium,Platelet,

leukocytesNative

Endothelium,Platelet,

leukocytes

B2-(CD18) Integrins

CD18/11aFirm adhession/transmigration

leukocytes

Leukocyteactivation

EndotheliumCD18/11b

(Mac)Neutrophils,monocytes,

natural killer cellsCD18/11c adhession

B2-(CD18) Integrins

VLA-4Firm adhession/transmigration

Lymphocytes,monocytes

Leukocyteactivation

Monocytes,endothelium,

epithelium


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Nitric Oxide

functions in control of vascular tone: vasodilation

initially known as endothelium-derived relaxingfactor

expressed by endothelial cells upregulated in inflammatory response to TNF, IL-

1, IL-2, and hemorrhage

Can easily traverse cell membranes

can reduce platelet adhesion and aggregation short half-life of a few seconds before oxidized

into nitrate and nitrite


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Prostacyclin

member of the eicosanoid family

primarily produced by endothelial cell

effective vasodilator

also inhibits platelet aggregation

Endothelial interaction with smooth muscle cells and with


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intraluminal platelets

Prostacyclin or

Prostaglandin I2 (PGI2) isderived from ArachidonicAcid (AA)

Nitric Oxide is derivedfrom L-Arginine

The resulting increase incyclic adenosinemonophosphate (cAMP)and cyclic guanosinemonophosphate (cGMP)results in

smooth muscle relation inhibition of platelet

thrombus formation

Endothelins (ET) are derived from big ET andthey counter the effects of prostacyclin and NO

E d h l


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Endothelins

21 amino acid peptide from a 38 amino-acid precursormolecule

Potent vasocontrictors

three members: ET-1, ET-2, and ET-3

ET-1 is the most potent endogenousvasoconstrictor snd is estimated to be 10x morepotent than angiotensin II

upregulated in response to hypotension, LPS, injury,

thrombin, TGF-B, IL-1, Angiotensin II, vasopressin,cathecolamines, and anoxia

half-life: between 4 and 7 minutes

Pl l A F (PAF)


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Platelet-Activating Factor (PAF)

phospholipid constituent of cell membranes

released by neutrophils, platelets, mast cells,monocytes and is expressed at the outer leaflet

of endothelial cells can further activate neutrophils and platelets

increase vascular permeability

PAF-actylhydrolase is the endogenous inhibitorof PAF

A l N P d (ANP)


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Atrial Natriuretic Peptides (ANP)

peptides that are released primarily by atrialtissue

induce vasodilation

Induce fluid and electrolyte excretion prevent reabsorption of sodium

potent inhibitors of aldosterone secretion


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SURGICALMETABOLISM


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initial hours after surgical or traumatic injury total body energy expenditure

urinary nitrogen wasting

necessary in the restorations of homeostasis:

augmented metabolic rates and oxygenconsumption

enzymatic preference for readily oxidizablesubtrates such as glucose

stimulation of the immune system

Metabolism During Fasting


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Metabolism During Fasting

Normal caloric requirement: 22 to 25 kcal/kg per day in stress up to 40 kcal/kg per day

During fasting, a healthy 70-kg adult will utilize 180 g ofglucose per day

sources of fuel: muscle protein and body fat Carbohydrate store of normal adult: 300 to 400g in the

form of glycogen (more are stored in muscle cells, 200-250g)

Musclesdo not contain

Glucose-6-phosphatase

Glycogen inmuscles can not

be utilizedreadily

Hepaticglycogen isused first

metabolic pathways


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GLYCOGENOLYSIS: utilization of glycogen stores Promoted mainly by glucagon, norepinephrine during

fasting

GLUCONEOGENESIS: synthesis of glucose from non-CHO sources, primarily by liver

Directly promoted by glucagon, epinephrine & cortisol

precursors: glycerol and amino acids

GLYCOLYSIS: release lactate within skeletal muscles,erythrocytes and leukocytes for gluconeogenesis

CORI CYCLE: recycling of lactate and pyruvate forgluconeogenesis; can provide up to 40% of plasma glucoseduring starvation

metabolic pathways...


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Metabolism Following Injury


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Metabolism Following Injury

Injuries or infections induce unique neuroendocrineand immunologic responses that differentiate injurymetabolism from that of unstressed fasting

The magnitude of metabolic expenditure appears tobe directly proportional to the severity of insult

The increase in energy expenditure is mediated inpart by sympathetic activation and catecholaminerelease

Lipid becomes the primary source of energy duringstressed states

F l tili ti f ll i t


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Fuel utilization following trauma

Acute injury is associated with significantalterations in substrate utilization

There is enhanced nitrogen loss,indicative of catabolism

Fat remains the primary fuel sourceunder these circumstances.

Lipid Metabolism


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Lipid Metabolism

Lipid influences the structural integrity of cellmembranes

Adipose predominant energy source duringcritical illness and after injury

LIPOLYSIS (fat mobilization) occurs mainly inresponse to catecholamine stimulus of thehormonesensitive triglyceride lipase

non protein, non carbohydrate fuel sourcesminimize protein catabolism in the injuredpatient

Dietary lipids requirespancreatic lipase and

1 2


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pancreatic lipase andphospholipase withinthe duodenum to

hydrolyze thetriglycerides into freefatty acids andmonoglycerides

FFA andmonoglycerides areabsorbed by gutenterocytes

Gut enterocyteresynthesizetriglycerides byesterification of themonoglycerides withfatty acyl coenzyme A(acyl-CoA)

Long chain triglycerides (12 carbons or more)undergo esterification and enter the circulationthrough lymphatic system as chylomicrons

Shorter fatty acid chains directly enter the portalcirculation and are transported to the liver byalbumin carriers

1

2

3

3

4

4

5

Lipolysis


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Lipolysis

In adipose tissues, triglyceride lipase hydrolyzetriglycerides into free fatty acid and glycerol

Free fatty acid reenter the capillary circulation andtransported by albumin to tissues requiring fuel source

Insulin inhibits lipolysis and favors triglyceridesynthesis

Fatty Acid Oxidation


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FFA absorbed by cells conjugate with acyl-CoA withinthe cytoplasm

carnitine shuttle transport fatty acyl-CoA from outermitochondrial membrane across inner membrane

Medium-chain triglycerides (MCTs), 6 to 12carbons in length, bypass the carnitine shuttle

fatty acyl-CoA undergoes beta oxidation inmitochondria

acetyl-CoA is produced Krebs Cycle12 ATP,carbon dioxide, and water

Excess acetyl-CoA ketogenesis

Fatty Acid Oxidation

Ketogenesis


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Ketogenesis

Increased lipolysis and reduced systemiccarbohydrate availability during starvation divertsexcess acetyl-CoA toward hepatic ketogenesis

Purpose: A number of extrahepatic tissues, but notthe liver itself, are capable of using ketones for fuel

The rate of ketogenesis appears to be inverselyrelated to the severity of injury

KETOSIS represents a state in which hepaticketone production exceeds extrahepatic ketoneutilization

C b h d t


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Carbohydrates

primarily digested in the small intestine

Disaccharidases dismantle the complexcarbohydrates into simple hexose units:

Glucose and galactose absorbed throughenergy-dependent active transport coupled to thesodium pump

Fructose absorbed through concentration-

dependent facilitated diffusion

CHO Metabolism


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oxidation of 1 g of carbohydrate = 4 kcal

IVF or parenteral nutrition = 3.4 kcal/g of dextrose

In starvation, glucose production occurs at theexpense of protein stores (i.e., skeletal muscle)

the PRIMARY GOAL for maintenance glucoseadministration in surgical patients is to minimizemuscle wasting

administration of insulin has been shown to

reverse protein catabolism by stimulating proteinsynthesis in skeletal muscles

CHO Metabolism

Glucose Catabolism


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occurs by:

> cleavage to pyruvate or lactate (pyruvic acid pathway) or by

> decarboxylation to pentoses (pentose shunt):

Glucose Transport


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Glucose Transport

membrane glucose transporters in human system.

a. Facilitated diffusion glucose transporters(GLUT)

permit the transport of glucose down aconcentration gradient

b. Na+/glucose secondary active transport system(SGLT)

transports glucose molecules against by activetransport

Five Functional Human GLUTs


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Description

GLUT1 transporter in human erythrocytes little is found in liver and skeletal muscle

GLUT2 important for rapid export of glucose resulting

from gluconeogenesis

GLUT3 highly expressed in neuronal tissue of the brain,kidney and placenta

GLUT4

primary glucose transporter of insulin sensitivetissues and skeletal and cardiac muscle

usually packaged as intracellular vesicles

GLUT5 primarily expressed in the jejunum predominantly a fructose transporter

Na+/glucose secondary active transport

t (SGLT)


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found in the intestinal epithelium and in proximalrenal tubules

transport both sodium and glucose intracellularly

SGLT1 is prevalent on brush borders of smallintestine enterocytes

enhances gut retention of water through osmoticabsorption

SGLT1 and SGLT2 are both associated withglucose reabsorption at proximal renal tubules

system (SGLT)

Protein & Amino Acid Metabolism


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Protein & Amino Acid Metabolism

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

After injury, the initial systemic proteolysis,mediated primarily by glucocorticoids, increase

urinary nitrogen excretion to levels in excessof 30 g/d loss in lean body mass of 1.5%per day

Protein catabolism after injury provides substratesfor gluconeogenesis and for the synthesis of acutephase proteins


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Severe trauma, burns and sepsis increaseprotein catabolism

skeletal muscles are depleted acutely after injurywhereas visceral tissues remain relatively

preserved ubiquitin proteosome system in muscle cells

- one of major pathways for protein degradationduring acute injury


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NUTRITION IN THESURGICAL PATIENT


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Goal of nutritional support : to prevent or reversethe catabolic effects of disease or injury; to meet theenergy requirements for metabolic processes, coretemperature maintenance, and tissue repair

Failure to provide adequate nonprotein energysources will lead to consumption of lean tissue stores

Overall nutritional assessment is undertaken to determine

the severity of nutrient deficiencies


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requirement for energy may be measured by indirect calorimetry is labor intensive and often

leads to overestimation of caloric requirements.

trends in serum markers (e.g., prealbumin level)

urinary nitrogen excretion proportional toresting energy expenditure

Harris-Benedict equations: estimate the basal energy

expenditure After trauma or sepsis, energy substrate demands are

increased, necessitating greater nonprotein caloriesbeyond calculated energy expenditure

Vitamins and Minerals


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Vitamins and Minerals

Vitamins not given in absence of deficiencies Patients maintained on elemental diets or parenteral

hyperalimentation require complete vitamin andmineral supplementation

Numerous commercial vitamin preparations areavailable for intravenous or intramuscular use

Essential fatty acid supplementation also may benecessary, especially in patients with depletion ofadipose stores

Overfeeding


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Overfeeding

results from overestimation of caloric needs may contribute to clinical deterioration via

increased oxygen consumption

increased carbon dioxide production

prolonged need for ventilatory support

suppression of leukocyte function

Hyperglycemia

increased risk of infection.


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Enteral Nutrition

Rationale for Enteral Nutrition


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Generally preferred over parenteral nutrition basedon

lower cost of enteral feeding

luminal nutrient contact reduces intestinalmucosal atrophy

Less infectious complications and acute phaseprotein production

Rationale for Enteral Nutrition

Indication


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Indication

burn patients early initiation of enteral feeding

surgical patients with moderate malnutrition(albumin level of 2.9 to 3.5 g/dL)

permanent neurologic impairment

oropharyngeal dysfunction

short-bowel syndrome

bone marrow transplantation

Healthy patients without malnutrition undergoinguncomplicated surgery

Initiation of Enteral Feeding


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Initiation of Enteral Feeding

occur immediately after adequate resuscitation most readily determined by adequate urineoutput

The presence of bowel sounds and the passageof flatus or stool are not absolute prerequisitesfor initiation of enteral nutrition

Gastric residuals of 200 mL or more in a 4- to 6-

hour period or abdominal distention requirescessation of feeding and adjustment of theinfusion rate

Enteral Formulas


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Enteral Formulas

functional status of the GIT determines the type ofenteral solutions to be used

patients who have not been fed via thegastrointestinal tract for prolonged periods less

likely to tolerate complex carbohydrates such aslactose

Factors that influence the choice of enteral formula:

the extent of organ dysfunction

nutrients needed to restore optimal function andhealing

cost

Low residue Isotonic formulas


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caloric density of 1.0 kcal/mL 1500 to 1800 mL are required to meet daily

requirements provide baseline CHO, CHON, electrolytes, water,

fat and fat soluble vitamins contain no fiber bulk and therefore leave minimum

residue standard or first line formulas for stable patient with

an intact GI tract

Low residue Isotonic formulas

Isotonic Formulas with Fiber


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Isotonic Formulas with Fiber

contain soluble and insoluble fiber delay intestinal transit time reduce the

incidence of diarrhea compared with nonfibersolutions

Fiber stimulates pancreatic lipase activity and isdegraded by gut bacteria into short-chain fattyacids, an important fuel for colonocytes

There are no contraindications

Immune-enhancing Formula


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Immune enhancing Formula

fortified with special nutrients

additives include glutamine, arginine, branched-chainamino acids, omega-3 fatty acids, nucleotides, andbeta carotene

The addition of amino acids to these formulasgenerally doubles the amount of protein (nitrogen)found in standard formula

cost can be prohibitive

Calorie-Dense Formula


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Calorie Dense Formula

greater caloric value for the same volume

provide 1.5 to 2 kcal/mL

for patients requiring fluid restriction or those

unable to tolerate large-volume infusions have higher osmolality than standard formulas

and are suitable for intragastric feedings

High-Protein Formulas


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High Protein Formulas

available in isotonic and nonisotonic mixtures

for critically ill or trauma patients with highprotein requirements

have nonprotein-calorie:nitrogen ratios

between 80:1 and 120:1.

Elemental Formulas


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Elemental Formulas

contain predigested nutrients and provide proteins inthe form of small peptides

primary advantage is ease of absorption

Disadvantage: inherent scarcity of fat, associated

vitamins, and trace elements limits its long-term use Due to its high osmolarity, dilution or slow infusion

rates usually are necessary

used frequently in patients with malabsorption, gut

impairment, and pancreatitis cost is significantly higher than standard formulas

Renal-Failure Formulas


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Renal Failure Formulas

lower fluid volume, but contains concentrations ofpotassium, phosphorus, and magnesium needed to meetdaily calorie requirements

almost exclusively contains essential amino acids

has a high nonprotein-calorie:nitrogen ratio

does not contain trace elements or vitamins

Pulmonary-Failure Formulas fat content is usually increased to 50% of the total

calories, with reduction in carbohydrate content

goal is to reduce carbon dioxide production and alleviateventilation burden for failing lungs

Hepatic-Failure Formulas


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p

50% of the proteins in hepatic-failure formulasare branched-chain amino acids

Goal: reduce aromatic amino acid levels andincrease the levels of branched-chain amino

acids, which can potentially reverseencephalopathy in patients with hepatic failure

use of these formulas is controversial,however, because no clear benefits have been

proven by clinical trials


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Options forEnteral Feeding

Nasoenteric Tubes


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Nasoenteric Tubes

for those with intact mentation and protectivelaryngeal reflexes

Radiographic confirmation is required to verifythe position of the nasogastric feeding tube

Disadvantages: clogging, kinking, andinadvertent displacement or removal of the tube,and nasopharyngeal complications

If nasoenteric feeding will be required for longer

than 30 days, access should be converted to apercutaneous one

Percutaneous EndoscopicGastrostomy (PEG)


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Gastrostomy (PEG)

most common indications:

impaired swallowing mechanisms

oropharyngeal or esophageal obstruction

major facial trauma contraindications: ascites, coagulopathy,

gastric varices, gastric neoplasm, and lack of asuitable abdominal site

Most tubes are 18F to 28F in size

may be used for 12 to 24 months.


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Identification of the PEG site requires endoscopictransillumination of the anterior stomach

A 14-gauge angiocatheter is passed through theabdominal wall into the fully insufflated stomach

A guidewire is threaded through the angiocatheterand pulled out through the mouth

The tapered end of the PEG tube is secured to theguidewire and is pulled into position out of the

abdominal wall The PEG tube is secured against the abdominal

wall

PEG-Jejunostomy


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y

In the PEG-J method, a 9F to 12F tube is passedthrough an existing PEG tube, past the pylorus,and into the duodenum with endoscopic orfluoroscopic guidance

For patients who cannot tolerate gastric feedingsor who have significant aspiration risks

Direct Percutaneous Endoscopic

Jejunostomy (DPEJ)


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J j y ( J)

uses the same techniques as PEG tube placementbut requires an enteroscope or colonoscope to reachthe jejunum

malfunctions are probably less frequent than PEG-J

kinking or clogging is usually averted by placement oflarger-caliber catheters

success rate of placement is variable because of thecomplexity of endoscopic skills required to locate a

suitable jejunal site

Surgical Gastrostomy andJejunostomy


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Jejunostomy

only absolute contraindication is distal intestinalobstruction

The biggest drawback usually is possible cloggingand knotting of the 6F catheter

Abdominal distention and cramps are commonadverse effects of early enteral nutrition

These are mostly correctable by temporarilydiscontinuing feedings and resuming at a lower

infusion rate.


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Pneumatosis intestinalis and small-bowelnecrosis are infrequent but significant problems inpatients receiving jejunal tube feedings

Therefore, enteral feedings in the critically ill patient

should be delayed until adequate resuscitation hasbeen achieved


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Parenteral Nutrition


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continuous infusion of a hyperosmolar solutioncontaining:

1. Carbohydrates2. Proteins3. Fat

4. other necessary nutrientsthrough an indwelling catheter inserted into thesuperior vena cava.

To obtain maximum benefit:calorie:protein ratio must be adequate (at

least 100 to 150 kcal/g nitrogen), and carbohydratesand proteins must be infused simultaneously.


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Principal indications for parenteral nutrition are:

1. Malnutrition

2. Sepsis

3. Surgical or traumatic injury in seriously illpatients for whom use of the gastrointestinaltract for feedings is not possible

4. supplement inadequate oral intake


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For safe and successful use:1. proper selection of patients with specific

nutritional needs

2. experience with the technique

3. awareness of the associated complications.

fundamental goals:

1. to provide sufficient calories and nitrogensubstrate to promote tissue repair

2. to maintain the integrity or growth of leantissue mass.

Total Parenteral Nutrition (TPN)


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also referred to as central parenteral nutrition

requires access to a large-diameter vein todeliver the entire nutritional requirements of

the individual Dextrose content of the solution is high (15 to

25%), and all other macronutrients andmicronutrients are deliverable by this route.

Peripheral Parenteral Nutrition


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lower osmolarity solution is secondary toreduced levels of dextrose (5 to 10%) andprotein (3%) is used to allow itsadministration via peripheral veins

not appropriate for repleting patients withsevere malnutrition

used for short periods (


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1. Technical Complications

long-term parenteral feeding sepsissecondary to contamination of the central

venous catheter2. Metabolic Complications

common complication in patients with latentdiabetes and in patients subjected to severesurgical stress or trauma


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3. Intestinal Atrophy Lack of intestinal stimulation is associated with

a. intestinal mucosal atrophy

b. diminished villous heightc. bacterial overgrowth

d. reduced lymphoid tissue size

e. reduced immunoglobulin A production

f. impaired gut immunity

Special Formulations


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Glutamine and Arginine Glutamine most abundant amino acid in the

human body, comprising nearly 2/3 of the freeintracellular amino acid pool.

Arginine nonessential amino acid in healthysubjects

immunoenhancing properties, wound-healing

benefits, and association with improvedsurvival in animal models of sepsis andinjury


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Omega-3 Fatty Acids canola oil or fish oil

displaces omega-6 fatty acids in cell membranes reduces proinflammatory response from

prostaglandin production

Nucleotides

increase cell proliferation, provide building blocksfor DNA synthesis, and improve helper T cellfunction

Nutrition-Induced InflammatoryModulation


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mode of nutritional supplementation mayinfluence stress-induced inflammatory

responses Enteral feedings feeding mode of choice

when possible

advantage: improved GI barrier function

Body's Response to Injury

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