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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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categorized by family
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,
categorized by family
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
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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
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