Systemic inflammation is a central feature

of both sepsis and severe trauma

*Sepsis: systemic inflammatory response to infection
This report reviews the autonomic, cellular and
hormonal responses to injury
to be able to develop therapies to intervene
during sepsis or after a severe injury, an
understanding of the complex pathways that
regulate local and systemic inflammation is
necessary
Introduction
Immune System
respond to and neutralize pathogenic
microorganisms;
coordinate tissue repair
(+) injury or
infection
Inflammatory
Response
Cell signalling
cell migration
mediator release
MINOR HOST INSULT local inflammatory
response; transient and in most cases
beneficial

MAJOR HOST INSULT immune reactions
can become amplified; systemic
inflammation and potentially detrimental
responses
Systemic Inflammatory Response
Syndrome (SIRS)
SIRS
(+) Two or more of following criteria
T 38C or 36C
HR 90 beats/min
RR 20 breaths/min or PaCO
2
32 mmHg
or mechanical ventilation
WBC count 12,000/L or 4000/L or 10%
band forms
Sepsis Identifiable source of infection + SIRS
Severe sepsis Sepsis + organ dysfunction
Septic shock Sepsis + cardiovascular collapse
Phases of Systemic Inflammatory Response
1. Acute proinflammatory state
innate immune system recognize ligands
activation of cellular processes to restore tissue
function and eradicate invading microorganisms

2. Anti-inflammatory or counter regulatory phase
Serves to modulate the proinflammatory phase
prevent excessive proinflammatory activities

Schematic representation of SIRS after injury:
Severe inflammation
may lead to:
multiple organ failure
(MOF) and
early death after
injury
EXCESSIVE counter regulatory anti-inflammatory response
(CARS) may induce prolonged immunosupressed state

Normal recovery requires a period of a systemic inflammation
followed by return to homeostasis
influences multiple organs

RECOGNIZE injury or infection signals
through
afferent signal pathways

When receptors are activated by
inflammatory mediators phenotypic
responses are produced through both
circulatory and neuronal pathways

CNS Regulation of Inflammation
Cholinergic Anti-Inflammatory Pathways
VAGUS NERVE
- ANTI-inflammatory pathways


efferent signals are transmitted
through neurotransmitter
acetylcholine
Activate nicotinic acetylcholine
receptors on immune mediator
cells

INHIBITION of
cytokine activity
reduce injury
from disease
processes
Hormone Signaling Pathways
HORMONES chemical signals that modulate
the function of target cells.
Categories:
polypeptides cytokines, glucagon, insulin
amino acids epinephrine, serotonin,
histamine
fatty acids glucocorticoids,
prostaglandins and leukotrienes

Hormone Regulation
Hypothalamus Anterior Pituitary
Posterior
Pituitary
CRH
TRH
GHRH
LHRH

ACTH Cortisol
TSH T3, T4,
GH Insulin-like
growth factor (IGF)
Gonadotropins
Sex hormones
Prolactin
Somatostatin
Endorphins
Vasopressin
Oxytocin

Further mediator release
Protein synthesis through intracellular
receptor binding either directly by hormone or
through secondary signalling molecule
- example of intracellular receptor:
Glucocorticoid Receptor
Effects of Hormones
Adrenocotricotropic Hormone (ACTH)
Activate receptor at zona fasciculata of the adrenal
gland to mediate cortisol release
stimulated by:
Corticotropin-releasing hormone (CRH)
Pain, anxiety
Catecholamines and pro-inflammatory cytokines
Excessive ACTH stimulation leads to
adrenocortical hypertrophy
Cortisol

glucocorticoid steroid hormone
released by adrenal cortex in response to
ACTH
Increased during stress
chronically elevated in certain disease
processes
Burn patients may exhibit elevation for 4 weeks
metabolic hyperglycemia
skeletal muscles &
adipose tissues
Release of substrates for
gluconeogenesis
wound healing Delays wound healing
Immunosuppressive
+ T-cell and natural killer cell
function
Inhibit leukocyte migration to
sites of inflammation
Inhibit intracellular killing in
monocytes
Effects of Cortisol
Macrophage Inhibitory Factor (MIF)
Counter regulatory mediator
reverses the immunosuppressive effects of
glucocorticoids

| activity of immunocytes against pathogens
Growth Hormone
Up-regulated by hypothalamic GH-releasing
hormone (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
Role of GH during inflammation...
(+) Critical illness (+) GH resistance &
+ IGF


phagocytic activity of immunocytes
T-cell

Therefore:
GH administration in critically ill patients
may be worsen inflammatory response
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)
act on both alpha and beta receptors
Metabolic effects: mainly catabolic
Immunomodulatory effects:
Mediated through beta2 receptors in
immunocytes increases leukocyte
demargination
inhibit release of inflammatory cytokines
Catecholamines

Pharmacologic Significance
Used to treat hypotension during septic shock
because it | cardiac output and subsequent | in
cardiac O
2
demand


Rx: Beta blockers: reduce cardiac stress
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 Hypokalemia
Metabolic Alkalosis
Edema
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
Either | or + in response to inflammatory stimuli
Increase = positive APP
Decrease = negative APP
C-reactive protein: most commonly used APP
as marker of inflammation
* major stimulus: Interleukin-6
produced by liver therefore if (+) hepatic
insufficiency, APPs are unreliable marker of
inflammation

Mediators
of Inflammation
exaggerated physiologic response which
involves a vascular and cellular response by
phagocytic cells to infection or injury

*classic signs of injury/inflammation:
Pain (dolor) Swelling (tumor)
Heat (calor) Loss of Function (functiolaesa)
Redness (rubor)

Inflammation
Cytokines
Protein signaling compounds
pro-inflammatory effects:
immunocyte proliferation eradication of
invading microorganisms
promote wound healing
Heat Shock Proteins (HSP)
intracellular proteins that are | in times of stress
Fxns:
chaperones for ligands such as bacterial DNA
and endotoxin
Presumed to protect cells from deleterious
effects of traumatic stress
When released by damaged
cells, they alert the immune
system of tissue damage
Reactive Oxygen Species (ROS)
highly reactive small molecules due to
unpaired outer orbit electrons
potent oxygen radicals:
Oxygen ions, superoxide anion, H
2
0
2
Hydroxyl radicals
Effect: oxidize unsaturated FA
Cell
membrane
Cellular damage
(host or pathogenic cells)
enzymes that protect cells from damaging effects
of ROS:
Superoxide dismutase:
superoxide H
2
O
2
+ O
2
Catalase: H
2
O
2
H
2
O + O
2
Glutathione peroxidase reduce H2O2 by
transferring energy of reactive peroxides to
glutathione
Endogenous Antioxidants
Eicosanoids
Physiologic roles of Eicosanoids
Leukotrienes
Vasoconstriction
Bronchospasm
Capillary permeability
Thromboxanes
Vasoconstriction
Platelet aggregation
Prostacycline
Vasodilation
Inhibit platelet aggregation
Prostaglandin
Vasodilation
Potentiates edema
Fatty Acid Metabolites
Dietary omega-3
and omega-6
fatty acids s
are substrates
for eicosanoid
production
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
Kinins mediate several inflammatory
process:
Vasodilation
Increased capillary permeability
Tissue edema
Pain pathway activation
Degree of elevation associated to magnitude of
injury and mortality

Kallikrein-Kinin System
Serotonin
derived from tryptophan
released at sites of injury, primarily by
platelets
Inflammatory effects:
vasocontriction, bronchoconstriction and platelet
aggregation
serotonin receptor blockade + production
of TNF and interleukin-1
Histamine
From decarboxylation of histidine
Histamine Receptors
H1 binding
Vasodilation
Bronchoconstriction
intestinal motility
myocardial contractility
H2 binding gastric acid secretion
H3 autoreceptor + histamine release
H4 binding
eosinophil and mast cell
chemotaxis
Cytokine Response
to Injury
Tumor Necrosis Factor (TNF)
Potent mediator of inflammatory response
Primarily synthesized by macrophages, monocytes
and T cells
Brief half life of 20min
Immunomodulatory roles:
coagulation activation
Macrophage phagocytosis
expression of adhesion molecules


Interleukin -1
inflammatory sequence similar to that of TNF
Released in response to cytokines and
foreign pathogens
Has 2 active subtypes: IL-1o and IL-1|
It is an endogenous pyrogen
activate
prostaglandin
activity
hypothalamus
fever
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 organ
transplant
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
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 tissue
injury
Has counter regulatory effects inhibition of
TNF and IL-1
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-10 +TNF
Interleukin-12
Regulator of cell-mediated immunity
Stimulates natural killer cell cytotoxicity and helper
T cell differentiation
Deficiency +phagocytosis 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, and
leukopenia during septic shock
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- from
T-cells
Interferons
Type I interferons
IFN-o, IFN-|, IFN-e
binds to common receptor, IFN-o receptor
induce maturation of dendritic cells
Alpha and beta interferons | cytotoxicity of natural
killer cells
Have been studied as therapeutic agents in
hepatitis C and relapsing MS

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 microbial
killing
+ levels is associated with increase susceptibility
to viral and bacterial pathogens
| chemoattractants and adhesion molecules to
site of inflammation
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 and
recruitment of functional leukocytes
may also be effective in wound healing

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 from
monocytes
Elevation is delayed: peak at 16 hours and remain
elevated beyond 30 hrs
Other mediators such as TNF: peak at 1-2 hrs
and becomes undetectable by 12 hrs
Cellular Response
to Injury
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 inhibit
breakdown by exonucleases
Addition of polyadenylated tail adds noncoding
sequence to the mRNA increase half life of
transcript
c. Once out of the nucleus inactivated or translated to
form proteins
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 protein
kinase A
Calcium can activate phospholipase C
receptors can
respond to
adrenaline and
serotonin
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 E
component
subsequently
activates 2
nd

messengers
Ligand-gated Ion Channels (LGIC)
transmembrane receptors that allow rapid influx of ions
Nicotinic acetylcholine receptor prototypical LGIC
Ligand binding

chemical signals converted
into an electrical signal

change in cell membrane
potential

On activation of the channel

ion influx into the cell
Receptor Tyrosine Kinases
cell signalling for several growth factors
On ligand binding,
RTKs dimerize


multiple
autophosphorylation
steps to recruit and
activate signalling
molecules
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)

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 inflammatory
cytokines and growth hormones
JAKs bind to cytokines and
dimerize.

Activated JAKs recruit and
phosphorylate STAT
molecules

Activated STAT proteins
further dimerize

STAT complexes
translocate into the
molecules and modulate
the transcription of target
genes

Mitogen-Activated Protein Kinases
Pathways mediated through MAPK
contribute to:
inflammatory signaling
regulation of cell proliferation and cell death
Activated receptors:

Dephosphorylation of MAPK mediators
inhibit their function

sequential stages of mediator
phosphorylation
activation of downstream effectors
Ligand
binding
c-Jun N-terminal
kinase (JNK)
Extracellular
regulated protein
kinase (ERK)
p38 kinase
immunocyte
development
forms
transcription
factor activated
protein1
Nuclear Factor kB
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 kB (I-kB)
On release, NF- kB travels to the nucleus and
promote gene expression
Toll-like Receptors and CD14
pattern recognition receptors
activated by pathogen-associated molecular
patterns (PAMP)
Function as effectors of innate immune
system
TLR4 recognize lipopolysaccharides (LPS)
TLR2 recognizes PAMP from gram-positive
bacteria

APOPTOSIS
Regulated cell death
organized mechanism for clearing senescent or
dysfunctional cells without promoting an inflammatory
response
Necrosis disorganized sequence; can activate
inflammatory response
regulatory factors:
Inhibitor of apoptosis proteins
Regulatory caspases (caspases 1, 8, and 10)
Caspases effectors of apoptotic signaling that
mediate organized breakdown of nuclear DNA

a. Extrinsic Pathway activated through binding of
death receptors: Fas, TNFR
Leads to activation of Fas-associated death domain
protein (FADD) and subsequent activation of
caspases
b. Intrinsic Pathway protein mediators influences
mitochondrial membrane permeability
Leads to release of mitochondrial Cytochrome C,
which ultimately activates caspases, and thus
induce apoptosis
APOPTOSIS
CELL-MEDIATED
INFLAMMATORY
RESPONSE
Platelets
Non-nucleated structures, but contains
mitochondria
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 the
blockade of COX
Lymphocytes and T-Cell Immunity
Lymphocytes are circulating immune cells
composed primarily of B cells, T cells and
natural killer cells
T-lymphocytes are mediators of adaptive
immunity
arginine is essential for T-cell proliferation and
receptor function
Helper T-lymphocytes are broadly categorized
into 2 groups:
T
H
1 cells
- cellular
immune
response

T
H
2 cells
- Humoral
response

activation of
monocytes,
B-lymphocytes,
and cytotoxic
T-lymphocytes

Inhibited by
IL-4 and Il-10

Glucocorticoid is a
potent stimulant

activation of
eosinophils,
mast cells, and
B-lymphocyte
Ig4 and IgE
production

Inhibited by
interferon-
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 mediators
including reactive oxygen species, histamine and
peroxidase
Mast Cells
role in anaphylactic response to allergens
Stimuli: allergen binding, infection and trauma
Action: produce histamine, cytokines,
eicosanoids, proteases and chemokines which
leads to
Vasodilation
capillary leakage
immunocyte recruitment
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

Neutrophils
Potent mediators of acute inflammation
Among the first responders to sites of inflammation
adherence to vascular endothelium is induced by
chemotactic 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
ENDOTHELIUM-
MEDIATED INJURY
Vascular Endothelium
critical function as barriers that regulate tissue
migration of circulating cells
Has anticoagulant properties
During sepsis, endothelial cell are differentially
modulated
decreased
production of
anticoagulant
factors
Procoagulant
shift
microthrombosis &
organ injury
Neutrophil-Endothelium interaction
Neutrophils migrate through actions of:
| vascular permeability
| chemoattractants
| SELECTINS adhesion factors that are
elaborated on cell surfaces
endothelium increases surfaces expression of
P-selectin to mediate neutrophil rolling
After 2 hours, however, cell surface expression
favors E-selectin expression
L-selectin and P-selectin glycoprotein ligand-1
(PSGL-1) are responsible for over 85% of
monocyte-to-monocyte and monocyte-to-
endothelium adhesion activity and targeted
immunocyte migration
Effective rolling involves a significant degree
of functional overlap between individual
selectins
Neutrophil-Endothelium interaction
Sequence of selectin-mediated neutrophil
interaction after inflammatory stimulus
Capture (tethering) Initial
recognition leukocytes
marginate toward the endothelial
surface
Fast Rollling rapid L-selectin
shedding from cell surfaces
Slow Rolling mediated by P-
selectin
Arrest (firm adhesion) leading
to transmigration
Molecules that mediate leukocyte-endothelial adhesion,
categorized by family
Adhesion
Molecule
Action Origin
Inducers of
expression
Target cells
Selectins
L-selectins
Fast rolling Leukocytes Native
Endothelium,Platelet
eosinophils
P-selectins
Slow rolling
Platelets and
endothelium
Thrombin,
histamine,
cytokine
Neutrophils,
monocytes
E-selectin
Very slow rolling Endothelium Cytokines
Neutrophils,
monocytes
lymphocytes
Immunoglobulins
ICAM-1
Firm adhession/
transmigration
Endothelium,
leukocytes, fibro-
blasts, epithelium
Cytokines
Leukocytes
ICAM-2
Firm adhession
Endothelium,
Platelet
Native
VCAM-1
Firm adhession/
transmigration
Endothelium
Cytokines

monocytes
Lymphocytes
Molecules that mediate leukocyte-endothelial adhesion,
categorized by family
Adhesion
Molecule
Action Origin
Inducers of
expression
Target cells
PECAM-1
Firm adhession/
transmigration
Endothelium,
Platelet,
leukocytes
Native
Endothelium,
Platelet,
leukocytes
B2-(CD18) Integrins
CD18/11a
Firm adhession/
transmigration
leukocytes
Leukocyte
activation
Endothelium
CD18/11b
(Mac)
Neutrophils,
monocytes,
natural killer cells
CD18/11c
adhession
B2-(CD18) Integrins
VLA-4
Firm adhession/
transmigration
Lymphocytes,
monocytes
Leukocyte
activation
Monocytes,
endothelium,
epithelium
Nitric Oxide
functions in control of vascular tone: vasodilation
initially known as endothelium-derived relaxing
factor
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
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
intraluminal platelets
Prostacyclin or
Prostaglandin I
2
(PGI2) is
derived from Arachidonic
Acid (AA)
Nitric Oxide is derived
from L-Arginine
The resulting increase in
cyclic adenosine
monophosphate (cAMP)
and cyclic guanosine
monophosphate (cGMP)
results in
smooth muscle relation
inhibition of platelet
thrombus formation
Endothelins (ET) are derived from big ET and
they counter the effects of prostacyclin and NO
Endothelins
21 amino acid peptide from a 38 amino-acid precursor
molecule
Potent vasocontrictors
three members: ET-1, ET-2, and ET-3
ET-1 is the most potent endogenous
vasoconstrictor snd is estimated to be 10x more
potent 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
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 inhibitor
of PAF
Atrial Natriuretic Peptides (ANP)
peptides that are released primarily by atrial
tissue
induce vasodilation
Induce fluid and electrolyte excretion
prevent reabsorption of sodium
potent inhibitors of aldosterone secretion
SURGICAL
METABOLISM
initial hours after surgical or traumatic injury
+ total body energy expenditure
| urinary nitrogen wasting
necessary in the restorations of homeostasis:
augmented metabolic rates and oxygen
consumption
enzymatic preference for readily oxidizable
subtrates such as glucose
stimulation of the immune system
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 of
glucose 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)

Muscles
do not contain
Glucose-6-
phosphatase
Glycogen in
muscles can not
be utilized
readily
Hepatic
glycogen is
used first
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 for
gluconeogenesis; can provide up to 40% of plasma glucose
during starvation
metabolic pathways...
Metabolism Following Injury
Injuries or infections induce unique neuroendocrine
and immunologic responses that differentiate injury
metabolism from that of unstressed fasting
The magnitude of metabolic expenditure appears to
be directly proportional to the severity of insult
The increase in energy expenditure is mediated in
part by sympathetic activation and catecholamine
release
Lipid becomes the primary source of energy during
stressed states
Fuel utilization following trauma
Acute injury is associated with significant
alterations in substrate utilization
There is enhanced nitrogen loss,
indicative of catabolism
Fat remains the primary fuel source
under these circumstances.
Lipid Metabolism
Lipid influences the structural integrity of cell
membranes
Adipose predominant energy source during
critical illness and after injury
LIPOLYSIS (fat mobilization) occurs mainly in
response to catecholamine stimulus of the
hormonesensitive triglyceride lipase
non protein, non carbohydrate fuel sources
minimize protein catabolism in the injured
patient
Dietary lipids requires
pancreatic lipase and
phospholipase within
the duodenum to
hydrolyze the
triglycerides into free
fatty acids and
monoglycerides
FFA and
monoglycerides are
absorbed by gut
enterocytes
Gut enterocyte
resynthesize
triglycerides by
esterification of the
monoglycerides with
fatty acyl coenzyme A
(acyl-CoA)
Long chain triglycerides (12 carbons or more)
undergo esterification and enter the circulation
through lymphatic system as chylomicrons
Shorter fatty acid chains directly enter the portal
circulation and are transported to the liver by
albumin carriers
1
1
2
2
3
3
4
4
5
Lipolysis
In adipose tissues, triglyceride lipase hydrolyze
triglycerides into free fatty acid and glycerol
Free fatty acid reenter the capillary circulation and
transported by albumin to tissues requiring fuel source
Insulin inhibits lipolysis and favors triglyceride
synthesis
FFA absorbed by cells conjugate with acyl-CoA within
the cytoplasm
carnitine shuttle transport fatty acyl-CoA from outer
mitochondrial membrane across inner membrane
Medium-chain triglycerides (MCTs), 6 to 12
carbons in length, bypass the carnitine shuttle
fatty acyl-CoA undergoes beta oxidation in
mitochondria
acetyl-CoA is produced Krebs Cycle 12 ATP,
carbon dioxide, and water
Excess acetyl-CoA ketogenesis

Fatty Acid Oxidation
Ketogenesis
Increased lipolysis and reduced systemic
carbohydrate availability during starvation diverts
excess acetyl-CoA toward hepatic ketogenesis
Purpose: A number of extrahepatic tissues, but not
the liver itself, are capable of using ketones for fuel
The rate of ketogenesis appears to be inversely
related to the severity of injury
KETOSIS represents a state in which hepatic
ketone production exceeds extrahepatic ketone
utilization

Carbohydrates
primarily digested in the small intestine
Disaccharidases dismantle the complex
carbohydrates into simple hexose units:
Glucose and galactose absorbed through
energy-dependent active transport coupled to the
sodium pump
Fructose absorbed through concentration-
dependent facilitated diffusion
oxidation of 1 g of carbohydrate = 4 kcal
IVF or parenteral nutrition = 3.4 kcal/g of dextrose
In starvation, glucose production occurs at the
expense of protein stores (i.e., skeletal muscle)
the PRIMARY GOAL for maintenance glucose
administration in surgical patients is to minimize
muscle wasting
administration of insulin has been shown to
reverse protein catabolism by stimulating protein
synthesis in skeletal muscles
CHO Metabolism
occurs by:
> cleavage to pyruvate or lactate (pyruvic acid pathway) or by
> decarboxylation to pentoses (pentose shunt):

Glucose Catabolism
Glucose Transport
membrane glucose transporters in human system.
a. Facilitated diffusion glucose transporters
(GLUT)
permit the transport of glucose down a
concentration gradient
b. Na
+
/glucose secondary active transport system
(SGLT)
transports glucose molecules against by active
transport

Five Functional Human GLUTs
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 sensitive
tissues and skeletal and cardiac muscle
usually packaged as intracellular vesicles
GLUT5
primarily expressed in the jejunum
predominantly a fructose transporter
found in the intestinal epithelium and in proximal
renal tubules
transport both sodium and glucose intracellularly
SGLT1 is prevalent on brush borders of small
intestine enterocytes
enhances gut retention of water through osmotic
absorption
SGLT1 and SGLT2 are both associated with
glucose reabsorption at proximal renal tubules
Na
+
/glucose secondary active transport
system (SGLT)
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 excess
of 30 g/d loss in lean body mass of 1.5%
per day
Protein catabolism after injury provides substrates
for gluconeogenesis and for the synthesis of acute
phase proteins
Severe trauma, burns and sepsis increase
protein catabolism
skeletal muscles are depleted acutely after injury
whereas visceral tissues remain relatively
preserved
ubiquitin proteosome system in muscle cells
- one of major pathways for protein degradation
during acute injury
NUTRITION IN THE
SURGICAL PATIENT
Goal of nutritional support : to prevent or reverse
the catabolic effects of disease or injury; to meet the
energy requirements for metabolic processes, core
temperature maintenance, and tissue repair
Failure to provide adequate nonprotein energy
sources will lead to consumption of lean tissue stores

Overall nutritional assessment is undertaken to determine
the severity of nutrient deficiencies
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 to
resting energy expenditure

Harris-Benedict equations: estimate the basal energy
expenditure
After trauma or sepsis, energy substrate demands are
increased, necessitating greater nonprotein calories
beyond calculated energy expenditure

Vitamins and Minerals
Vitamins not given in absence of deficiencies
Patients maintained on elemental diets or parenteral
hyperalimentation require complete vitamin and
mineral supplementation
Numerous commercial vitamin preparations are
available for intravenous or intramuscular use
Essential fatty acid supplementation also may be
necessary, especially in patients with depletion of
adipose stores
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.
Enteral Nutrition
Generally preferred over parenteral nutrition based
on
lower cost of enteral feeding
luminal nutrient contact reduces intestinal
mucosal atrophy
Less infectious complications and acute phase
protein production
Rationale for Enteral Nutrition
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 undergoing
uncomplicated surgery
Initiation of Enteral Feeding
occur immediately after adequate resuscitation
most readily determined by adequate urine
output
The presence of bowel sounds and the passage
of flatus or stool are not absolute prerequisites
for initiation of enteral nutrition
Gastric residuals of 200 mL or more in a 4- to 6-
hour period or abdominal distention requires
cessation of feeding and adjustment of the
infusion rate
Enteral Formulas
functional status of the GIT determines the type of
enteral solutions to be used
patients who have not been fed via the
gastrointestinal tract for prolonged periods less
likely to tolerate complex carbohydrates such as
lactose
Factors that influence the choice of enteral formula:
the extent of organ dysfunction
nutrients needed to restore optimal function and
healing
cost
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
contain soluble and insoluble fiber
delay intestinal transit time reduce the
incidence of diarrhea compared with nonfiber
solutions
Fiber stimulates pancreatic lipase activity and is
degraded by gut bacteria into short-chain fatty
acids, an important fuel for colonocytes
There are no contraindications
Immune-enhancing Formula
fortified with special nutrients
additives include glutamine, arginine, branched-chain
amino acids, omega-3 fatty acids, nucleotides, and
beta carotene
The addition of amino acids to these formulas
generally doubles the amount of protein (nitrogen)
found in standard formula
cost can be prohibitive
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
available in isotonic and nonisotonic mixtures
for critically ill or trauma patients with high
protein requirements
have nonprotein-calorie:nitrogen ratios
between 80:1 and 120:1.
Elemental Formulas
contain predigested nutrients and provide proteins in
the 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
lower fluid volume, but contains concentrations of
potassium, phosphorus, and magnesium needed to meet
daily 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 alleviate
ventilation burden for failing lungs
Hepatic-Failure Formulas
50% of the proteins in hepatic-failure formulas
are branched-chain amino acids
Goal: reduce aromatic amino acid levels and
increase the levels of branched-chain amino
acids, which can potentially reverse
encephalopathy in patients with hepatic failure
use of these formulas is controversial,
however, because no clear benefits have been
proven by clinical trials
Options for
Enteral Feeding
Nasoenteric Tubes
for those with intact mentation and protective
laryngeal reflexes
Radiographic confirmation is required to verify
the position of the nasogastric feeding tube
Disadvantages: clogging, kinking, and
inadvertent 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 a
percutaneous one
Percutaneous Endoscopic
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 a
suitable abdominal site
Most tubes are 18F to 28F in size
may be used for 12 to 24 months.
Identification of the PEG site requires endoscopic
transillumination of the anterior stomach
A 14-gauge angiocatheter is passed through the
abdominal wall into the fully insufflated stomach
A guidewire is threaded through the angiocatheter
and pulled out through the mouth
The tapered end of the PEG tube is secured to the
guidewire and is pulled into position out of the
abdominal wall
The PEG tube is secured against the abdominal
wall
PEG-Jejunostomy
In the PEG-J method, a 9F to 12F tube is passed
through an existing PEG tube, past the pylorus,
and into the duodenum with endoscopic or
fluoroscopic guidance
For patients who cannot tolerate gastric feedings
or who have significant aspiration risks
Direct Percutaneous Endoscopic
Jejunostomy (DPEJ)
uses the same techniques as PEG tube placement
but requires an enteroscope or colonoscope to reach
the jejunum
malfunctions are probably less frequent than PEG-J
kinking or clogging is usually averted by placement of
larger-caliber catheters
success rate of placement is variable because of the
complexity of endoscopic skills required to locate a
suitable jejunal site
Surgical Gastrostomy and
Jejunostomy
only absolute contraindication is distal intestinal
obstruction
The biggest drawback usually is possible clogging
and knotting of the 6F catheter
Abdominal distention and cramps are common
adverse effects of early enteral nutrition
These are mostly correctable by temporarily
discontinuing feedings and resuming at a lower
infusion rate.
Pneumatosis intestinalis and small-bowel
necrosis are infrequent but significant problems in
patients receiving jejunal tube feedings
Therefore, enteral feedings in the critically ill patient
should be delayed until adequate resuscitation has
been achieved
Parenteral Nutrition
continuous infusion of a hyperosmolar solution
containing:
1. Carbohydrates
2. Proteins
3. Fat
4. other necessary nutrients
through an indwelling catheter inserted into the
superior vena cava.

To obtain maximum benefit:
calorie:protein ratio must be adequate (at
least 100 to 150 kcal/g nitrogen), and carbohydrates
and proteins must be infused simultaneously.

Principal indications for parenteral nutrition are:
1. Malnutrition
2. Sepsis
3. Surgical or traumatic injury in seriously ill
patients for whom use of the gastrointestinal
tract for feedings is not possible
4. supplement inadequate oral intake

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 nitrogen
substrate to promote tissue repair
2. to maintain the integrity or growth of lean
tissue mass.
Total Parenteral Nutrition (TPN)
also referred to as central parenteral nutrition
requires access to a large-diameter vein to
deliver the entire nutritional requirements of
the individual
Dextrose content of the solution is high (15 to
25%), and all other macronutrients and
micronutrients are deliverable by this route.

Peripheral Parenteral Nutrition
lower osmolarity solution is secondary to
reduced levels of dextrose (5 to 10%) and
protein (3%) is used to allow its
administration via peripheral veins

not appropriate for repleting patients with
severe malnutrition

used for short periods (<2 weeks)
Complications of Parenteral Nutrition
1. Technical Complications
long-term parenteral feeding sepsis
secondary to contamination of the central
venous catheter
2. Metabolic Complications
common complication in patients with latent
diabetes and in patients subjected to severe
surgical stress or trauma



3. Intestinal Atrophy
Lack of intestinal stimulation is associated with
a. intestinal mucosal atrophy
b. diminished villous height
c. bacterial overgrowth
d. reduced lymphoid tissue size
e. reduced immunoglobulin A production
f. impaired gut immunity
Special Formulations
Glutamine and Arginine
Glutamine most abundant amino acid in the
human body, comprising nearly 2/3 of the free
intracellular amino acid pool.
Arginine nonessential amino acid in healthy
subjects
immunoenhancing properties, wound-healing
benefits, and association with improved
survival in animal models of sepsis and
injury



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 blocks
for DNA synthesis, and improve helper T cell
function

Nutrition-Induced Inflammatory
Modulation
mode of nutritional supplementation may
influence stress-induced inflammatory
responses
Enteral feedings feeding mode of choice
when possible
advantage: improved GI barrier function