CHAPTER 2: SYSTEMIC RESPONSE TO INJURY AND

METABOLIC SUPPORT
Minor host insults instigate local inflammatory response that is transient and
beneficial while Major host insults may propagate reactions that can be amplified
resulting in systemic inflammatory response that can be detrimental.
● KEYPOINTS
○ Systemic inflammation is characterized by exaggerated immune
responses to either sterile or infectious process. The cause of
inflammatory activation needs to be addressed to resolve the
dysregulated immune state
○ An understanding of the signaling mechanisms and pathways underlying
systemic inflammation can help guide therapeutic interventions in injured
and/or septic patients.
○ Management of such patients is optimized w/ the use of evidence-based
algorithm-driven therapy.
○ Nutritional assessments, whether clinical or laboratory guided, and
intervention should be considered at an early juncture in all surgical and
critically ill patients.
○ Excessive feeding should be avoided in an effort to limit complications
including ventilator-dependency, aspiration events, and infections.

SIRS
● 2 phases:
○ Pro-inflammatory phase
○ Anti-inflammatory phase - to modulate inflammatory response
● Coordinated pro and anti-inflammatory phases direct a return to homeostasis.
● Temp: >38 or <36
● HR >90bpm
● RR >20
● WBC <4000 or >12000

Response to injury (Autonomic or CNS, Hormonal, Cellular)

I. Autonomic
● CNS orchestrates inflammatory response.
● CNS influences many organs via neurohormonal (i.e. Vasopressin) or
endocrine signals (i.e. CRH --> ACTH --> Cortisol)
● CNS -----------------------> many organs (resulting to i.e. fever, anorexia,
inflammatory response)
● Afferent sensory signal comes from vagus nerve
 ○ Vagus ---------> CNS --------> Many organs
● Vagus nerve exerts homeostatic influences also including enhancing gut
motility, reducing HR, and regulating inflammation. This is called Cholinergic
anti-inflammatory pathway.
○ PNS ---> vagus nerve (sensory) ----> CNS ---> vagus nerve (motor) --->
organs
○ This allows for rapid response to inflammatory stimuli and also for
potential regulation of early pro-inflammatory mediator release such as
TNF.
○ In the presence of systemic inflammation, vagus nerve may inhibit
cytokine release and reduce injury from diseases like pancreatitis,
ischemia and reperfusion injury via Nicotinic Ach receptor.
○ Studies shown that patient undergone vagotomy have enhanced
inflammatory profiles.

II. Hormonal Response to Injury

● Hormones are released to modulate functions of target cells.
● Hormone receptors are present on or within the cell and allows signal
transduction intracellularly via 3 major pathways:
○ Receptor kinases - IGF receptors, insulin receptors
○ G-protein receptors - neurotransmitters, prostaglandin receptors
○ Ligand-gated ion channels - permits ion transport when activated
● On activation of hormone receptors, signal is then amplified thru secondary
signaling molecules leading to downstream effects such as protein synthesis
and mediator release.
● ACTH release follows circadian rhythms but during stress or injury it becomes
blunted.
○ ACTH release is directly proportional to severity of injury
○ Triggers: CRH, pain, anxiety, vasopressin, Angiotensin II, Cholecystokinin,
VIP, Catecholamines, and proinflammatory cytokines.

● 1. Cortisol is released in response to ACTH (in times of stress)

○ potentiates actions of glucagon and epinephrine ---> hyperglycemia
○ Decreases glycogenesis, increases gluconeogenesis
◆ protein catabolism in skeletal muscles
◆ lactate and AA are recycled by liver in gluconeogenesis
◆ fats catabolism
◆ FA, glycerol, and TG release in adipose tissues (for energy stores)
○ Impaired wound healing
◆ bec TGF-B and IGF-I is decreased d/t acquired GH resistance.
◆ 😎 Can be ameliorated by giving Vitamin A.

○ Immunosuppressive
◆ used in organ transplant etc.
 ○ Can induce immunologic changes/ Attenuates immune response
◆ Thymic involution
◆ Depression of CMI manifested as decreasing T-cells and NK cells killer
functions, decreasing T-cells production, delayed Hypersensitivity
response etc.
◆ Inhibits leucocyte migration (by dec adhesion molecules)
◆ Inhibits monocytes' intracellular killing function
◆ Inhibits neutrophil superoxide reactivity, suppresses chemotaxis.
◆ Macrophage MIF (migration-inhibiting factor) counter-regulates the
anti-inflammatory effects of cortisol.
◆ 😎 Cortisol augments biochemical processes (catabolism), attenuates
cellular immune responses and wound healing.

● 2. GH is decreased during critical illness

○ Usually Anabolic
○ Proteogenic, Lipolytic, insulin-resistance (hyperglycemia)
○ Primary (direct GH actions) and Secondary effect (upregulation of IGF-1
by liver)
◆ IGF effects:
◆ Proteogenic, Lipogenic, Glycogenic
◆ In adipose tissue: Lipolytic, inc. glucose uptake
◆ In skeletal muscle: Proteogenic, inc glucose uptake
○ 😎 😎 Critical illness is associated w/ acquired GH resistance and thus
decreased IGF-1. Thus, we have catabolic effects during critical illness.
○ Studies shown that giving GH during critical illness is associated w/ inc
mortality. Though unclear mechanism, it is thought to be d/t insulin
resistance and hyperglycemia brought about by GH.

● 3. Catecholamines inc during critical illness.

○ After injury, levels inc 2-3x lasting for 1-2days before going back to
baseline level.
○ Epinephrine:
◆ Hepatic gluconeogenic, glycogenolytic, lipolytic, proteolytic; thus,
hyperglycemia
◆ Insulin-resistance in skeletal muscle (Periphery)
◆ Inhibits release of inflammatory cytokines: TNF, IL1, IL6
◆ Enhances release of anti-inflammatory cytokine IL10.
◆ Inhibits leucocyte migration (like cortisol) resulting to neutrophilia and
lymphocytosis.
◆ Increases cardiac stress on pt during septic shock. Thus,
cardioprotective strategies (like giving BBlockers) for pts undergoing
surgery decreases cardiac-related deaths.
◆ 😎 Catecholamines augments catabolism but attenuates cell immune
 ◆

response via inc anti-inflam cytokines.

● 4. Aldosterone
● 5. Insulin
○ Hyperglycemia and insulin-resistance are HALLMARKS of critical
illness d/t catabolic effects of mediators such as: Catecholamines,
cortisol, glucagon, and GH.
○ Given to counteract the effects of hyperglycemia.
○ Anabolic
◆ hepatic glycogenesis, glycolysis, peripheral glucose uptake,
lipogenesis, proteogenesis.
○ Hyperglycemia results to immunosuppressive effects d/t:
◆ Glycosylation of Ig
◆ Dec. phagocytosis
◆ Dec. respiratory burst of monocytes
◆ Thus, insulin therapy is beneficial to avoid infectious complications
and dec mortality.

MEDIATORS OF INFLAMMATION
● 1. Acute phase proteins stimulated by IL-6.
○ a. Hepatic CRP - opsonin! marker of pro-inflammatory response during
ongoing infection or traumatic injury; unremarkable marker in the setting
of hepatic insufficiency.
○ b. Ferritin - binds and sequesters Iron to inhibit microbial scavenging.
○ c. Fibrinogen - coagulation factor; promotes endothelial repair.
Correlates w/ ESR (Coats RBC and makes it denser)
○ d. Hepcidin - prevents release of Iron bound to ferritin; anemia of chronic
disease
○ e. Serum Amyloid A (SAA) - prolonged elevation can lead to amyloidosis.
A protein that is misfolded and deposits to tissues.
○ f. **Transferrin - downregulated! Internalized by macrophages to
sequester Iron.
● 2. Cytokines
○ Protein signaling compounds mediating sequence of cellular response
(i.e. cell migration, DNA replication, cell turnover, immunocyte proliferation
etc.)
○ At local site of injury: Eradication of microorganism and promotion of
wound healing.
○ If exaggerated Pro-inflammatory cytokine release occurs may result to
hemodynamic instability (septic shock) and metabolic derangements
(muscle wasting)
○ Anti-inflammatory cytokines may also result to immunosuppression and
 ○
immune dysfunction since its an opposing force to pro-inflam cascade.
● 3. Heat-Shock Proteins
○ Intracellular proteins that are increased during times of stress (burn,
trauma, infection)
○ Protects cells from deleterious effects of traumatic stress.
○ Destroyed cells release HSP, and HSP alerts system of the tissue damage
○ For protein folding, protein targeting
○ Binds to both autologous and foreign proteins such as bacterial DNA and
endotoxin.
● 4. ROS
○ highly reactive d/t unpaired outer electron
○ 😎 damages cell thru oxidation of UFA of cell membranes
○ by-product of O2 metabolism and anaerobic processes
◆ Produced mainly in mitochondrial ETC, peroxisomes FA metabolism,
cytochrome p450 reactions, and oxidative burst of phagocytic cells.
○ 😎 Host cells are protected to ROS effects bec we have SOD, Hydrogen
peroxide, catalase, glutathione peroxidase. Enzymes are balanced w/ ROS
production but during times of stress or ischemia, enzymatic clearance
mechanisms are consumed, and eventually on restoration of perfusion
there will be imbalance thus leads to reperfusion injury.
● 5. Eicosanoids
○ Produced when Phospholipid (cell membrane) is oxidized into Arachidonic
Acid w/ Phospholipase A2. AA undergoes either COX or LOX to produce
different eicosanoids (i.e. PG, TX, LT, HETE)
○ They are not stored in cells! Only rapidly generated in response to:
◆ Stress like hypoxia, ischemia, tissue injury, LPS,
◆ Norepinephrine, vasopressin, Angiotensin II, bradykinin, serotonin,
Ach, cytokines, and histamine
○ Eicosanoids activation also leads to:
◆ Formation Lipoxin
◆ An anti-inflammatory compound that inhibits chemotaxis and
activates NF-KB
◆ Eicosanoids production are blocked by cortisol, NSAIDs, LT inhibitors
○ Functions:
◆ Neurotransmission
◆ Vasomotor regulation
◆ Immune cell regulation
◆ 😎 Generation of pro-inflammatory response w/ deleterious host
effects (Acute lung injury, Renal failure, Pancreatitis)
◆ LT - capillary leakage, leucocyte adherence, neutrophil activation,
bronchoconstriction, vasoconstriction
◆ Metabolic effects
◆ COX inhibits insulin release by B-cells
 LOX stimulates insulin release by B-cells
◆
PGE2 inhibits gluconeogenesis and inhibits hormone-stimulated
◆
lipolysis
● 6. Fatty Acid Metabolites
○ Omega-3-FA have specific anti-inflammatory effects
◆ inhibition of NF-KB
◆ Inhibition of TNF release from Kupffer cells
◆ inhibits leucocyte adhesion and migration
○ Used in chronic AI diseases such as RA, SLE, Psoriasis etc.
● 7. 😎 Kallikrein-Kinin System
○ Group of proteins that contribute to inflammation, bp control, coagulation,
and pain responses.
○ Pre-Kallikrein -----> Kallikrein (protease that participates in coag'n
cascade)
◆ Stimulated by (+)Hageman factor, Trypsin, Plasmin, factor XI, Collagen
○ HMWK -----> Bradykinin
◆ Stimulated by Kallikrein
○ Kinins (Bradykinin and Kallikrein)
◆ vasodilation
◆ inc capillary permeability
◆ tissue edema
◆ pain pathway activation
◆ inhibition of gluconeogenesis
◆ inc bronchoconstriction
◆ Inc renal vasodilation thus renal perfusion pressure reduction
◆ leads to activation of RAAS
○ 😎 😎 Kinins are inc during gram-negative bacteremia, hemorrhage,
hypotension and tissue injury.
◆ Elevation is directly proportional to magnitude or severity of injury.
◆ One of the culprits in Septic Shock together with anaphylotoxins in
complement system.
 ● 8. Serotonin
○ synthesized by neurons, GI tract, and platelets
○ Pro-inflammatory
◆ increases production of TNF and IL-1
○ stimulates vasoconstriction, bronchoconstriction, platelet aggregation
○ Released by platelets at site of injury
● 9. Histamine
○ synthesized by decarboxylation of Histidine
○ 4 Histamine Receptor types
◆ H1: mediates vasodilation, intestinal motility, bronchoconstriction,
myocardial contractility
◆ H2: gastric parietal cell
◆ H3: down-regulation of histamine release
◆ H4: found in bone marrow, eosinophils, and mast cells

CYTOKINES RESPONSE TO INJURY

h. TNF
● A cytokine that is rapidly mobilized during stressors such as injury or infection
● A potent mediator of subsequent inflammatory response
● Synthesized by macrophages, monocytes, and T-cells (which are abundant in
●
peritoneum and splanchnic tissues)
● At high doses, associated w/ hemodynamic compromise.
○ At low dose, combined w/ low dose IL-1 , leads to hemodynamic
compromise also.
● Function:
○ Stimulates muscle breakdown and cachexia through inc catabolism and
insulin resistance.
○ Mediates coagulation activation
○ Expression of adhesion molecules, PGE2, glucocorticoids, eicosanoids
● 2 receptors
○ TNFR-1: found on all tissues! mediates apoptosis
○ TNFR-2: found on immunocytes! leads to NF-KB activation thus
amplification of inflammatory signals.

i. IL-1
● mediates inflammatory sequence similar to TNF
● Released in response to other cytokines (TNF, IL-2, IFN-Y), foreign substances
● At high doses, Associated w/ hemodynamic compromise
○ At low dose, combined w/ low dose IL-1 , leads to hemodynamic
compromise also.
● Acts on hypothalamus to stimulate PG to cause fever

j. IL-2
● Upregulated in response to IL-1
● Promoter of T-cell proliferation and differentiation, Ig production.
● Binds to its receptor located on leucocytes.
○ IL-2R blockade induces immunosuppression thus is used in organ
transplantation.

k. IL-4
● Released by activated T-Helper cells.
● Stimulates T-cell differentiation (TH0 --> TH2), proliferation of T-cells and
B-cell activation
● Induces class switching to produce IgG and IgE (for helminthic and allergic
reaction)

l. IL-5
○ Released by activated T-Helper cells
○ Stimulates differentiation of Tcells, proliferation of Tcells and Bcell
activation
○ Induces class switching to produce IgA.

m. IL-6
 ● Inhibits TNF and IL-1 (to counter-regulate inflammatory response)
● Activates acute phase reactants (APRs)

o. IL-8
● stimulates release of IFN-Y; powerful chemoattractant for Neutrophils
(together w/ C5a, LTB4, C3a)

p. IL-10
● anti-inflammatory; inhibits secretion of pro-inflammatory cytokines (TNF
and IL-1) by down-regulation of NF-KB

q. IL-12
● Regulator of CMI; stimulates lymphocytes to inc secretion of IFN-Y
● stimulates NK cell and T-cell differentiation (TH0 --> TH1)
● Its release is inhibited by IL-10.

hr. IL-15
● Potent inhibitor of lymphocyte apoptosis (by enhancing Bcl2 expression
which is an anti-apoptotic molecule)

hh. Interferons
● inhibits viral replication thru activations of antiviral genes.
● Type 1: IFN-A, IFN-B, and IFN-w (omega)
○ Adaptive immune response
◆ induces maturation of dendritic cells
◆ MHC-I expression
◆ Inc cytotoxicity of NK cells
● Type 2: IFN-Y
○ secreted by T-cells, NK cells, APCs in response to bacterial antigens, IL2,
IL12.
○ Activates JAK/STAT pathway --> subsequent induction of biologic
responses
◆ enhances phagocytosis and microbial killing of macrophages, inc
release of ROS

SUMMARY:
Hot T-bone stEAK
IL-1 = Fever (hot)
IL-2 = stimulates Tcells
IL-3 = stimulates bone marrow
IL-4 = igE production
IL-5 = IgA production
IL-6 = aKute phase protein production
C3a, C4a, C5a = SRSA (slow reacting substance of anaphylaxis)
C3b and IgG = opsonins
IL8, LTB4, C5a, microbial products = neutrophil chemoattractants
IL-10 vs IFN-Y
TH1 vs TH2

● Macrophages secretion: To induce inflammatory response

○ IL-1 and TNF-A
○ IL-6 to (+) APRs
○ IL-8 (chemoattractant)
○ IL-12 (for TH0 to differentiate to TH1; whatever is needed between TH1 or
TH2); IFN-Y secretion
○ IL-4 (for TH0 to differentiate to TH2; whatever is needed between TH1 or
TH2); IL-4,5,10 secretion
● NK cells secretion:
○ IFN-Y (recruits and activates NK cells and mø to phagocytose virus;
inhibits TH2)
● TH1 secretion (TH1 > TH2 during acute infection, bacterial infection, virus
infection)
○ IL-2 (for TH1 proliferation)
○ IFN-Y (stimulates macrophages and CD8 to phagocytose bacteria and
virus respectively; inhibits TH2)
● TH2 secretion (TH2 > TH1 during parasitic infection, mucosal infection,
chronic infection etc)
○ IL-4 (class switching to IgG and IgE)
○ IL-5 (class switching to IgA)
○ IL-10 (inhibits TH1)
● All T-cells secretion:
○ IL-2 (stimulates growth of TH0, CD8, T-regs, and NK cells)
○ IL-3 (stimulates bone marrow for growth and differentiation of BM stem
cells)
● During Adaptive immunity:
○ APC (dendritic cells, macrophages) are activated when lymphocytes (TH0
or CD4 in general) and APCs interact leading to series of growth,
differentiation, activation of immunes cells.
○ Macrophage-Lymphocyte interaction leads to secretion of IL-12 to make
TH1. TH1 secretes IFN-Y to activate many macrophages thus adaptive
immunity.
◆ APC has MHC II
◆ Lymphocyte has CD4
III. CELLULAR RESPONSE TO INJURY
● 1. Gene expression and Gene regulation
○ Gene regulation
◆ Transcription, mRNA processing, protein packaging
● 2. Cell Signaling Pathways
○ G-protein Receptors
◆ Transmembrane receptors where ligand binds to and results to signal
transduction during inflammatory response.
◆ Conformational change of receptors --> activation of 2nd messengers
(cAMP or Calcium) --> response
◆ cAMP - activates Protein Kinase A
◆ Ca - activates Phospholipase C
○ Ligand-Gated Ion channels
◆ Transmembrane receptors allowing rapid influx of ions (Na, Ca, K)
upon ligand binding converting that chemical signal to electrical
signals
◆ Essential in signal transduction of neurotransmitters.
○ Receptor Tyrosine Kinases (RTKs)
◆ Transmembrane receptors involved in cell signaling of Growth
Factors (PDGF, IGF, EDGF, VEGF)
◆ Dimerization of receptors --> autophosphorylation --> recruitment of
2nd signal molecules (i.e Phospholipase C)
 ◆ Activation of this is needed in gene transcription and cell proliferation
◆ 😎 😎 Associated w/ development of cancers

○ JAK/STAT (Janus Kinase/Signal Transducer and Activator of

Transcription)
◆ mediates signal transduction of several cytokines (IFN-Y, IL6, IL10,
IL12).
◆ Cytokines binds to JAK --> Dimerization --> autophosphorylation of
STAT --> STAT dimerizes and goes to nucleus --> transcription
◆ 😎 😎 Its a rapid pathway for membrane to nucleus signal transduction

○ MAPK (Mitogen-Activated Protein Kinases)

◆ Pathways using MAPK contribute to inflammatory signaling and
regulation of cell proliferation and cell death.
◆ It involves sequential stages of mediator phosphorylation resulting to
activation of downstream effectors (i.e. c-JUN, JNK, ERK etc)
○ NF-KB (Nuclear Factor Kappa Beta)
◆ a transcription factor that regulates gene products expressed after
inflammatory stimuli.
◆ 😎 It is tonically inhibited by I-KB (Inhibitor of KB). I-KB is degraded

during inflammatory process liberating/yielding NF-KB free.

◆ NFKB resides in cytosol --> goes to nucleus --> stimulates gene
expression
○ 😎 TLR and CD14 (cell surface receptor; marker of monocyte and
macrophage)
◆ TLR's, found in immunocytes, are receptors that recognizes PAMPs
(Pathogen associated Molecular patterns- such as LPS, endotoxin,
microbial pathogens.)
◆ Innate immune system responds to PAMPs when
◆ TLR/CD14 complex when bound to a PAMP activates cell mechanisms
like MAPK, NFKB, Cytokine gene expression.
◆ TLR4 = recognizes LPS of gm-
◆ TLR2 =recognizes gm+
◆ TLR loss of function results to inc risk of infection in critically-ill
patients.
○ 😎 Markers:
◆ APC/Macrophages: CD14, CD40, B7(co-stimulatory), MHC II (binds to
underlined markers below)
◆ T-helper: CD4, CD40L, CD28(co-stimulatory), TCR
◆ Cytotoxic Tcell: CD8
◆ B-cells: CD19, CD20, CD21
◆ NK cells: CD16, CD56
◆ HSC: CD34
Cell-Mediated Inflammatory Response
h. Platelets
● Contains mediators for inflammatory signals (chemoattractants) and
coagulation
○ Released by platelets: Serotonin, PAF, PGE2
◆ Responsible for migration of neutrophils and monocytes to sites of
injury; occurs within 3hours of injury
● 😎 Hallmark of septic response: Thrombocytopenia :D

i. Lymphocytes
● T-cells, B-cells, NK cells
● Recruited to sites of injury
● T-cells
○ TH1 - Cellular response; secretes IFN-Y, IL-2 and 12; defense against
bacterial pathogens however 😎 during severe trauma or sepsis TH2 >
TH1 resulting to exacerbation of immune dysregulation.
○ TH2 - Humoral response; secretes IL-4,5,6,9, and 10
○ 😎 T-regs (T-Regulatory cells) - predominant in burn injury to inc TGF-B

for wound healing. But downside is it inhibits T-cells function (since TH0 is
directed towards more Tregs than TH1 or TH2 differentiation) thus
immunosuppression in burn pts. (REASON WHY BURN PATIENTS ARE
IMMUNOSUPPRESSED OTHER THAN THE REASON OF LOSS OF SKIN AS
BARRIER)
○ Nutritional supplementation to enhance T-cell function and production is
diet rich in Arginine.

j. Eosinophils
● anti-helminthic
● activated by IL-3, IL-5, GM-CSF, PAF, chemoattractants.
● Results to release of: ROS, Histamine, Peroxidase.

k. Mast Cells
● Located in tissues so they are important in primary response to injury
● Releases TNF to recruit neutrophils to site of injury.
● Produces histamine, cytokines, eicosanoids, proteases, and chemokines on
activation following allergen binding, infection, or trauma.

l. Monocytes
● Found in blood; goes to tissues and transforms into Macrophage, osteoclast,
and dendritic cells.
● Macrophages are the main effector cells of immune response!
○ Phagocytosis
○ Release of inflam mediators
 ○ clearance of apoptotic cells

m. Neutrophils
● Among first responders to sites of infection and injury
○ Macrophages releases IL-1 and TNF to recruit inflammatory cells.
Neutrophils are one of the first responders there.
● Potent mediators of acute inflammation
● Activated by TNF, IL-1, and other inflammatory stimuli.
● Phagocytoses, releases lytic enzymes, generates large amts of ROS.

Endothelium-Mediated Injury Response

h. Vascular Endothelium
● Has anti-coagulant properties
○ Innate production of Heparin sulfate, Dermatan Sulfate, Tissue factor
pathway inhibitor, Protein S, Thrombomodulin, Plasminogen, and tPA
● Function as barrier to circulating cells
● Shifts to pro-coagulant property during Sepsis via decreased anticoagulant
factors leading to microthrombosis and organ injury.

i. Neutrophil-Endothelium Interaction
● During inflammatory response, immunocyte migration to site of injury is d/t:
○ Increased vascular permeability
○ Chemoattractants
○ Increased endothelial adhesion molecules (Selectins)
● Prolonged activation of neutrophils can lead to further tissue injury d/t
massive production of toxic ROS and lysosomal enzymes (that degrades
basement membranes and activates MPO)

j. Nitric Oxide (NO)

● aka EDRF; expressed in endothelial cells; stimulated by NO synthase
○ NO synthase is up-regulated during inflammation
○ 😎 one of the reasons behind hypotension in septic shock

◆ Together with anaphylotoxins (SRSA) and kinins.

○ However, NOS inhibitor drug results to more organ dysfunction
● Smooth muscle relaxation (vasodilator)
● Decreases platelet adhesion and aggregation

k. Prostacyclin (PGI2)
● Vasodilator and inhibits platelet aggregation
● impaired during systemic inflammation thus making endothelium more pro-
coagulant
 l. Endothelins (ET)
● vasoconstrictor; ET-1 is the most potent! (10x more potent than Angiotensin
II)
● Upregulated in response to hypotension, LPS, injury, thrombin, TGF-B, IL1,
Angiotensin II, Vasopressin, Catecholamines, and anoxia.
● Very little is stored in endothelial cells. Upregulation is basically a
transcriptional process.
● Contributes to pulmonary abnormalities during sepsis as it inc pulmonary
vascular resistance leading to pulmonary edema. May compromise tissue
oxygenation at higher concentration.
● Levels in plasma correlates severity of injury or infection.

m. Platelet-Activating Factor (PAF)

● natural constituent of cell membrane
● also Released by platelets, neutrophils, mast cells, and monocytes during
acute inflammation
● Further activate neutrophils and platelets and increases vascular
permeability.

o. Atrial-Natriuretic Peptide (ANP)

● Released by atrial tissue, but also synthesized by kidney, brain, gut, adrenal
glands, and endothelium.
● Potent inhibitor of Aldosterone

SURGICAL METABOLISM
I. Metabolism During Fasting
● To Maintain our Basal metabolic needs, our body utilizes 😎 22-25kcal/kg/day
of energy from CHO, Protein and fats.
○ 40kcal/kg/day - Burn patients
○ 30kcal/kg/day - post-surgical patients
● Normal adult body contains:
○ 400g of Glycogen
◆ 100g of Glycogen - stored in liver; are utilized and depleted within
16hrs of fasting via glycogenolysis)
◆ 300g of Glycogen - stored in skeletal, cardiac, and smooth muscle;
are NOT readily available for systemic use bec we lack G6Pase. Thus,
We need other sources of glucose from gluconeogenesis when liver
stores of glycogen is depleted.
◆ One of which is AA and lactate release from protein catabolism.
○ 6kgs of Protein (in a healthy 70kg person; 8-9% of TBW) (70kgs x 0.08 =
6.3kgs)
 ◆ 4kcal/g x 6kgs = 24,000kcal (enough to sustain us for 12days if you
are to maintain 25kcal/kg/day if you are 80kgs which is 2000kcal/day)
○ 12kgs of Fats (in a healthy 80kg person; 17-18% of TBW)
◆ 9kcal/g x 12,000g (12kgs) = 108,000kcal (enough to sustain us for
54days)
● 😎 During Fasting:

○ 100g Glycogen - utilized and depleted within 16hrs (short-term fasting)

○ 6000g Protein - utilized after 16hrs; can make us alive for 12 more days
without eating.
○ 12000g Fats - utilized after 16hrs; can make us alive for 54 more days
without eating.
● A. During short-term fasting (<5days): Our body uses 180g/day of glucose
to support the highly glycolytic cells in our body for us to still function during
fasting (RBC, WBC, Renal medulla, neurons). This glucose comes from:
○ a. Hepatic glycogenolysis (100g of glycogen from liver storage)
○ b. Hepatic gluconeogenesis
◆ Recycling of Lactate and pyruvate from utilization of glucose by highly
glycolytic cells (Cori Cycle)
◆ Proteins of muscles
◆ AA from protein such as Alanine and Glutamine
◆ 75g/day of Protein should be degraded to provide for AA
substrate for hepatic gluconeogenesis, thus muscle wasting.
◆ Fats of Adipose tissues
◆ Mobilization of lipid stores for energy decreases rate of glycolysis,
gluconeogenesis, proteolysis
◆ Glycerol from Fats (Fats = Glycerol + FFA; other FFA or excess FFA
will be converted to ketones during prolonged starvation)
◆ 160g/day of fats should be degraded to provide glycerol and FFA
for hepatic gluconeogenesis and ketone production.
● In prolonged starvation (>5days): Ketones (from FFA) are eventually used as
vital organs started to adapt to the situation (ketoadaptation). Renal
gluconeogenesis also occurs.
○ Systemic proteolysis is reduced!
○ Ketones are the most impt fuel source for the brain after 2 days of fasting
○ Principal fuel source of the brain by 24days
○ Ketones are used by heart, kidney, and muscle
◆ Ketones are used by many tissues but not liver :(
◆ Ketosis occurs when liver production of ketones exceeds utilization of
ketones by extra-hepatic tissues
◆ Rate of Ketogenesis is inversely proportional to severity of injury
◆ This is bec of during major trauma, sepsis or infection, there is
insulin resistance --> inc insulin levels --> rapid FA beta oxidation
--> less ketones are produced.
 ○Ketones spare utilization of glucose by inhibiting pyruvate dehydrogenase
○Kidney uses glutamine and glutamate (AA substrate from muscle
proteolysis) for gluconeogenesis providing 50% of glucose source during
prolonged starvation.
● Summary:
○ During starvation
◆ Liver glycogen stores
◆ Liver gluconeogenesis (from muscle proteins, fats, Cori Cycle)
◆ AA (Pyruvate and Glutamate) from muscles
◆ Lactate from muscles are recycled
◆ FA beta-oxidation
◆ 😎 Ketone production (occurs when Acetyl CoA cant enter Krebs

when glucose are depleted since TCA intermediates are already

consumed during prolonged starvation); less to occur in patients
w/ critical illness, trauma or infection because of insulin-
resistance leading to high levels of insulin.
◆ High insulin promotes FA oxidation
◆ Low insulin promotes Ketogenesis
◆ Ketosis usually found in T1DM and prolonged starvation.
◆ Renal gluconeogenesis during prolonged starvation

II. Metabolism After Injury/Trauma

● Magnitude of metabolic expenditure is directly proportional to severity of
injury (highest demand is severe infections and thermal injuries). 😎 Lipids
become the primary source of energy during critical illness and stressed
states.
● 1. Lipid Metabolism (EPINEPHRINE and TNF)
○ Primary source of energy (around 50-80%) during critical illness and
after injury is Fats! (Triglycerides). Mostly coming from exogenous source
(diet)
◆ Bec integrity of cell membranes are compromised
◆ Bec Catecholamines are increased leading to inc activity of HSL
(cleaves Triglycerides)
◆ Other hormones increased such as ACTH, thyroid hormone,
cortisol, glucagon, GH, and dec in insulin.
◆ Bec LPL is inhibited by TNF during trauma or sepsis (thus, decreasing
TG synthesis)
○ Dietary TG are degraded and re-synthesized inside enterocyte to form
chylomicron; those w/ short chain FA directly goes to portal circulation.
● 2. Carbohydrate Metabolism
○ Glucose and Galactose are absorbed with Na (active transport) while
Fructose is via facilitated diffusion. Neither galactose, fructose, or
mannitol evokes insulin response.
 ○ In starvation, glucose production occurs in expense of protein, thus,
muscle wasting. Our goal during maintenance period is to administer small
amounts of glucose daily to spare muscles for wasting (proteolysis), and
also to dec ketogenesis by sparing TCA intermediates to be used for
gluconeogenesis. 😎 This is not the case during injury or trauma where
muscle wasting is inevitable. However, administration of insulin
decreases proteolysis, instead it promotes proteogenesis.
○ During injury or severe infection, 😎 peripheral glucose intolerance
ensues leading to hyperglycemia despite insulin administration.
◆ Bec skeletal muscle's pyruvate dehydrogenase is reduced during
stressed states
◆ Pyruvate cant enter TCA leading to shunting to liver for
gluconeogenesis
◆ 😎 This mechanism is to make glucose available for essential/vital

organs (including nervous tissues, wbc, rbc) during stressed

states and not to go to skeletal muscles and adipose tissues (d/t
catecholamines)
◆ Inc plasma glucose concentration is directly proportional to
severity of injury
◆ Glycogen stored in skeletal muscles are mobilized and converted
to G6P by series of steps in glycogenolysis. This is mediated by
epinephrine.
○ Glucose are transported into cells via GLUT (facilitated diffusion) or SGLT
(secondary active transport; found in PCT and intestinal lumen)
◆ These transporters are packaged into vesicles; and with insulin, these
vesicles dock into cell surface.
◆ 😎 GLUT 4 are primary transporter of insulin-sensitive tissues. It's

function has impt implications in Type2 DM patients.

◆ GLUT 4: skeletal muscle, heart muscle, adipose tissue.
● 3. Protein Metabolism (CORTISOL!)
○ Every 6g of protein, yields 1g of Nitrogen
○ After injury, systemic 😎 proteolysis occurs mediated by cortisol.
Proteolysis occurs to produce substrates (AA) for gluconeogenesis
◆ 😎 1.5% lean body mass (muscle protein) is loss every day during

stressed states
◆ For example, 10days of no nutrition leads to 15% weight loss during
stressed states
○ Ubiquitin-proteosome pathway is the major pathway for protein
degradation in muscle cells during acute injury.
◆ It is accelerated by elevated cortisol, insulin resistance, tissue
hypoxia, and acidosis.
● SUMMARY:
 ○Hyperglycemia
◆ D/t insulin resistance caused by cortisol, dec glucagon,
catecholamines
◆ Dec pyruvate dehydrogenase (to reserve glucose to be used by vital
organs)
○ Muscle wasting
◆ Starvation: D/t to no available glucose, thus muscle breakdown.
◆ Tx: Give glucose
◆ Injury/Stress/Trauma: D/t cortisol leading to proteolysis; also d/t TNF
and IL-1
◆ Tx: insulin to promote gluconeogenesis
○ Lipolysis
◆ D/t catecholamines that increases HSL thus lipolysis
◆ D/t TNF that inhibits LPL thus dec lipogenesis
● Refeeding Syndrome
○ Potentially lethal condition that can occur w/ rapid excessive feeding of
patients w/ underlying severe malnutrition d/t starvation, alcoholism,
delayed nutritional support, anorexia nervosa, or massive weight loss in
obese patients.
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◆ 2-48hrs after injury
◆ Characterized by Shock (resulting to hypovolemia) and reduced REE
◆ Tx during this time:
◆ Restore blood flow
◆ Stop all bleeding
◆ Maintain tissue oxygenation
○ b. Flow Phase (Catabolism)
◆ Phase when patient is hemodynamically stable.
◆ Phase of hypermetabolism and catabolism (resulting to altered
immune and hormonal response)
○ c. Recovery Phase (Anabolism)
◆ Return to anabolism and normal metabolic state

SUMMARY:
 ● Our body utilizes glycogen, fats, protein (in order) during starvation and
critical illness
● Muscle wasting is inevitable during stress, trauma injury, infection even with
glucose maintenance.
○ Tx: Glucose + protein (or insulin alone to favor proteogenesis than
proteolysis)
● Muscle wasting is preventable during starvation by giving glucose.
● Primary source of energy are Fats.
○ Ketosis occurs if insulin is decreased. Example: Type1DM, prolonged
starvation. Acetyl Coa from FA oxidation converts to Ketones when all
glucose and TCA intermediates are depleted.
○ Ketosis does not occur if insulin is increased. Example: T2DM, insulin-
resistance during critical illness, trauma, sepsis. Acetyl Coa from FA
oxidation can enter Krebs since glucose is still present inside the cell
● Glucose intolerance during critical illness, trauma, or infection is d/t:
○ Hormones that makes us insulin-resistant i.e. Cortisol, epinephrine,
glucagon.
○ Dec activity of Pyruvate dehydrogenase in skeletal muscle (to make
glucose available in needed areas) thus shunting Pyruvate to liver for
gluconeogenesis.

NUTRITION IN SURGICAL PATIENTS

● Vitamins and Minerals
○ Not given in post-op patients in the absence of pre-operative deficiency.
○ Given in patients on parenteral hyperalimentation.
● Overfeeding
○ May contribute to post-op patients' deterioration via inc oxygen
consumption, inc CO2 production, prolonged need for ventilatory support,
fatty liver, hyperglycemia, suppression of wbc function, and inc risk of
infection.
● I. Enteral Nutrition
○ Rationale:
◆ Better than parenteral nutrition
◆ Less expensive
◆ Luminal nutrient contact decreases intestinal mucosal atrophy
◆ Reduced infectious complications bec no IV route
○ Enteral Formula (depends on the extent of organ dysfunction, and
nutrients needed for optimal function and healing):
◆ a. Low-Residue-Isotonic (LRI) Formula or Isotonic Formula w/o
Fiber
◆ First-line formula for stable patients w/ intact GIT
 ◆ Provides 1kcal/ml; usually needs 1800mL to meet daily
requirements
◆ Provides baseline carbohydrates, protein, fat, electrolytes, and
water
◆ It has no fiber thus leaves minimum residue inside the colon.
◆
◆ 😎 **Non-fiber diet helps in post-op bowel surg patient bec it
leaves minimum residue to colon thus less irritating to GIT.
◆ b. Isotonic Formula w/ Fiber
◆ Contains soluble and insoluble fiber that delays intestinal transit
time
◆ Usually Soy-based
◆ Lower chance of diarrhea compared to non-fiber formula
◆ Colonocytes needs to be fueled up to be able to do its function.
Fiber solutions are degraded by gut bacteria liberating short-
chain FA that is used as fuel for colonocytes.
◆ 😎 **Fiber adds up bulk to the stool.
◆ In case of diarrhea or loose watery stool, soluble fiber delays
transit time and absorbs the water from the stool (sponge
effect)
◆ In case of constipation d/t narrow lumen, hard stool etc,
insoluble fiber helps by adding bulk to stool pulling water from
colon to soften stool thus easy passage of stool.
◆ c. Immune-Enhancing Formula
◆ Contains Arginine, Glutamine, Branched-chain AA, Omega-3 FA,
nucleotides, and Beta carotene
◆ d. Calorie-Dense Formula
◆ Provides 1.5-2kcal/mL; thus, used in patients that has fluid
restrictions or unable to tolerate large fluid infusions
parenterally.
◆ e. High-Protein Formula
◆ Proposed for critically ill or trauma patients w/ high protein
requirements.
◆ Probably to patients already have muscle wasting
◆ f. Elemental Formula
◆ Contents:
◆ Pre-digested nutrients predominantly proteins in the form
of small peptides. (i.e. Peptamen)
◆ Less in complex carbohydrates, fats, vitamins, and trace
elements
◆ Expensive
◆ Use in patients w/ malabsorption, gut impairment, and
pancreatitis
 ◆ g. Renal Formula
◆ Contents:
◆ Less fluid volume
◆ Less concentrations of K, P, and Mg (those that are renally
excreted)
◆ No Trace elements or Vitamins
◆ Contains essential AA
◆ Pulmonary-Failure Formula
◆ Contents:
◆ Reduced carbohydrates and Increased Fat up to 50%
◆ Goal is to reduce CO2 production and alleviate ventilation
burden of failing lungs
◆ Carbohydrates --> Glucose --> Inc O2 consumption --> Inc
CO2 production --> Inc Ventilation
◆ Hepatic-Failure Formula
◆ Contents:
◆ Inc. branched-chain AA
◆ Protein restriction
◆ Goal is to reduce aromatic AA levels and 😎 inc
branched-chain AA (BCAA - Valine Isoleucine Leucine)
◆ 😎 BCAA helps detoxify ammonia in skeletal muscles

via amidation process.

◆ 😎 Tx for Encephalopathy includes:

◆ BCAA supplementation
◆ Lactulose acidifies colon to convert ammonia (NH3) to
ammonium (NH4+) which is excretable.
◆ Lactulose is fermented by gut bacteria to produce Acetic
acid or Lactic acid.
○ Access
◆ NasoEnteric Tubes
◆ NGT is indicated to patients w/ decreased mentation and dec
laryngeal reflexes (to minimize aspiration)
◆ NasoJejunal route (NJT) has fewer pulmonary complications
(aspiration) compared to NGT
◆ Small-bowel feeding is more reliable for delivering nutrition
compared to NGT
◆😎 Done if patient feeding will not go longer than 30days.
Otherwise, use percutaneous routes.
◆ Percutaneous Endoscopic Gastrostomy (PEG)
◆ Tube is placed into stomach w/ endoscopic guidance; Use for
feeding and/or decompression.
◆ MC indications:
 ◆ Impaired swallowing mechanism
◆ Oropharyngeal or esophageal obstruction
◆ Major facial trauma
◆ Used for:
◆ Debilitated patients who uses oral route frequently but can
hardly be fed or taken care of
◆ For patients who needs passive gastric decompression (bec
PEG may be attached to a drainage bag to decompress
stomach)
◆ Contraindications:
◆ Ascites, Coagulopathy, Gastric varices, Gastric neoplasm, lack
of suitable abdominal site
◆ Complications:
◆ Wound infection, Necrotizing fasciitis, Peritonitis, Aspiration,
Leaks, Dislodgment, Bowel perforation, Enteric Fistulas,
Bleeding, Aspiration pneumonia
◆ Percutaneous Endoscopic Gastrostomy-Jejunostomy (PEG-J)
◆ Insertion of a new tube into the existing PEG tube and then go
past pylorus into duodenum
◆ Done past the pylorus
◆ Indicated to patients who cant tolerate gastric feedings or has
significant aspiration risks
◆ Direct Percutaneous Endoscopic Jejunostomy (DPEJ)
◆ Same method as PEG but directly inserting tube to extend into
jejunum.
◆ Less chance to malfunction than PEG-J
◆ If no endoscope is available, surgical jejunostomy can be done.
◆ Surgical Gastrostomy and Jejunostomy
◆ Indicated for patients w/ complex abdominal trauma or surgery
**NGT, NJT, PEG, DPEJ

**PEG-J
○ Complications of Early Enteral Nutrition
◆ Formula intolerance
◆ Abdominal cramps
◆ Pneumatosis intestinalis and Small bowel necrosis
◆ Risk factors: Hyperosmolarity of solutions, bacterial overgrowth,
 ◆
accumulation of metabolic products
◆ Pathophysiology: bowel distention --> bowel ischemia --> dec
bowel perfusion
◆ When complications arise, discontinue feeding until patient is
stabilized!
◆ Risk factors: Cardio and circulatory shock, vasopressor use, DM,
COPD
◆ 😎 Thus, delay the enteral nutrition until patient is adequately

resuscitated/stabilized. If delay not possible, dilute the standard

enteral formula.

● II. Parenteral Nutrition

○ 😎 Basic solution of: (compared to crystalloid IV with 5% dextrose)
◆ 15-25% dextrose and
◆ 3-5% crystalline Amino acids
○ Continuous infusion of hyperosmolar solution containing carbohydrates,
fats, proteins via indwelling catheter in SVC
○ 😎 Carbohydrates and Protein MUST be infused simultaneously bec if
not, there would be significant decrease in Nitrogen utilization (Negative
nitrogen balance)
◆ Positive Nitrogen Balance is needed to achieve growth and weight
gain.
◆ Positive Nitrogen balance occurs when more Protein is used in
growth than excreted after protein infusion.
○ Has higher risk of infectious complications than enteral feedings
(especially if use in a short-term basis <7days)
○ Indications:
◆ Malnutrition
◆ Sepsis
◆ Surgical or traumatic injury in a seriously-ill patient where GI feeding is
not possible
○ Goal of Enteral and Parenteral Nutrition: 😎 Provide sufficient Calories
and Nitrogen substrate to promote tissue repair and to maintain integrity
or growth of lean tissue mass.
◆ Positive nitrogen balance requires sufficient amount of calories and
Potassium.
○ 2 Types:
◆ 1. Total Parenteral Nutrition (TPN) aka Central Parenteral Nutrition
◆ Requires access using large-diameter vein to deliver entire
nutritional requirements; delivering large volume of solution
◆ Usually SVC
◆ Higher osmolarity solution
 ◆ Dextrose content here is high (15-20%); all other
macronutrients and micronutrients are deliverable here.
◆ Used for longer period of time (>2weeks)
◆ Suitable for severe malnutrition
◆ 2. Peripheral Parenteral Nutrition (PPN)
◆ Requires access via peripheral veins; delivers small volume of
solution
◆ Lower osmolarity solution
◆ Reduced level of dextrose (5-10%) and 3% protein
◆ Some nutrients cant be supplemented bec they cant be
concentrated in small volume.
◆ Used for short period of time (<2weeks)
◆ mild to moderate malnutrition
◆ Not appropriate for severe malnutrition patients unless TPN is
not available
○ Monitor
◆ Electrolyte imbalance - every 2-3days
◆ Acid-Base disorders
◆ Septic complications
◆ Urinary output
◆ Glucose level (urine and blood) - to add insulin? adjust infusion?
decrease dextrose solution?
◆ Vital signs
◆ Weight
◆ Blood counts, BUN, LFT, Phosphate, Mag - weekly basis

○ Prolonged Parenteral Nutrition

◆ Vitamin deficiencies
◆ i.e. Zn deficiency - eczematoid rash
◆ Trace Mineral Deficiencies
◆ Eczematoid rash
◆ Microcytic anemia - Glucose intolerance and Chromium
deficiency
◆ Vitamin K deficiency
◆ Should be supplemented on a weekly basis since Parenteral
solutions do not contain Vitamin K.
◆ Essential FA deficiency
◆ Scaly dermatitis, loss of hair
○ TPN should be accompanied w/ the infusion or administration of the
ff:
◆ Potassium
◆ Bec as glucose increases in plasma during TPN, hypokalemia
ensues as they are co-transported into the cells together.
 ◆ Also bec K is needed to achieve positive Nitrogen balance
◆Essential FA
◆ Bec majority of parenteral nutrition solutions does not contain
this.
○ TPN contains:
◆ Carbohydrates - to spare muscle proteins as source of energy during
starvation or acute injury.
◆ Proteins - to have Positive Nitrogen balance thus tissue repair, growth
and development, and weight gain.
○ Complications:
◆ Technical
◆ Sepsis secondary to contamination of central venous catheter
◆ Symptoms: Sudden dev't of glucose intolerance (wowo
temperature increase) in patient w/ no problem in
hyperalimentation previously. And removal of catheter results
to rapid defervescence within 1-2days. If fever continuous,
investigate for other source of infection, then reinsert the
catheter to opposite subclavian vein or IJV after 12-24hrs .
◆ Persistence of fever warrants removal of catheter to be
submitted for culture.
◆ Iatrogenic Injury d/t Placing i.e. PNX, hydrothorax, air embolism,
hemothorax, thoracic duct injury, arrhythmia, cardiac tamponade
◆ Metabolic
◆ Hyperglycemia if given too rapidly or patient has glucose
intolerance (T2DM)
◆ Tx: Volume replacement, correction of electrolyte imbalances,
and insulin
◆ Cholestasis and Gallstone formation
◆ Mild elevation of liver enzymes, AlkaPhos, and bilirubin
◆ Intestinal atrophy
◆ D/t lack of intestinal stimulation
◆ Tx: Provide some nutrition enterally
○ Special Formulations
◆ Glutamine
◆ Non-essential Amino Acid; 75% found in skeletal muscles and
lungs.
◆ 😎 Source of energy or fuel by immunocytes and enterocytes

during critical illness or trauma. Thus, Glutamine supplementation

enhances positive Nitrogen balance as well, like Potassium.
◆ Use for nucleotide synthesis of rapidly dividing cells like
enterocytes;
◆ Use as energy source of immunocytes (macrophages and
lymphocytes)
 ◆ Arginine
◆ Non-essential Amino Acid
◆
😎 Important in wound healing and has immuno-enhancing
property
◆ Results to Net Nitrogen excretion and Protein synthesis
◆ Omega-3 FA
◆ Reduces body's pro-inflammatory response during injury

SUMMARY:
● Positive Nitrogen Balance needs adequate Calorie:Protein ratio given
simultaneously and Potassium.
● Enteral Nutrition is the ideal route bec of less complications. Consider
Parenteral if Enteral is contraindicated.
○ Nasoenteric access is preferred to all patients unless contraindicated or if
nutrition will take <30days.
○ Percutaneous access is preferred if >30days nutrition required or if
nasoenteric access is not possible or contraindicated.
● Parenteral Nutrition
○ TPN is used if severe malnutrition or if <2weeks usage.
◆ Some of micronutrients and macronutrients cant be given through
PPN bec of small peripheral veins or needs large volume of infusion
which is only applicable in TPN.
○ PPN is used for less severe malnutrition or if >2weeks usage.
○ Supplements like EFA and K needed.
● Monitor patients response.
○ Give supplements as needed.
● WOF complications