Systemic Response to

Injury & Metabolic

Support
Schwartz 10th Ed Chapter 2

Josef S. Lim, MD, FPSGS, FPCS, PALES

 Overview
 SRIS: central feature of sepsis & trauma
 Occurs as a consequence of local/systemmic
realease of “Damage associated”/”pathogen
associated” molecules, using signaling pathways
for homeostasis.
 Keypoints
 Endogenous (DAMPs) are produced following
tissue and cellular injury.

 These molecules interact with immune and

nonimmune cell receptors to initiate a “sterile”
systemic inflammatory response following
severe traumatic injury.
 keypoints
 In many cases, DAMP molecules are sensed by
pattern recognition receptors (PRRs),
 which are the same receptors that cells use to
sense invading pathogens.
 This explains, in part, the similar clinical picture
of systemic inflammation observed in injured
and/or septic patients.
 keypoints
 The CNS receives information with regard to
injury-induced inflammation via soluble
mediators as well as direct neural projections
that transmit information to regulatory areas in
the brain.
 The resulting neuroendocrine reflex plays an
important modulatory role in the immune
response.
 keypoints
 Inflammatory signals activate key cellular stress
responses
(the oxidative stress response, the heat shock protein response,
the unfolded protein response, autophagy, and programmed cell
death)
which serve to mobilize cellular defenses and
resources in an attempt to restore homeostasis.
 keypoints
 the cells, mediators, signaling mechanisms, and
pathways that compose and regulate the SIR are
closely networked and tightly regulated by
transcriptional events as well as by epigenetic
mechanisms, posttranslational modification, and
microRNA synthesis.
 keypoints
 Nutritional assessments, whether clinical or
laboratory guided, and intervention should be
considered at an early juncture in all surgical and
critically ill patients.
 Management of critically ill and injured patients
is optimized with the use of evidence-based and
algorithm-driven therapy.
 THE DETECTION OF CELLULAR INJURY

 The Detection of Injury is Mediated by

Members of the Damage-Associated Molecular
Pattern Family
 Traumatic injury activates the immune system
to produce a systemic inflammatory response
to limit damage and to restore homeostasis.

2 general responses:
(a) an acute proinflammatory response resulting from
immune system recognition of ligands
(b) an anti- inflammatory response to modulate the
proinflammatory phase and return to
homeostasis

* Suppression of adaptive immunity

 Schematic diagram of SRIS
FIG 2-1
MOF

SIRS

R
E
C
OMOF
V
CARS E
R
Y
 The clinical features of the injury-mediated systemic
inflammatory response:
body temperature,
heart rate,
respirations,
WBC
are similar to those observed with infection
 Clinical Spectrum of SIRS TABLE2-1

 Infection  Sepsis
 Identifiable source of microbial  Infection + SIRS
insult

 SIRS = 2 or more:
 Severe Sepsis
 Temp ≥38˚C or ≤36˚C
 Sepsis + Organ Dysfunction
 HR ≥ 90 bpm
 RR ≥ 20 breaths/min or
PaCO2 ≤ 32 mmHg or
mechanical ventilation
 WBC ≥ 12,000/µL or ≤
 Septic Shock
4000/µL or ≥ 10% band forms  Sepsis + Cardiovascular Collapse
(requires vasopressors)
 Damage-associated molecular patterns (DAMPs)
and their receptors TABLE 2-2

DAMP MOLECULE PUTATIVE RECEPTOR(S)

HMGB1 TLRs (2,4,9), RAGE

Heat shock proteins TLR2, TLR4, CD40, CD14

S100 protein RAGE

Mitochondrial DNA TLR9

Hyaluronan TLR2, TLR4, CD44

Biglycan TLR2 and TLR4

Formyl peptides (mitochondrial) Formyl peptide receptor 1

IL-1  IL-1 receptor

 High-Mobility Group Protein B1.

 The best-characterized DAMP

 rapidly released into the circulation within 30

minutes ff trauma.
 DNA repair and transcription
 secreted from immune-competent cells
stimulated by PAMPs (e.g., endotoxin) or by
inflammatory cytokines (e.g., TNF & IL1)
 Excess HMGB1

 promote a self-injurious innate immune

response.
 exogenous administration of HMGB1 to normal
animals produces fever, weight loss, epithelial
barrier dysfunction, and even death.
 A Role for Mitochondrial DAMPs in the Injury-
Mediated Inflammatory Response

 can act as DAMPs by triggering an

inflammatory response to necrosis and cellular
stress.
 Specifically, the release of (mtDNA) and

formyl peptides from damaged mitochondria has

been implicated in activation of the macrophage
inflammasome a cytosolic signaling complex that responds to cellular stress.
 DAMPs Are Ligands for Pattern Recognition
Receptors

 classes of receptors that are important for

sensing damaged cells and cell debris are part of
the larger group of germline encoded (PRRs).
 4 distinct classes:
 Toll-Like Receptors,
 C-Type Lectin Receptors.
 Nucleotide-Binding Oligomerization Domain-Like ReceptorFamily.
 Soluble Pattern Recognition Molecules: The Pentraxins.
 TOLL LIKE RECEPTORS

 Best characterized PRRs in mammalian cells

 Drosophila – key component in defense against
fungal infection
 Expressed in both imune & non immune cells
 Significantly increased after Traumatic blunt
injury
 CENTRAL NERVOUS SYSTEM
REGULATION OF INFLAMMATION

 (CNS) communicates with the body through ordered

systems of sensory and motor neurons, which receive
information to generate a coordinated response.
 DAMPs and inflammatory molecules convey signals to
the CNS via multiples routes.
 inflammatory signaling molecules reach neurons and
glial cells through the fenestrated endothelium of the
circumventricular organs (CVO)

 or via a leaky blood brain barrier in pathologic settings

following a traumatic brain injury

 Inflammatory stimuli in the CNS result in behavioral

changes, such as increased sleep, lethargy, reduced
appetite, and the most common: fever.
CNS REGULATION OF INFLAMMATION
 Neuroendocrine Response to Injury

 Hypothalamic Pituitary-Adrenal Axis

Release of Glucocorticoids

 Sympathetic Nervous System

Cathecholamines, Epi & Norepinephrine
 HORMONES REGULATED BY THE HYPOTHALAMUS,
PITUITARY & ANS

 Hypothalamus: CRH, TRH, GHRH , LHRH

 Anterior Pituitary : ACTH, Cortisol, TSH,

Thyroxine, T3, GH, Gonadotrophins , Sex
hormones, Insulin-like growth factor , Somatostatin
, Prolactin, Endorphins

 Posterior Pituitary : Vasopressin, Oxytocin

 Autonomic System : Norepinephrine
, Epinephrine, Aldosterone

 Renin-Angiotensin System : Insulin, Glucagon

, Enkephalins
 Hypothalamic Pituitary Adrenal
Axis
 Releases CRH from the PVN.
 Mediated by circulating cytokines:

* Innate immune response:

(TNF, IL1B, IL6, Type 1 IFN a & B)
* Adaptive immune response:
(IL2, IFN d )
 HPA axis
 Direct neural input via afferent vagal fibers that
interconnect with neurons in the hypothalamus
can also trigger CRH release.

 CRH acts on the anterior pituitary to secrete

(ACTH) into the systemic circulation.

 pain, anxiety, vasopressin, angiotensin II,

cholecystokinin, ViP, and catecholamines all
contribute to ACTH release
 HPA Axis
 ACTH acts on the zona fasciculata of the
adrenal gland to synthesize and secrete
glucocorticoids.

 Cortisol : major glucocorticoid in humans

: essential for survival during significant
physiologic stress.
 Glucocorticoids
 Cortisol – elevated following injury,
 duration of elevation depends on severity of injury
 Potentiates hyperglycemia
 Hepatic gluconeogenesis
 Muscle and adipose tissue –> induces insulin
resistance
 Skeletal m.–> protein degradation, lactate release

 Adipose -> reduces release of TG, FFA, glycerol

 Adrenal insufficiency

 inadequate cortisol and aldosterone.

 atrophic adrenal glands fr exogenous steroid
administration who undergo a stressor such as
surgery.
 tachycardia, hypotension, weakness, nausea,
vomiting, and fever.

 Hypoglycemia , hyponatremia , hyperkalemia

 Exogenous administration
 Adrenal suppression in the acutely ill
 Acute Adrenal Insufficiency
 Atrophy of the adrenal glands
 Weakness, n/v, fever, hypotension
 Hypoglycemia, hyponatremia, hyperkalemia
 Exogenous administration
 Immunosuppression
 Thymic involution, decreased T-killer & NK fxn
graft vs host rxns, delayed hypersensitivity responses,
inability of monocyte intracellular killing,
inhibition of superoxide reactivity and chemotaxis in
neutrophils
 Down regulates pro-inflammatory cytokine
production (TNF-α, IL-1, IL-6)
 Increases anti-inflammatory mediator IL-10
 Useful in septic shock, surgical trauma, and CABG
 Adrenocorticotropic Hormone
 Synthesized anterior pituitary
 Regulated by circadian signals
 Pattern is dramatically altered in injured patients
 Elevation is proportional to injury severity
 Released by: pain, anxiety, vasopressin,
angiotensin II, cholecystokinin, catecholamines,
and pro-inflammatory cytokines
 ACTH signals increase glucocorticoid production
 Macrophage Inhibitory Factor
 Glucocorticoid antagonist
 produced by anterior pituitary & T-lymphocytes
 Reverses immunosuppressive effects of
glucocorticoids
 Potentiates G- and G+ septic shock
 Experimentally improves survival
 Growth Hormone
 During stress -> protein synth, fat mobilization,
and skeletal cartilage growth
 2˚ to release of insulin-like growth factor (IGF1)
 Injury reduces IGF1 levels
 IGF1 inhibited by pro-inflammatory cytokines
 TNF-α, IL-1α, IL-6
 GH admin to pediatric burn patients shows
improvement in their clinical course
 Ghrelin
 a natural ligand for the GH-secretagogue
receptor 1a (GHS-R1a)
 is an appetite stimulant secreted by the stomach.
 Expressed by immune cells, B and T cells, and
neutrophils.
 promote GH secretion ,glucose homeostasis,
lipid metabolism, and immune function
 The Role of Catecholamines in Postinjury
Inflammation.
 activation of the sympathetic NS results in secretion of
ACh from the preganglionic fibers innervating the
adrenal medulla.

 The adrenal medulla is a special case of autonomic

innervation / postganglionic neuron.

 ACh signaling to chromaffin cells ensures epinephrine

(EPI) and norepinephrine (NE) release
 Catecholamines
 Severe injury activates the adrenergic system
 Norepi and Epi immediatel increase 3-4x and remain
elevated 24-48hrs after injury

 Epinephrine
 hepatic glycogenolysis, gluconeogenesis, lipolysis,
and ketogenesis
 Decreases insulin and glucagon secretion
 Peripheral- lipolysis, insulin resistance in skeletal m.
 = stress induced hyperglycemia
 Epinephrine – other effects
 Increase secretion of T3, T4, and renin
 Reduces release of aldosterone
 Enhances leukocyte demargination and
lymphocytosis
 Aldosterone
 Synthesized, stored, released from the adrenal zona
glomerulosa
 Maintains intravascular volume
 Conserves sodium
 Eliminates potassium and hydrogen ions

 Acts on the early distal convoluted tubules

 Deficiency- hypotension, hyperkalemia

 Excess- edema, HTN, hypokalemia, metab alkalosis
 Insulin
 Stress inhibited release + peripheral insulin
resistance = hyperglycemia
 Injury has 2 phases of insulin release
 Within hours- release is suppressed
 Later- normal/xs insulin production with peripheral
insulin resistance
 Activated lymphocytes have insulin receptors ->
enhanced Tcell proliferation and cytotoxicity
 Tight control of glucose levels esp. in diabetics
significantly reduces mortality after injury
 Hormone Signaling
 Hormone classifications
 polypeptide (cytokine, insulin)
 amino acid (epinephrine, serotonin, or histamine)

 fatty acid (cortisol, leukotrienes)

 Pathways
 Receptor Kinases – insulin
 Guanine nucleotide binding (G-protein) - prostaglandins

 Ligand Gated ion channels

 Signaling
 Humoral – inflammatory mediators in the circulation
can induce fever and anorexia i.e. TNF-α
 Neural – parasympathetic vagal stimulation attenuates
the inflammatory response via Ach release
 Reduces HR, increases gut motility, dilates arterioles,
constricts pupils, and decreases inflammation
 Reduces macrophage activation
 Reduces macrophage release of pro-inflammatory mediators
(TNF-α, IL-1, IL-18)
 Mediators of Inflammation
 Heat Shock Proteins
 Reactive Oxygen Metabolites
 Eicosanoids
 Fatty Acid Metabolites
 Kallikrein-Kinin System
 Serotonin
 Histamine
 Cytokines
 Heat Shock Proteins
 Induced by stress, inflammation, burn
injury,infection.
 Intracellularly modify and transport proteins
 “intracellular chaperones”
 Requires gene induction by HS transcription
factors.
 presumed to protect cells from the deleterious
effects of traumatic stress
ROS
 Reactive Oxygen Species
 Short-lived
 Cause tissue injury by oxidation of unsaturated fatty
acids within cell membranes
 Produced by anaerobic glucose oxidation and reduction
to superoxide anion in leukocytes
 Further metabolized to hydrogen peroxide and
hydroxyl radicals
 Cells are protected by oxygen scavengers – glutathione
and catalases
 In ischemia- production of oxygen metabolites are
activated but nonfunctional due to no oxygen supply.
After reperfusion, large amounts are produced causing
injury
 Eicosanoids
Phospholipids
Glucocorticoids
(Cortisol) Phospholipase A2
Corticosteroids

Arachadonic Acid
Cyclooxygenase 1 & 2 Lipoxygenase

Cyclic endoperoxidases Hydroperoxyeicosatetraenoic acid

(PGG2, PGH2) (HPETE)

Prostaglandins Hydroxyeicosatetraenoic
PGD2, PGE2, PGF2α, PGI2 Acid HETE

Thromboxane Leukotrienes
TXA2
 Eicosanoids
 Secreted by nucleated cells (not lymphocytes)
 Induced by hypoxic injury, direct tissue injury,
endotoxin, norepinephrine, vasopressin, ang II,
bradykinin, serotonin, ACh, cytokines, histamine

 Diverse systemic effects

 Adverse effects include acute lung injury, pancreatitis,
renal failure
 NSAIDs acetylate COX which reduce prostaglandin
levels
 Eicosanoid Effects
 Pancreas – glucagon secretion-  Hematologic
PGD2, PGE2  platelet aggregation- TXA2
 Liver – glucagon stimulated  Capillary leakage- PGE2, LT
glucose production- PGE2  PMN adherence and activation-
 Fat – lipolysis- PGE2 LT
 Bone – resorption- PGE2, PGF2α,  Pituitary
PGI2  Prolactin- PGE1
 Parathyroid – PTH secretion-  LH- PGE1, PGE2, 5-HETE
PGE2  TSH- PGA1, PGB1, PGE1,
PGE1α
 Pulmonary – Bronchoconstriction-
PGF2α, TXA2, LTC4, LTD4,  GH- PGE1
LTE4  Renal – renin secretion- PGE2,
 Immune – suppress lymphocytes- PGI2
PGE2  GI – cytoprotective- PGE2
 Fatty Acid Metabolites
 Omega 6 FA – precursors of inflammatory mediators
(LT, PG, platelet activating, factor)
 found in enteral nutrition formulas
 Substituting Omega 3 FA attenuate the inflammatory
response
 Reduces TNFα, IL6, PGE2
 Reduces the metabolic rate, normalizes glucose metabolism,
attenuates weight loss, improves nitrogen balance, reduces
endotoxin induced acute lung injury, minimizes reperfusion
injury to the myocardium, small intestine, and skeletal
muscles.
F.A.
K-K.S.
 Kallikrein-Kinin System
 Bradykinins are potent vasodilators
 Stimulated by hypoxic and ischemic injury
 Hemorrhage, sepsis, endotoxemia, tissue injury
 Magnitude proportional to severity of injury
 Produced by kininogen degradation by kallikrein
 Kinins increase capillary permeability (edema), pain,
inhibit gluconeogenesis, renal vasodilation, incr
bronchoconstriction
 In clinical trials, bradykinin antagonists help reverse G-
sepsis, but do not improve survival
 Serotonin
 Monoamine neurotransmitter(5HT) from
tryptophan
 Present in GIT chromaffin cells & platelets
 Vasoconstriction, bronchoconstriction, platelet
aggregation
 Myocardial chronotrope and inotrope via cAMP
 Unclear role in inflammation
 Histamine
 Stored in neurons, skin, gastric mucosa, mast
cells, basophils, and platelets
 H1 – bronchoconstriction, increases intestinal
motility and myocardial contractility
 H2 – inhibits histamine release
 H1/H2 – hypotension, decreased venous
return/peripheral blood pooling, increased
capillary permeability, myocardial failure.
 Cytokines
 Most potent mediators of inflammation
 Local- eradicate microorganisms, promote wound healing
 Overwhelming response- hemodynamic instability (septic
shock) or metabolic derangements (muscle wasting)
 Uncontrolled- end-organ failure, death
 Self-regulatory production of anti-inflammatory cytokines,
but inappropriate release may render the patient
immunocompromised and susceptible to infection
 Tumor Necrosis Factor α
 Secreted from monocytes, macrophages, Tcells
 Responds early, T ½ < 20min
 Potent evocation of cytokine cascade
 Induces muscle catabolism/cachexia,
coagulation, PGE2, PAF, glucocorticoids,
eicosanoids
 Circulating TNF receptors compete with cellular
receptors and may act as a counter regulatory
system to prevent excessive TNF-α activity
 Interleukin-1
 Released by activated macrophages, endothelial cells
 IL1α- cell membrane associated
 IL1β- circulation
 Synergistic with TNF- α
 T ½ = 6 min
 Induces febrile response by stimulating PG activity in the
anterior hypothalamus
 Release of β-endorphins after surgery reduce perception of
pain
 Interleukin-2
 Promotes T-lymphocyte proliferation, Ig
production, gut barrier integrity
 T ½ < 10 min
 Major injury or perioperative blood transfusions
reduce IL-2 activity leading to a transient
immunocompromised state
 Regulates lymphocyte apoptosis
 Interleukin-4
 Produced by type 2 T Helper lymphocytes
 Important in antibody-mediated switching and
antigen presentation
 Induces class switching to promote IgE & IgG4
 Important in allergic and antihelmintic responses
 Anti-inflammatory- downregulates IL-1, TNF-α,
IL-6, IL-8 and oxygen radical production
 Increases macrophage susceptibility to anti-
inflammatory effects of glucocorticoids
 Interleukin-5
 Released from T lymphocytes, eosinophils, mast
cells and basophils
 Promotes eosinophil proliferation and airway
inflammation
 Interleukin-6
 Induced by IL-1 and TNF-α
 Levels are detectable within 60 min of injury, peak 4-6
hours, and persist up to 10 days
 Levels are proportional to extent of tissue injury
 Pro-inflammatory
 Mediates hepatic acute phase response during injury and
convalescence
 Induces and prolongs neutrophil activity
 Anti-inflammatory
 Attenuate TNF-α and IL-1 activity
 Promote release of circulating TNF- α receptors & IL-1
antagonists
 Interleukin-8
 Released from monocytes, macrophages, T
lymphocytes
 Activity similar to IL-6
 Chemoattractant for PMNs, basophils,
eosinophils, and lymphocytes, activates PMNs
 Proposed biomarker for risk of multiple organ
failure
 Interleukin-10
 Anti-inflammatory
 Released from T lymphocytes
 Down-regulates TNF-α activity
 Also attenuates IL-18 mRNA in monocytes
 Studies in animal sepsis and ARDS models
suggest induced IL-10 decreases the systemic
inflammatory response and reduces mortality
 Interleukin-12
 Promotes differentiation of type 1 T Helper cells
 Promotes PMN and coagulation activation
 In primate studies, IL-12 induces inflammatory
responses independent of TNF-α and IL-1
 In animal studies of fecal peritonitis and burns,
IL-12 administration increases survival, whereas
IL-12 neutralization increases mortality
 Interleukin-13
 Similar to IL-4, overall anti-inflammatory
 Modulates macrophage function
 Unlike IL-4, has no effect on T lymphocytes
 Inhibits NO production
 Inhibits pro-inflammatory cytokines
 Attenuates leukocyte interaction with activated
endothelial surfaces
 Interleukin-15
 Derived from macrophages
 Shares receptor components with IL-2, and
shares promoting lymphocyte activation/prolif.
 In neutrophils, it induces IL-8 and nuclear factor
кB -> enhanced phagocytosis against fungal
infections
 Interleukin-18
 Formerly IFN-γ-inducing factor
 Produced by macrophages
 Pro-inflammatory, similar to IL-12
 Increased levels are pronounced (especially in
G- sepsis) and can last up to 21 days
 Interferons
 Helper T lymphocytes activated by bacterial
antigens, IL-2, IL-12, or IL-18 produce IFN-γ
 IFN-γ can induce IL-2, IL-12, or IL-18
 Detectable in circulation by 6 hrs and remain
elevated for up to 8 days
 Activate circulating and tissue macrophages
 Induces acute lung inflammation by activating
alveolar macrophages after surgery or trauma
 Granulocyte-Macrophage Colony-
Stimulating Factor
 Delays apoptosis of macrophages and PMNs
 Promotes the maturation and recruitment of PMNs
in inflammation and perhaps wound healing
 May contribute to organ injury such as ARDS
 Peri-operative GM-CSF undergoing major
oncologic procedures and burn patients
demonstrate enhances neutrophil counts and fcn
 High Mobility Group Box 1
 DNA transcription factor
 Expressed 24-48 hrs after injury
 Associated with weight loss, food aversion,
shock, SIRS and Sepsis
 Peak levels are associated with ARDS and death
 Cell Signaling Pathways
 Heat Shock Proteins
 produced in response to ischemia/injury
 HS Factors are activated upon injury, undergo
conformational changes, translocate into the nucleus,
and bind HSP promoter regions
 Attenuate inflammatory response

 Ligand Gated Ion Channels

 When activated by a ligand, a rapid influx of ions
cross the cell membrane. i.e. neurotransmitters
 Cell Signaling Pathways
 G-protein receptors
 Largest family of signaling receptors
 Adjacent effector protein activated receptor
 Second messengers – cAMP or calcium
 Can result in gene transcription or activation of
phospholipase C
 Tyrosine Kinases
 When activated, receptors dimerize, phosphorylate, and
recruit secondary signaling molecules
 Used in gene transcription and cell proliferation
 i.e. insulin, PGDF, IGF-1
 Cell Signaling Pathways
 Janus Kinase/Signal Transduction and Activator of
Transcription (JAK-STAT)
 IL-6, IL-10, IL-12, IL-13, IFN-γ
 Ligand binds to the receptor, receptor dimerizes, enzymatic
activation via phosphorylation propagates through the JAK
domain and recruits STAT to the cytosolic receptor portion.
 STAT dimerizes and translocates into the nucleus as a
transcription factor
 Suppressors of cytokine signaling (SOCS) block JAK-STAT
 AUTOPHAGY

 APOPTOSIS

 NECROPTOSIS
 APOPTOSIS
 Regulated cell death
 normal function of cellular disposal w/o
activating the immune/inflammatory system
 2 receptors
 TNFR-1 : inflammation, apoptosis, circulatory shock
 TNFR-2 : no inflammation or shock

 CD95 (Fas) receptor similar structure to TNFR-1

 Initiates apoptosis
 Cell Mediated Inflammation
 Platelets
 nonnucleated (contain both mitochondria and mediators of
coagulation and inflammatory signaling)
 derived from bone marrow megakaryocytes.
 critically important in the hemostatic response and are
activated by several factors, including exposed collagen
 Thrombocytopenia- hallmark of septic response

 Eosinophils
 Primarily “Antihelmenthic”
 Reside in the GI, lung, and GU tissues
 Activated by IL-3, GM-CSF, IL-5, PAF, and anaphylatoxins
C3a and C5a
 Cell Mediated Inflammation
 Lymphocytes & T –Cell Immunity
 T-helpers produce IL-3, TNF-α, GM-CSF
 TH1: IFN-γ, IL-2, IL-12
 TH2: IL-4, IL-5, IL-6, IL-9, IL-10, IL-13
 Severe infection – shift toward more TH2
 Mast Cells
 First responders to injury
 Produce histamine, cytokines, eicosanoids, proteases,
chemokines, TNF-α (stored in granules)
 Cause vasodilation, capillary leakage, and recruit immunocytes
 Cell Mediated Inflammation
 Monocytes
 mononuclear phagocytes that circulate in the bloodstream
and can differentiate into macrophages, osteoclasts, and
dendritic cells on migrating into tissues.
 Macrophages are the main effector cells of the immune
response to infection and injury, primarily through
mechanisms that include phagocytosis of microbial
pathogens, release of inflammatory mediators, and clearance
of apoptotic cells
 Cell Mediated Injury
 Neutrophils:
 1st responders to sites of infection and injury
 potent mediators of acute inflammation.

 circulating immunocytes with short half-lives (4 to

10 hours).
 are able to phagocytose, release lytic enzymes, and
generate large amounts of toxic reactive oxygen
species on activation
 Endothelium-Mediated Injury
 Neutrophil-Endothelium Interaction
 Increased vascular permeability – facilitate oxygen
delivery and immunocyte migration
 Accumulation of neutrophils at injury sites can cause
cytotoxicity to vital organs
 Ischemia-reperfusion injury potentiates this response
by releasing oxygen metabolites and lysosomal enz.
 Neutrophils – rolling 10-20min (p-selectin), >20min
 Nitric Oxide
 EDRF
 Derived from endothelial surfaces responding to
Ach, hypoxia, endotoxin, cellular injury, or shear
stresses of circulating blood
 T ½ = seconds
 Reduces microthrombosis, mediates protein
synthesis in hepatocytes
 Formed from oxidation of L-arginine via NOS
(+calmodulin, Ca2+, NADPH)
 Prostacyclin (PGI2)
 Endothelium derived in response to shear stress
and hypoxia
 Vasodilator
 Platelet deactivation (increases cAMP)
 Clinically used to reduce pulmonary
hypertension (especially pediatric)
 Endothelins
 Produced as a response to a variety of factors –
injury, anoxia, thrombin, IL-1, vasopressin
 ET-1 is a potent vasoconstrictor, 10x more
potent than angiotensin II
 Platelet Activating Factor
 Phospholipid component of cell membranes,
constitutively expressed at low levels
 Released by PMNs, platelets, mast cells,
monocytes during acute inflammation
 Further activates PMNs and platelets
 Increases vascular permeability
 PAF antagonists reduce ischemia/reperfusion
injury
SURGICAL METABOLISM
 Metabolism During Fasting
 Comparable to changes seen Mass (kg) Energy Days
(Kcal) Available
in acute injury
Water 49 0 0
 Requires 25-40 kcal/kg/day
of carbs, protein, fat
Protein 6 24,000 13
 Normal adult body contains
300-400g carbs (glycogen) –
Glycogen 0.2 800 0.4
75-100g hepatic, 200-250g
muscle (not available
Fat 15 140,000 78
systemically due to deficiency
of G6P)
Total 70.2 164,800 91.4
 Metabolism During Fasting
 A healthy 70kg adult will use 180 g /d of glucose
to support obligate glycolytic cells (neurons,
RBCs, PMNs, renal medulla, skeletal m.)
 Glucagon, Norepi, vasopressin, AngII promote
utilization of glycogen stores
 Glucagon, Epi, and cortisol promote
gluconeogenesis
 Precursors include lactate (sk.m., rbc, pmn),
glycerol, and aa (ala, glutamine)
Metabolism of Simple Starvation
 Lactate is not sufficient for glucose demands
 Protein must be degraded (75 g/d) for hepatic
gluconeogenesis
 Proteolysis from decreased insulin and increased
cortisol
 Elevated urinary nitrogen (7 -> 30 g/d)
Metabolism of Prolonged Starvation
 Proteolysis is reduced to 20g/d and urinary nitrogen
excretion stabilizes to 2-5g/d
 Organs (myocardium, brain, renal cortex, sk.m) adapt
to ketone bodies in 2-24 days
 Kidneys utilize glutamine and glutamate in
gluconeogenesis
 Adipose stores provide up to 40% calories (approx 160
g FFA and glycerol)
 Stimulated by reduced insulin and increased glucagon and
catecholamines
 Metabolism Following Injury
 Magnitude of expenditure is proportional to the
severity of injury
 Changes in
 Lipid Absorption
 Lipid Oxidation

 Carbohydrate metabolism
 Lipid Absorption
 Oxidation of 1g fat = 9 kcal energy
 Dietary lipids require pancreatic lipase and phospholipase to
hydrolyze TG into FFA and monoglycerides within the
duodenum
 After gut absorption, enterocytes resynthesize TG from
monoglycerides + fatty acyl-CoA
 Long chain TG (>12 carbons) enter the circulation as
chylomicrons. Shorter FA chains directly enter portal circulation
and are transported via albumin
 Under stress, hepatocytes utilize FFA as fuel
 Systemically TG and chylomicrons are used from hydrolysis with
lipoprotein lipase (suppressed by trauma and sepsis)
 Fatty Acid Oxidation
 FFA + acyl-CoA = LCT are transported across
the mitochondrial inner membrane via the
carnitine shuttle
 Medium-chain TG (MCT) 6-12 carbons long,
freely cross the mitochondrial membrane
 Fatty acyl-CoA undergoes β-oxidation to acetyl-
CoA to enter TCA cycle for oxidation to ATP,
CO2, and water
 Excess acetyl-CoA is used for ketogenesis
 Carbohydrate Metabolism
 Carbohydrates + pancreatic intestinal enzymes
yield dimeric units (sucrase, lactase, maltase)
 Intestinal brush border disaccharidases break
them into simple hexose units which are
transported into the intestinal mucosa
 Glucose and galactose are absorbed via a sodium
dependent active transport pump
 Fructose absorption via facilitated diffusion
 Carbohydrate Metabolism
 1g carbohydrate = 4 kcal energy
 IV/parenteral nutrition 3.4 kcal/g dextrose
 In surgical patients dextrose administration is to
minimize muscle wasting
 Glucose can be utilized in a variety of pathways
– phosphorylation to G6P then glycogenesis or
glycogenolysis, pyruvic acid pathway, or pentose
shunt
Protein and Amino Acid Metabolism
 Average adult protein intake 80-120 g/day
 every 6 g protein yields 1 g nitrogen
 1g protein = 4 kcal energy

 Following injury, glucocorticoids increase

urinary nitrogen excretion (>30g/d), peak at 7d,
persist 3-7 wks
 Nutrition in the Surgical Patient
 Nutritional assessment to determine the severity
of deficiencies/excess
 Wt loss, chronic illnesses, dietary habits,
quality/quantity of food, social habits, meds
 Physical exam – loss of muscle/adipose tissue,
organ dysfunction
 Biochemical – Cr excretion, albumin,
prealbumin, total lymphocyte count, transferrin
 Surgical Nutrition
 Support the requirements for protein synthesis
 Nonprotein calorie : nitrogen ratio = 150:1
 A lower rate of 80-100:1 may be beneficial in some
critically ill or hypermetabolic patients

 Basal Energy Expenditure (BEE):

men = 66.47 + 13.75(W) + 5(H) – 6.76(A) kcal/d
women = 655.1 + 9.56(W) + 1.85(H) – 4.68 (A) kcal/d
W= wt in kg, H= Ht in cm, A= age in years
 Enteral Feeding
 Lesser expenses and risks than parenteral
 Reduced intestinal atrophy
 44% reduction in infections over parenteral in
the critically ill
 Healthy patients without malnutrition
undergoing uncomplicated surgery can tolerate
10 d of maintenance IV fluids only before
significant protein catabolism begins
 Initiation of Enteral Feeding
 Immediately after adequate fluid resuscitation
(UOP)
 Not absolute prerequisites: presence of bowel
sounds, passage of flatus or stool
 Gastric residuals of >200ml in 4-6 hrs or
abdominal distention requires
cessation/lowering the rate
 Enteral Formulas
 Low-residue isotonic
 caloric density 1.0kcal/ml, 1500-1800 ml/day
 Provide carbs, protein, lytes, water, fat, water sol vitamins,
calorie:Nitrogen of 150:1.
 No fiber bulk = minimum residue
 Standard for stable patients with an intact GI tract
 Isotonic with fiber
 Soluble and insoluble fiber (soy)
 Delay GI transit time and reduce diarrhea
 Not contraindicated in the critically ill
 Enteral Formulas
 Immune-Enhancing
 Glutamine, argenine, omega-3 FA, nucleotides, beta-carotene.
 Benefits not consistent in trials
 Expensive
 Calorie-Dense
 1.5-2 kcal/ml, higher osmolality (ok for intragastric feeding)
 for fluid restriction/inability to tolerate larger volumes
 High-Protein
 Isotonic and nonisotonic available
 calorie:Nitrogen ratio of 80-120:1
 Enteral Formulas
 Elemental
 Contain predigested nutrients, small peptides
 Limited complex carbs and fat (long/med chains)
 Easily absorbed, but limited long term use
 High osmolality = slow infusion or diluted
 Expensive

 Renal-Failure
 Lower fluid volume, K, phos, and Mg
 Essential aa, high calorie : nitrogen ratio, no vitamins
 Enteral Formulas
 Pulmonary-Failure
 Fat content is increased to 50% of total calories
 Reduces CO2 production and ventilation burden

 Hepatic-Failure
 50% of aa are branched chains (Leu, Ile, Val)
 Potentially reverses encephalopathy

 Controversial, no clear benefits in trials

 Enteral Access
 Nasogastric Tube - requires intact mental status and laryngeal
reflexes to reduce aspiration
 Difficult to place, requires radiographic confirmation
 If required >30 d, convert to PEG
 Problems: clogging, kinking, inadvertent removal
 Percutaneous Endoscopic Gastrostomy –
 Impaired swallowing/obstruction, major facial trauma
 Contraindications: ascites, coagulophathy, gastric varices, gastric neoplasm,
lack of suitable location
 Tubes can be use for 12-24 mos
 Requires endoscopic transillumination of abdominal wall and passage of
catheter into an insufflated stomach
 Complications in 3% of cases: infection, peritonitis, aspiration/pneumonia,
leaks, dislodgement, bowel perforation, enteric fistulas, bleeding
 Percutaneous Endoscopic
Gastrostomy-Jejunostomy
 Feeding administered past the pylorus
 Cannot tolerate gastric feedings/signif aspiration
 Passes a catheter through an existing PEG past
the pylorus into the duodenum
 Long term malfunction >50% due to retrograde
tube migration into the stomach, kinking,
clogging
 Direct Percutaneous Endoscopic
Jejunostomy
 Same technique as PEG placement but requires
an enteroscope/colonscope to reach the
jejunum
 Less malfunction than PEG-J
 Kinking/clogging reduced by placing larger
caliber catheters
 Surgical Gastrostomy and
Jejunostomy

 With complex abdominal trauma/laparatomy

there may be an opportunity for placement
 Contraindication: distal obstruction, severe
intestinal wall edema, radiation enteritis,
inflammatory bowel disease, ascites, severe
immunodeficiency, bowel ischemia
 Adverse effects: abdominal/bowel distention,
cramps, pneumatosis intestinalis, small bowel
necrosis
 Parenteral Nutrition
 Continuous infusion of hyperosmolar carbs,
proteins, fats and other nutrients through a
catheter into the SVC
 Optimal > 100-150 kcal/g nitrogens
 Higher rates of infection compared to enteral
 Studies with parenteral nutrition and complete
bowel rest results in increased stress hormone
and inflammatory responses
 Parenteral Nutrition Rationale
 Seriously ill patients with malnutrition, sepsis or
surgery/trauma when use of the GI tract for
feeding is not possible
 Short bowel syndrome after massive resection
 Prolonged paralytic ileus (>7 days)

 Severe intestinal malabsorption

 Functional GI disorders – esophageal dyskinesia

 Etc.
 Total Parenteral Nutrition
 Central parenteral nutrition, aka TPN
 Requires access to a large diameter vein
 Dextrose content is high (15-25%)
 Peripheral Parenteral Nutrition
 Lower osmolality
 Reduced dextrose (5-10%)
 Protein (3%)
 Not appropriate for severe malnutrition due to
need for larger volumes of some nutrients
 Shorter periods, < 2 wks
 Parenteral Nutrition
 Dextrose 15-25%
 Amino acids 3-5%
 Vitamins (Vit K is not included)
 Lipid emulsions to prevent essential FA
deficiency (10-15% of calories)
 Prepared by the pharmacy from commercially
available kits
 If prolonged – supplement trace minerals
 Zinc (eczematous rash), copper (microcytic anemia),
chromium (glucose intolerance)
 Parenteral Nutrition
 Insulin supplement to insure glucose tolerance
 IV fluids/electrolytes if high fluid losses
 Freq. monitor fluid status, vital signs, UOP,
electrolytes, BUN, and LFTs. Glucose q6h
 Complications
 Hyperglycemia – pt with impaired glc tolerance or high infusion
rate
 Tx- volume replacement, correct electrolytes, insulin
 Avoid by monitoring daily fluid balance, glc, & lytes
 Overfeeding – results in CO2 retention and respiratory
insufficiency
 Hepatic steatosis
 Cholestasis and gallstones
 Hepatic abnormalities – serum transaminase, alk phos and
bilirubin
 Intestinal - atrophy from disuse, bacterial overgrowth, reduced
lymphoid tissue and IgA production, impaired gut immunity
 Special Formulations
 Glutamine and Arginine
 Glutamine – nonessential aa, comprises 66% of free amino acids
 During stress glu is depleted and shunted as a fuel source to
visceral organs and tumors
 Inconclusive data for benefits of increased supplementation
 Arginine – nonessential aa, promotes net nitrogen retention and
protein synthesis in the critically ill/injured. Benefits still under
investigation.
 Omega-3 Fatty Acids
 Canola or fish oil. Displaces omega-6 FAs, theoretically reducing
pro-inflammatory responses
 Nucleotides
 ? Increase cell proliferation, DNA synthesis, T Helper cell
function
 The End

 Thank you..