CHAPTER 1

THE SYSTEMIC RESPONSE TO INJURY

Outline:

ENDOCRINE RESPONSE TO INJURY

Overview of Hormone-Mediated Response
Hormone-Mediated Receptor Activity
Hormone-Mediated Intracellular Pathways
Hormones Under Anterior Pituitary Regulation
Corticotropin-Releasing Hormone
Adrenocorticotropic Hormone
Cortisol/Glucocorticoids
Thyrotropin Releasing Hormone and Thyroid0-Stimulating Hormone
Growth Hormones
Gonadotropins and Sex Hormones
Prolactin
Endogenous Opioids
Hormones Under Anterior Pituitary Regulation
Arginine Vasopressin
Oxytocin
Hormones of the Autonomic System
Catecholamines
Aldosterone
Renin-Angiotensin
Insulin
Glucagon

IMMUNE RESPONSE TO INJURY

Cytokine-mediated response
Tumor Necrosis Factor-alpha
Interleukin-1, 2, 4, 6, 8, 10, 12, 13
Interferon-
Granulocyte/Macrophage Colony-Stimulating Factor
Programmed Cell Death
Hormones and Cytokine Interactions
Cortisol/Glucocorticoids
Catecholamines

OTHER MEDIATORS OF IMMUNE RESPONSE

Endothelial Cell Mediators
Endothelial Cell Function
Enothelium-Derived Nitric Oxide
Prostacyclin
Endothelins
Platelet-Activating Factor
Atrial-Natriuretic Peptides
Intracellular Mediators
Heat-Shock Proteins
Reactive Oxygen Metabolites
Other Inflammatory Mediators
Eicosanoids
Kallikrein-Kinin System
Serotonin
Histamine
METABOLIC RESPONSE TO INJURY
Metabolic Response to Fasting
Substrate Metabolism
Metabolism After Injury
Energy Balance
Lipid Metabolism
Carbohydrate Metabolism
Protein and Amino Acid sMetabolism

NUTRITION IN THE SURGICAL PATIENT

Surgery, Trauma, Sepsis
Catabolic Phase
Early Anabolic Phase
Late Anabolic Phase
Assessment and Requirements
Indications and Methods for Nutritional Support
Indications for the Use of Intravenous Feedings

ENDOCRINE RESPONSE TO INJURY

OVERVIEW OF HORMONE-MEDIATED RESPONSE

 hormone response pathways are activated by:
1. mediators released by injured tissue
2. neural and nociceptive input from site of injury
3. baroreceptor stimulation from intravascular volume depletion
 these hormones are divided into (see Table 1-1):
1. those under hypothalamopituitary control
2. those under autonomic nervous system control

Hormone-Mediated Receptor Activity

 (see Table 1-2 and 1-3)
 “central concept” is the hormone (ligand)-receptor interaction and subsequent postreceptor activity
 3 major types of hormone receptors (based on mechanism of signal transduction):
1. receptor kinases with ligands, e.g. insulin
2. guanine nucleotide-binding or G protein-coupled receptors that are activated by peptide
hormones, neurotransmitters, and prostaglandins
3. ligand-gated ion channels (see Figure 1-1)

Hormone-Mediated Intracellular Pathways

 modulation of cAMP - one of the most common intracellular second messengers of hormones
 adenylate cyclase - activated by receptor occupation by hormones; converts ATP to cAMP, which
activates various intracellular protein kinases
 ↑ cAMP results in functional lymphocyte responses that are generally immunosuppressive
 hormonal actions are further mediated by intracellular receptors that also have binding affinities for
the targeted gene sequence on the DNA, classic e.g. glucocorticoid receptor

HORMONES UNDER ANTERIOR PITUITARY REGULATION (see Figure 1-2)

Corticotropin-Releasing Hormone (CRH)

 pain, fear, anxiety or emotional arousal → stimulate CRH synthesis by paraventricular nucleus of
hypothalamus
 CRH then stimulates ACTH production and release; CRH stimulates adenylate cyclase which ↑ cAMP
 which activates pathways that ↑ ACTH production
 activators of CRH: proinflammatory cytokines, AVP, angiotensin II, serotonin, acetylcholine, IL-1, IL-6
 CRH release inhibited by: GABA, ANP, endogenous opioids, L-arginine

Adrenocorticotropic Hormone
 precursor complex is proopiomelanocortin (POMC)
 POMC components:
1. α-melanocyte-stimulating hormone (α-MSH)
2. β-lipotropin
3. β-endorphin (an endogenous opioid)
4. ACTH
 ACTH release regulated by circadian rhythm, greatest elevation is late at night and lasts until just
before sunrise; this pattern is altered in injured subjects; CRH and ACTH elevation proportional to the
severity of injury
 other mediators (other than pain and anxiety) more active in the injured patient:
1. vasopressin
2. angiotensin II
3. cholecystokinin
4. VIP
5. catecholamines
6. oxytocin
7. proinflammatory cytokines
 within the adrenal gland (zona fasciculata), ACTH activates adenylate cyclase (↑ cAMP) and the
mitochondrial cyt P-450 system; this chain of activities leads to ↑ glucocorticoid production
 excess ACTH stimulation results in adrenocortical hypertrophy

Cortisol/Glucocorticoids
 cortisol - major glucocorticoid in humans; essential for survival after significant stress
 levels can remain persistently elevated depending on systemic stress
 burn patients - ↑ cortisol up to 4 weeks; soft tissue injury and hemorrhage - ↑ up to a week
 coexisting systemic stress, e.g. infection, can prolong ↑ ACTH
 cortisol potentiates glucagon and epinephrine, leading to hypeerglycemia
 in the liver, favors gluconeogenesis
 peripherally, ↓ insulin binding to insulin receptors in muscles and adipose tissue
 in the skeletal muscle, cortisol induces proteolysis augments the release of lactate which results to
net effect of shifting subtrates for hepatic gluconeogenesis
 cortisol stimulates lipolytic activities of ACTH, GH, glucagon, and epinephrine
 plasma cortisol - 10% free, active form; 90% protein bound (albumin and corticosteroid-binding
protein [CBG])
 in injury, ↑ cortisol and ↓ albumin and CBG (by as much as 50%) leads to further increase in free
cortisol level up to 10x normal
 acute adrenal insufficiency is most commonly associated with adrenal suppression from use of
exogenous glucocorticoids with consequent adrenal atrophy
 symptoms: weakness, nausea/vomiting, fever, hypotension
 signs: hypoglycemia (from ↓ gluconeogenesis), hyponatremia, hyperkalemia (from insufficient
aldosterone acitivity)
 glucocorticoids are immunosuppressants:
1. lymphopenia
2. monocytopenia
3. eosinopenia
1. neutrophilia
 immunologic changes:
1. thymic involution
2. ↓ T-killer and natural-killer function
 3. altered neutrophil function (superoxide activity and depressed chemotaxis)
4. omnibus inhibition of immunocyte proinflammatory cytokine synthesis and secretion

Thyrotropin Releasing Hormone and Thyroid-Stimulating Hormone

 TRH stimulates TSH synthesis, storage, release
 TSH stimulates T4 production; T4 converted to T3 (more potent) by peripheral tissues
 T4 and T3 inhibit TRH and TSH (negative feedback)
 stimulate TSH release:
1. TRH
2. estrogen
 inhibit TSH release:
1. T3
2. T4
3. corticosteriods
4. GH
5. somatostatin
6. fasting
 thyronines (thyroid hormones):
1. enhance membrane transport of glucose; increase glucose oxidation
2. increase fat formation in excessive glucose intake
 leads to overall elevation of oxygen consumption and heat production
 after major injury: reduced T3 and TSH; impaired peripheral conversion of T4 to T3
 instead T4 is converted to reverse T3 (rT3)
 elevated rT3 but reduced T4 and T3 is an observation characteristic of acute injury, referred to as
euthyroid sick syndrome or non-thyroidal sickness
 total T4 is reduced but free T4 is constant; reduced free T4 in severe injury is predictive of high
mortality
 ↓ thyronines decreases cellular and humoral immunity; ↑ thyronines increase both types of immunity

Growth Hormones
 GHRH stimulates release of GH in pulsatile fashion mostly during sleeping hours
 other stimluli to release GH:
1. autonomic stimulation
2. thyroxine
3. AVP
4. ACTH
5. α-MSH
6. glucagon
7. sex hormones
8. physical exercise
9. sleep
10. stress
11. hypovolemia
12. fasting hypoglycemia
13. decrease in fatty acids
14. incease in amino acids
 inhibits GH release:
1. hyperglycemia
2. hypertriglyceridemia
3. somatostatin
4. β-adrenergic stimulation
5. cortisol
 role of GH during stress:
1. promote protein synthesis
2. enhance mobilization of fat stores
 GH inhibits insulin, leading to hyperglycemia
 GH causes secondary release of insulin-like growth factor-1 (IGF-1), formerly somatomedins, which
mediates hepatic protein synthesis and glycogenesis
 GH increases after injury, major surgery, anesthesia
 GH and IGF-1 are immunostimulatory and promote tissue proliferation

Gonadotropins and Sex Hormones

 LHRH or GnRH stimulate FSH and LH
 injury, stress, or severe illness suppress LH and FSH release, resulting to decrease estrogen and
androgen secretion which accounts for menstrual irregularity and decrease in libido
 estrogens and androgens are predominantly immunosuppressive (castration enhances immunologic
function)

Prolactin
 stimulants for release: CRH, TRH, GHRH, serotonin, VIP
 injury/surgery causes hyperprolactinemia which results to amenorrhea
 immunostimulatory

Endogenous Opioids
 β-endorphins attenuate pain perception; can induce hypotension
 enkephalins produce hypertension
 in GIT, activation of opioid receptors reduces peristalsis and suppresses fluid secretion
 endorphins increase natural killer cell cytotoxicity and T-cell blastogenesis
 IL-1 activates release of POMC

HORMONES UNDER ANTERIOR PITUITARY REGULATION

Arginine Vasopressin
 major stimulus for AVP release is elevated plasma osmolarity (detected by Na-sensitive hypothalamic
osmoreceptors)
 as little as 10% change in effective circulating volume can be sensed by baroreceptors, left atrium
stretch receptors, chemoreceptors leading to AVP release
 AVP release enhanced by:
1. β-adrenergic agonists
2. angiotensin II stimulation
3. opioids
4. anesthesia
5. pain
6. increase in glucose concentration
 in kidney, AVP promotes water reabsorption from distal tubules and collecting tubules
 AVP elevates after trauma, hemorrhage, and surgery; typically lasts 1 week
 SIADH - excessive AVP secretion; seen in head trauma and burns
7. decreased urine output
8. increased urine concentration - >100 mOsm/kG H20
9. dilutional hyponatremia - plasma osmolality <275 mOsm/kG H20
 central diabetes insipidus
10. (-) AVP
11. voluminous output of dilute urine
12. common in comatose patients

Oxytocin
 role in injury response in unknown

HORMONES OF THE AUTONOMIC SYSTEM

Catecholamines
 norepinephrine and epinephrine: increased 3-4x above baseline immediately after injury, peak in 24-
48h, then levels return to baseline
 epinephrine on liver:
1. promote glycogenolysis, gluconeogenesis, lipolysis, ketogenesis
2. decrease insulin, increase glucagons
 epinephrine on peripheral tissues: to promote stress-induced hyperglycemia
1. increase lipolysis (adipose)
2. inhibit insulin-facilitated glucose uptake (skeletal muscle)
 catecholamines: increase TH and PTH, renin; decrease aldosterone
 catecholamines decrease immune responsiveness in lymphocytes; enhances leukocyte
demargination, results in neutrophilia and lymphocytosis

Aldosterone
 from adrenal zona glomerulosa
 release induced by:
1. ACTH – most potent stimulus
2. angiotensin II
3. hyperkalemia
 major function: maintain intravascular volume by conserving Na and eliminating K and H+
 vasopressin acts in concert with aldosterone to increase water influx in the renal tubules
 aldosterone deficiency:
1. hypotension
2. hyperkalemia
 excess:
1. edema
2. hypertension
3. hypokalemia
4. metabolic alkalosis
 ACTH stimulates brief burst of aldosterone release
 angiotensin II stimulates protracted release
 aldosterone release is influenced by circadian rhythm, this is lost in injured patients

Renin-Angiotensin: participates in response to injury by maintaining volume homeostatis

Renin
 synthesized and stored in renal juxtaglomelular apparatus - composed of: JG neurogenic receptor,
JG cell (baroreceptor that increases renin secretion in response to decrease in BP), and macula
densa (detects changes in chloride concentration in renal tubules)
 inactive form: prorenin
 activated by:
1. ACTH
2. AVP
3. glucagon
4. prostaglandins
5. potassium
6. magnesium
7. calcium
Angiotensin
 synthesized in liver (primary) and kidney
 renin (present in kidney) catalyzes: angiotensinogen  angiotnesin I
 ACE (present in endothelial surfaces) catalyzes: angiotensin I  angiotnesin II, in the pulmonary
circulation
Angiotensin II
 potent vasoconstrictor
 stimulates aldosterone and vasopressin synthesis
 chronotropic, inotropic
 potentiates epinephrine release by adrenal medulla
  CRH release
 activates sympathetic nervous system
 induces glycogenolysis and gluconeogenesis

Insulin
 from pancreatic β-islet cells
 normal metabolism: release stimulated by glucose (major stimuli), amino acids, free fatty acids,
ketone bodies
 normal response altered during stress, by hormonal and neural influences
 epinephrine and sympathetic stimuli inhibit insulin production
 peripherally: cortisol, estrogen, and progesterone
 interfere with glucose uptake
 net effect of impaired insulin production and function (after injury): stress-induced hyperglycemia
 insulin exerts global anabolic effect
 in injured patient, biphasic pattern of release
 first phase: few hours after injury, relative suppression of insulin release (as influenced by
catecholamines and sympathetic stimulation)
 later phase: return to normal or excessive but with persistent hyperglycemia (demonstrating
peripheral resistance to insulin)
 insulin enhances T lymphocyte proliferation and cytotoxicity

Glucagon
 from pancreatic -islet cells
 catabolic
 primary stimulants: plasma glucose and exercise
 stimulates hepatic glycogenolysis and gluconeogenesis, which under basal conditions account for
~75% glucose production by liver
 glucagons release after injury is initially decreased, returns to normal after 12h
 by 24h to 3 days, supranormal levels

IMMUNE RESPONSE TO INJURY

Cytokine-mediated response
 cytokine activity is primarily local cell-to-cell initiation (paracrine)
 cytokines are small polypeptides or glycoproteins
 exert influence at very low concentrations
 not stored as pre-formed molecules
 rapid appearance after injury; reflects active gene transcription and translation by injured cell
 binds to specific cell receptors and activates intracellular signaling pathways
 influence immune cell production, differentiation, proliferation, and survival
 regulate other cytokines that may have pro-inflammatory or anti-inflammatory properties
 with overlapping activity
 manifestions of cytokine effect: fever, leukocytosis, alterations in respiratory and heart rate – referred
to as systemic inflammatory response syndrome (SIRS)
 exaggerated, acute production of pro-inflammatory cytokines causes hemodynamic instability in
septic shock

Tumor Necrosis Factor-alpha

 one of the earliest and most potent mediators of host response
 sources: monocytes/macrophages and T-cells
 Kupffer cells: single largest concentrated population of macrophages in body
 release in response to injury is rapid and short-lived; monophasic TNF appearance curve, peak 90
 min, then return to undetectable levels within 4h; with half-life of 15-8 min but can induce marked
metabolic and hemodynamic changes and activate cytokines
 there are endogenous modulators that are responsible for the abbreviated appearance of TNF
 major cytokine related to muscle catabolism and cachexia during stress
 TNF--induced muscle catabolism is by a ubiquitin-proteasome proteolytic pathway (increase in
expression of ubiquitin gene)
 other functions:
1. activation of coagulation
2. promote release of PGE2, PAF, glucocorticoids, eicosanoids

Interleukin-1
 biosynthesis and release induced by TNF-
 source: macrophages and endothelial cells
 pro-inflammatory species: IL-1, IL-1 (produced in great quantities and induces systemic
derangements after injury)
 potency and effects of IL-1 reflect those of TNF-: similar physiologic and metabolic alterations
 increased doses: TNF- and IL-1 independently causes hemodynamic decompensatoin
 decreased doses: same response if administered simultaneously (synergism)
 effects:
1. classic febrile response to injury by stimulating local prostaglandin activity in the anterior
hypothalamus
2. induction of anorexia (effect on hypothalamic satiety center)
3. augment T-cell proliferation by enhancing IL-2 production
4. attenuated pain perception after surgery by release of -endorphins from pituitary and increase in
number of central opioid-like receptors
5. potent stimulant of ACTH and glucocorticoids
 antagonist: IL-1 receptor antagonist (IL-1ra)
 inflammatory cascade initiated by TNF- and IL-1: IL-2, IL-4, IL-6, IL-8, granulocyte/macrophage
colony stimulating factor (GM-CSF), and IFN-

Interleukin-2
 half-life <10 min
 IL-2 secretion by lymphocytes impaired after acute injury, cancer, AIDS, and peri-operative blood
transfusion
 contributes to transient immunocompromised state of surgery patient

Interleukin-4
 produced by activated T-cells
 effects on hemopoietic cells include induction of B lymphocyte proliferation
 potent anti-inflammatory cytokine; downregulate IL-1, TNF-, IL-6, IL-8, superoxide production
 importance of IL-4: capacity to downregulate response of inflammatory macrophages exposed to
stimuli such as bacterial endotoxin or proinflammatory cytokine
 can induce programmed cell death
 increased macrophage susceptibility to anti-inflammatory effects of glucocorticoids
 share properties with IL-3

Interleukin-6
 used as indicator of systemic inflammatory response and predictor of preoperative morbidity, because
of observed elevation of IL-6 blood levels in acute injury
 TNF- and IL-1 are major inducers
 produced by virtually all types of cells
 after injury, detectable by 60 min, peak at 4-6h, persists for 12 days
 proportional to extent of tissue injury during operation rather than duration of surgery
 IL-1 and IL-6 are important indicators of hepatic acute-phase prot xxx
Interleukin-8
 activity temporally associated with IL-6 after injury
 a biomarker for risk of multiorgan failure
 PMN activator and potent chemoattractant
 does not produce hemodynamic instability

Interleukin-10
 modulate TNF- activity
 neutralization of IL-10 during injury-induced inflammation by promoting IL-!ra and sTNFR production
 mortality increases when IL-10 is blocked with an anti-IL-10 antibody

Interleukin-12
 promote differentiation of T-helper cells and production of IFN-; pivotal molecule in cell-mediated
immunity after injury or infection
 may prevent apoptosis in certain T lymphocyte populations

Interleukin-13
 shares many IL-4 properties
 produced during T-helper cell responses
 has influence on B-lymphocyte subpopulations
 inibit nitric oxide production
 net effect of IL-13, along with IL-4 and IL-10 is anti-inflammatory

IFN-
 T-helper cells activated by the antigens IL-2 and IL-12 produce IFN-; IFN- can induce production of
IL-2 and IL-12 in T-helper cells
 detectable n vitro by 6h; half-life 30 min; peak 48-72h; persists for 7-8 days
 has important role in activating circulation and tissue macrophages

Granulocyte/Macrophage Colony-Stimulating Factor

 induced by IL-2 and endotoxin
 delays apoptosis of macrophages and PMNs
 promotes maturation and recruitment of functional leukocytes
 suppress IL-10 production
 perioperative GM-CSF administration in major oncologic procedures augment neutrophil numbers
and function

Programmed cell death (apoptosis)

 principal mechanism (in normal host) by which senescent or dysfunctional cells, including
macrophages and PMNs, are systemically disposed of without activating other immunocytes or the
release of proinflammatory contents
 signals inducing normal apoptosis differ from cell to cell, but converge in a common final pathway
 these signals arise extracellularly: hormonal or paracrine
 inflammatory milieu disrupts the normal apoptotic machinery, delays disposal of activated
macrophages and PMNs
 delay normal temporal sequence of macrophage and PMN apoptosis (in vitro):
1. TNF
2. IL-1
3. IL-3
4. IL-6
5. GM-CSF
6. G-CSF
7. IFN-γ
 accelerate apoptosis in activated monocytes:
1. IL-4
2. IL-10
 prolonged survival of inflammatory immunocytes may perpetuate and ugment the inflammatory
response to injury and infection, precipitating multiple organ failure and eventual death in severely
injured and critically ill patients

Hormones and Cytokine Interactions

Cortisol
 hypercortisolemia differentially influences leukocyte counts and cytokine expression in temporal
fashion
Glucocorticoids
 administration immediately before or concomitantly with endotoxin infusion in healthy human beings
can attenuate symptoms (fever, tachycardia), catecholamine response, and acute-phase response
 it increases IL-10 release, however, which release may contribute to the acute anti-inflammatory
effect of glucocorticoids
 can influence the regulation of T-lymphocyte proliferation or apoptosis (requires elevation of
intracellular cAMP)
 IL-2, IL-4, and IL-10 protects these lymphocytes from glucocorticoid-induced apoptosis
 IL-1, and TNF, and IL-6 can activate hypothalamus-pituitary-adrenal axis and induce the release of
CRH and ACTH, leading to increases glucocorticoids
 glucocorticoids, in turn, inhibit endotoxin-induced production of TNF at the level of mRNA translation
 dexamethasone also inhibits neutrophil apoptosis and prolongs their functional responsiveness; this
can be detrimental to the patient because of perpetuated injurious effects of activated neutrophils

Cathecholamines
 inhibit endotoxin-induced macrophage production of TNF-α in vitro
 in normal human subjects, short-term preexposure to epinephrine effectively inhibits endotoxin-
induced TNF production; concurrent increase in production of anti-inflammatory IL-10
 endo- or exogenous epinephrine may serve to limit excessive proinflammatory effects of cytokines in
the early phase of systemic infection

Other Mediators of Injury Response

Endothelial Cell Mediators

Endothelial Cell Function

 in a paracrine fashion, TNF-α, ILL-1, endotoxin, thrombin, histamine, and IFN-γ stimulates or
activates the endothelial cell during local tissue injury
 in response, the endothelial cell releases several mediators:
1. IL-1
2. PAF
3. PI2 and PGE2
4. GM-CSF
5. growth factors
6. endothelin
7. nitric oxide
8. TXA2
 activated endothelial cells also release collagenases capable of digesting their own basement
membranes; for neovascularization and vascular remodeling at sites of injury to facilitate adequate
oxygen supply and immunocyte transport
 ACE convert AI to AII on the surface of endothelial cells, making it a potent regulator of vascular tone
 endothelial cell mediators can modulate cardiovascular and renal function and influence the
hypothalamus-pituitary-adrenal axis
 activated endothelial cell upregulates its expression of leukocyte adhesion receptor molecules such
as E-selectin (former endothelial-leukocyte adhesion molecule-1, ELAM-1), P-selectin, and
intercellular adhesion molecules (ICAM-1, ICAM-2)
 adhesion of leukocytes and platelets to the endothelial surface occurs early in the endothelial-derived
inflammatory process
 expression of E-selectin on endothelial cell surfaces maximal at 4-6h
 recovery from the inflammatory process is characterized by internalization of these adhesion
molecules within the endothelial cell
 neutrophil adhesion to the endothelium during injury is clinically important for increasing vascular
permeability and passage of leukocytes into injured tissues
 local injuries and inflammatory mediator stimulation promote margination of circulating PMNs to the
endothelial surfaces
 these marginated PMNs are deformable and travel along the endothelial surfaces at reduced
velocities, referred to as rolling (a process of transient attachment and detachment between receptors
of PMNs and endothelium
 the subsequent development of stronger receptor adhesions, PMN activation by endothelial
mediators, and release of PMN proteinases at endothelial junctions precedes the migration of PMNs
out of the vascular compartment, a process called diapedesis
 activated PMNs and the subsequent release of inflammatory mediators and reactive oxygen
metabolites are implicated in capillary leakage, acute lung injury, and postischemic injury

Endothelium-Derived Nitric Oxide (EDNO)

 also endothelium-derived relaxing factor (EDRF)
 released in response to:
1. acetylcholine stimulation
2. hypoxia
3. endotoxin
4. cellular injury
5. mechanical shear stress from circulating blood
 induction of vascular smooth muscle relaxation by EDNO increases cGMP within myocytes
 cGMP is present in platelets an can be activated by EDNO; increased EDNO in platelets reduces
adhesion and aggregation
 EDNO induces vasodilation and platelet deactivation
 EDNO is a readily diffusible substance with a half-life of a few seconds; decomposes spontaneously
into nitrate and nitrite
 formed from oxidation of L-arginine, catalyzed by NO synthase
 in addition to the endothelium, this enzymatic activity is also present in:
1. PMNs
2. macrophages
3. renal cells
4. Kupffer cells
5. cerebellar neurons
 in normal vasculature, EDNO blockade induces vasoconstriction, readily reversed with L-arginine
administration; this demonstrates constant state of vasodilation because of continuous release of
EDNO
 elevations of EDNO in septic shock and trauma are associated with low systemic vascular resistance

Prostacyclin
 also PGI2
 endothelium-derived vasodilator synthesized in response to vascular shear stress and hypoxia
 functions similar to EDNO
 derived from arachidonic acid
 causes relaxation and platelet deactivation by increasing cAMP
 used to reduce pulmonary hypertension, particularly in pedia patients
Endothelins (ETs)
 elaborated by vascular endothelial cells in response to injury, thrombin, IL-1, AII, arginine
vasopressin, catecholamines, and anoxia
 a small peptide with potent vasoconstrictor properties
 ET-1 is the most biologically active and potent vasoconstrictor known; 10x more potent than
angiotensin II (AII)
 ET receptors linked to the formation of EDNO and PGI2, which are negative feedback mechanisms,
and the vasoconstrictor activity of ET can be reversed by acetylcholine, which stimulates EDNO
production
 EDNO and ET interact to maintain physiologic tone in vascular smooth muscles
 Increased ET are correlated with the severity of injury after major trauma, major surgical procedures,
and cardiogenic or septic shock

Platelet-Activating Factor
 another endothelium-derived product
 a phospholipid constituent of cell membranes that can be induced by TNF, IL-1, AVP, and AII
 this inflammatory mediator stimulates production of TXA2, a potent vasoconstrictor
 can induce:
1. hypotension and increase vascular permeability
2. hemoconcentration
3. pulmonary hypertension
4. bronchoconstriction
5. primed PMN acivity
6. eosinophil chemotaxis/degranulation
7. thrombocytopenia
8. general leukocytosis by way of margination
 administration of PAF antagonists in human endotoxemia partially attenuates myalgias and rigors, but
they do not reverse hemodynamic derangements
 alters the shape of endothelial cells, causing them to contract and increase permeability sufficiently to
permit passage of macromolecules, such as albumin, across cell junctions
 chemotactant for leukocyte adherence to vascular wall and facilitates migration out of the vascular
compartment
 other cells that secrete PAF:
1. macrophages
2. PMNs
3. basophils
4. mast cells
5. eosinophils

Arial Natriuretic Peptides

 released by CNS and by specialized endothelium found in atrial tissues in response to wall tension
 potent inhibitors of aldosterone secretion and prevent reabsorption of sodium
 role of ANP in human response to injury is unknown

Intracellular Mediators

Heat-Shock Proteins
 production induced by:
1. heat
2. hypoxia
3. trauma
4. heavy metals
5. hemorrhage
 presumed to protect cell during stress states
 function intracellularly in the assembly, disassembly, stability, and transport of proteins
 classic example of HSP activity is the intracellular transport of steroid molecules
 gene expression occurs in parallel with hormonal activities of the hypothalamus-pituitary-adrenal axis
 relevance in human response to injury can only be inferred from animal data

Reactive Oxygen Metabolites (ROMs)

 short-lived, highly reactive molecular oxygen species with an unpaired outer orbit
 cause tissue injury by peroxidation of cell membrane fatty acids
 produced by complex processes that involve anaerobic glucose oxidation coupled with reduction of
oxygen to superoxide anion–a potent ROM, metabolized to form other reactive species, such as
hydrogen peroxide and hydroxyl radical
 cells are not immune to their own ROMs, but are protected by oxygen scavengers (glutathione and
catalases)
 in ischemic tissues, the intracellular mechanism for ROM production becomes fully activated but are
non-functional because of lack of oxygen supply
 with restoration of blood flow and oxygen, large quantities of ROMs are produced that can induce
reperfusion injury
 activated leukocytes are potent generators of ROMs
 ROMs also can induce apoptosis

Other Inflammatory Mediators

Eicosanoids
 encompasses prostaglandins, thromboxanes, leukotrienes; consists of oxidation derivatives of the
membrane phospholipid arachidonic acid (eicosatetraenoic acid)
 secreted by virtually all nucleated cells except lymphocytes
 synthesis of arachidonic acid from phospholipids require enzymatic activation of phospholipase A2
(see Figure 1-19)
 synthesis of prostaglandins and thromboxanes is inhibited by NSAIDs and salicylates, which are
cycloxygenase inhibitors
 eicosanoids are not stored in cells but are synthesized rapidly on stimulation by hypoxic and ischemic
injury, endotoxin, norepinephrine, AVP, AII, bradykinin, serotonin, acetylcholine, histamine
 products of arachidonic acid metabolism are functionally cell/tissue specific
 vascular endothelium primarily synthesizes PGI2
 thromboxane synthase converts platelet prostaglandins to TXA2
 macrophages syntesize cycloxygenase and lipoxygenase products
 second messengers mediate much of eicosanoid activity
 diverse effects systemically (see Table 1-7)
 promote changes in vascular permeability, leukocyte migration, vasodilation
 potentially contribute to acute lung injury, pancreatitis, and renal failure
 leukotrienes are produced by lung cells, connective tissue, smooth muscle, macrophages, and mast
cells that mediate anaphylaxis; they promote capillary leakage, leukocyte adherence, neutrophil
activation, bronchoconstriction, and vasoconstriction
 products of cycloxygenase pathway inhibit insulin release; lipoxyenase ~ promote insulin release
 hepatocytes have receptors for PGE2, when activated inhibit gluconeogenesis
 PGE2 inhibits lipolysis; suppress T lymphocyte proliferation by mitogens, an effect mediated by
downregulation of IL-2 production
 Indomethacin, a PGE2 inhibitor, enhances lymphocyte activation

Kallikrein-Kinin System
 bradikinins are potent vasodilators produced through kininogen degradation by the serine protease
kallikrein
 kallikrein exists in blood and tissues in an inactive form, activated by chemical an physical factors:
Hageman factor, trypsin, plasmin, factor XI, glass surfaces, kaolin, and collagen
 kinins are rapidly metabolized
 kinase II is identical to ACE; ACE inhibitors partially blocks kinin degradation and enhance kinin-
induced injurious effects on the bronchial tree
 kinins:
1. increase capillary permeability and tissue edema
2. evoke pain
3. increase bronchoconstriction
4. increase renin formation, which promotes sodium and water retention
 bradykinin release is stimulated by hypoxic and ischemic injury
 increased kallikrein activity and bradykinin levels have been detected after hemorrhage, sepsis,
endotoxemia, and tissue injury; these observations are correlated to the magnitude of injury and
mortality
 clinical trials using bradykinin antagonists to reduce deleterious sequelae of septic shock have
demonstrated only modest effects and no overall improvement in survival
 kinins increase glucose clearance by inhibiting gluconeogenesis

Serotonin (5-hydroxytryptamine, 5-HT)

 tryptophan derivative neurotransmitter found in the intestine and platelets
 patients with midgut carcinoid tumors often secrete excessive 5-HT
 stimulates vasoconstriction, bronchoconstriction, and platelet aggregation
 also has chronotropic and inotropic effects
 although released at site of injury, role in the injury response is unclear

Histamine
 derived from histidine and stored in neurons, skin, gastric mucosa, mast cells, basophils, and
platelets
 two receptors for histamine binding:
1. H1 binding – mediates increased uptake of histamine precursor, L-histidine; stimulates
bronchoconstriction, intestinal motility, and myocardial contractility
2. H2 binding inhibits histamine release
 H1 and H2 receptor activation induces vasodilation and increases vascular permeability
 histamine administration causes:
1. hypotension
2. peripheral pooling of blood
3. increased capillary permeability
4. decreased venous return
5. myocardial failure
 histamine released in hemorrhagic shock, trauma, thermal injury, endotoxemia, and sepsis
 histamine levels are correlated with mortality from septic shock

Metabolic Response to Injury

Ebb phase
 earliest moments to hours after injury
 associated with hemodynamic instability or reductions in effective circulating blood volume
 metabolic consequences are less well studied, generally associated with reductions in total body
energy expenditure and urinary nitrogen loss
 associated with neuroendocrine hormone appearance, including catecholamines and cortisol
Flow phase
 ushered in by compensatory mechanisms resulting from volume repletion and cessation of initial
injury conditions
 metabolic response serves to direct energy and protein substrates both to preserve organ function
and repair damaged tissues; includes an increase in whole-body oxygen consumption and metabolic
rate, enhancement of enzyme pathways for oxidation of energy substrates and stimulation of the
immune system to repair tissue and prevent additional breaks in epithelial barriers
 a reprioritization of substrate processing occurs to support the production of acute-phase reactants,
immunoreactive proteins, and coagulation factors
 wound healing begins in early flow phase

Metabolic Response to Fasting

 factors such as antecedent health status, age, lean body mass influence the absolute rates of
substrate utilization after fasting or injury

Substrate Metabolism
 a healthy adult of 70 kg body weight expends 1700-1800 kcal/day of energy obtained from the
oxidation of lipid, carbohydrate, and protein
 obligate glycolytic cells (neurons, leukocytes, erythrocytes) require 180 g of glucose/24h for basal
energy needs
 during acute starvation, glucose is derived from existing storage pools, including ~75g glucose stored
as hepatic glycogen
 skeletal muscle cannot directly release free glucose because it lacks glucose-6-phosphatase
 reduction of circulating glucose during prolonged fasting stimulates hormonal release that modulates
gluconeogenesis and substrate substitution for those tissues which require glucose for energy
 glucose concentration falls within hours after onset of fasting in association with decreases in insulin
and increases in glucagon, GH, catecholamines, AVP, and angiotensin II
 glucagon and epinephrine enhance cAMP to promote glycogenolysis, and cortisol and glucagon
promote gluconeogenesis
 norepinephrine, AVP, and angiotensin II also promote glycogenolysis
 effect of these actions: increase in glucose production
 sustained glucose production depends on the presentation of amino acids, glycerol, and fatty acids to
the liver
 primary gluconeogenic precursors used by the liver and kidney for gluconeogenesis are lactate,
glycerol, and amino acids such as alanine and glutamine
 skeletal muscle releases lactate by the breakdown of endogenous glycogen stores and by glycolysis
of transported glucose
 lactate is also released by erythrocytes and WBC after aerobic glycolysis; lactate is reconverted to
glucose in the liver by the Cori cycle
 quantity of glucose made from lactate produced by skeletal muscle is not sufficient to maintain
glucose homeostasis; consequently, ~75g of protein must be degraded daily during fasting and
starvation to provide gluconeogenic amino acids to the liver
 proteolysis, results from decreased insulin and increased cortisol, increases urinary nitrogen
excretion from the normal 6-8g/day to ~8-11g/day within the initial 5 days of fasting
 amino nitrogen load resulting from deamination of amino acids for gluconeogenesis increases urinary
ammonia excretion; renal excretion of ammonium ion is the primary route of alpha-amino nitrogen
during starvation because the normally active hepatic enzymes are diminished
 the kidney may account for up to 45% of glucose production during late starvation
 after ~5days, the rate of whole-body proteolysis diminishes to15-20g/day, and urinary nitrogen
excretion satbilizes at 2-5g/day for several weeks
 reduction in proteolysis due to adaptation to ketone oxidation as predominant energy source; so
protein need for gluconeogenesis is reduced
 energy requirements for gluconeogenesis and basal enzymatic and muscular function can be met by
mobilization of 160g triglycerides from adipose tissue (free fatty acid and glycerol form) in a resting
70-kg subject
 lipid stores provide up to 40% of caloric expenditure during starvation
 ketone bodies inhibit pyruvate dehydrogenase and spare glucose
 whole-body energy expenditure decreases during prolonged fasting as a consequence of decreased
sympathetic nervous system activity, reduced muscle activity, reduced secretory enzyme production,
and intestinal energy needs
Metabolism After Injury

Energy Balance
 injury of any magnitude is associated with increases in energy expenditure and oxygen consumption
that vary directly with severity of injury or burn surface area
 increase is initially due to increases sympathetic activity and increased catecholamines

Lipid Metabolism
 lipolysis is enhanced by immediate elevations in ACTH, cortisol, catecholamines, glucagon, and GH,
reduction in insulin, and increased sympathetic activity
 lipolysis observed during ebb phase is due to elevated levels of free fatty acids (FFA) and glycerol
 during flow phase, net lipolysis continues, are reflected by increased concentrations and clearance of
plasma FFA
 high FFA concentration inhibits fatty acid synthesis
 ketogenesis is decreased after major injury, severe shock, and sepsis
 after minor injury, ketogenesis increases, but to a lesser extent than that seen during non-stressed
starvation

Carbohydrate Metabolism
 glucose intolerance is well-documented in injured patients
 during early flow phase, state of relative insulin reistance
 50-60% increase in net splanchnic glucose output in septic patients; 50-100% increase in thermally
injured patients
 increases in plasma glucose are proportional to the severity of injury, to some extent correlated to
survival
 insulin resistance is of teleologic benefit to the host in that the accompanying neuroendocrine
hormone response precludes the adaptation to ketone body production
 glucose must be provided to inflammatory and healing cells in the wound; glucose uptake and lactate
production in wounded tissue is increased, wound inflammatory cells require glucose as an energy
substrate

Protein and Amino Acid Metabolism

 intake of protein for a healthy young adult is approximately 80-120g, or 13-20g of nitrogen per day
 daily fecal excretion of nitrogen 2-3g; urinary, 13-20g
 after injury, daily nitrogen excretion in the urine increases to 30-50g are urea nitrogen and represents
net proteolysis
 increased urea excretion also associated with urinary loss of sulfur, phosphorus, potassium,
magnesium, creatinine (indicates breakdown of intracellular compounds and loss of lean tissue)
 skeletal muscle is depleted, while visceral tissues, such as liver and kidney, are relatively preserved
 severe trauma, burns, and sepsis are associated with increased whole-body protein turnover and
increased net protein catabolism (see Figure 1-8)
 rise in urinary nitrogen and negative nitrogen balance begin shortly after injury, peak at about the first
week, may continue for 3-7 weeks
 young, healthy males lose more protein in response to injury than do women or the elderly
 after trauma, substrate cycling occurs between skeletal muscle, liver, and the wound
 increases by several times in the splanchnic uptake of alanine and glutamine in conjunction with
similar trends for peripheral tissue efflux are observed after injury
 glutamine may is a major energy source for lymphocytes, fibroblasts, and the GI tract
 glutamine may act as a conditionally essential amino acid during periods of catabolism

Nutrition in the Surgical Patient

Surgery, Trauma, Sepsis

 in contrast to energy and protein conservation during unstressed starvation, the injured patient
manifests increases in energy expenditure and nitrogen loss (se Figure 1-35)
 inability to downregulate body energy expenditure and nitrogen losses may rapidly deplete labile and
functional energy stores
 postinjury metabolic environment precludes the efficient oxidation of fat and production on ketones,
thereby promoting continued erosion of protein; unchecked, this enhanced net protein catabolism
may lead to organ failure
 flow phase metabolic and endocrine events occasioned by injury may be divided into several phases:
catabolic, early anabolic, and late anabolic

Catabolic Phase
 termed adrenergic-corticoid phase
 glucose turnover is increased; Cori cycle activity is stimulated and 3-carbon intermediates are
converted back to glucose in the liver
 lipolysis is stimulated

Early Anabolic Phase

 transition from catabolic to anabolic phase occur within 3-8 days after uncomplicated elective surgery
 may be delayed for weeks in patients with extensive cross-sectional injury, sepsis, or ungrafted
thermal injury
 this turning point, corticoid-withdrawal phase, is characterized by a sharp decline in nitrogen excretion
and restoration of appropriate potassium-nitrogen balance
 biochemically characterized by reprioritization of acute-phase reactants, as early inflammatory
response proteins are supplanted by tissue repair and anabolic factors
 may last from few weeks to a few months depending on the capacity to ingest adequate nutrition and
the extent of protein erosion
 nitrogen balance is positive (synthesis of proteins), rapid and progressive gain in weight and
muscular strength
 positive nitrogen balance reaches a maximum of approximately 4g/day which represents the
synthesis of ~2g of protein and the gain of over 100g of lean body mass/day

Late Anabolic Phase

 final phase of convalescence; may last from several weeks to several months after severe injury
 gradual restoration of adipose stores, positive nitrogen balance returns to normal
 weight gain much slower
 for most, the phase ends with a gradual return to the previous normal body weight

Assessment and Requirements

 basal energy expenditure (BEE) can be estimated by Harris and Benedict equation
 BEE men = 66.47 + 13.75(weight in kg) + 5.0(height in cm) – 6.76(age in years) kcal/day
 BEE women = 655.1 + 9.56(weight in kg) + 1.85(height in cm) – 4.68(age in years) kcal/day
 nonprotein calories are supplied in excess of energy substrate demands because the use of
exogenous nutrients is decreased and energy substrate demands are increased after injury
 appropriate nonprotein caloric needs are 1.2-1.5 times resting energy expenditure (REE) during
enteral nutrition and 1.5-2.0 times REE during intravenous nutrition