Systemic and Metabolic

Response to Injury
Gerardo R. Wenceslao, MD, FPCS, FPSGS
Diplomate, Philippine Board of Surgery
Fellow, Philippine College of Surgeon
Systemic and Metabolic
Response to Injury
Phases of SIRS:

Acute pro-inflammatory response

Anti-inflammatory phase
By way of the parasympathetic nervous system
through neurotransmitter Acetylcholine

Regulates early inflammatory release from TNF

Inhibits cytokine activity and reduce injury from

severe inflammatory response
Systemic inflammatory response syndrome is a syndrome initiated by multiple
risk factors. Trauma, surgery, and infection trigger the innate immune system
to produce pro-inflammatory mediators. The magnitude of this response is
determined by host genetics, health, and immunity to a given risk factor. An
overzealous systemic immune response, from which the host is unable to re-
cover, culminates in death via ARDS, MOF, and/or DIC. Animals predisposed
to the high immune responders are theoretically more likely to succumb than
are those predisposed to a moderate immune response
 Hormonal Response to
Injury
Adrenocorticotropic Hormones
Released by the anterior pituitary gland

ACTH release is in proportional to the

severity of injury

Stimulates production of glucocorticoids

and mineralocorticoids
 Hormonal Response to Injury
Stimuli for release of ACTH

Corticotropin releasing hormone

Pain

Anxiety

Angiotensin II

Chocystokinin

Catecholamines

VIP
 Hormonal Response to
Injury
Cortisol
A glucocorticoid hormone from the adrenal gland

Released during stress

Chronically elevated in certain disease process

Potentiates the actions of glucagon and epinephrine

Decreases glycogenesis

Increases gluconeogenesis
 Hormonal Response to
Injury
Cortisol
Facilitates breakdown of protein and AA

Mediates the release of lactates

Release fatty acids, triglycerides and glycerol

Impairs wound healing

Reduces Transforming Growth Factor B (TGF-b)

Can be ameliorated by vitamin A

 Hormonal Response to
Injury
Cortisol and Glucocorticoids

Immunosuppressive properties
Thymic involution

Decreased Killer Cells and function

Inhibits leukocyte migration

Inhibits intracellular killing properties of

monocytes
 Hormonal Response to
Injury
Aldosterone

Mineralocorticoid from zona glomerulosa of adrenal cortex

Released is by:
ACTH

Angiotensin II

Decreased intravascular volume

Hyperkalemia

Increases intravascular volume by:

Retain Na
Eliminate K and H
 Hormonal Response to
Injury
Renin-Angiotensin - Aldosterone

Activation of Protein to Renin

Decreased perfusion

B-adrenergic stimulation

Decreased Na delivery to the distal tubules

Renin
Converts angiotensinogen-angiotensin I

Angiotensin I
Converted to angiotensin II in the lungs by angiotensin-
converting enzyme
 Hormonal Response to
Injury
Angiotensin II
Potent vasoconstrictor

Increased heart rate and contractility

Increased vascular permeability

Stimulates Aldosterone secretion from the adrenal cortex

Increased Na and water resorption from the renal

tubules

Eliminates K and H
 Hormonal Response to
Injury

Metabolic activity of Angiotensin II

Stimulation of hepatic glycogenolysis

Stimulation of gluconeogenesis
 Hormonal Response to
Injury
Aldosterone Deficiency
Hypotension

Hyperkalemia

Aldosterone Excess
Edema

Hypertension

Hypokalemia

Metabolic alkalosis
 Hormonal Response to
Injury
ADH
From the supraoptic paraventricular
nuclei of the hypothalamus

Stored in the posterior pituitary

Plasma osmolality - primary stimulus

Released is facilitated by B-adrenergic

and angiotensin II stimulation
 Hormonal Response to
Injury
ADH

Osmoregulator
Resorption of solute free water in the distal tubule
and collecting ducts

Vasoactive
Vasoconstriction

Metabolic
Glycogenolysis/Gluconeogenesis
 Hormonal Response to
Injury

Catecholamines
Levels are increased 3 - 4x after an
injury

Peak level 24 - 48 hours after the

injury
 Hormonal Response to
Injury
Catecholamines
Epinephrine
Secreted by chromaffin cells of the adrenal medulla

Hemodynamic actions

Alpha mediated vasoconstriction

Beta mediated vasodilatation and increased heart rate

Low dose epinephrine - beta mediated

High dose epinephrine - alpha mediated

 Hormonal Response to
Injury
Catecholamines

Metabolic
Increase glucose production in the liver

Decrease glucose uptake in the periphery

Increase glucagon,decrease insulin secretion

Increased peripheral resistance to insulin

Promotes lipolysis and proteolysis

 Hormonal Response to
Injury
Catecholamines

Impairs wound healing

Increased production of TGFb and INF-1

Immunodepressant
Through the activation of B2 receptors on
immunocytes

Inhibit the release of inflammatory cytokines

Enhances the release of anti-inflammatory

mediator-interleukin 10
 Hormonal Response to
Injury
Insulin
Initial suppression after injury mediated by
catecholamines and symphatetic nervous system

Secretion is stimulated by:

Glucose

Fatty acids

Ketone bodies
 Hormonal Response to
Injury
Insulin
Stimulates hepatic glycogenesis

Glycolysis

Lipogenesis

Protein synthesis

Increased amino acid transfer to the liver and

peripheral tissues

Peripheral glucose uptake

 Hormonal Response to
Injury
Insulin

Suppression of insulin secretion

Hyperglycemia

Suppresses the immune system by:

Glycosylation of immunoglobulin

Decreased phagocytosis
 Hormonal Response to
Injury
Growth Hormones and Insulin-like
Growth Factors

Secreted by the pituitary gland

Metabolic effects
Increase protein synthesis and lipogenesis

Increase glycogenesis

Increase glucose uptake and lipid utilization

 Hormonal Response to
Injury
Growth Hormones and Insulin
like Growth Factors

Immunomodulatory function
Enhances the phagocytic activity of
immunocytes through increased
lysozomal superoxide production

Increase T cell production

 Hormonal Response to
Injury
Macrophage Migration-Inhibitng
Factor (MIF)
Stored and secreted by the anterior pituitary
and macrophages

Counteracts the anti-inflammatory effects of

cortisol on immunocytes

Increases the activity of immunocytes on

pathogens
 Hormonal Response to
Injury

Acute Phase Proteins

Not reliable as an index of inflammation
in the presence of hepatic insufficiency

Do not show diurnal variations

Not modulated by feeding

 Hormonal Response to
Injury
Acute Phase Proteins

Ceruloplasmin, haptoglobin, C-reactive proteins

Produced by the liver thru the initiation of:

IL-6

TNF-a

IL-1

Anti-oxidants (ceruloplasmins)

Serves as Opsonins (C-reactive proteins)

Alpha 1 anti trypsin

Mediator of Inflammation
Cytokine mediated response
Regulate the production and actions of other
cytokines which can be pro-inflammatory or
anti-inflammatory

Eradicate invading microorganism and

promote wound healing

They are responsible for inflammatory

response such as fever, leukocytosis.. etc
Mediators of Inflammation
Cytokine mediated response
Exaggerated pro-inflammatory response
is responsible for manifestations seen in
septic shock

Chronic production of cytokines results

to muscle wasting and cachexia

Lessens the pain perception by

increasing B-endomorphins production
Immune Response to Injury
Types of Cytokines

Tumor Necrosis Factor-alpha (TNF-a)

Produced from monocytes/macrophages T-
cells. Kupffer cells and endothelial cells

Earliest and most potent mediator of

inflammatory response to injury

Release in response to injury is rapid but

short lived
 Types of Cytokines
TNF-a
Major cytokine related to muscle
catabolism and cachexia during stress

Amino acid from skeletal muscles

mobilized are used as fuel substrates

Activates coagulation and promotes

release of prostaglandin (PGE2), PAF,
glucocorticoids, eiconasoids
 Types of Cytokines
Effects of IL-1
Febrile response to injury by stimulating prostaglandin
(PGE2) activity in the hypothalamus

Anorexia by activating the satiety center in the

hypothalamus

Proteolysis of skeletal muscle

Initiates hyperglycemic response

Increasing B-endomorphin release - less pain perception

Mediators of Inflammation
Cytokine mediated response

Cytokines (TNF-a and IL-1)

Decreased circulating levels of iron and zinc

Has an inhibitory effect on microbes using

ion for growth

Increased Copper

Due to increased ceruloplasmin

 Types of Cytokines
Interleukin 2
A true lymphokine - an
immunostimulant

Release is triggered by antigen

stimulation of lymphocytes

Promotes T-lymphocyte proliferation

and immunoglobulin production
 Types of Cytokines
Anti-inflammatory cytokines

Interleukin 10
Strongest anti-inflammatory cytokine

Interleukin 6
Stimulate PGE2 - febrile response

Regulates hepatic acute phase response

Enhances immune function

Interleukin 13
Mediators of Inflammation

Pyrogenic Interleukins
IL-1

IL-6

TNF
Mediators of Inflammation

Interferons
A cytokine produced by leukocytes, T
cells and fibroblast

Produces protein that inhibits cell

replication
Mediators of Inflammation
Interferons

Type 1

Enhances the adaptive immune system by maturation of dendritic

cells and expression of class 1 MHC

Used as therapeutic agents in Hepatitis C and relapsing multiple

sclerosis

Type 2

Enhances the phagocytic activity of macrophages

Increased microbial killing capability by releasing oxygen radicals

Regulates immnocytes to the site of inflammation

Mediators of Inflammation
Reactive Oxygen Species
They can cause injury to both host cells and invading
microorganism by oxidation of unsaturated fatty acids
with the cell membrane

They produced as by-product of oxygen metabolism

and by anaerobic process

Host cells are protected from ROS by antioxidants -

glutathione peroxidase, catalase, superoxide dismutase

Responsible for re-perfusion injury

Mediators of Inflammation
Reactive Oxygen Species

Main areas of ROS production

Fatty acid metabolism

Cytochrome P-450 reaction

Respiratory phagocytic cells

Mitochondria
Mediators of Inflammation
Eicosanoids
Derived from oxidation of membrane phospholipid-arachidonic acid

Production leads to formation of Lipoxin-inhibits chemotaxis

They are not stored in the cells but are produced rapidly in response to:

Injury

Epinephrine

Vasopressin

Bradykinin

Acetylcholine

Angiotensin II
Mediators of Inflammation

Eicosanoids
Generate mostly pro-inflammatory reaction
with deleterious effects on the host such as:

Acute Lung Injury

Renal Failure

Pancreatitis
Mediators of Inflammation
Eicosanoids

Prostaglandin
Promotes inflammation

Thromboxane
Vasoconstrictor and platelet aggregating factor

Leukotriens
Capillary leakage, bronchospasm, vasoconstriction
Mediators of Inflammation
Eicasanoids

Metabolic Effect
Cyclooxygenase pathway

Inhibits insulin release by B-cells

Lipooxygenase pathway

Increases B cell activity

Inhibits gluconeogenesis (Prostaglandin E2)

Mediators of Inflammation

Eicosanoids

The following blocks the effect of

Eicosanoids
Glucocorticoids

NSAID

Leukotriene inhibitors
Mediators of Inflammation

Kallikrein-Kinin System
Group of proteins that contributes to:

Pain response

Inflammation

Coagulation

Blood pressure control

Mediators of Inflammation
Kallikrein-Kinin System

Kallikrein plays a role in coagulation cascade it is

activated:
Hageman factor

Trypsin

Plasmin

Factor XI

Glass surface
Mediators of Inflammation
Kallikrein-Kinin System

Bradykinin - produced in the liver

Vasodilatation

Activates renin-angiotensin-aldosterone

Increased capillary permeability

Tissue edema

Broncho-constriction

Inhibits gluconeogenesis
Mediators of Inflammation
Kallikrein-Kinin System

Bradykinin and Kallikrein are in elevated in:

Gram negative bacteremia

Endotoxemia

Tissue injury

Hemorrhage

Hypotension
Mediators of Inflammation

Serotonin
Derived from tryptophan

Produced by neurons in the CNS and

enterochromaffin cells of the GI tract
and platelets
Mediators of Inflammation

Serotonin

Functions
Vaso and broncho-constrictor

Platelet aggregation

Inotropic and chronotropic effect on

the heart
Mediators of Inflammation

Histamine
Derived from decarboxylation of AA Histidine

They are stored or rapidly released in

neurons, skin and gastric mucosa,mast cells,
basophils and platelets

Increased histamine release is seen in:

Hemorrhagic shock, sepsis, thermal injury

Mediators of Inflammation
Histamine

Receptors
H1

Mediates vasodilatation, broncho-constriction,

intestinal motility and myocardial conractility

H2 - gastric parietal acid secretion

H3 - down regulates histamine release

H4 - in the bone marrow, associated with chemotaxis

of eosinophils and mast cells
Mediators of Inflammation

Heat Shock Protein

Protein modifiers and transporters
that protect cells from deleterious
effects of traumatic stress

Responsible for protein folding and

targeting
Mediators of Inflammation
Mediators of Inflammation

Fatty Acid Metabolites

Precursor of Eicosanoids

Omega 6 fatty acid

Primary lipid source in enteral

nutrition

has pro and anti inflammatory effects

Mediators of Inflammation

Fatty Acid Metabolites

Omega 3
Anti-inflammatory effect by:

Inhibits the release of TNF

Inhibits leukocyte adhesion and

aggregation
 Endothelium Mediated
Injury
Vascular Endothelium
Anticoagulant properties

Heparin sulfate, plasminogen, tissue

plasminogen activator, dermatan
sulfate

Barrier that regulates the migration of

cells
 Endothelium-Mediated
Inflammatory Response
Migration of the inflammatory cells at the site
of injury (Margination)

Attachment to the endothelium mediated by

E-Selectin, P-Selectin and L-Selectin

Become bound to the endothelial cells by

Integrins

Migrate between endothelial cells (Diapedesis)

 Cell-Mediated
Inflammatory Response
Platelets
Derived from bone marrow megakaryocytes

Important in hemostatic response

Release substances that attract neutrophils and monocytes

Important source of Eicosanoids

Lymphocyte and T cell immunity

Eosinophil
Primarily an antihelmintic

Found mostly in tissues such as lungs and GI

Activation lead to release of toxic mediators - ROS, Histamine and

Peroxidase
 Cell-Mediated
Inflammatory Response
Neutrophils
Among the first responders to the site of infection

Through chemotactic mediators from the site of

injury they adhere to the vascular endothelium
and promote cell migration into the injured
tissue

Short half life 4 - 10 hours

Can phagocytose, release lytic enzymes and ROS

 Cell-Mediated
Inflammatory Response
Mast Cells
They are located in the tissues

Source of TNF, recruitment of neutrophils and clearance of pathogens

Play an important role in anaphylactic response to allergens

Monocytes
Phagocytes that can differentiate into macrophages, osteoclast and
dendritic cells

Macrophages - main effector of immune response

Main effector cells in response infection and injury through

phagocytosis, clearance of apoptopic cells and release of inflammatory
mediators
 Endothelium Mediated
Injury
Atrial Natiuretic Peptide
Primarily from atrial tissue but also formed in the gut, kidney, brain
and adrenals

Vasodilator

Potent Inhibitor aldosterone

Prostacyclin
Eicasanoid produced by endothelial cells

Decreased production during systemic inflammation

Vasodilator

Platelet deactivator
Surgical Metabolism
Normal metabolic activity is described as the macronutrients, carbohydrates,
and fat are converted to energy or fat and protein intake is diverted to protein
synthesis and maintenance of lean body mass. These pathways are controlled
by hormonal balance with the anabolic hormones maintaining protein
synthesis. There is continuous balance of energy between the fat and energy
store
Surgical Metabolism
Protein
Nearly all are functional

Daily requirement 0.8 - 1 gm/day

Daily synthesis is used to:

Maintain skin and muscle mass

Maintain the structural protein of the gut, enzymes,

plasma proteins

Provides circulating pool of amino acids

Surgical Metabolism
Surgical during short term fasting

Reduction of circulating glucose

Stimulates release of hormones that modulates

glycogenolysis and gluconeogenesis

Obligate glycolytic cells - requires 180 g of glucose

Neurons

Leukocytes

Erythrocytes

Kidneys
Surgical Metabolism
Substances that promotes
Glycogenolysis
Norepinephrine

Angiotensin II

Vasopressin

Glucagon
Surgical Metabolism
Metabolism during fasting:
Stored source of fuel

Glycogen - 300 to 400 gm

Muscle glycogen - 200 to 250 gm

Lacks glucose-6-phosphatase

Cannot release free glucose

Hepatic glycogen - 75 to 100 gm

Readily available but limited

Depleted within < 16 hours

Surgical Metabolism
Substances used for Gluconeogenesis
Lactate

Pyruvate

Glycerol

Amino acids

Alanine

Glutamine
Surgical Metabolism
Site of Gluconeogenesis
Liver - primary site

Kidney

Substances that promotes Gluconeogenesis

Glucagon

Epinephrine

Cortisol
 Surgical Metabolism
Sources of Lactate

Skeletal muscle
Breakdown of endogenous glycogen( glycogenolysis)

Glycolysis of transported glucose

Not enough to maintain systemic glucose during fasting

Erythrocytes

White Blood Cells

Anaerobic glycolysis of glucose

Lactate is reconverted to glucose in the liver (Cori cycle)

Cori Cycle
Glucose-Alanine Cycle
Surgical Metabolism
Protein metabolism in short term fasting
75 gm/day for hepatic gluconeogenesis

Elevated urinary nitrogen excretion to > 30gm/day (n.v. 7 -

10 gm/day)

Proteolysis mainly occurs within the skeletal muscles

Proteolysis is prompted by:

Deceased insulin

Increased cortisol

Increased glucagon
Surgical Metabolism
Prolonged fasting (>5 days)

Decrease in alanine
Proteolysis is reduced to 20 gm/day

2 - 5 gm/day - urinary nitrogen excretion

Glucose utilizing tissues begin to adapt and use ketone as

primary source of fuel

Kidneys participates in gluconeogenesis using Glutamate and

Glutamine

Kidneys account to 45% glucose production

Surgical Metabolism
Metabolism during prolonged Fasting

Body Fat
Provides 40% or more of calories

Mobilized thru reduction of insulin,increase in glucagon

and catecholamines

Main provider of energy during fasting through oxidation

of fatty acids and glycerol

Glycerol - used in gluconeogenesis

Free fatty acids (ketone bodies) - used as fuel (heart,

kidney, muscle, liver)
Surgical Metabolism
Metabolism during prolonged fasting

Mobilization of lipid stores results to:

Decreased proteolysis

Decreased glycolysis

Decreased Gluconeogenesis

Decreased over all glucose requirement to sustain the

host

Ketone bodies spare glucose utilization by inhibiting

pyruvate dehydrogenase
Necrotizing fasciitis. A large open wound
will cause severe catabolism and hypermetabolism
Surgical Metabolism
Metabolism during stress

Ebb phase - 24 to 36 hours

Decrease in blood pressure, cardiac output

Decrease in body temperature

Reduced oxygen consumption

Elevated blood glucose level

Insulin level are low

Surgical Metabolism
Metabolism during stress

Flow phase

Catabolic - 3 to 10 days after the injury

Negative nitrogen balance

Increased body temperature

Anabolic - 10 to 60 days after the injury

Hypermetabolism, increased glucose production

Increased oxygen consumption

Increased hormonal stimulation

 Metabolism Following
Injury
Lipid Metabolism following Injury
Serves as non-protein and non-carbohydrate fuel source

Maintains structural integrity of cell membranes and immune

response

Minimize protein catabolism

Lipolysis

Cathecholamine

Triglyceride lipase

Hormonal influences

Cortisol, glucagon, ACTH, growth hormone, reduction of

insulin
 Metabolism Following
Injury
Lipid Absorption
Exogenous triglycerides - main source

Converted in the gut by the action of phospholipase into

free fatty acids and monoglycerides

Monoglycerides are resynthesize into triglycerides by the

action of fatty acyl coenzyme A

Long chain triglycerides - enter into the circulation

through the lymphatic system as chylomicrons

Short chain triglycerides - enter directly into the portal

circulation
 Metabolism Following
Injury
Lipolysis and fatty acid oxidation
Triglyceride lipase - converts TG into free fatty acids
and glycerol

Free fatty acid - transported by albumin into tissues

requiring fuel (heart and skeletal muscle)

Glycerol - for fuel depend on tissue glycerol kinase -

abundant in the liver and kidneys

Free fatty acids absorbed by the cell - conjugated with

acyl-CoA
 Metabolism Following
Injury
Lipolysis and Fatty Acid Oxidation
Fatty acyl CoA - undergoes oxidation at the
mitochondria of the cell to produce acetyl
CoA

Acetyl CoA - enters the TCA cycle for further

oxidation to yield 12 ATP molecules, carbon
dioxide and water

Excess acetyl CoA - precursor for ketogenesis

 Ketogenesis
Increased lipolysis and reduced systemic
CHO diverts acetyl-CoA towards hepatic
ketogenesis

Rate of ketogenesis is inversely proportion

to the severity of injury

Major trauma

Rapid tissue oxidation of fatty acids

The hypermetabolic,catabolic response to stress is "Maladaptive"
as energy demands increase but production is very inefficient,
leading to heat (wasted energy). The hormonal environment is
imbalanced with a resulting excess gluconeogenesis by the liver
using amino acids as substrate. Protein stores are consumed,
especially the important amino acid glutamine. The fat mass is
in large part spared as a source of needed energy
Surgical Metabolism
Metabolism during stress

Cytokines

Hormonal changes
Increased cortisol

Increased catecholamines
Increased glucagon
Surgical Metabolism
Metabolism during Stress or Trauma

Hyperglycemia
Increased glucose production by:

Glycogenolysis within the muscle mediated by

epinephrine

Epinephrine - activates phosphorylase kinase

Activates glycogen phosphorylase

Release of Glucose 1 phosphate from

glycogen
Surgical Metabolism
Metabolism during stress

Hyperglycemia
Increases gluconeogenesis

Primarily from the breakdown of skeletal muscle

Reduced pyruvate dehydrogenase

Diminishes entry of pyruvic acid to TCA

Pyruvic acid is shunted to the liver for

gluconeogenesis
Surgical Metabolism
Metabolism during stress

Poor utilization of glucose

Due to cortisol and catecholamines

Reduced skeletal muscle pyruvate dehydrogenase

Inadequate lipolysis
Continued insulin production due to hyperglycemia

Decreased lipoprotein lipase

Increased protein breakdown

Surgical Metabolism

Metabolism under stress or

injury
Hyperglycemia and insulin resistance
are hallmarks of critical illness
Surgical Metabolism
Respiratory Quotient (RQ)
Ratio of CO2 produced to O2 consumed

RQ-0.7 - greater fatty acid oxidation for fuel

RQ-1 - CHO oxidation for fuel (overfeeding)

RQ-.85 - oxidation of fatty acid and CHO
are equal
Surgical Metabolism
Respiratory Quotient >1
Glucosuria

Conversion to fat

Elevation of CO2

Immune suppression
Surgical Metabolism
Metabolism under stress or injury

Hyperglycemia during critical illness

results to glycosylation of
immunoglobulins

Decreased phagocytosis

Decreased monocytes
Surgical Metabolism
Metabolism after Stress or Injury
Poor utilization of glucose

Increased proteolysis

Impaired entry of AA into muscle cells

Mediated by glucocorticoids

Increased urinary nitrogen excretion (> 30 gm/day)

Peak excretion of nitrogen - 7 days

May persist as long as 3 - 7 weeks

Surgical Metabolism
Protein and AA metabolism
80 -120 g/day of protein

Average protein intake

6 gm of protein - 1 gm of nitrogen

1 gm of protein - 4 kcal of energy

Skeletal muscle are preferentially depleted after injury

Protein may also be lost in large open wounds,

peritonitis/ascites
The catabolic state. The loss of urinary nirogen indicates
loss of body protein equivalent to 1 to 2 lb of muscle per day.
Again the process persists for weeks to months
Surgical Metabolism
Metabolism after Stress or Injury
Inappropriate increase in proteolysis

> 30 gm of urinary nitrogen/day = loss of > 1.5%

of lean mass/day

> 25 - 30% loss of lean mass/day - not

compatible with life

Amino acids - not considered a long term fuel

reserve
Systemic and Metabolic
Response to Injury
Factors that determines response to stress
or injury

Body Composition
Post-traumatic nitrogen excretion correlates with
mass of total protein

Nutritional Status
There is causal relationship between pre-operative
protein depletion and post-op complication

Type of Stress, intensity and duration

Systemic and Metabolic
Response to Injury
Factors that determine host response to
Stress or Injury

Age
Increase in fat mass and decrease in muscle
mass that occurs in aging

Gender
Lean body mass in proportion to body weight is
lower in females than in males
The End