6/18/2008

Response to Injury
Romeo R. Fernandez,MD

General Statements
Series of changes following injury Local(site of injury)/within the body generally Magnitude of change proportional to injury Changes activate defense mechanisms to restore pre-injury state Magnitude of the defense mechanism varies directly with the change

General Statements
Defense Mechanism need energy Defense mechanism may be life saving Disadvantageous/troublesome in some occassions Modify defense mechanisms to suit the situation.

Features of injured patient unmodified by Medical Intervention

EBB phase First 2 hours Cold Hypotensive FLOW phase Catabolic Anabolic

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RESPONSES
INFLAMMATION NEURAL RESPONSE ENDOCRINE HORMONAL RESPONSE

ROLE OF INFLAMMATION AS A RESPONSE IN STRESS

TO ACTIVATE CELLULAR PROCESSES 1. TO RESTORE FUNCTION. 2. TO REMOVE THE INVADING ORGANISM.

Process of Wound Healing

Clinical Spectrum of Infection and SIRS Term Infection SIRS DEFINITION Identifiable source of microbial insult 2 or more of the ff: T>38C or <36C,HR >90/m; RR>20/m;PCO2<32mmhg; mechanical ventilation; WBC>12,000 or <4,000; >10 band forms Identifiable source of infection and SIRS Sepsis and organ dysfunction Sepsis +cardiovascular collapse (requiring vasomotor support

Sepsis Severe sepsis Septic shock

First Hit

Second Hit

Mediators
Amplified Systemic Inflammatory Response

1st degree MODS

Systemic Inflammatory Response

2nd degree MODS

Recovery Death Recovery

Death

Cytokines Eicosanoids Nitric oxide Complement Fragments Endotoxin Heat shock proteins Reactive O2 metabolites Kallikrein-kinin system Fatty acid metabolites

2 Hit Theory in MODS

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CYTOKINES
Glycoprotein secreted for the purpose of altering function of target cells in an endocrine like fashion. Not from specialized cells but from activated cells

Nitric Oxide
Formerly known as endothelium derived relaxing factor Activates guanylate cyclase in smooth muscle to form cyclic guanosine monophosphate dependent vasodilation

EICOSANOIDS
Membrane Phospholipids Phospholipase Arachidonic Acid Cyclooxygenase PGG2 PGH2 Thromboxane A2 Prostacyclin Lipoxygenase Leukotrienes

PROINFLAMMATORY INTERLEUKINS
IL-1 IL-6 IL-8
VASODILATATION INCREASED VASCULAR PERMEABILITY CHEMOATTRACTANT TO NEUTROPHILS AND MONONUCLEAR PHAGOCYTES

ANTIINFLAMMATORY INTERLEUKINS
IL-4 IL-10 IL-13 VASODILATATION INCREASED VASCULAR PERMEABILITY CHEMOATTRACTANT TO NEUTROPHILS AND MONONUCLEAR PHAGOCYTES
S I R S
MOF RECOVERY

C A R S
HOURS

MOF

DAYS

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Selected Human Trials of Anticytokime Therapy

Reference Knaus et al 1996 Abraham et al 1997 Agent IL-1 receptor antagonist TNF receptor protein Population Severe sepsis or shock Severe sepsis or shock Severe Sepsis
Primary Outcome Reduced risk of early death

Dose related lower mortality rate

Clark et al 1998 Monoclonal

Antibody to TNF-a

30% mortality rate, no benefit

Abraham et al 1998

Monoclonal Antibody to TNF-a

Septic Shock

41% mortality , no benefit

Selected Human Trials of Anticytokime Therapy

Reference Abraham et al 1995 Cohen et al 1996 Fisher et al 1996 Agent Monoclonal Antibody to TNF Monoclonal Antibody to TNF Population Septic shock Septic shock
Primary Outcome 46% mortality, reduced trend 40% mortality, no benefit

Because of complex interaction occuring between inflammatory cell and their mediators, single agent treatment may not halt the uncontrolled inflammatory response seen in shock associated with sepsis, SIRS and MODS.

Fusion protein to Septic shock TNF receptor

dose related higher mortality rate

Reinhart et al 1996

Monoclonal Antibody to TNF

Severe sepsis or 41% mortality , shock no benefit

Afferent Nerve - Symphathetic Nervous System Activation

Norepinephrine(nerve endings) Epinephrine( Adrenals) Vasoconstriction Tachycardia Increase C O Hyperglycemia

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Endocrine Response
Maintain body fluids balance A. Fluid Conserving Measures
B. Blood Flow Regulating Measures

To see to it that energy source is available for repair and survival.

INCREASED PLASMA OSMOLALITY

DECREASED EFFECTIVE CIRCULATORY VOLUME

Decreased blood flow Renin

Juxtaglomerular apparatus

POSTERIOR PITUITARY

Reabsorption of water in the renal distal tubules and Collecting ducts. Splanchnic vasoconstriction

Angiotensinogen ACE Angiotensin II

Angiotensin I

VASOPRESSIN ADH

Enhances glycogenolysis and gluconeogenesis.

Aldosterone Restoration of blood volume Fluid Conserving Measure

Fluid Conserving Measure

Aldosterone
Maintain intravascular volume by conserving Sodium. Eliminate Potassium and Hydrogen ion.

DECREASED EFFECTIVE CIRCULATORY VOLUME

STRETCH RECEPTORS

VASOMOTOR CENTER

CATECHOLAMINES VASOCONSTRICTION INCREASE HEART RATE INCREASE BLOOD PRESSURE

Blood Flow Regulating Measure

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Angiotensin II
Vasoconstrictor Stimulates aldosterone and vasopressin synthesis Stimulates heart rate and contractility Stimulates epinephrine and CRH release Activates sympathetic nervous system Induces glycogenolysis and gluconeogenesis
Blood Flow Regulating Measure HYOTHALAMUS

Injury
Proinflammatory cytokines Arginine AngiotensinII

Corticotrophin Releasing Hormone

ANTERIOR PITUITARY

ACTH
ENERGY SOURCING

Cortisol

cortisol

Energy Sourcing

Injury
HYPOTHALAMUS

liver

Promotes enzymatic activities Leading to gluconeogenesis

HYPERGLYCEMIA
Induces proteolysis and lactate release in skeletal muscle. peripheral Induces lipolysis . Inhibit glucose uptake by adipose tissue .

Growth hormone releasing hormone Promotes protein synthesis. Enhances mobilization of fat stores.

ANTERIOR PITUITARY

Growth hormone
ENERGY SOURCING

INCREASED PLASMA OSMOLALITY

DECREASED EFFECTIVE CIRCULATORY VOLUME

Cathecolamines
Glycogenolysis Gluconeogenesis] Lipolysis Ketogenesis Anti-insulin Promote glucagon secretion Increase intracellular cAMP leading to decrease immune response

POSTERIOR PITUITARY

Enhances glycogenolysis and gluconeogenesis.

VASOPRESSIN ADH ENERGY SOURCING

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Physiological Changes during Catabolism Carbohydrate

Physiological Changes during Catabolism Fats

Increased Glycogenolysis Increased hepatic Gluconeogenesis Insulin resistance of tissues Hyperglycemia

Increased Lipolysis Free FA used as substrate(except brain) FFA to ketones for brain Glycerol converted to glucose in the liver

Physiological Changes during Catabolism Proteins

Increased skeletal muscle breakdown AA converted to glucose in liver and used as substrate for Acute Phase Protein production Negative Nitrogen Balance

Total energy expenditure increased in proportion to injury and other modifying factors.

Progressive reduction of fat and muscle mass until stimulus for catabolism ends.