First Hit

Second Hit

SYSTEMIC RESPONSE TO INJURY

1st degree MODS

Systemic Inflammatory Response

Amplified Systemic Inflammatory Response

2nd degree MODS

Recovery Death Recovery

Death

2 Hit Theory in MODS

Clinical Spectrum of Infection and SIRS

S I R S

MOF RECOVERY

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

C A R S
HOURS

MOF

Sepsis

Severe sepsis Sepsis and organ dysfunction

DAYS

Septic shock

Sepsis +cardiovascular collapse (requiring vasomotor support

What happens after injury?

Multiple axes in Response to Injury

Hemodynamic changes Immunologic changes Metabolic changes

Mediators released by the injured tissue Neural and nociceptive inputs from the site of injury Baroceptor stimulation from intravascular volume depletion

CNS Regulation of Infection

Mediators
s ACTH y Glucocorticoids m p a t h e t i c

CNS M V Acetylcholine sv

Injury site TNF, IL-1

Inflammatory cascade Injury

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

Injury
HYOTHALAMUS Proinflammatory cytokines Arginine AngiotensinII

cortisol
Promotes enzymatic activities Leading to gluconeogenesis

liver

Corticotrophin Releasing Hormone peripheral ANTERIOR PITUITARY

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

ACTH

Cortisol

Injury
HYPOTHALAMUS

INCREASED PLASMA OSMOLALITY

DECREASED EFFECTIVE CIRCULATORY VOLUME

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

POSTERIOR PITUITARY

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

ANTERIOR PITUITARY

Growth hormone

VASOPRESSIN

Enhances glycogenolysis and gluconeogenesis.

Cathecolamines

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

Decreased blood flow

Juxtaglomerular apparatus

Renin Angiotensinogen ACE Angiotensin II Aldosterone Restoration of blood volume Angiotensin I

Angiotensin II

Aldosterone

Vasoconstrictor Stimulates aldosterone and vasopressin synthesis Stimulates heart rate and contractility Stimulates epinephrine and CRH release Activates sympathetic nervous system Induces glycogenolysis and gluconeogenesis

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

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

Nitric Oxide

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

CYTOKINES

Interferon gamma
Together with ILIL-12 and ILIL-18, activate Th0 helper cells to Th1 cells capable of secreting several proinflammatory cytokines (independently or synergystically act together). Inhibits differentiation of lymphocytes to Th2(producer of antiinflammatory 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

PROINFLAMMATORY INTERLEUKINS

ANTIINFLAMMATORY INTERLEUKINS

ILIL-1 ILIL-6 ILIL-8

VASODILATATION INCREASED VASCULAR PERMEABILITY CHEMOATTRACTANT TO NEUTROPHILS AND MONONUCLEAR PHAGOCYTES

ILIL-4 ILIL-10 ILIL-13

VASODILATATION INCREASED VASCULAR PERMEABILITY CHEMOATTRACTANT TO NEUTROPHILS AND MONONUCLEAR PHAGOCYTES

LPS

Tumor Necrosis Factor

Th0

MICROPHAGE

Obtained from LPS challenged animals Capable of killing cells in vitro Cause necrosis of transplantable tumor in mice Also known as cachectin
Th1 Cell

ROS NO TNF IL-1 IL-6 IL-8

IL-12 IL-18

IL-4 IL-4 IL-10 IL-10

I N F L A M M A T I O N

IFN IFN gamma gamma

Th2 cell

TH1

IL-12, IL-18, TNF,IL-1, IL-21, TGF-B, IFN-y

IL-4, IL-5, IL-6,IL-10, Glucocorticoids

TH2

IL-3
IL-2 IL-3 IL-6 IL-12 IFN-y TNF-a GM-CSF TNF-B

IL-4 IL-5

Injury Severity More severe

IL-6 IL-9 IL-10 IL-13 TNF-a GM-CSF

Less severe

Cell mediated immunity

Antibody mediated immunity