Surgery

Dr. Runez

SYSTEMIC RESPONSE TO INJURY

Causes: - Traumatic injury, a body wound or shock produced by sudden physical injury, as from violence or injury. - Other injuries from external physical causes, such as radiation injury, burn injury or frostbite - Injury from infection - Injury from toxin, or as adverse effect of pharmaceutical drug - Metabolic injury y The inflammatory response to injury and activation of cellular processes are inherently designed to neutralize pathogenic microorganisms as well as coordinate tissue repair. Minor insults initiate local inflammatory response that in most cases beneficial Major insults may propagate reactions that can become amplified, resulting in systemic inflammation and potential detrimental response.

2. Anti-inflammatory or counterregulatory phase- prevents excessive proinflammation activities as well as restoring homeostasis. Systemic Inflammatory Response Syndrome (SIRS) - Associated with an overwhelming proinflammatory response - Without appropriate and timely intervention, can lead to multiple organ failure DEATH Clinical Spectrum of SIRS (2 or more) - Temperature > 38 degrees C or <36 degrees C - Heart rate > 90 beats/minute - Respiratory rate > 20/min or PaCO2 < 32mmHg - WBC > 12,000 or <4,000 Definition of Terms y Infection- identifiable source of microbial insult y Sepsis- identifiable source of infection + SIRS y Severe sepsis- Sepsis + organ failure y Septic shock- Sepsis + cardiovascular collapse (requiring vasopressor support) **SIRS is non-specific and can be caused by ischemia, inflammation, trauma, infection or a combination of several insults. SIRS: 3 STAGE PROCESS - Stage 1 Following an insult, local cytokine is produced with the goal of inciting an inflammatory response, thereby promoting wound repair and recruitment of the reticular endothelial system. - Stage 2- Small quantities of local cytokines are released into circulation to improve the local response. This leads to growth factor stimulation and the recruitment of macrophages and platelets. This acute phase response is typically well controlled by a decrease in the proinflammatory mediators and by the release of endogenous antagonists. The goal is homeostasis. - Stage 3- If homeostasis is not restored, a significant systemic response occurs. The cytokine release leads to destruction rather

y y

Response to Injury - Inflammation is the body s reaction to invasion by an infectious agent, antigen challenge or even just physical, chemical or traumatic damage. - The development of inflammatory reactions is controlled by: a.)cytokines b.) products of plasma enzyme systems (complement, the coagulation clotting, kinin and fibrinolytic pathways). c.) lipid mediators (prostaglandins and leukotrienes) released. d.) vasoactive mediators released Systemic Response to Injury 1. Proinflammatory Phase- characterized by activation of cellular processes designed to restore tissue function and eradicate microorganisms.

Med20141

Surgery

Dr. Runez

than protection. A consequence of this is the activation of numerous humoral cascades and the activation of the reticular endothelial system and subsequent loss of circulatory integrity. This leads to end-organ dysfunction. Multi-hit theory in SIRS Progression - The event that initiates the SIRS cascade primes the pump. With each additional event, an altered or exaggerated response occurs, leading to progressive illness. The key to preventing the multiple hits is adequate identification of the cause of SIRS and appropriate resuscitation and therapy. CNS Regulation of Inflammation - Inflammation originating from a specific location sends afferent signals to the hypothalamus, which in turn rapidly relays opposing anti-inflammatory messages to the site of inflammation to reduce inflammatory mediator release by immunocytes. Cholinergic Anti-Inflammatory Pathways - Signals discharged from the vagus nerve are precisely targeted at the site of injury or infection, unlike hormonal anti-inflammatory mediators that are released into the circulation and allowed to travel to the site of injury.

Produced in response to biological stress Principal effects are increased production of androgens and cortisol from the adrenal cortex Disruption of the circadian rhythm (i.e. peak elevations of ACTH occurs late at night until the hour immediately before sunrise). Pain, anxiety, vasopression, angiotensin II, cholecystokinin, vasoactive intestinal peptide, catecholamines and proinflammatory cytokines are all potent mediators of ACTH release

Cortisol and Glucocorticoids - Cortisol is the major glucocorticoid in humans and is essential for survival during significant physiologic tress. - During injury, cortisol potentiates the release of free fatty acids, triglycerides, and glycerol from adipose tissue as a means of providing additional energy sources (gluconeogenesis) Macrophage Migration Inhibiting Factor - Neurohormone that is stored and secreted by the anterior pituitary - Counterregulatory mediator that potentially reverses the anti-inflammatory effects of cortisol. Growth Hormone - Promotes protein synthesis and also enhances the mobilization of fat stores - Insulin-like growth factor (IGF), formerly called somatomedin C, promotes amino acid incorporation, cellular proliferation and attenuated proteolysis. Catecholamines - The hypermetabolic state observed following severe injury is attributed to the activation of the adrenergic system, both epinephrine and norepinephrine are increased 3 to 4 fold in the plasma following injury, with elevations lasting 24 to 48 hours before returning toward baseline levels.

INJURY
(Hormonal Response, Inflammatory Response, CellMediated) Hormonal Response to Injury 1. Adrenocorticotropic Hormone (ACTH)- elevated 2. Cortisol- elevated 3. Growth hormone- elevated 4. Catecholamines- elevated 5. Aldosterone- elevated 6. Insulin- inhibited ACTH - Hormone produced and secreted by the anterior pituitary gland - Important component of the hypothalamicpituitary-adrenal axis Med20142

Surgery

Dr. Runez

In the liver, epinephrine promotes glycogenolysis, gluconeogenesis, lipolysis and ketogenesis.

y y

Aldosterone - Major action is to maintain intravascular volume by conserving sodium and eliminating potassium and hydrogen ions in the kidney. Insulin - First phase suppresses overall insulin release and occurs within a few hours after injury - Later phase is characterized by a return to normal or excessive insulin production, but with persistent hyperglycemia, consistent with peripheral resistance to insulin. Acute Phase Proteins - Nonspecific biochemical markers produced by hepatocytes in response to tissue injury, infection or inflammation. - Clinically, only C-reactive protein (CRP) has been consistently used as a marker of injury response due to its dynamic reflection of inflammation. MEDIATORS OF INFLAMMATION 1. Cytokines 2. Heat shock proteins 3. Reactive oxygen metabolites 4. Eicosanoids 5. Fatty acid metabolites 6. Kallikrein-Kinin System 7. Serotonin 8. Histamine Cytokines - Most potent mediators of inflammatory response - Tissue macrophages, monocytes, mast cells, platelets and endothelial cells are able to produce a multitude of cytokines. Cytokine Actions y Autocrine- if cytokine acts on the cell that secretes it. Med20143

Paracrine- if the target is restricted to the immediate vicinity of a cytokine s secretion. Endocrine- if the cytokine diffuses to distant regions of the body (carried by blood or plasma).

**Overwhelming production of proinflammatory cytokines in response to injury can cause hemodynamic instability (shock) or metabolic derangements (muscle wasting). **If uncontrolled, the outcome of these exaggerated response is end-organ failure and death. Cytokine Response to Injury - The central role of cytokines is to control the direction, amplitude and duration of immune responses and to control the (re)modeling of tissues. - Unscheduled remodeling is that which accompanies inflammation, infection, wounding and repair. Reactive Oxygen Response - Produced by anaerobic glucose oxidation and cause tissue injury by oxidation of unsaturated fatty acids within cell membranes. - Superoxide anion is an oxygen metabolite that is further metabolized to hydrogen peroxide and hydroxyl radicals. - Oxygen scavengers such as glutathione and catalases protect cells from damage by oxygen metabolites. Eicosanoids - Not stored within cells but are synthesized rapidly upon stimulation of hypoxic injury, direct tissue injury, endotoxin, norepinephrine and cytokines. - Induces the production of cyclooxygenase enzyme (COX-2) which converts arachidonic acid to prostaglandin E2. - PGE2 increases fluid leakage from blood vessels.

Surgery

Dr. Runez

Fatty Acid Metabolites - Omega 6 fatty acids serve as precursors of inflammatory mediators associated with injury and stress response (leukotrienes, prostaglandins, platelet-activating factor). - In contrast, Omega 3 fatty acids have an antiinflammatory effect. Histamine - Both H1 and H2 activation induce hypotension, peripheral pooling of blood, increased capillary permeability, decreased venous return, and myocardial failure. CELL-MEDIATED INFLAMMATORY RESPONSE y Platelets- clot formation at the site of injury releases inflammatory mediators and serve as the principal chemoattractant for neutrophils and monocytes. The migration of platelets and neutrophils through the vascular endothelium occurs within 3 hours of injury and is enhanced by serotonin release, platelet activating factor, and prostaglandin E2. Eosinophils migrate to inflamed endothelium and release cytoplasmic granules that are cytotoxic. Mast cells are important as first-responders at sites of injury because they are pre-existent in tissues. In response to trauma, mast cells produce histamine, cytokines, eicosanoids, protesases and chemokines, the immediate result is vasodilatation. Increased vascular permeability during inflammation is intended to facilitate oxygen delivery and immunocyte migration to sites of injury. However, the accumulation and infiltration of inflammatory leukocytes, especially neutrophils at sites of injury, contribute to the cytotoxicity of vital tissues and result in organ dysfunction. Nitric oxide (NO) is derived from endothelial surfaces in response to Ach stimulation , hypoxia, endotoxin or cellular injury. Constant output of NO maintains vascular smooth muscle relaxation.

y y

NO reduces microthrombosis by reducing platelet adhesion and aggregation. Prostacyclin in response to injury and hypoxia induces vasorelaxation and platelet deactivation. Endothelin is the most biologically active and the most potent known vasoconstrictor. Ten times more potent than angiotensin. Atrial natriuretic peptides induce vasodilatation as well as fluid and electrolyte excretions. Potent inhibitors of aldosterone secretion and prevent reabsorption of sodium.

**The balance of SIRS and CARS determines a patient s prognosis after an insult. If this process is not choreographed properly, major problems including failure of multiple organs and death can occur.

Med20144