1. 1 Hadassah University Hospital Dr. Slosser Dr. Slosser Plastic Surgery Seminars Plastic Surgery Seminars June 15, 2001 June 15, 2001

2. 2 Introduction In history burn injury described as an “ internal inflammation”.

3. 3 Causes of death: w 90% due to INFECTION w 60% pneumonia w 40% sepsis (Gram N) w < 10% wound sepsis

4. 4 3 LINES of Resistance: w Mechanical barrier w The nonspecific immune response w The specific immune response

5. 5 SUPRESSION OF THE IMMUNE RESPONCE w Open contaminated wound w Increase metabolic requirements w Decrease nutritional intake

6. 6 Mechanical Barrier w Normal skin w G.I. Mucosa w Respiratory mucosa

7. 7SKIN w Burn damages the skin ( physical barrier allowing microbial invasion). w All lines - entry points to offending organisms. w Eschar w Eschar - ideal ground for microorganisms (avascular tissue is not accessible to most systemic antibiotics).

8. 8 ESCHAR Toxic Products Lipid Protein Complex (LPC) w LPC - is produced by cross linkage of a complex of 6 skin cell membrane- lipid- associated proteins. w Damages cell ultrastructure and its metabolic function. w Inhibits T-cell proliferation. w Inhibits IgG production. w LPC effects continue until eschar excision

9. 9 Hansbrough 1984 - show that immediate eschar excision avoided immunosupression.

10. 10 G.I. Mucosal Barrier w Translocation of microbes and endotoxins occurs rapidly+extensively after burn injury. - 1 hour after burn - proportional to the severity. w Translocation increases with parenteral nutrition and reduced with enteral feeding.

11. 11 Respiratory Mucosal Barrier w In inhalation injury, damaged epithelium allows bacterial invasion. w Intubation allows for colonization of airway with opportunistic organisms.

12. 12 Nonspecific Immune Responce w A- Vascular component w B- Cellular component w C- Humoral component

13. 13 A- VASCULAR COMPONENT w Minor thermal injury - Local vasodilatation. - Increase capillary permeability. - Chemotaxis of PMN & monocytes. w Severe thermal injury - Venous stasis. - Microvascular thrombosis. - Endothelial cell slough.

14. 14 B- CELLULAR ROLE w Phagocytes ( blood born and tissue) w Neutrophils (PMN) w Macrophages - monocytes - fixed phagocytic cells of RES

15. 15 C- HUMORAL ROLE w Arachidonic acid metabolites w Endotoxines w Thromboxane w Complement system w Fibronectin

16. 16 Chemical mediators w Serotonin -from platelets, mast cells w Histamine- mast cells, basophils w Platelet activating factor (PAF) - basophils, neutrophils, macropages w Hyaluronidase w Peroxides, free radicals

17. 17 Chemical mediators w Neutrophil chemotactic factor (NCF) - mast cells w IL-8 -monocytes, lymphocytes w C3a - complement C3 w C5a - complement C5 w Bradykinine - kinin system (kininogen) w Fibrinopeptides - clotting system

18. 18 Chemical mediators w Prostaglandin E2 (PGE-2) - cyclo- oxygenase pathway w Leukotriene B4 (LTB-4) -lipoxygenase pathway w Leukotriene D4 (LTD-4) -lipoxygenase pathway

19. 19 Effect of Endogenous Mediators on Inflammation Postburn w Increased microvascular permeability Vasoactive amines (histamine) Kinin system (bradykinine) Acidic lipides ( Pg, Pc, Leukotrienes C-4, D-4, E-4. Complement system byproducts C3a

20. 20 Effect of Endogenous Mediators on Inflammation Postburn w Leukocytic infiltration ( chemotaxis) Complement system byproducts -C5a Acidic lipids ( Leukotriens B4) Lysosomal components (cationic proteins) w Tissue damage Lysosomal components (neutral proteases)

21. 21 SPECIFIC Immune Responce COMPOSED OF TWO COMPONENTS w Cell mediated immunity component (T-lymphocytes and its subgroups) w Humoral immunity component (B- lymphocytes and its product antibodies)

22. 22 CELL MEDIATED Immunity w T-lymphocytes subdivided according to function into: Cytotoxic T-cells (killer) Helper T-cells Supressor T-cells

23. 23 CELL MEDIATED Immunity w Cytokines - w Cytokines - intracellular signalling proteins which amplify the nonspecific defence response and recruit other noncommitted lymphoid cells as well as monocytes, neutrophils and eosinophils. w Macrophages w Macrophages play a key role

24. 24 CELL MEDIATED Immunity w Some key lymphokines are: Interleukin 1 Interleukin 2 TNF

25. 25 HUMORAL Mediated Immunity w B-cells under influence of the T- cells committed to become antibody producing cell when stimulated by the presence of particular antigens

26. 26 FUNCTIONS of ANTIBODIES w Opsonization of bacteria w Neutralization of viruses and bacterial toxins w Bactericidal antibodies lyse bacteria on contact in presence of compliment

27. 27 Effect of BURN on the Specific Immune Responce w CELL MEDIATED IMMUNITY -Prolonged survival of skin allografts -Altered skin test reactivity - energy -T-lymphocytes (A)-decrease in total count (B)-depressed primary and secondary responses to T-dependent antigens -Blast transformation- diminished response to mitogens/ MLS -Cytotoxity - reduced activity -T-cell subpopulations - increase in nonspecific supressor T-cells

28. 28 Postburn Alteration in Humoral Immunity w B-lymphocytes - increase in number with a T- or B-cell shift w Immunoglobulins - reduction in IgG with lesser reductions in IgA and IgM w Antibody responce - increase in anamnestic secondary responce; decrease in primary humoral antibody responce w Proteins - increase in levels of acute phase reactants (C-active protein, haptoglobine); decrease in alpha2- macro globulin and prealbumin

29. 29 IMMUNIZATION THERAPY w ACTIVE IMMUNIZATION -Psedomonas aeruginosa -dominant pathogen in burn patients w PASSIVE IMMUNIZATION -Administration of immunoglobulins

30. 30 IMMUNOMODULATION w A - General support - Fluid resuscitation -Early nutrition -Early excision w B - Remove supressors ( Plasma exchange, early wound excision, topical Cerium nitrate, Polymyxin B ) w C - Stimulate target cells

31. 31 Immunomodulating Agents w Killed vaccine of Corynebacter parvum w IL-1, IL-2 w FFP w Vitamin A and Vitamin E w Thymosin w Levamisole w TP-5 ( Thymopentin) w Fibronectine w Cyclophosphamide