Systamic infalmatory response syndrome sirs
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Systamic infalmatory response syndrome sirs
- 1. Immune system, Systemic Inflammatory Response Syndrome (SIRS) NAHAS. N CLINICAL PERFUSIONIST
- 2. Introduction Immune system offer protection to the organism from a variety of pathologic insult ( e.g., surgical trauma, contact of blood with foreign surfaces, etc.,) Comprises two fundamental features Innate immunity Acquired immunity Innate immunity depends on a variety of immunologic effector mechanisms, neither specific for a particular infectious agent nor improved by repeated encounters with the same antigen.
- 4. Innate system comprises, * Phagocytic cells - neutrophils, monocytes/macrophages, and natural killer cells * Endothelial cells * Soluble factors such as complement, cytokines/chemokines, * Acute phaseproteins Adaptive or Acquired immune response is mediated by * T lymphocytes * B lymphocytes
- 6. THE SYSTEMIC INFLAMMATORY RESPONSE TO CARDIOPULMONARY BYPASS On the basis of clinical and experimental studies, which indicate that various conditions, both infectious and noninfectious, induce similar host response, the syndrome, ‘‘systemic inflammatory response syndrome’’ (SIRS) to a wide variety of insults.
- 7. Initiation of Systemic Inflammatory Response after Bypass SIRAB is initiated by a number of injurious processes, these processes generate microemboli, disrupt hemostasis, and lead to a generalized whole body inflammatory response. The damaging effects of CPB are most commonly attributed to Contact of blood with the foreign surface of the extracorporeal circuit Altered arterial blood flow patterns Shear stress generated by bloodpumps Cardiotomy suction devices (including intracardiac venting) Tissue ischemia and reperfusion Hypothermia Relative anemia Anticoagulation agents used during the period of bypass
- 8. Clinical manifestations: Two or more of the following clinical manifestations must be fulfilled for the diagnosis: Body temperature higher than 38◦C or lower than 36 ◦C Heart rate more than 90 beats/min Respiratory rate more than 20/min or PaCO2 less than 32 mm Hg Leukocyte count more than 12,000 cells/mm3 or less than 4,000 cells/mm3, The presence of more than 10% immature neutrophils In its most severe form, a spectrum of injury may be observed that includes one or more the following clinical manifestations: Pulmonary, renal, gut, central nervous system, and myocardial dysfunction Coagulopathy and hemolysis Pyrexia, increased susceptibility to infections and leukocytosis
- 11. The Cellular Components of Blood Red blood cell Vascular endothelium Leukocytes neutrophils Monocytes Platelets Coagulation system Humoral Components of Blood Coagulation system kallikrein system, fibrinolysis pathway Complement system
- 12. Complement system A primitive recognition system capable of self-/non–self-discrimination. One of the most important immunologic mechanisms involved in the inflammatory process. Functions include mediating inflammation, opsonization of antigenic particles, and causing membrane damage to pathogens. The complement components interact with each other so that the products of one reaction form the enzyme for the next. A small initial stimulus can trigger a cascade of activity with consequent biologic activation and amplification.
- 13. • There are three different pathways of complement system activation (classical, lectin, alternative) leading to a common terminal sequence. • The classical and the alternative pathways both culminate in the production of C3 convertase molecules, which cleave the central component of the complement system, C3 into the active C3a and C3b fragments
- 14. C5a acts as a chemotactic and activating agent for neutrophils and other myeloid cells, leading to both their recruitment and release of lysosomal enzymes, reactive oxygen species, and other inflammatory mediators.
- 15. Activation of the complement system is observed during or shortly after CPB, mainly through the alternative pathway, and is induced by i. Blood contact with the non physiologic surface, ii. Ischemia reperfusion iii. Protamine administration iv. The subsequent formation of heparin–protamine complexes
- 16. Compliments contribution to SIRAB Cardiogenic shock. Prolonged non pulsatile perfusion or periods of circulatory arrest lead to end organ ischemia. End-organ hypoxic insult results in cytokines and oxygen free radical release. When reperfusion is initiated ischemic reperfusion injury results. Endotoxemia. Endotoxin is frequently detected in high concentration in systemic circulation after CPB. It is a potent stimulant of both complement and of endothelial cell activation. Precise mechanism of release is not clear but may derive from a translocation of bacteria from the gut resulting from systemic stress of CPB. Endotoxin is associated with profound fall in SVR after CPB.
- 17. C o a g u l a t i o n S y s t e m Activation of the cascade can be by either intrinsic or extrinsic pathways, (each of which consists of a series of enzymes) With the activation of the coagulation cascade, the fibrinolytic system is coactivated
- 18. Intrinsic Cascade Begins with the activation of factor XII upon contact of blood with collagen in the damaged vascular wall, or exposure to an artificial surface, Ends with the formation of fibrin through a cascade including activated factors XI, IX, X, and thrombin
- 19. Extrinsic Cascade initiated by exposure of blood to nonvascular tissue cells that express a protein called tissue factor, which binds to factor VII and activates it. This in turn activates factor X. Once factor Xa is generated, the remainder of the cascade is similar to the intrinsic pathway
- 21. CPB effects Results in the activation of both clotting and fibrinolysis pathways. fibrin formation platelet activation activation of vascular endothelium increased postoperative bleeding time, blood loss, reduction in platelet adhesion and aggregation capabilities
- 22. Fibrinolysis The continuous generation of cross-linked fibrin would create a clot capable of obstructing normal blood flow. Therefore, the fibrinolytic system exists as a counterbalance to the coagulation system. Plasminogen is an inactive protein synthesised mainly by the endothelium, and can be converted to its active form plasmin by tissue plasminogen activator (t-PA). Plasmin then has the ability to degrade fibrin strands, preventing the build-up of excess clot. Fibrinolytic activity as shown by increases in D- dimer levels, and t-PA activity Elevated D-dimer levels have been correlated with increased blood loss and postoperative bleeding time.
- 23. Cytokines A number of hormone-like proteins. Are cell signaling molecules that aid cell to cell communication in immune responses and stimulate the movement of cells towards sites of infection and trauma. Common Such as interferon, lymphokine, interleukin, lymphotoxin, lymphocyte activating factor, and others
- 25. Characteristic Features of Cytokines endogenous polypeptides or glycoproteins Cytokine production is transient and the radius of action is usually short. Most cytokine actions serves in intercellular signaling molecules and participate in the regulation of cellular growth, function and differentiation. Induced by tumour necrosis factor (TNF), in accordance with the many other similarities seen between the action of IL-1 and TNF.
- 27. INTERLEUKIN-1 (IL-1) first leukocyte-derived cytokine mediates fever, synthesis of hepatic acute phase proteins, release of growth factors and immunoregulatory cytokines, changes in endothelial cell function and permeability, and decreased vascular resistance TUMOUR NECROSIS FACTOR a leukocyte-derived endotoxin-induced factor, is termed TNF- alpha Its effects on neutrophils include production of oxidative burst, degranulation, increased phagocytic activity and increased expression of leukocyte adhesion molecules INTERLEUKIN-6 (IL-6) A pro-inflammatory cytokine involved in the pathogenesis of various autoimmune and chronic inflammatory diseases. Synthesized by monocytes, endothelial cells and fibroblasts during systemic inflammation
- 28. Endothelial cells activated during CPB by a variety of agonists. The principal agonists are thrombin, C5a, and the cytokines IL-1 and TNF-α IL-1 and TNF-α induce the early expression of P-selectin and the later synthesis and expression of E-selectin, which are involved in the initial stages of neutrophil and monocyte adhesion Bind neutrophils and monocytes to the endothelium and initiate trafficking to the extravascular space. Regional vasoconstriction reduces blood flow rates within local vascular beds allowing neutrophils to play an important role in the multi-step model of leukocyte interaction with the endothelium, consisting of “attachment”, “rolling”, “activation”, “firm adhesion” and “extravasation”
- 29. CPB reduces the ability of the endothelium to produce factors important for promoting vascular patency and the prevention of thrombosis such as Nitric oxide (NO) Prostacyclin and adenosine. The production of vasoactive factors such as endothelin and angiotensin is increased leading to vasomotor and organ dysfunction
- 30. Leukocyte Activation CPB during cardiac surgery causes leukocyte activation(monocyte and neutrophil) Neutrophil activation and its cytotoxic capability are an essential aspect of body’s ability to fight infection. Leukocyte activation occurs as a result of elevated levels of thrombin, kallikrein C5a. Other mediators are interleukin (IL)-1, TNF-α, IL-8, C5b-9, Factor XIIa, and histamine. C5a is a potent protein that induces neutrophil chemotaxis, degranulation, and superoxide generation.
- 31. Fate of activated Neutrophils Activated neutrophils can de-granulate releasing cytotoxic enzymes, oxygen free radicals, and hydrogen peroxide. Also directly activate endothelial cells. Neutrophil activation and its cytotoxic capability are an essential aspect of body’s ability to fight infection. Neutrophil activation(firm adhesion and sequestration) can lead to obstruction of capillaries and local ischemia.
- 32. Fate of Monocyte activation Monocyte activation during CPB plays a major role in thrombin generation. Mediates the endocytosis of haemoglobin:haptoglobin (Hb:Hp) complexes. Upon migration to tissue they become tissue macrophages which participates in both specific and non specific immune pathways. Macrophages can exhibit both pro and anti inflammatory properties depending on the signal they receive from cells.
- 33. Platelets Numerous factors associated with CPB contribute toward the changes occur in platelets. physical factors- hypothermia and shear forces Hemodilution Blood exposure to artificial surfaces Thrombocytopenia is well documented in association with CPB. Mechanical disruption as well as adhesion to the extracorporeal circuit along with sequestration in organs may also contribute to this true drop in platelet counts. activated platelets attach to vascular endothelium and play an important role in neutrophil adhesion and transmigration.
- 34. SYSTEMIC IMMUNE RESPONSE AFTER CARDIOPULMONARY BYPASS To examines the effect of CPB on adaptive immunity and, specifically, T- cell function. The cellular and humoral constituents of the adaptive immune system undergo changes in both function and number after CPB.
- 35. Immunodeficiency and Cardiopulmonary Bypass Cardiac surgeries are highly immuno-suppressive. The immunosuppression is also related to volume of blood transfused The quantitative and qualitative exhaustion of humoral and cell mediated mechanisms may have an adverse effect Infections are directly related to duration of CPB. Sepsis related multi organ failure can occur in patients experiencing one or more complications (example renal failure or low cardiac output)
- 36. Humoral Immunity Serum levels of immunoglobulins and complement are markedly diminished. Host defense is quantitatively affected. Leukocyte counts fall with the onset of CPB. The sequestration of leukocytes in tissue is increased after their activation by anaphylatoxins C3a and C5a. The chemotactic ability of granulocytes is impaired. Phagocytic function of leukocytes is impaired. Metabolic function of leukocytes is impaired
- 37. Natural Killer Cells Natural killer cells are a heterogeneous subpopulation of lymphoid cells. Natural killer cells have been shown to produce cytotoxic responses in virus-infected cells and transformed target cells (e.g., tumor cells). CPB decreases both number and function of natural killer cells.
- 38. Reticuloendothelial System Made up of tissue macrophages in the spleen, lymph nodes, lung, and liver. These cells are initially derived from blood-borne monocytes. CPB depresses the function of reticulo endothelial system. This results in increase of microparticles generated by cpb The normal function of the reticuloendothelial system includes the clearing of bacteria, endotoxins, platelets, denatured proteins, chylomicrons, plasma hemoglobin, thrombin, fibrin, fibrin degradation products, thromboplastin, plasminogen activator from the circulating blood
- 39. THERAPEUTIC AVENUES OF SIRAB Maintaining an adequate perfusion pressure before the discontinuation of bypass. Maintaining an optimal cardiac output after CPB increases the clearance of inflammatory proteins and mediators. Better myocardial preservation and organ perfusion reduces to some extend the deleterious effect of humoral activation. Develop a CPB system that does not produce contact activation of blood components.( Ideal )
- 40. Pharmacologic Manipulation Corticosteroids They possess anti-inflammatory properties and influence the water/electrolyte balance and the metabolism of carbohydrate, protein, lipid. Inhibit the formation of C3 and C 5 convertases in vitro Inhibit leukocyte recruitment, the formation of the enzyme required for converting plasminogen into plasmin, and phospholipase. Steroids are unable to prevent the postoperative decrease in pulmonary compliance and may delay early extubation; in addition, steroids increase the susceptibility to infection by promoting an immune compromised
- 41. Aprotinin It inhibits several proteinases, including trypsin, chymotrypsin, plasmin, kallikrein, urokinase, and thrombin. The hemostatic action: limiting fibrinolysis through inhibition of plasmin and kallikrein, and also by preserving platelet function. Anti-inflammatory effects: Reducing endothelial cell activation and leukocyte contact activation, Reduction of systemic proinflammatory mediators such as IL-6 and IL-8. High-dose aprotinin reduces transfusion requirements, reduced risk of stroke and a tendency toward reduction of atrial fibrillation.
- 42. Neutrophil activation remodeling Lowering the temperature of the patient. Use of cyclo-oxygenase inhibitors. Use of cytokine receptor antagonists .
- 43. OTHERS Heparin bonded circuits heparin bonded circuits in CPB has enabled reductions in the dosage of heparin administered prior to initiation of bypass Heparin coating improves the biocompatibility of extracorporeal circuits as demonstrated by improved clinical outcomes, and reduced neurocognitive dysfunction, complement activation, transfusion requirements, and ischemic myocardial damage. Pulsatile perfusion may be beneficial with respect to heamodynamics, microcirculation and organ dysfunction
- 44. Depletion of leukocytes and inflammatory Mediators: Ultrafiltration: Conducting ultrafiltration at the termination of CPB, such as MUF, CUF (reverses hemodilution, and decreases tissue edema and circulating inflammatory mediators) leading to clinical outcome improvement
- 45. Leukocyte filters Introduction of leukocyte-depleting filters into the CPB circuit Reported benefits include reduced circulating activated leucocytes, transfusion requirements, renal dysfunction pulmonary inflammation leading to expedited extubation and improved clinical outcomes
- 47. CONCLUSION CPB is far from perfect. Still no single anti-inflammatory or immunologic therapy is found for routine clinical use.
Notas do Editor
- The innate response can activate and amplify the acquired response, which, in turn, is able to direct elements of the innate system, such as phagocytes or complement factors. CPB is accompanied by the activation of both innate and acquired immunity mounting a complex inflammatory response
- CPB also induces the cellular and humoral constituents of the immune system to undergo quantitative and qualitative changes, leading to a temporary immune deficiency
- The repeated passage of blood through the nonphysiologic extracorporeal circuit leads to a ‘‘contact activation’’ response, which is initiated by the activation of contact protein cascades upon exposure of the blood to the nonendothelialized surface of the CPB machine. The end result of this activation is the formation of bradykinin, and the conversion of plasminogen into plasmin. This, in addition to initiating fibrinolysis, can trigger the classical complement cascade. Therefore, multiple inflammatory mediators are released upon exposure to the extracorporeal circuit. These responses disrupt hemostasis and lead to a generalized whole body inflammatory response, which is set in motion by a sequence of chemokine-mediated events that activate vascular endothelium and potentiates further neutrophil-mediated injury
- Many of the deleterious effects of CPB were secondary to the exposure of blood to non-endothelial surfaces in the bypass circuit, which initiate a ‘‘whole body inflammatory response. This response was characterized by activation of Coagulation system kallikrein system, fibrinolysis pathway Complement system
- Consist of more than 30 protiens.
- Each pathway consists of a series of preformed, inactive proteins that, upon activation, activate the next protein in the pathway.This results in massive amplification of the initial activating event and to a cascade of different members being activated; the primary trigger, therefore, leads to the production of a large number of different effector functions. Such an amplification system needs tight control, and so it is no surprise that nearly half the proteins in the complement system are regulatory molecules. The classical pathway, is initiated by the binding of antibodies to target antigens on an appropriate surface. The clustered Fc regions of the antibodies are recognized by the first component of the classical pathway,C1, thereby initiating the cascade of activation leading to the production of the classical pathway C3 convertase. The alternative pathway, which is the most primitive part of the system, operates by a feedback loop in which the C3b component interacts with factor B (and subsequent activation of factor B by factor D) to generate the alternative pathway C3convertase.
- The final path way of the complement system is the lytic or terminal pathway. This pathway is initiated by C3b, produced by either the classical or alternative pathway C3 convertase. C3b activates C5 to generate C5a, a soluble molecule, and C5b, which is bound to the cellsurface. This leads to the subsequent binding to the surface of C6, C7, and C8 and the polymerization of C9. The terminal complex is capable of inserting itself into cell membrane lipid bilayers, allowing passage of water and ions, resulting in cell lysis. C4d-CRP, formed following CRP mediated activation of the cascade, is an index of the contribution of CRP to activation of the complement cascade.
- Activation of the complement system is observed during or shortly after CPB, mainly through the alternative pathway, and is induced by blood contact with the non physiologic surface, and later by ischemia reperfusion. Protamine administration and the subsequent formation of heparin–protamine complexes can further activate the complement through the classical pathway. This, in turn, mediates cellular damage, endothelial cell and leukocyte activation, histamine release, increased vascular permeability, and generalized inflammatory response.
- With the activation of the coagulation cascade, the fibrinolytic system is coactivated, which limits the amount of fibrin clot formed, and localizes clot formation to the site of injury.
- CPB results in increased fibrinolytic activity caused by elevated levels of factor XIIa and kallikrein. the factor VIIa-tissue factor complex and factor Xa have been shown to activate cells through protease activated receptors and this, in turn, generates cellular responses similar to those mediated by thrombin activation of protease activated receptor-1
- endogenous polypeptides or glycoproteins and produced by a variety of cell types. Cytokine production is transient and the radius of action is usually short (typical action is autocrine or paracrine, not endocrine) and they produce their action by binding to specific high-affinity cell surface receptors Most cytokine actions can be attributed to an altered pattern of gene expression in the target cells and thus they serve as All of these cytokines are also induced by tumour necrosis factor (TNF), in accordance with the many other similarities seen between the action of IL-1 and TNF
- Endotoxins (lipopolysaccharide), human complement-derived fragments C5a and C3a induce monocytes to produce IL-1 in vitro after a brief exposure period.
- This schematic diagram depicts the role of the endothelium in the regulation of vascular tone and illustrates important early events known to occur in systemic inflammatory response syndrome (SIRS) at the level of the endothelium. The endothelium regulates local vascular tone and adapts organ blood flow to metabolic needs, by altering the balance of 4 key mediators: nitric oxide (NO), prostacyclin (PGI2), thromboxane (TXA2), and endothelin (ET). Endotoxin (lipopolysaccharide [LPS]) binds to macrophages to release cytokines, which bind to and activate the endothelium. This increases production of these vasoactive agents, in particular NO, by up-regulating the inducible form of NO synthase (iNOS). This alters the dynamic balance of these 4 vasoactive agents over time and appears to play a central role in the hemodynamic sequelae of SIRS. cNOS = constitutive form of NOS; COX-1 = cyclooxygenase 1; COX-2 = cyclooxygenase 2; PLA2= phospholipase 2; AA = arachidonic acid; l-ARG = l-arginine; pro-ET = proendothelin; ECE = endothelin-converting enzyme.
- cytotoxic enzymes (neutrophil elastase, lysozymes, and myeloperoxidase) activate endothelial cells thereby increasing perivascular oedema and leukocyte transmigration into extracellular matrix. These cytotoxins present in granules of neutrophils and newly synthesized molecules. There are two forms of neutrophil granules 1) Primary azurophilgranules (predominantly inracellular role) 2) Secondary(extracellular role)
- Monocyte activation during CPB plays a major role in thrombin generation via expression of tissue factor and release of inflammatory mediators such as TNF-α, IL-1, IL-6, and IL-8. Administration of haptoglobin, which is the physiologic fHb scavenger, appears to be a logical choice for reducing fHb concentrations. Hemolysis increasing levels of plasma-free hemoglobin (PfHb) and decreasing levels of haptoglobin during and after cardiopulmonary bypass (CPB)
- These include physical factors (such as hypothermia and shear forces), exposure to artificial surfaces, the use of exogenous drugs, and the release of endogenous chemicals. Thrombocytopenia - haemodilution occurs from the use of crystalloid fluids for priming the extracorporeal circuit
- The secretion of IgG, IgM and IgA by B is diminished after cpb Host defense is quantitatively affected, resulting in reduced opsonization of bacteria in vitro. The chemotactic ability of granulocytes is impaired, which may also contribute to a higher susceptibility to bacterial infections
- Natural killer cells are a heterogeneous subpopulation of lymphoid cells that are not T or B lymphocytes
- Proactive strategies Maintaining an adequate perfusion pressure before the discontinuation of bypass use of vasoconstrictor and inotropic drugs, recognizing that such treatment does not address the pathologic basis.
- High dose methylprednisolone (30mg/kg) at the time induction reduces complement activation
- Aprotinin (Trasylol) is a serine protease inhibitor isolated from bovine lung. was the ability of aprotinin to reduce blood loss after surgery using CPB noted. Aprotinin has been used in the past in a variety of clinical situations, including acute pancreatitis, adult respiratory distress syndrome, septic shock, and hemorrhagic shock.
- The prevention of neutrophil activation would be of use in preventing many problems associated with CPB Lowering the temperature of the patient has also been shown to reduce adherence of neutrophils to the endothelium. The use of cyclo-oxygenase inhibitors and cytokine receptor antagonists may result in inhibition of T-and B-cell proliferation and lymphokine generation.
- Schematic diagram of the balance between beneficial and adverse effects and the resultant clinical sequelae of the inflammatory response following cardiac surgery.