1. Factors Influencing the Extent of the Inflammatory Response to Cardiac Surgery Eugene Yevstratov MD 2003

2. Preoperative Factors Preexisting disorders Disordered cytokine balance Patients with preoperative left ventricular disfunction undergoing CPB Poorly controlled diabetes

3. Perioperative Hemodynamic Factors Perioperative hemodynamic instability Low cardiac output syndrome Postoperative splanchnic hypoperfusion Splanchnic ischemia

4. Anesthetic Techniques Thoracic Epidural Anesthesia Thoracic Epidural Anesthesia Lung Management during Cardiopulmonary Bypass Lung Management during Cardiopulmonary Bypass Anesthetic Agents and Adjuvant Drugs Anesthetic Agents and Adjuvant Drugs

6. Opioids DRUG Rou te Dose (mg) Interv al Infusion Rate Onset (min) Duration (hr) Fentanyl IV.05- 0.100 15-30 min 50-100 mcg/h 1-20.5-1.0 Morphine IM2-10 4 hrs - 15-304-5 IV2-10 2-4 hrs1-4 mg/hr 2-34-5 Meperidi ne IV10-30 2-4 hrs 10-50 mg/hr 1-22-4 IM 50-1004-6 hrs - 30-454-6 Codeine PO30-60 4-6 hrs - 20-304-6 IM60 2-3 hrs - 15-30 -

7. Recommendations for Opioids 1.Morphine is the preferred analgesic agent for critically ill patients. 2.Fentanyl is the preferred analgesic agent for critically ill patients with hemodynamic instability and for patients manifesting symptoms of histamine release with morphine or morphine allergy 3.Hydromorphone can serve as an acceptable alternative to morphine

8. NOT RECOMMENDED 1.MEPERIDINE has an active metabolite, normeperidine, that may accumulate and produce central nervous system excitation. 2.Opiate agonist-antagonist (nalbuphine, butorphanol, buprenorphine) have a plateau effect. 3.NSAID drugs have no analgesic advantages over opioids and have side effects such as GI bleeding, bleeding secondary to platelet inhibition, and the development of renal insufficiency

9. Benzodiazepines DRUG T1/ 2 metabolite t/1/2 bolus dose infusion onset (min) duration (hr) Chlordiazep oxide 5 - 30 14-95 25-50 mg (70kg) - 1-5.25-1.0 Diazepam20- 50 30-2001-5 mg - 1-5.25-1.0 Lorazepam10- 20 *none*.05mg/kg (max 2mg) upto 0.025 mg/kg/hr4012-24 Midazolam 1- 12 1-2.5 to 10 upto 0.05 mg/kg/hr1-52

10. Recommendations for sedation 1.Midazolam or propofol are the preferred agents only for short-term (<24 hrs) treatment of anxiety in the critically ill adult. 2.Lorazepam is the preferred agent for the prolonged treatment of anxiety in the critically ill adult. 3.Haloperidol is the preferred agent for the treatment of delirium in the critically ill adult

11. NOT RECOMMENDED 1.Etomidate, used long-term, is associated with adrenocortical suppression and increased mortality. 2.Ketamine increases blood pressure, heart rate, and intracranial pressure 3.Barbiturates lack amnestic and analgesic properties and produce myocardial depression and vasodilation that commonly result in tachycardia and hypotension

12. Propofol Propofol may preserve hepatosplanchnic blood flow during CPB, thereby aiding maintenance of the mucosal barrier. It alters the balance between proinflammatory and antiinflammatory cytokines, increasing production of the antiinflammatory cytokine IL-10 and IL-1ra, while decreasing neutrophil IL-8 secretion, and scavenges reactive oxygen species. Low concentrations of propofol reduce neutrophil uptake in the coronary circulation following myocardial ischemia and reperfusion. Propofol impairs several aspects of monocyte and neutrophil function, including the respiratory burst, polarization, chemotaxis, ect....

13. Sodium thiopental Sodium thiopental impairs the neutrophil respiratory burst,polarization, chemotaxis, adherence, phagocytosis and killing,and coronary uptake of neutrophils following myocardial ischemia and reperfusion. At therapeutic concentrations, thiopental also inhibits the monocyte respiratory burst. In high concentrations thiopental affects Escherichia coli clearance in vitro and neutrophil and monocyte phagocytosis. The effect of thiopental on the respiratory burst of neutrophils appears less pronounced compared to propofol.

14. Ketamine Ketamine attenuates the increase of serum IL-6 concentrations during and following CPB and reduces coronary uptake of neutrophils following myocardial ischemia and reperfusion.Ketamine affects E. coli clearance and neutrophil and monocyte phagocytosis in vitro, although only in high concentrations.Methohexitone has only minimal effects on the respiratory burst of neutrophils in vitro.

15. Morphine Morphine down-regulates the activity of lymphocytes, granulocytes, and macrophages, and suppresses the antibody response. Microinjection of morphine into the lateral ventricle of the rat induces pronounced, dose-dependent reductions in lymphocyte proliferation to T- and B-cell mitogens, natural killer cell cytotoxicity, and the production of IL-2 and interferon-.Morphine also increases the secretion of CRH, ACTH, and glucocorticoids, i.e., substances with inhibitory effects on the immune system. Certain immunomodulatory actions of morphine, including NO release and inhibition of cell adhesion, appear to be mediated specifically via the 3 receptor

16. Fentanyl Fentanyl increases concentrations of IL-1ra in in vitro monocyte cultures. In an isolated blood primed CPB circuit, fentanyl increased CD11b, augmented the reduction in lymphocyte HLA-DR expression, and attenuated the increase seen in monocyte HLA-DR expression. However, fentanyl, unlike morphine, appears to lack the ability to bind to the 3 receptor, diminishing its ability to down-regulate the inflammatory response to CPB.

17. Midazolam Midazolam, the best studied benzodiazepine, has little influence on host defense mechanisms. Midazolam decreases neutrophil IL-8 secretion in response to lipopolysaccharide but does not alter IL-8 production.Midazolam reduces postischemic uptake of neutrophils in the coronary circulation following myocardial ischemia and reperfusion. Midazolam, at clinically relevant concentrations in vitro, does not attenuate neutrophil polarization and has minimal effects on the neutrophil respiratory burst,neutrophil phagocytosis, and clearance of E. Coli.

18. Sevoflurane, isoflurane, enflurane Sevoflurane, isoflurane, and enflurane decrease proinflammatory cytokine (IL-1, TNF- ) release by human peripheral mononuclear cells in vitro. Isoflurane decreases alveolar macrophage phagocytosis and microbicidal function to a greater extent compared with propofol. Halothane, isoflurane, and enflurane attenuate free radical–mediated myocardial injury. Isoflurane and halothane (but not sevoflurane) appear to attenuate hydroxyl radical production in the ischemic rat heart.Sevoflurane and isoflurane and halothane reduce neutrophil and platelet uptake in the coronary circulation and preserve cardiac function following myocardial ischemia and reperfusion.This effect is mediated at least in part via reduced neutrophil expression of the adhesion molecule CD11b

19. Clonidine Clonidine appears to exert antiinflammatory actions in such diverse areas as acute pain models, in extrinsic asthma,and angiotensin-converting enzyme inhibitor– induced inflammation. It appears that the antiinflammatory action of clonidine is a property of 2 adrenoceptor activation. Furthermore, 2 adrenoceptor agonists may regulate cytokine production via stimulation of 2 receptors on macrophages to augment TNF- release in response to endotoxin. While use of clonidine during CABG does not appear to influence the perioperative stress response, its immunomodulatory effects in the context of CPB remain to be characterized.

20. Surgical Factors Proinflammatory cytokine concentrations in patients undergoing heart transplantation are greater than in CABG patients. Proinflammatory cytokine concentrations in patients undergoing heart transplantation are greater than in CABG patients. Patients undergoing valve surgery appear to have similar immunologic response profiles to CABG patients. Patients undergoing valve surgery appear to have similar immunologic response profiles to CABG patients. In general, indices of inflammation appear to correlate with overall severity of illness rather than specific surgical procedure In general, indices of inflammation appear to correlate with overall severity of illness rather than specific surgical procedure.

21. Extracorporeal Perfusion Factors Composition of the priming solution Composition of the priming solution Cardioplegia Cardioplegia Pulsatile or nonpulsatile perfusion Pulsatile or nonpulsatile perfusion Type of oxygenator and pump Type of oxygenator and pump Type of extracorporeal circuit Type of extracorporeal circuit Temperature during CPB Temperature during CPB Large pressure changes across the CPB circuit“shear stress Large pressure changes across the CPB circuit“shear stress

22. Transfusio Transfusion Allogeneic Transfusion Allogeneic Transfusion Autotransfusion Autotransfusion

23. Postoperative Factors Continuous Renal Replacement Therapies Continuous Renal Replacement Therapies Continuous renal replacement therapies such as hemofiltration appear to remove both mediators, including TNF- and IL-1, and their inhibitors, such as TNFsr1, TNFsr2, and IL-1ra, from the plasma of patients with SIRS. Mechanical Ventilation Mechanical Ventilation patients with acute respiratory distress syndrome, ventilation strategies that minimize overdistention and recruitment– derecruitment of the lung attenuate the inflammatory response. patients with acute respiratory distress syndrome, ventilation strategies that minimize overdistention and recruitment– derecruitment of the lung attenuate the inflammatory response.

25. Strategies to Reduce Endotoxemia Selective Digestive Decontamination Selective Digestive Decontamination Enteral Nutrition and Immunonutrition Enteral Nutrition and Immunonutrition Optimization of intravascular volume status Optimization of intravascular volume status Pharmacologic interventions to maximize splanchnic perfusion Pharmacologic interventions to maximize splanchnic perfusion The elective use of mechanical circulatory support The elective use of mechanical circulatory support

26. Filtration Techniques Hemofiltration Hemofiltration Leukocyte Depletion Leukocyte Depletion

27. Agents That May Suppress the Inflammatory Response Serine Protease Inhibitors. Serine Protease Inhibitors. Aprotinin. Aprotinin. Pentoxifylline. Pentoxifylline. Free Radical Scavengers and Antioxidants. Free Radical Scavengers and Antioxidants.

28. Immunomodulation The Corticosteroid Controversy The Corticosteroid Controversy Cyclooxygenase Inhibitors Cyclooxygenase Inhibitors Complement-directed Therapies Complement-directed Therapies Antimediator Therapies Antimediator Therapies Therapies to Attenuate Endothelial Injury Therapies to Attenuate Endothelial Injury

29. Conclusions The goal of modulation of the perioperative inflammatory response is to attenuate its deleterious effects while preserving the ability of the patient to mount an appropriate defense to the physiologic trespasses of the perioperative period. Although knowledge is growing about the role of altered immune function, the role of immunomodulatory therapies will remain investigational (especially in view of the failures of these therapies in recent sepsis trials) until the initiating events in postoperative SIRS become clearer.

30. The End. 2003 Eugene Yevstratov MD Eugene Yevstratov MD.