Factors Influencing the Extent of the Inflammatory Response

to Cardiac Surgery

Eugene Yevstratov MD2003

Preoperative FactorsPreoperative Factors

• Preexisting disorders

• Disordered cytokine balance

• Patients with preoperative left ventricular disfunction undergoing CPB

• Poorly controlled diabetes

Perioperative Hemodynamic Perioperative Hemodynamic FactorsFactors

• Perioperative hemodynamic instability

• Low cardiac output syndrome

• Postoperative splanchnic hypoperfusion

• Splanchnic ischemia

Anesthetic TechniquesAnesthetic Techniques

• Thoracic Epidural AnesthesiaThoracic Epidural Anesthesia

• Lung Management during Lung Management during Cardiopulmonary BypassCardiopulmonary Bypass

• Anesthetic Agents and Adjuvant Anesthetic Agents and Adjuvant DrugsDrugs

OpioidsOpioids

DRUGRoute

Dose (mg)

Interval

Infusion Rate

Onset (min)

Duration (hr)

Fentanyl IV.05-

0.10015-30 min

50-100 mcg/h

1-2 0.5-1.0

Morphine IM 2-10 4 hrs - 15-30 4-5

IV 2-10 2-4 hrs 1-4 mg/hr 2-3 4-5Meperidine IV 10-30 2-4 hrs

10-50 mg/hr 1-2 2-4

IM 50-100 4-6 hrs - 30-45 4-6

Codeine PO 30-60 4-6 hrs - 20-30 4-6

IM 60 2-3 hrs - 15-30 -

Recommendations for Opioids1.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

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

Benzodiazepines Benzodiazepines

DRUGT1/2

metabolite t/1/2

bolus dose infusion onset (min)

duration (hr)

Chlordiazepoxide

5 - 30

14-9525-50 mg (70kg) - 1-5 .25-1.0

Diazepam 20-50 30-200 1-5 mg - 1-5 .25-1.0

Lorazepam 10-20 *none*

.05mg/kg (max 2mg)

upto 0.025 mg/kg/hr 40 12-24

Midazolam 1-12 1-2 .5 to 10

upto 0.05 mg/kg/hr 1-5 2

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

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

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

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

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

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

FentanylFentanyl 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.

MidazolamMidazolam, 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.

Sevoflurane, isoflurane, enfluraneSevoflurane, isoflurane, enflurane Sevoflurane, isoflurane, and enfluraneSevoflurane, isoflurane, and enflurane decrease decrease proinflammatory cytokine (IL-1  , TNF-  ) release by proinflammatory cytokine (IL-1  , TNF-  ) release by human peripheral mononuclear cells human peripheral mononuclear cells in vitroin vitro. Isoflurane . Isoflurane decreases alveolar macrophage phagocytosis and decreases alveolar macrophage phagocytosis and microbicidal function to a greater extent compared with microbicidal function to a greater extent compared with propofol. Halothane, isoflurane, and enflurane attenuate propofol. Halothane, isoflurane, and enflurane attenuate free radical–mediated myocardial injury. Isoflurane and free radical–mediated myocardial injury. Isoflurane and halothane (but not sevoflurane) appear to attenuate halothane (but not sevoflurane) appear to attenuate hydroxyl radical production in the ischemic rat hydroxyl radical production in the ischemic rat heart.Sevoflurane and isoflurane and halothane reduce heart.Sevoflurane and isoflurane and halothane reduce neutrophil and platelet uptake in the coronary circulation neutrophil and platelet uptake in the coronary circulation and preserve cardiac function following myocardial and preserve cardiac function following myocardial ischemia and reperfusion.This effect is mediated at least in ischemia and reperfusion.This effect is mediated at least in part part viavia reduced neutrophil expression of the adhesion reduced neutrophil expression of the adhesion molecule CD11bmolecule CD11b

Clonidine Clonidine ClonidineClonidine appears to exert antiinflammatory actions in appears to exert antiinflammatory actions in such diverse areas as acute pain models, in extrinsic such diverse areas as acute pain models, in extrinsic asthma,and angiotensin-converting enzyme inhibitor–asthma,and angiotensin-converting enzyme inhibitor–induced inflammation. It appears that the induced inflammation. It appears that the antiinflammatory action of clonidine is a property of antiinflammatory action of clonidine is a property of    22

adrenoceptor activation. Furthermore, adrenoceptor activation. Furthermore,   22 adrenoceptor adrenoceptor

agonists may regulate cytokine production agonists may regulate cytokine production viavia stimulation of stimulation of    22 receptors on macrophages to augment receptors on macrophages to augment

TNF- TNF-    release in response to endotoxin. While use of release in response to endotoxin. While use of clonidine during CABG does not appear to influence clonidine during CABG does not appear to influence the perioperative stress response, its the perioperative stress response, its immunomodulatory effects in the context of CPB immunomodulatory effects in the context of CPB remain to be characterized.remain to be characterized.

Surgical FactorsSurgical Factors

• Proinflammatory cytokine concentrationsProinflammatory cytokine concentrations in in patients undergoing heart transplantation are patients undergoing heart transplantation are greater than in CABG patients.greater than in CABG patients.

• Patients undergoingPatients undergoing valve surgery appear to have valve surgery appear to have similar immunologic response profiles to CABG similar immunologic response profiles to CABG patients.patients.

• In generalIn general, indices of inflammation appear to , indices of inflammation appear to correlate with overall severity of illness rather correlate with overall severity of illness rather than specific surgical procedurethan specific surgical procedure.

Extracorporeal Perfusion Extracorporeal Perfusion FactorsFactors

• CComposition of the priming solutionomposition of the priming solution

• CCardioplegiaardioplegia

• PPulsatile or nonpulsatile perfusionulsatile or nonpulsatile perfusion

• TType of oxygenator and pumpype of oxygenator and pump

• TType of extracorporeal circuitype of extracorporeal circuit

• TTemperature during CPB emperature during CPB

• LLarge pressure changes across the CPB arge pressure changes across the CPB circuit“shear stresscircuit“shear stress

TransfusioTransfusion

• Allogeneic TransfusionAllogeneic Transfusion

• AutotransfusionAutotransfusion

Postoperative FactorsPostoperative Factors • Continuous Renal Replacement TherapiesContinuous Renal Replacement TherapiesContinuous renal replacement therapies such as hemofiltration Continuous renal replacement therapies such as hemofiltration

appear to remove both mediators, including TNF- and IL-1 , appear to remove both mediators, including TNF- and IL-1 , and their inhibitors, such as TNFsr1, TNFsr2, and IL-1ra, and their inhibitors, such as TNFsr1, TNFsr2, and IL-1ra, from the plasma of patients with SIRS.from the plasma of patients with SIRS.

• Mechanical VentilationMechanical Ventilation patients with acute respiratory distress syndrome, ventilation patients with acute respiratory distress syndrome, ventilation

strategies that minimize overdistention and recruitment– strategies that minimize overdistention and recruitment– derecruitment of the lung attenuate the inflammatory derecruitment of the lung attenuate the inflammatory response.response.

Strategies to Reduce Strategies to Reduce EndotoxemiaEndotoxemia

• Selective Digestive DecontaminationSelective Digestive Decontamination• Enteral Nutrition and ImmunonutritionEnteral Nutrition and Immunonutrition • Optimization of intravascular volume Optimization of intravascular volume

status status • Pharmacologic interventions to maximize Pharmacologic interventions to maximize

splanchnic perfusion splanchnic perfusion • The elective use of mechanical The elective use of mechanical

circulatory supportcirculatory support

Filtration TechniquesFiltration Techniques

• HemofiltrationHemofiltration

• Leukocyte DepletionLeukocyte Depletion

Agents That May Suppress the Agents That May Suppress the Inflammatory ResponseInflammatory Response

• Serine Protease Inhibitors.Serine Protease Inhibitors.

• Aprotinin.Aprotinin.

• Pentoxifylline.Pentoxifylline.

• Free Radical Scavengers and Free Radical Scavengers and Antioxidants.Antioxidants.

ImmunomodulationImmunomodulation

• The Corticosteroid ControversyThe Corticosteroid Controversy

• Cyclooxygenase InhibitorsCyclooxygenase Inhibitors

• Complement-directed TherapiesComplement-directed Therapies

• Antimediator TherapiesAntimediator Therapies

• Therapies to Attenuate Therapies to Attenuate Endothelial InjuryEndothelial Injury

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

The End.

2003

Eugene Yevstratov MDEugene Yevstratov MD.