Systemic Inflammatory Response Syndrome in Cardiopulmonary Bypass

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Systemic Inflammatory Response Syndrome in Cardiopulmonary Bypass Outline

Principles of Cardiopulmonary Bypass Seoul National University Hospital Department of Thoracic & Cardiovascular Surgery

Cardiac Surgery History Pre-heart-lung machine era• 1938. Gross. First successful PDA ligation • 1944. Crafoord. Resection of coarctation of aorta• 1945. Blalock. Blalock-Taussig operation• 1946. Gross. Surgical closure of AP window • 1958. Glenn. Glenn shunt

First Blalock-Taussig Shunt “ Most powerful stimulus to the development of cardiac surgery ”

Cardiac Surgery History Era of cardiopulmonary bypass• 1953. Gibbon. ASD closure• 1953. Lillehei. VSD closure• 1954. Lillehei. TOF correction• 1956. Kirklin. TAPVR correction• 1957. Kirkin. DORV correction

Cardiac Surgery History Era of cardiopulmonary bypass • 1959. Senning. Atrial switch operation for TGA• 1966. Ross. Ross procedure for TOF with PA • 1971. Fontan. Fontan operation for TA• 1975. Jatene. Arterial switch operation for TGA• 1983. Norwood. Norwood procedure for HLHS• 1985. Bailey. Pediatric heart transplantation

Cardiopulmonary Bypass Development • 1951. Dodrill. Mitral valve surgery under left heart bypass • 1952. Dodrill. Relief of PS under right heart bypass • 1953. Lewis. ASD closure under surface cooling • 1953. Gibbon. ASD closure by heart-lung machine • 1954. Lillihei. VSD closure under controlled cross- circulation • 1954. Kirklin. Establishment of CPB with oxygenator in cardiac surgery

Cardiopulmonary Bypass Controlled Cross-circulation • 1954. Lillehei 1st surgical closure of VSD under controlled cross-circulation • Used in 45 patients between 1954 to 1955 • VSD TOFAVSD Dr.Lillehei

Cardiopulmonary Bypass J. Gibbon and heart-lung machine

Single Ventricle Physiology Francis Fontan • Fontan operation for tricuspid atresia in 1971

Cardiopulmonary Bypass Circuit

Scheme of CPB Circuit • Pump• Oxygenator• Heat exchanger• Reservoir• Filter• Sucker & vent• Cardioplegic solution delivery system

Cardiopulmonary Bypass

Heart-Lung Machine

Development of CPB Prerequisite – Understanding of physiology of circulation– Preventing the blood form clotting– Pumping blood to pump– Ventilating the blood

Development of Pump • Sigmamotor pump This device had occlusive fingers that rhythmically compressed the tubing to propel the blood in a forward direction• Roller pump• Centrifugal pump 1. Cone shaped impellers encased in a cone- shaped housing using principle of a constrained vortex to generate pressure & flow 2. Delplim pump has impeller blades that rotate and generate flow & pressure within the head

Development of Oxygenator • Solid disc oxygenator• Screen oxygenator• Solid disc with rotation screens• Bubble oxygenator• Membrane oxygenator 1. Silicone elastomers 2. Microporous polypropylene a. Sheet-type oxygenator b. Hollow-fiber type oxygenator

Development of Filtration • Screen-type filters have pores in the medium that are of a particular size. For its better design and lesser trauma, screen-type filter became more popular. • The depth filters contain a medium through which the blood flows. This large wet surface blocks many particles and thus prevents them from being carried in the fluid stream; they are retained on the internal medium surface by adsorptive forces.

Size of Arterial Cannula Arterial Cannula for Various Weights and BSA Maximal Flow Rate Weight kg BSA( ㎡ ) Cannula Size (Fr) cc/min 1.5-4.0 0.13-0.26 8 800 4.1-9.0 0.26-0.48 10 1200 9.1-14.0 0.48-0.56 12 1800 14.1-20.0 0.56-0.71 14 2800 20.1-26.0 0.71-0.84 16 3500 26.1-34.0 0.84-1.00 18 5000 34.1-50.0 1.00-1.40 20 5000 50.1-66.0 1.40-1.63 22 8000 over 66.1 over 1.63 24 8500

Size of Venous Cannula Venous Cannula for Various Weights and BSA Weight kg BSA ㎡ Single Cannula Size (Fr) Flow ＞ 6 0.3 24 1200cc 6-8 0.3-0.45 26 1400cc 8-10 0.45-050 28-30 1600cc 10-40 0.50-1.10 40 or (32-40 two 1800cc ＞ 40 ＞ 1.1 stage cannula) 2600cc Double Cannula Size(fr) Weight kg BSA ㎡ SVC IVC Flow ＜ 5 0.28 12 16 12: 350cc 5-10 0.28-0.50 16 20 14: 450cc 11-15 0.51-0.57 20 24 16: 600cc 16-25 0.58-0.83 24 28 20: 900cc 25-50 0.83-1.40 28 32 ＞ 50 ＞ 1.4 36 40

Cannulation & Flow Rate Estimated Patient Maximum Estimated Blood Flow Double Single Weight Flow BSA 2.4L/Min/M² Venous Venous Arterial 1-2kg 350mL/min 0.16m² 380mL/min 12-14 Fr 1/4˝ 14 Fr1/4˝ 8 Fr 1/4˝ 2-4kg 800mL/min 0.26m² 625mL/min 12-14 Fr 1/4˝ 18 Fr1/4˝ 8 Fr 1/4˝ 4-8kg 1200mL/min 0.44m² 1056mL/min 16-18 Fr 1/4˝ 24 Fr1/4˝ 10 Fr 1/4˝ 10-14kg 1800mL/min 0.56m² 1500mL/min 20-22 Fr 3/8˝ 32 Fr3/8˝ 12Fr 1/4˝ 30-70kg 5000mL/min 2.2m² 5000mL/min 32-36 Fr 3/8˝ 36 Fr3/8˝ 16 Fr 3/8˝ 15-30kg 3000mL/min 0.97m² 2500mL/min 30-32 Fr 3/8˝ 36 Fr3/8˝ 14 Fr 3/8˝

Prime Estimation for ECC Patient blood volume: cc+ (weight × BV) +Pump Prime Volume: (PPV)= =Total Circulating Volume: TCV ccRequired Red Cells:RRC cc(TCV × desired % HT) – - Patient Red Cells: PRC(PBV × patient % HT) cc= =Total Red Cells needed : TRC ccNote: 1. Desired % HT : 0.26 for hypothemia 0.22 for profound hypothermia 2. HT of packed cells: 0.65-0.70 volume 300mL/bag HT of whole blood: 0.35-0.40 volume 500mL/bag

Blood Volume Estimation Weight ㎏ Blood Volume cc/ ㎏ Newborn to 10 ㎏ s 85 cc/ ㎏ 11 to 10 ㎏ 80 cc/ ㎏ 21 to 30 75 cc/ ㎏ 31 to 40 70 cc/ ㎏ 41 to ㎏ over 65 cc/ ㎏

Pulsatile Bypass Flow Advantages• Increased urine volume• Less metabolic acidosis• Decreased stress hormone• Decreased peripheral vascular R• Increased oxygen consumption• Improved myocardial perfusion• Improve cerebral circulation• Smaller transfusion volume

Cardiopulmonary Bypass Determination of body perfusion • Externally controlled variables • Patient response to CPB • Damaging effect of CPB

Cardiopulmonary Bypass Externally Controlled Variables• Systemic blood flow• Temperature of perfusate & patient• Arterial input pressure wave form• Systemic venous pressure• Pulmonary venous pressure• Hemoglobin• Albumin concentration• Glucose concentration• Ionic composition• Arterial O2 & CO2 level

Cardiopulmonary Bypass  Differences between pediatric & adult 1. Exposed to biologic extremes. 1) Deep hypothermia 2) Hemodilution 3) Low perfusion pressure 4) Wide variation in pump flow rates 2. Variations in glucose supplementation 3. Cannula placement 4. Presence of aortopulmonary collaterals 5. Patient age and brain mass

Cardiopulmonary Bypass Differences between infants & adults• Smaller circulating blood volume• Higher oxygen consumption rate• Reactive pulmonary vascular bed• Presence of intra- & extracardiac shunt• Immature organ system• Altered thermoregulation• Poor tolerance to microemboli

Cardiopulmonary Bypass Patient’s response • Change of systemic vascular resistance• Increased venous tone• Decreased oxygen consumption• Mixed venous oxygen level• Depression of cell mediated immune response• Metabolic acidosis• Catecholamine response• Change of water body composition• Thermal balance with hypothermic bypass

Cardiopulmonary Bypass Factors of fluid shift during CPB1. Temperature2. Flow rate3. Hemodilution4. Plasma colloid oncotic pressure5. Interstitial fluid pressure6. Capillary permeability7. Urinary output

Cardiopulmonary Bypass Fluid balance• General effect• Preoperative factors Whether heart failure or not• Hemodilution & diminished colloidal oncotic pressure Main cause of fluid retention• Hypothermia Less potent cause of tissue edema• Oxygenator• Interstitial fluid pressure• Capillary permeability• Osmotically active components• Myocardial edema

Cardiopulmonary Bypass Body water change• In oxygenator, denaturation of protein & destabilization of soluble fat may affect colloidal property of blood & also damage of platelet & WBC cause vasoactive substance and microemboli may contribute to edema. • Increase of Hct due to plasma volume shifted to the interstitial space or excreted as urine and plasma volume decrease in 24 hours after CPB, especially in 2nd day and regain ECF or total body water from 2-5 days postoperatively in usual patients. • Interstitial fluid pressure is different due to compliance of tissue, noncompliant in subcutaneous tissue & muscle, less in myocardium, compliant in stomach.

Cardiopulmonary Bypass Damaging effects• Exposure of blood to abnormal events Damage, activation & depletion of blood elements• Exposure to nonendothelial surface• Shear stress• Incorporation of abnormal substance• Altered arterial blood flow pattern

Cardiopulmonary Bypass Systemic responses • Injury to blood elements• Emboli• Initial events-blood contact • Platelet activation• Coagulation cascade• Contact system• Fibrinolysis• Vasoactive substance

Cardiopulmonary Bypass Injury to blood elements• Contact with synthetic non-endothelial cell surfaces, turbulence, cavitation, osmotic forces and shear stresses activate but also injure blood elements. • Plasma proteins and lipoproteins are progressively denatured during CPB • Protein denaturation increases plasma viscosity, decreases the solubility of plasma proteins, produces macromolecules that aggregate, increase polarity and the number of reactive side groups, and alters the electrophoretic pattern of plasma proteins. • Denatured proteins are probably removed from plasma by the reticuloendothelial system

Cardiopulmonary Bypass Embolization• The CPB system produce a variety of gaseous, blood- derived and foreign emboli • The CPB circuits can not prevent generation of emboli but are designed to prevent or remove macroemboli, defined as emboli greater than 40um. • The architecture of the vascular system dictates that macroemboli(40-400um) cause more ischemic organ damage than microemboli • Massive air embolism, macrogaseous emboli, nitrogen emboli, fat, platelet aggregates, spallation of tubing and exogenous emboli must be prevented and filtered

Cardiopulmonary Bypass  Inflammatory response 1. Contact of blood component with artificial surface 2. Ischemia-reperfusion injury 3. Endotoxemia 4. Operative trauma

Cardiopulmonary Bypass Whole body inflammation 1. Material-independent factor 1) Hypooncotic pressure by priming Endotoxin translocation Cytokine release 2) Retransfusion of shed blood Highly activated by tissue contact High concentration of plasminogen activator 2. Material-dependent factor 1) Surface characteristics activate complement system 2) Blood pumps Shear forces causing hemolysis, lipid membrane ghosts, spoliation from the tubing cause impaired microcirculation

Foreign Surface Activation  Deleterious effects of interaction• Protein denaturation• Activation of clotting factors• Platelet aggregation• Lipid peroxidation• Activation of complement cascade Postoperative pathophysiologic effects • Impairment of alveolar gas exchange• Renal insufficiency• Coagulopathy• Cerebral dysfunction• Vague systemic toxicity reaction

Cardiopulmonary Bypass Complement Activation • Complement system is composed of more than 20 plasma proteins ( integral part of humoral immune system and are in a concerted fashion to promote host defe nse mechanisms )

Inflammatory Mediators • C3a and C5a are potent inflammatory mediators known as anaphylatoxins. • These anaphylatoxins are smooth muscle spasmogens and result in tissue changes including vasoconstriction, increased vascular permeability, induction of histamine release and modulation of host immune responses. • Overall levels of C3a are directly dependent on the duration of CPB, younger age at operation. • C5a is unique in that it is rapidly bound to circulating neutrophils that are sequestered in the pulmonary circulation. • The C5a stimulated cell release superoxides, lysosomal enzymes and proteases. A rise of this magnitude implies extensive degranulation or destruction neutrophils circulating in the course of CPB.

Organ Preservation Optimal conditions 1. Prevention of ischemia-reperfusion injury 2. Minimization of cell swelling and edema 3. Prevention of intracellular acidosis 4. Provision of substrate for regeneration of high-energy phosphate on reperfusion

Cardiopulmonary Bypass Vasomotor activity• Minimal perfusion pressure : 35 – 45 mmHg mean• Bypass flow in normothermia : 2.2-2.4 L/min/BSA• Relative vascular resistance to blood flow 1. Arterial system (93%) Aorta 4%, large artery 5%, main branch 10%, terminal branch 6%, arteriole 41%, capillary 27% 2. Venous system (7%) Venule 4%, terminal vein 0.3%, main branch 0.7%, large vein 0.5%, vena cava 1.5%

Cardiopulmonary Bypass Vasomotor activity• Phenomenon A * Initial severe drop in peripheral circulatory vascular resistance at the beginning of CPB, commonly occurs and lasts 5-10 minutes * Dilution of catacholamine * Homologous blood syndrome (incompatibility reaction of blood) * Trauma state evokes release of histamine. * Cold crystalloid priming affect smooth muscle tone.• Phenomenon B * Gradual recovery & progressive increase in peripheral resistance * Diuresis & shift of fluid from vascular to cell & intercellular space * Viscosity change with velocity gradient * Hypothermia itself

Cardiopulmonary Bypass Venous compliance• Effect of CPB on venous tone Low venous pressure, low temperature during CPB cause vasoconstriction, but before CPB, anesthesia, drugs, surgical manipulation also decrease venous tone. • Vasomotor state before & after surgery Compensatory venous constriction is masked following cardiac surgery with 75-80% reduction of venous capacitance in early postoperative period.• Vasodilator on venous tone after CPB Nitroglycerin : primary on venous capacitance, effective vasodilation and return of venous capacitance to normal Nitroprusside & N-G : equivalent effect on reducing arterial resistance, sometimes N-P reduce coronary perfusion

Venous Vasomotor Dynamics • Neural effects * Mainly determined by norepinephrine * Sympathetic innervation & smooth muscles are plentiful in cutaneous and splanchnic veins, while little in skeletal veins (but not insignificant due to big muscle mass)• Smooth muscle * Activity tone by norepinephrine * Low BT – active vasoconstriction in cutaneous veins• Passive effects * As a result of distensible and compliant nature of elastin and collagen fiber• Resistance in veins

Cardiopulmonary Bypass Hypothermia 1. Aim Protect the tissue from ischemia secondary to inadequate perfusion and oxygenation during CPB 2. Pitfalls 1) Alterations in microcirculation associated with reduced microcirculatory flow rates and tissue perfusion 2) More or less production of some cytokines than normothermic CPB 3) More pronounced alterations of platelet aggregation and endothelial related coagulation than normothermic CPB (steep relation between PT, aPTT and temperature)

Cardiopulmonary Bypass Hypothermia • Oxygen consumption • Phenomena during hypothermia & arrest 1. No-reflow phenomena 2. Change in plasma volume • Damaging effect of circulatory arrest 1. Brain function 2. Renal function 3. Liver function 4. Cardiac function : increase intracellular ionized calcium by hypothermia– aggravated injury • Hematologic effect of hypothermia

Cardiopulmonary Bypass Hypothermic adverse effects 1. Activates kallikrein which increase circulating kinin (vasoactive peptides that produce vasodilatation & increase vascular permeability). 2. Produces platelet dysfunction ; temperature dependent morphologic alterations in membrane and function 3. Fibrinolytic activity is altered by hypothermia alone.

Systemic Hypothermia Hematologic effect • Platelet membrane dysfunction • Fibrinolysis • Depression of clotting factor

Disadvantages of Hypothermia • Attenuation of coagulation system• Attenuation of glucose regulation• Attenuation of endocrine system• Attenuation of immune system• Damaging effects associated with rapid perfusion cooling in the kidney, liver, lung, myocardium • Longer duration of CPB

Systemic Hypothermia Adverse effects 1. Cardiac arrhythmia 2. Myocardial ischemia 3. Coagulopathy 4. Decreased myocardial contractility 5. Left shift of oxyhemoglobin dissociation 6. Impaired function of immune system

Prebypass Hypothermia Potential benefits 1. Modest reduction benefit (2-5 degree) 1) Inhibition of neurotransmitter release (eg ; glutamate) 2) Reduction of calcium-mediated cell injury 3) Reduction of free radical formation 4) Attenuation of inflammatory responses 2. Adverse consequence 1) Bleeding 2) Infection 3) Cardiovascular events

Postoperative Hypothermia Adverse Effects 1. Respiratory Diaphragmatic function is impaired. 2. Coagulation Hypothermia reduces platelet aggregation and endothelial-associated coagulation with increases in postoperative bleeding. 3. Hemodynamics Increases in the incidence of atrial fibrillation Temperature-dependent release of cytokines (TNF, interleukin-1, beta & 6) 4. Splanchnic Splanchnic hypoperfusion was common after CPB and associated with postoperative complication. 5. Neurologic Cerebral metabolism is reduced 5% to 7% for each degree centigrade reduction in temperature.

Myocardial Protection Adverse effects of cooling 1. Impairs the Na-K adenosine triphosphate (ATPase) 2. Impairs the mitochondrial adenosine triphosphate (ATP) translocase 3. Impairs sarcoplasmic reticular Ca ATPase 4. Impairs oxygen–hemoglobin dissociation Thus hindering cell volume control, energy metabolism, Ca sequestration, and oxygen delivery

Myocardial Protection Disadvantages of hypothermia 1. Effects on membrane stability 2. Effects on enzyme function 3. Effects on tissue calcium accumulation 4. Effects on cellular volume regulation

Cardiopulmonary Bypass Endocrine Response• Increase catecholamine secretion• Increase vasopressin or ADH secretion• Paradoxical rise of atrial natriuretic hormone • Altered response of cortisol secretion• Hyperglycemia• Lipid metabolism is dominant due to abnormal glucose metabolism (increase free fatty acid)

Cardiopulmonary Bypass Mechanisms of hyperglycemia 1. Reduction in GFR or increased tubular reabsorption 1) Alterations in glucose transport mechanism 2) Nonpulsatile flow on organ function 3) Decreased hematocrit and albumin level as a decrease in ECF volume 2. Input of glucose from exogenous sources, and glycogenolysis or gluconeogenesis 3. Hormonal and metabolic factors provide the basis to develop hyperglycemia.

Cardiopulmonary Bypass  Causes of hyperglycemia* Usually returns to normal within 12 hours1. Increased glycogenolysis secondary to epinephrine increase during CPB2. Abnormal pancreatic insulin response due to hypothermia 3. Impaired glucose transport & utilization 4. Binding of endogenous insulin to artificial surface during CPB

Hyperglycemia after CPB Pitfalls• Osmotic diuresis• Dehydration• Glycosylation of protein• Increased cerebral hemorrhage

Cardiopulmonary Bypass Effects on cerebral function• Normally, cerebral blood flow is independent of cerebral perfusion pressure over a range of 50-150mmHg, with the primary determinant of flow being cerebral metabolic rate. Outside of this range of autoregulation, CBF is directly related to CPP. • Variables such as the methods of acid-base management, mean arterial pressure, flow rate, and type of perfusion, and their effect on cerebral circulation remain controversial. • Global increase in CBF due to elevation of PaCO2, and associated cerebral vasodilation may critically reduce perfusion pressure and jeopardize of areas of brain dependent on flow through stenosed vessels. • Cerebral hyperperfusion may potentially deliver more gaseous and particulate microemboli into cerebral circulation. • Cerebral blood flow is also affected by anesthetic agents.

Cardiopulmonary Bypass Hematologic effect• Platelet dysfunction & thrombocytopenia Foreign surface Blood –gas interface Hypothermia • Reduction of coagulation factors, fibrinogen, and plasminogen • Reduction & damage of RBC

Cardiopulmonary Bypass General renal effect • Ischemia as a major factor in renal dysfunction with prolonged bypass • Early recognition of renal failure correlated with decreased renal perfusion • Vascular effect due to dilution of circulatory catacholamine• Microemboli & hemolysis cause renal dysfunction.• Hemodilution protect renal damage due to increased renal plasma flow. • Hypothermia decrease renal glomerular filtration due to cortical vasoconstriction. • Osmolar & oncotic agents : neutral effect for hemodilution • Endocrine action : increase ADH due to low LA pressure & hypotension, nonpulsatile flow

Cardiopulmonary Bypass Edema after CPB in neonate 1. Capillary permeability is naturally higher in younger people 2. Greater exposure to bypass prosthetic surface area relative to neonate’s endothelial surface area 3. Larger ratio of prime volume to blood volume than in older 4. Exposure to greater extremes of temperature as well as low-flow or circulatory arrest, thereby increasesing the risk of ischemia-reperfusion injury

Cardiopulmonary Bypass  Pulmonary effects1. Lung fluid exchange : excessive pulmonary capillary fluid filtration due to capillary damage induced by complement release and/or activation of coagulation cascade 2. Hemodilution reduce complications of intravascular coagulopathy, coagulation and increase pulmonary lymph flow and decrease blood use. 3. Pulmonary capillary hydrostatic pressure : effective left ventricle venting 4. Interacting causes of alveolar collapse 5. Pleural cavity : opening the pleura lower lung volume and increase the amount of alveolar collapse 6. Decrease in lung volume due to chest wall pain & increase in interstitial fluid in the lung

Ideal Perfusion Flow Rate Normothermia (whole blood) Body Weight(kg) Flow(ml/kg/min) 5 under 200 5-10 170 10-20 135 20-30 100 30-60 85 60 over 60-70

Cardiopulmonary Bypass Difference between infants & adult• Smaller circulating blood volume• High oxygen consumption rate• Reactive pulmonary vascular bed• Presence of intra- & extracardiac shunt• Immature organ system• Altered thermoregulation• Poor tolerance to microemboli

Recommended Pump Flow Rate Normothermic Cardiopulmonary Bypass Patient weight (kg) Pump flow rate (ml/kg/min) < 3 150-200 3-10 125-175 10-15 120-150 15-30 100-120 30-50 75-120 >50 50-75

Minimal Pump Flow Rate Temperature CMRO2 Predicted MPFR (c) (ml/100g/min) (ml/kg/min) 37 1.48 100 32 0.823 56 30 0.654 44 28 0.513 34 25 0.362 24 20 0.201 14 18 0.159 11 15 0.112 8

Optimal Flow during CPB • Normal flow & value , total body perfusion supplied by left ventricle, an extracorporeal pump, or both Normal value; Flow 3.2L/BSA/min Oxygen uptake(VO2) 100-130ml/BSA/min Hemoglobin value 15gm% Hematocrit 45% Normal systemic transport(SOT) 20 vol.% x 3.2L/BSA/min or (640ml/O2/min)

Optimal Flow during CPB Organ Blood Flow Rates During Profoundly Hypothermia(20℃), Nonpulsatile, Hemodiluted Cardiopulmonary Bypass. Organ Blood Flow Rate (mL.minc -¹. 100 gm-¹) Organ 1.5* 1.0* 0.5* Whole body 10.29± 0.080 6.86±0.053 3.44±0.026 Brain 45±6.3(5.4%) 41±7.9(7.1%) 23±2.8(8.2%) Heart 280±84 170±48 52±9.3 Lung 3.8±0.96 2.8±0.75 1.0±0.28 Liver 70±36 36±8.4 12±2.5 Kindney Medulla 55±14.2 18±5.7 8.4±1.52 Cortex 580±112 410±63 220±22

Optimal Flow during CPB Safe Duration of Circulatory Arrest Temperature C˚ Oxygen Consumption Circulatory Arrest 37 100% 4-5 29 50% 8-10 22 25% 16-20 16 12% 32-40 10 6% 64-80

Cardiac Venting • Effects 1. Myocardial effect Decrease intraventricular pressure 2. Pulmonary effect Decrease pulmonary venous pressure 3. Evaluate valve function• Complications 1. Myocardial injury at apex 2. Air embolism 3. Bleeding 4. Arrhythmia

Coronary Blood Flow  Regulating factors 1. Hydrostatic pressures 2. Anatomic factors 3. Metabolic control 4. Autoregulation * well correlates with myocardial oxygen consumption a) Myocardial tension development b) External work c) Heart rate d) Contractility

Coronary Vasomotor Dysfunction • Endothelial dependant cyclic guanosine monophosphate – mediated vasorelaxation (response to acetylcholine) • Endothelial independant cyclic GMP-mediated vasorelaxation (response to Na-nitroprusside, nitroglycerin)• Beta-adrenergic cyclic adenosine monophosphate – mediated vasorelaxation (response to isuprel)

Cardiopulmonary Bypass Factors influencing blood pressure• Alteration in vascular response• Anesthetic agents• Operative trauma• Perfusion flow rate• Priming hemodilutional factor• Perfusate colloidal osmotic pressure• Temperature• Anatomic factors, such as PDA, collaterals

Cardiopulmonary Bypass Vasodilatory hypotension 1. Etiology 1) Endothelial injury 2) Release of cytokines 3) Other inflammatory mediator 2. Treatment 1) Pressor catecholamines 2) Arginine vasopressin (pitressin) Presence of arginine vasopressin deficiency Predisposing factors 1) Hyponatremia 2) Atrial stretch receptor activation (ANP increase) 3) Autonomic dysfunction

Multiorgan Failure  Definition * Laboratory indices of cellular death in every tissue and with intractable loss of peripheral vascular response similar to sepsis. * This situation, in general, is accompanied by excessive whole body edema, so-called, capillary leak syndrome, organ recovery cannot be achieved.

Cardiopulmonary Bypass Abdominal complications• Incidence About 1%, frequent in valve surgery Gastrointestinal ulceration associated with bleeding Acute gastric dilation, Cholecystitis, Acute appendicitis Acute pancreatitis• G-I bleeding Ulcer history in 50%, frequent in old age, men, valvular disease• Acute pancreatitis 0.03% of CPB, mortality 30%, not related amylase level hypercalcemia, embolism, low perfusion• Intestinal ischemia & infarction Very rare, due to embolism, cardiac failure, splanchnic pooling (CPB effect), digitalis

Cardiopulmonary Bypass Potassium kinetics• Urinary loss Not related to urine volume, not equilibrium to interstitial space• Hemodilution Move to interstitial space• Acid-base balance• Glucose metabolism• Catecholamine Intrinsic catecholamine decrease serum potassium level• Propranolol (beta-adrenergic blocking agents) Inhibit the decrease in serum potassium

Assisted Circulation Control blood activation 1. Surface modifications 1) Physical modification 2) Chemical modification by grafting a hydrophilic component 3) Surface modification by inclusion of bioactive components 4) Biomembrane mimicry 5) Cellular seeding and lining 2. Inhibition of initial events leading to blood activation 1) Platelet anesthesia 2) Contact phase inhibition 3) Complement inhibition 4) Monocyte inhibition 3. End point inhibition of biologic cascades 1) Antifibrinolytic drugs 2) Modulation of neutrophil-mediated injury

Coagulation Function Test • Coagulation time, whole blood coagulation time (WBCT), Activated clotting time (ACT) Assess the integrity of the coagulation system• Partial thromboplastin time Identify the abnormality existing in the intrinsic system• Prothrombin time (Quick test) Measure the integrity of the extrinsic system (factor VII)• Thromboplastin generation time Measure intrinsic system (factor VIII, IX)• Thrombin time Identify qualitative or quantitative fibrinogen defect

Protein C System Action 1. Plasma factors protein C and S 2. Endothelium-bound thrombomodulin 1) Thrombomodulim binds circulating thrombin to form a complex that catalyzes the conversion of protein C to activated protein C. 2) Activated protein C together with its cofactor protein S, inhibits further thrombin generation by inactivating factor Va & VIIIa. 3) Activated protein C neutralize plasmogen activator inhibitor PAI-1, PAI-3, & enhance fibrinolysis. 3. Congenital deficiency of protein C Resistance of factor Va —> hypercoagulable state 4. Aprotinin is an inhibitor of activated protein C.

Nature of Aprotinin 1. Nature Aprotinin, a polybasic polypetide, naturally occurring serine protease inhibitor derived from bovine lung 2. Action 1) Decrease fibrinolytic action 2) Decrease platelet activation 3) Inhibit kallikrein activation 4) Inhibit neutrophil activation 5) Reduce cellular & immune inflammatory reaction

Nafamostat Mesilate • Nafamostat mesilate is a synthetic, specific, and reversible serine protease inhibitor • Nafamostat mesilate has a potent inhibitory activity on thrombin, XIIa, Xa, kallikrein, plasmin, C1r and C1s subcomponent proteins of complement system, and trypsin, all classified as trypsin-like serine proteases, which are known to have a substrate specificity for arginyl and lysyl residue–containing substrates. • Hydrolysis of NM occurs mainly in the blood and liver, followed by glucuronic acid conjugation, with a half-life of 8 minutes in human plasma. • Nafamostat mesilate almost completely inhibits either the formation or activity of XIIa and kallikrein, two of the key enzymes of the contact system, and is thought to interact directly with platelets to reduce aggregability.

Use of Desmopressin Actions* Desmopressin acetate is a synthetic vasopressin analogue that lacks vasoconstrictor abilities * This reduces bleeding time and surgical blood loss by inducing release of circulating level of coagulation factor VIII & Von Willebrand factor* It improves hemostasis in patients with certain congenital or acquired disorder of platelet function

Actions of Adrenomedulin • Adrenomodulin is potent vasodilator peptide initially isolated from adrenal medulla,but in the vascular beds of organs such as heart,lungs, and kidneys • Synthesized & secreted by the endothelial cells and smooth muscle cells of the pulmonary vasculature • Impaired ability to synthesize or secrete ADM in pulmonary circulation contribute development of pulmonary hypertension • Multiple biologic effects involved in cardiovascular homeostasis

Issues for Heparin Use • Dose of heparin• Evaluation to assess anticoagulation• Heparin titration during CPB• Protamine dose for reversal• Assessment of adequate reversal• Heparin resistance• Heparin rebound• Complications of heparin therapy

Properties of Heparin • Heparin consists of a group of glycosaminoglycans with molecular weights from 3000 to 30000 daltons and is prepared from beef lung or porcine intestinal mucosa and is a heterogenous mixture of polysaccharides with molecular weights upto 1000 daltons • Heparin inhibits both Factor Xa and thrombin. The active site is a pentasaccharide which binds to antithrombin III, a serine protease inhibitor in plasma. Additional saccharide units are needed for heparin to bind factor Xa and thrombin. • Intravenous bolus injection 100, 400, or 800u/kg will produce anticoagulant activity half-lives of 1, 2.5, and 5 hours respectively. • Extravascular depots, hemodilution, and hypothermia all affect the anticoagulant effect of heparin • Heparin is removed primarily by reticuloendothelial system, and inactivated in the liver by heparinase and excreted in the urine

Actions of Heparin Anticoagulation properties• Heparin exerts its anticoagulant effect by enhancing the action of antithrombin III, the major naturally circulating inhibitor of coagulation • Heparin binds antithrombin III causing a conformational change that exposes additional binding sites on the antithrombin III molecule • This increases the ability of antithrombin III to bind with factors XIIa, XIa, IXa, and Xa thus accelerating their inhibition and preventing the formation of fibrin • The ACT is a gross test of coagulation and as such is affected by all aspects of the coagulation cascade, except factor XIII. • In addition to residual heparin, destruction of serine proteases, hypofibrinogenemia, fibrinolysis, and platelet abnormalities, both qualitative and quantitative , can all influence the ACT.

Action of Heparin Additional properties• Modulate the inflammatory response by inhibiting activation of polymorphonuclear leucocytes as well as components of complement cascade • Production & release of several endothelial vasoactive mediators including endothelin and nitric oxide • Protecting effect in the setting of myocardial ischemia and reperfusion injury • Heparin activates lipoprotein lipase which releases free fatty acids from plasma triglyceride

Alternatives of Heparin • Some low molecular weight heparins may lack some side-effects of commercial heparin • Framin, a low molecular weight heparin, attenuates both platelet activation and complement activation. Low molecular weight heparins tend to inhibit Factor Xa more than thrombin and also require anti-thrombin III as a co-factor • Hirudin, the natural anticoagulant found in leeches, reversibly inhibits thrombin with very high affinity and produced by recombinant DNA technology • Other thrombin inhibitors include boroarginines and chloromethyketones

Adverse Effects of Heparin • Heparin increases the sensitivity of platelets to platelet agonists; ADP, epinephrine and collagen • Heparin may also affect complement activation and neutrophil release • Heparin contributes to activation of platelets, complements, neutrophils and plasminogen during CPB • Therefore heparin directly contributes to the whole body inflammatory response