Anesthesia for Cardiac Surgery

Jonathan Parmet M.D.

Society Hill Anesthesia Consultants

Case Discussion

• 52 year old morbidly obese female scheduled for CABG

• she has normal ventricular function • she has 100% LAD occlusion not amenable

to coronary stenting• Has a history of NIDDM, and HTN

Case Discussion

• What anesthetic monitors ?– PA catheter?

• Should the patient be fast tracked ?• What are the anesthetic considerations?

– Push for extubation on the table?

Overview

• Anesthetic monitoring– PA catheter– Transesophageal echocardiography– Cerebral oximetry

• Anesthetic for Patients with CAD requiring cardiopulmonary bypass

• Pharmacologic agents administered• Fast track

Open Heart historyPhiladelphia’s role

• 1948-Boston/ Philadelphia- Dwight Harken/ Charles Bailey- beating heart mitral commisurotomy

• 1952- Minnesota- Lillehel/Lewis- Hypothermia (based on work by Bigelow)- open heart with- clamping venous inflow to heart-

• 1953- Philadelphia-Gibbons- TJH first successful use of CPB with oxygenator

• 1955- Mayo clinic- bubble oxygenator

Monitors

• Large bore IV- 18-16 gauge• Invasive arterial monitoring right radial,

brachial, or femoral• Pulmonary arterial catheter – mixed

venous, continuous cardiac output• Trans-esophageal echocardiography• Cerebral Oximetry• Bis

Pulmonary Arterial Catheter

• Used for cardiac filling pressures, tissue perfusion (mixed venous sat), cardiac output

• Outcome studies do not support the use of a PA catheter– Connors ( JAMA 1996) – increased morbidity

in ICU patients with PA catheters vs no PA cath– Schwann Anesth Analg. 2011 Nov;113(5):994-1002.

Lack of effectiveness of the pulmonary artery catheter in cardiac surgery.

Anesth Analg. 2011 Nov;113(5):994-1002

Anesth Analg. 2011 Nov;113(5):994-1002

Study Assertions

• Increased morbidity in patients with PA catheter

• Increased use of inotropes in PA group• Increased fluid administration in PA group• PA catheter not confer any beneficial effect

in the CABG population – might be harmful ?

Anesth Analg. 2011 Nov;113(5):994-1002

Limitations

• Data collection > 10 years old– How applicable to patients today

• Variations in institution use from 1-99%• Medications not included in propensity

matching– beta blockers and statins, anti hypertensives, aprotinin (?)

• Despite propensity matching Bias that patients with severe disease received catheters

• TEE patients not included

How do PA catheters increase morbidity?

• Complications of insertion, arrhythmias, pulmonary hemorrhage, infection- not reported

• 3% increase in fluid 200 ml, 7% increase in fluid balance 200 ml, 8% increase use of inotropes

• Increased morbidity due to misinterpretation of information

Anesth Analg. 2011 Nov;113(5):994-1002

Benefits of Transesophageal Echocardiography

Monitor LV function

Assess intravascular volume status

Assess myocardial ischemia/ dysfunction

Valve function

Intracardiac defects

Aortic pathology

Unexplained cardiovascular deterioration

Detect new wall motin abnormalities

Guidelines for Perioperative Transesophageal EchocardiographyAn Updated Report by the American Society of Anesthesiologists and the

Society of Cardiovascular Anesthesiologists Task Force. Anesthesiology:May 2010 - Volume 112 - Issue 5 - pp 1084-1096

Transesophageal Echo in Myocardial revascularization: Influence on intraoperative

decsion making. Leung A&A 1996

• 75 cases• 584 interventions• TEE single most guide in 17%• TEE guided fluid therapy in 30%• Vasopressor guide in 3%• Not an outcome study- Does not define

patients do better with TEE monitoring

Intraoperative Echocardiography is indicated in High-risk coronary artery bypass grafting.Ann

thoracic Surg. Savage 1997

• 82 high risk CABG patients• 33% one major surgical intervention based

on echo• 51% one major anesthetic/hemodynamic

change• No improved outcomes with TEE

– 3 patients detected severe atherosclerosis of Aorta off pump

– 6 patients alternative cannulation sites– 16 patients undiagnosed valve disease

The role of intraoperative transesophageal echocardiography in patients having CABG.

Ann Thorac Surg 2004 Qaddoura• New prebypass findings in 10%

– PFO in 22- 7 closed– Sig MR, TR, AR 12- repair in 5– AV (lambl’s) 2- AV explored– Aortic Atheroma 5- op cab

• Surgical plan altered in 3.4%• New Postbypass in 3.2%

– New mr 3 – repair 2– Depressed LVF 6- IABP placed- 5

Case Discussion• 57 year old male for redo-CABG. h/o

IDDM, hyperlipidemia, obese• 10 hour surgical procedure/ 3 hour pump

time/ 2 hour cross clamp• Post-op – called to see patient for occipital

alopecia• 3 years later complains of inability to

concentrate and perform his tasks as an accountant

• Files law suite for having received head trauma during surgical procedure

Neurologic changes associated with Cardiopulmonary bypass

• 3-5 % of CPB suffer perioperative stroke• 30-50% of CPB suffer neuro-cognitive

dysfunction– The incidence varies with the type of neuro

psychological testing

Adverse Cerebral Outcomes after Coronary Bypass Surgery NEJM 1996 McSPI

• N= 2108• Type I- Stoke stupor• Type II- deterioration in intellectual

function, memory deficit• 3.1% type I, 6.1% type II• 21% type I died vs 10% type II• Incidence increased in patients > 70 yrs

NEJM 1996

Factors Associated with Adverse Neurologic Outcome

• Advanced Age• History of previous neurologic event• Low flow (Cerebral saturation measure of

oxygen extraction• Hypertension• DM• Atherosclerotic Disease• Open chamber procedures• Use of Cardiopulmonary Bypass

Etiology of Adverse Neurologic outcome

• Embolic – Microemboli (CPB)– Macroemboli ( aortic manipulation Aortic cross

clamp and cannulation )

• Hypoperfusion– Carotid Stenosis (increased incidence in DM)– Microvascular stenosis (increased incidence in

females and DM)

Strategies to minimize emboli/ factors affecting cerebral blood flow

• Minimize aortic manipulation– Single clamp technique– Off pump CABG (OpCAB)

• Maintain cerebral blood flow– Maintain higher perfusion pressure– Blood gas measurement

• Decrease CMO2-– Temperature (80’s-90’s hypothermia 24 degrees)

late 90’s til now moderate hypothermia during cpb

– Anesthetic agents (propofol, Ca channel blockers

Does cardiopulmonary bypass contribute to neurologic dysfunction?

• Ann thorac Surg 2003– N= 52, 29 opCAB, 23 onCPB– TCD, CMRI, Neuropsych testing– opCAB less emboli than on CPB– No difference cognitive decline 3 months after

surgery

Cognitive and Cardiac outcomes 5 years after off pump vs on pump CABG

• JAMA 2007– 231 low risk CABG (123 opCAB, 117 onCPB)– Measure Cognitive status after 5 years– 62/123 (50.4%) opCAB, 59/117 (50.4%) on

CPB cognitive decline

In low-risk CABG patients, avoiding the use of CPB had no effect on 5 year cognitive decline

Is it aging?

• A 25-30% cognitive impairment has been demonstrated in the older major vascular, orthopedic, and thoracic surgical populations Lancet 1996

• What is the effect of bypass versus the effect of aging?

Cerebral oximetry

• Monitor for cerebral ischemia– Near Infrared- 70% venous/ 30% arterial

• 3-5 % of CPB patients suffer perioperative stroke

• There is patient to patient baseline variability

Cerebral Oximetry

Lower baseline levels associated with increased patient morbidity and mortality

( Murkin Anesth & analg 2007, Heringlake Anesthesiology 2011)

Indirect measure of tissue perfusion not just cerebral perfusion

Murkin. Anesth & Analgesia 2007

Murkin. Anesth & Analgesia 2007

Murkin. Anesth & Analgesia 2007

Interventions

• Check head insure in neutral position• PaCO2< 35 Increased to > 40mmHg• If MAP < 50 increased > 60• If CVP > 10• If cardiac index < 2.0 (CPB) increased > 2.5• Persistent decrease Increase FIO2/ pulsitile

pressure/ propofol 50-100/ transfuse if hct < 20%

Murkin. Anesth & Analgesia 2007

Preoperative Cerebral Oxygen Saturation and Clinical Outcomes in Cardiac

Surgery

Anesthesiology:January 2011 - Volume 114 - Issue 1 - pp 58-69

Cerebral Desaturation Algorithm

• Increase FIO2 to 100%

• Assess head and cannula position• If PaCO2 < 40 mmhg increase to > 40

mmhg• Increase MAP > 60 mmhg• If Hct < 20 % consider transfusion of PRBC• Increase anesthetic depth

Case Presentation

• 57 yr old female for CABG/ Mitral valve annuloplasty

• A-line/ large bore IV/ PA catheter/ TEE/ Cerebral Oximeter

• Induction of anesthesia- 100% oxygen, sevoflurane/ 250-500 microgms fentanyl/ 1-4 mg midazolam/ 10 mg vecuronium

Anesthesia objectives for patients undergoing cardiopulmonary bypass

• Anesthesia– Analgesia

• Narcotic (fentanyl 10-20 micrograms/kg)• Amnesia (midazolam- 1- 5 mg)• Inhalation agents ( desflurane, sevoflurane,

isoflurane)

– Muscle relaxation• Long acting Nondepolarizing muscle relaxant

pancuronium ( no longer available)

Intermediate acting nondepolarizing muscle relaxant

Principles of Anesthetic: Major Determinants of Myocardial Oxygen

Consumption

• Heart rate– Increases in heart rate – increase contractility– Increase oxygen consumption– Decrease myocardial oxygen supply

• Contractility• Wall tension

– Law of Laplace

Ischemic preconditioning

- Cath lab- PTCA- human observation of ischemic preconditioning

– 1st balloon inflation ST-segment elevation with chest pain

– 2nd balloon inflation- reduction in ST-segment with decreased chest pain

– A small period of sub-lethal ischemia prior to a prolong period of ischemia induces a complex series of reactions which reduces myocardial injury• adenosine and bradykinin activate G-proteins in the myocyte pathways in turn activates complex cascade

(open KATP channels, protein kinase C, (-) guanine nucleotide, ROS) - Tanaka K. Mechanisms of cardioprotection by volatile anesthesthics. Anesthesiology 2004, 100:707-21

Effects of sulfonylureas on Ischemic preconditioning

Ischemic Preconditioning

The Inhalational Anesthetics

• Sevoflurane– Most data on sevoflurane

• Isoflurane– Kersten JS. Isoflurane mimics ischemic preconditioning via activation of KATP channels. Anesthesiology 1997;87:1182-90

• DesfluraneNo study favor one volatile agent over another. Maintain volatile anesthetic throughout the procedure

De Hert SG. Effects of propofol, desflurane, and sevofluraneOn recovery of myocardial function after coronary surgery.Anesthesiology.2003;99:314-23

De Hert SG. Effects of propofol,, and sevofluraneOn recovery of myocardial function after coronary surgery.

Anesthesiology.2003;99:314-23

Myocardial damage prevented by volatile anesthetics Journal cardiothoracic and Vascular Anesthesia 2006

Glucose control for Cardiac Surgery

• Maintain tight glucose control• Blood sugars < 180 mg/dl• If > bolus between 2-3 units regular (short

acting) insulin• CPB associated w/ increase in blood

glucose

Blood glucose control in patients undergoing cardiac surgery

• Elevated blood glucose levels in patients with myocardial infarctions have a 30% worse outcome

• Elevated blood glucose implicated in worsening the severity of stroke

• The society of thoracic surgeons guideline series: Blood glucose management during adult cardiac surgery 2009

• Higher glucose levels during and after cardiac surgery independent predictor of mortality

Case Discussion

• 51 year old male for CABG. Severe 3 vessel disease. History of increased cholesterol

• Intraoperative sugars prior to CPB normal• Sugars on CPB increase to 200 gm/dl• Should the blood sugar be treated?• What if the sugar was 145?

Deleterious effects of hyperglycemia

• Increases myocardial infarction size in dogs• Inhibits ischemic preconditioning• Amplifies reperfusion injury• Produces coronary endothelial dysfunction

facilitating myocardial ischemia• Inhibits neutrophils• Positive effects of Insulin

– Decrease free fatty acids and decreases free radical formation

• Fish – 200 patients undergoing coronary artery bypass grafting (2003)– Postop glucose > 250 mg/dl => 10 fold increase

in complications

• Gandhi- 400- retrospective cardiac surgery- elevated blood glucose independent predictor of poor outcome (2005)

Intensive Insulin Therapy in Critically Ill Patients N Engl J Med 2001; 345:1359-1367

Van de Berghe• Prospective randomized to intensive

treatment (bs- < 110 mg/dl) conservative treatment (bs- 180-200 mg/dl)

• Pt population 59% CABG, 27% Valve, 14% combined procedure

• 39% intensive hypo, 6% hypo• The key point is Blood glucose control not

occur intraoperatively, only on admission to the unit

Intensive Insulin Therapy in Critically Ill Patients N Engl J Med 2001; 345:1359-1367

Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery

bypass grafting. J thorac Card Surg 2003;125:1007-21 Funary

• CABG- n=3554• 1987-1991 subcut insulin (n=942)• 1991-2001 Continuous infusion

– 1991 to 1998 target sugar- 150-200 mg/dl– 1999- 2001 sugar 125-175 mg/dl– 2001- sugar 100-150

Funary J thoracic and Cardiovascular Surgery 2003

• Overall mortality 388/ 3554 =2.8%• Mortality in Sub Cut =4.5% 40/942• Mortality in Continuous infusion = 1.6%

– P<0.05

• Conclusion: improved blood sugar control improve overall mortality– ? Which blood glucose range

Copyright ©2003 The American Association for Thoracic Surgery

Furnary, A. P. et al.; J Thorac Cardiovasc Surg 2003;125:1007-1021

No Caption Found

Tight Glycemic control in diabetic coronary artery bypass graft patients improves

perioperative outcomes. Lazar Circulation 2004

• N= 141 patients• Randomized to tight control GIK solution

– Target blood glucose 125-200 mg/dl

• Subcuntaneous Injections– Blood glucose < 250 mg/dl

• GIK started before CPB, but discontinued on CPB- restart with Aortic unclamped

• Continued 12 hrs postop

Figure 4. Cardiac index.

Lazar H L et al. Circulation 2004;109:1497-1502

Copyright © American Heart Association

Poor intraoperative blood glucose control associated with a worsened hospital outcome after cardiac

surgery in diabetic patients. Anesthesiology 2005

• N= 200• Maintain intraop blood glucose 150<to

<200 mg/dl• Insulin infusion started intraop• Postop maintain blood glucose < 140 mg/dl• 71 patients had intraop insulin infusion• 35 patients uncontrolled sugars

Poor intraoperative blood glucose control is associated with a worsened hospital outcome after

cardiac surgery in diabetic patients. Ouattara Anesthesiology 2005;103:677-8

Intensive versus convention glucose management in the critically ill. The Nice-sugar investigation. NEJM

2009

• N= 6104

N= 3050 conventional N= 3012 intensive• 206 of the intensive rx group had severe

hypoglycemia• 15 in the conventional group had severe

hypoglycemia• 27% intensive group died *• 24.9% conventional group died *

• Intensive glucose control– 81-108 gm/dl

• Conventional glucose control< 180 gm/dl

Non surgical population- different treatment protocol- high incidenceOf hypoglycemia in intensive group

Conclusions

• Elevated blood glucose preop is associated with poor outcomes postop

• Intraoperative insulin infusions reduce mortality in the postoperative period (perhaps)

• During CPB insulin administration if Blood glucose > 140

• Continue infusion in the postoperative period

Blood Conservation in Cardiac Surgery

• Case conference November 2, 2012

Case Presentation

• 76 year old male for CABG (1 bypass) and mitral valve repair. He has Aortic insufficiency ( mild to moderate). He appears frail. Pre op platelet count is 100K

• Undergoes 1 vessel bypass/ Mitral valve repair. After chest closure chest tube drainage at 300 for one hour. No thrombus in the chest tube

• Second Hour 200 cc of chest tube drainage

Case

• Transfused 5-7 units PRBC, 12 units FFP, 18 units Platelets, cryo, Recombinant Factor VII (90 ug/kg)

• Lowest intraoperative Hgb 6 gm/dl• After 4 hours chest tube drainage decrease• TEE no evidence of tamponade• 2 days postoperative chest X-ray reveals

ARDS• Aggressive diuresis chest X-ray resolves

• Does packed red blood cell transfusion affect patient outcome independently?

• Does the number of packed red blood cells administered affect patient outcome?

• Does blood component therapy affect patient outcome?

ASA refresher course 2012

Background

• 30% of patients post cardiopulmonary bypass develop microvascular bleeding

• 10% of hospital transfusions are allocated to patients cardiac surgical patients

• 34%-50% of CABG patients are transfused• However significant risk is associated with

allogenic red blood transfusions

Transfusion in Coronary Artery Bypass Grafting is Associated with Reduced Long-

Term Survival Ann Thorac Surg 2006;81:1650-1657

• N= 10,289 isolated CABG patients• 1995-2002• 49% of patients received PRBC

– Est 5,041 transfused

• 9.8 % Platelets• 2.8% FFP• 0.5% Cryo• 2,067 deaths

Koch. Transfusion and long-term survival. Ann Thorac Surg 2006;81;1650

Koch. Ann Thorac Surg 2006;81:1650-7

Conclusion

• Perioperative PRBC transfusion is associated with adverse long-term sequela in isolated CABG. Attention should be directed toward blood conservation methods and a more judicious use of PRBC.

• With increased units of PRBC there was an increase in patient mortality

Criticism

• Observational study– Not randomized– No indication of transfusion trigger– Blood transfusions could be the cause or just a

marker of patients that were sicker and had a tendency to bleed• Included in analysis greater than 2 PRBC

The Association of perioperative red blood cell transfusions and decreased long term survival after

cardiac surgery. A&A 2009. 1741-46 Surgenor

• Northern New England Cardiac disease group– 8 medical centers

• 9,079 CABG 2001 to 2004• 36% of patients PRBC 1-2 units• Risk factors for transfusion

– Increasing age– Anemia– Female (decreased BMI)– Co-morbid disease

Figure 1. Adjusted survival by red blood cell use.

Surgenor S D et al. Anesth Analg 2009;108:1741-1746

©2009 by Lippincott Williams & Wilkins

Conclusion

• “ For anesthesiologists and cardiac surgeons, transfusion of just 1 or 2 units is often viewed as minor and routine decision”– That decision places patients at significant risk

• Exposure of 1 to 2 units of PRBCs was associated with a 16% increased hazard of decreased survival after cardiac surgery

Why?

• Shelf life of PRBC = 42 days• 20-40% of PRBC > 28 days• Could prolonged storage time be associated

with increased morbidity and mortality?– In Cardiac patients increased risk of death,

renal dysfunction ,respiratory dysfunction and ICU

– PRBC greater than 28 Days undergo conformational changes

Stored PRBC changes

• Post operative infectious process– Inhibition of immune system (non leukocyte

washed)

Damage of the microcirculation from transfused Packed RBCs that have abnormal morphology

Long term inhibition of the recipients immune function

Stimulation of the inflammatory response

Duration of Red-Cell Storage and Complications after Cardiac Surgery. N

Engl J Med 2008; 358:1229-1239. Koch

• 2872 CABG 14 day PRBC from 1998-2006• 3130 CABG >14 days (old blood)• Mean storage for 14 day blood- 11 days• Mean storage for old blood- 20 days

Duration of Red-Cell Storage and Complications after Cardiac Surgery. N Engl J Med 2008;

358:1229-1239

• PRBCs stored greater than 14 days had

increased risk of perioperative complications and reduced short term and long term survival

Respiratory failure, septicemia, renal failure, and multisystem organ failure.

Duration of Red-Cell Storage and Complications after Cardiac Surgery. N Engl J

Med 2008; 358:1229-1239

Duration of Red-Cell Storage and Complications after Cardiac Surgery. N Engl J

Med 2008; 358:1229-1239

Duration of Red-Cell Storage and Complications after Cardiac Surgery. N Engl J

Med 2008; 358:1229-1239• Greater in hospital mortality

– 2.8% vs 1.7% older vs newer

• More likely develop renal failure– 2.7% vs 1.6 % older vs newer

• Septicemia– 4.0% vs 2..8% older vs newer

• Multisystem organ failure– 0.7% vs 0.2%

Reasons for increased morbidity and mortality

• Conformational changes decreases PRBC viability

• Decreased deformability results in impairing microvascular flow

• Decrease 2-3 DPG - decrease oxygen delivery

• Increased adhessiveness and aggregabilty• Decreased nitric oxide and accumulation of

proinflammatory substances

Questions

• How can we reduce blood transfusions?– Blood conservation strategies

• Does component transfusion carry the same risk?– Platelets– Fresh frozen plasma– Cryo

Coagulation and Cardiopulmonary Bypass

Case Presentation

• 50 year old male for redosternotomy along with revision aortic root replacement. He has severe aortic insufficiency

• Receives 300 units / kg of Heparin with targeted ACT > 400

• Duration of Cardiopulmonary Bypass = 4hrs

• Off CPB 1:100 reversal of protamin• ACT returns to baseline

Case Presentation

• No thrombus is formed and the patient demonstrates diffuse microvascular bleeding

• Receives empiric 4 units of FFP / 2 (6) packs of platelets- continues to bleed

• Receives cryoprecipitate • Receives Recombinant Factor VII (45

ug/kg)• Receives Prothrombin Concentrate (45

units/kg)

Overview• Coagulation Cascade

– Classic Coagulation Cascade– Current Depiction of In vivo clot formation

• Cardiopulmonary Bypass and effect on the Coagulation Cascade

• Anticoagulation for Cardiopulmonary bypass (measure of anticoagulation)

• Reversal of anticoagulation– Measure of reversal of anticoagulation

Coagulation Cascade

• Classic coagulation CascadeIntrinsic Pathway

Extrinsic Pathway

• 2 phase Model of Coagulation– Initiation Phase– Propagation Phase

Waterfall / cascade model of Coagulation

Utility of Classic Cascade

Not an adequate representation of in vivo events

• Dovetail with coagulation tests: pro-thrombin time (PT, extrinsic) and activated partial thromboplastin time (aPTT intrinsic)

• Also helps explain factor deficiencies (hemophilia) and effect of anticoagulants (coumadin, heparin) with respect to coagulation tests

Question

• Can you have a normal ACT with an abnormal PT and Normal PTT ? i.e. defect in extrinsic pathway

• Can you have a normal ACT with abnormal PTT and normal PT ? i.e. defect in intrinsic pathway

Waterfall / Coag Cascade

• Intrinsic or contact pathway has no role in early events in clotting in vivo.

• The end result of the intrinsic and extrinsic pathways: prothrombin cleaved to thrombin => fibrinogen to fibrin.

• However thrombus formation is a much more dynamic process involving platelet activation and adhesion, interacting with coagulation factors,VonWillebrand factor, Ca++

Basics of Coagulation

• Platelets are bound to sites of injury, they serve both to localize and to accelerate the soluble coagulation process i.e. activate factors

• Thrombin generated during the initiation phase potently Activates Platelets

2 Phase Model of Coagulation

Initiation phase

Platelets+Tissue Factor + VIIa+ = Extrinsic Xase=> Xa and IXa

Factor Va-Xa-Ca++

(prothrombinase) + platelets=>small amounts of thrombin

IIa cleaves VIII + V + IX => intrinsic Xase=> 30 increase in

thrombin generation

• AS a result of the intrinsic Xase- Explosive thrombin generation results and produces enough fibrin to stabilize clot formation

Initiation Phase

• TF-VIIa (extrinsic Xase)=> Catalyzes X to Xa => which complexes on the platelet with factor Va small amounts of thrombin

• Thrombin then initiates the propagation phase which ends in explosive generation of thrombin and fibrin gel

• Most lab tests only address the initiation phase

Propagation Phase

• Thrombin generated in the initiation phase potently activates platelets along with cleaving factors VIIIa, and Va

• Prior to this Factor VIII complexed with VWF is released and activated to complex with factor IX forming an enzymatic complex (intrinsic Xase) which generates Xa

• 50 fold increase in thrombin production• Factor XI further amplifies the reaction

Clot Architecture

• Amplification of thrombin generation permits the formation of fibrin clot

• Clots vary in fibrin thickness• Paradoxically thicker clots have more

permeability between fibrin strands making them more susceptable to lysis

• Thin clots develop a more occlusive network

Clot Architecture

• High thrombin clots have tighter cross- linking and are more resistant to lysis

• Low thrombin clots have less cross linking and are susceptable to lysis

• High fibrin concentrations also more resistant to lysis

• Low fibrin concentrations more susceptable to lysis

Conclusion• Disruption of the endothelium (EC) => TF

initiates the coagulation system along with platelet activation/adhesion which forms a platelet plug and starts the process of clot

• End pathway prothrombin- thrombin (II)Fibrinogen- fibrin (I)

• Fibrin strands cross link to form clot

Review

• Initiation Phase– Extrinsic Xase- TF- VII- plt=> Xa =>IXa-

Va=> IIa

• Propagation Phase– Intrinsic Xase- VIII-IX=> Xa=> Va=> Iia– Prothrombinase Xa+Va=>explosive thrombin

• In order to form thrombus need platelets for activation of coagulation factors

Normal hemostasis. 1, Initial plug formation begins with von Willebrand factor (VWF) binding to collagen in the wound and platelets (plt) adhering to VWF. 2, Coagulation is initiated by

small amounts of active factor VII (FVIIa) in blood binding to the expo...

Sniecinski R M , Chandler W L Anesth Analg 2011;113:1319-1333

©2011 by Lippincott Williams & Wilkins

Arterial Clot vs Venous Clot

• Arterial thrombus formation relies heavily on acute platelet plugging– Anticoagulants for arterial thrombus attack

platelet function- ADP inhibitors/phosphatidylserine ( clopidorel, ticagrolar), GP IIa/IIIb inhibitors

• Venous thrombus formation relies heavily on thrombin generation (Coumadin, heparin pradaxa)

Platelets 3 A’s

• Activation and formation of platelet / platelet bonds

• Adhesion to endothelium• Aggregation

Platelets

Platelets must activate and adhere to the injured vessel nearly instantaneously

• platelet–coagulation factor interactions culminate fibrin formation

• Most potent platelet activator?

Protease Activated Receptor-1PAR-1

Platelets• Platelet Activation

–Shape change-Change in shape from Sphere to disc to finger like projections

–Exposure and activation of GPIb and GP IIb/IIIa permit binding of fibrinogen and platelet adhesion to the exposed vessel wall

–Dense granules (ADP, TA-2 and Serotonin) and alpha granules (growth factor, PF-4 and fibrinogen, VWF) migrate to center and then periphery

Dense Granule Release

• ADP- potent stimulant to attract other platelets for aggregation

• Thromboxane-A2- platelet attraction and also vasoconstriction

• Serotonin- platelet attraction and vasoconstriction

Platelet Activation major goals

• recruitment of additional platelets• vasoconstriction of smaller arteries to slow

bleeding (Thromboxane, serotonin)• local release of ligands to stabilize platelet–

platelet matrix• localization and acceleration of platelet

associated fibrin formation• protection of clot from fibrinolysis

Adhesion and Activation

Platelet Adhesion under shear stress

Platelet Adhesion

–VwF affinity to GPIba slows the platelet down and has the platelet change from sphere to disc.

–At same time platelet activated and GPIIb/IIIa changes and binds to VWF

–Platelet covers endothelium

• Release of alpha and dense granules contents– ADP, Ca++, serotonin, thromboxane A2

• Recruits other platelet• GPIIb/IIIa change and permit growth of

platelet plug

Platelet Aggregation

Platelet Aggregation

• platelet–ligand–platelet matrix in which fibrinogen or vWf serves as the bridging ligand

• GPIIb/IIIa is the most abundant glycoprotein on the platelet surface

• activated platelets provide specific receptors for factors VII, VIII, Xa, IXa, and Va

Factor XIII

• Factor XIIIa stimulated by thrombin• bind to fibrin and stabilizes fibrin and cross

links with fibrin to stabilize clot• Binds antiplasmin to prevent clot lysis• Clot less likely to be dissolve

Endogenous Anticoagulants

• Directed at inhibiting Platelets– Arterial circulation

• Directed at inhibiting thrombin– Venous circulation

Endogenous anticoagulantsArterial

• Endothelial Cell surface carries a net negative surface charge

• nitric oxide and prostacylin (PGI2) inhibit platelet clot (adhesion and aggregation)

• Healthy endothelial cells also synthesize ADPase (inhibits Platelet aggregation)

Endogenous Anticoagulantsvenous

• Endothelial cells synthesize an endogenous heparin congener, heparan sulfate works via antithrombin III => X, IX, XI,II

• Activated protein C (APC) cleaves factors IXa and VIIIa, thereby down regulating thrombin formation (also anti inflammation)

• Tissue factor pathway inhibitor (TFPI) cleaves Tf-VII

Tissue Plasminogen Activator

• Thrombin, and Xa stimulate release of t-PA– Cleaves plasminogen to plasmin– Release of fibrin split products (D-dimer)– Effect of TPA blunted by plasminogen

activator inhibitor

• Also Thrombin Activator Fibrinolysis Inhibitor (plasmin or thrombin for stimulus)

Fibrinolysis

Summary• Denuding the endothelium results in release

of tissue factor which activates factor VII platelets and thrombin (initiation Phase or the extrinsic pathway)

• Denuding the endothelium results in cleaving serine protease and activation of platelets, XII which stimulates the intrinsic pathway

• Both pathways result in thrombin then cleaving fibrinogen to fibrin

CPB: Upsetting the balance

• Heparin– Paralysis of the coagulation cascade by heparin

• Hemodilution• Hypothermia• Coagulation cascade• Platelet defect• Complement system• Leukocyte Activation (inflammatory

Response)

Heparin

• Variability on its effect from patient to patient (as measured by the Act)

• Stimulates ATIII (1,000 fold)– Inhibits II, Xa, IX, XI

• Inhibits Platelets (direct, indirect)– VWF effect on GP1b receptors– No effect on GP IIb/IIIa

• Bound to protein and sequestered into the endothelial cells – mechanism of heparin rebound

Hemodilution

• Pump Prime- 1 to 2 L of crystalloid• Hematocrit decrease from 40 to 25%• Coagulation factors decrease 60-70%

– Factors II, V, fall significantly and factor II correlate with post op bleeding

• With increased duration of CPB factors decrease further due to activation on CPB

Changes in Coag factors before and after bypass

Fall in thrombin potential and increased chest tube drainage

Hypothermia

• 100 decrease in temperature results in 50% inhibition of enzymatic activity

• 33-37 nonsignificant reduction in coagulation enzyme activity below 33 sig

• Temperature of 320C inhibits platelet activation and aggregation by thrombin

• Fibrinolysis not inhibited by <330 C

Activation of Coagulation Cascade

• CPB induces contact activation• Auto cleave Factor XII =>preKallikrein

=> Kinins ( bradykinin)– Intrinsic coagulation cascade=> thrombin and

fibrin and EC => TPA

• TF initiator of clottting (dominant source of clotting factor activation)

• Intense thrombin and fibrin generation over the first 5 min despite maximal heparinization (ACT > 480)

• 5 minutes of CPB thrombin and fibrin levels increase 20 fold

• Soluble Thrombin/Fibrin not circulate in blood- thrombin/fibrin measured is non hemostatic

• Total fibrin reduced on bypass (heparin)• After reperfusion increase in thrombin/ and

fibrin increase

CPBPlatelet dysfunction

• CPB decreases plt count beyond amount attributed to hemodilution

• CPB-induced functional platelet defects may produce bleeding that requires platelet transfusion despite seemingly adequate platelet counts

• CPB activates platelets, (release of the contents of internal granules alpha and dense)

Post CPB Platelet dysfunction• Blunted response to stimulation (in vitro)• Higher concentrations of thrombin, ADP,

and collagen needed to activate and aggregate

• CPB activates plts- release of dense and alpha granules

• Platelets adhere to exposed endothelium, CPB circuit binding to fibrinogen

• Net result- Spent platelets or dysfunctional platelets

Platelets

• Binding of Platelets to fibrin through the GPIIb/IIIa can tear the receptor through sheer forces

• Results in dysfunctional platelets• Protease activated receptor (par-1) cleaved • Use of Lysine or Kallekrien inhibitors

preserve Par-1 and preserve GP1b receptors (decrease platelet activation)

Platelets

• Young platelets exhibit more robust response to activation

• Older platelets less of a response• CPB demonstrates older platelets• Conclusion – set up post bypass platelet

dysfunction

CPB Stimulates Fibrinolysis

• Increase release of TPA with bypass due to EC cell (animal models) stimulation

• Stimulus for TPA release XII, HMWK, bradykinin, TF, thrombin

• 10-100 increase in plasmin production with CPB– Plasmin antiplatelet effects (platelet activation)

• Fibrin formation=> fibrin degradation (result of cpb)

• Plasmin also cause platelet GPIb, GP IIb/IIIa to internalize

Complement Activation

• Increase markers of complement activation associated with increased perioperative blood loss

• Administration of protamine induces complement surge

• Complement also stimulates inflammatory cascade, leukocytes, platelets, and ECs

Inflammatory Response

• Leukocytes bind and are activated by the CPB tubing => TF

• Leukocytes and TF found in shed blood• Decrease Protein C activation=> thrombin

formation• Inflammatory response procoagulant

CPB effect on Coagulation

Monitoring anticoagulation

J Parmet

Team Leader

Cardiac Anesthesiology

Pennsylvania Hospital

Case Presentation

• 51 yr old male for coronary artery revascularization

• h/o cocaine use and abuse• h/o v fib arrest with successful resucitation• Not cooled allowed to awake• Neurologically intact, strange affect

Case presentation

• Smooth induction/ intubation/ invasive line placement

• During swan patient require supplemental muscle relaxation

• Continued high requirement for muscle relaxation

• Difficulties ventilating Carbon dioxide

Case Presentation

• Propofol infusion started/ continued increased muscle relaxation/ pt temperature not decreasing

• Heparinized with 300 units/ kg => ACT =380

• Do you want to initiate Cardiopulmonary bypass?

Case Presentation

• Give another 10K heparin• Want to initiate bypass? • Repeat ACT after cooling?

Case presentation

• Decided give 10K of heparin• Repeat ACT 340 sec• What now?• More Heparin?• Thaw FFP?• Cancel case? Get HIT work up? Measure

antithrombin III levels?

Questions?

• What ACT for CPB?• Where does this number come from?• Why do we use the ACT?• Are there other options?

Monitoring Anticoagulation for CPB - Effects of heparin? Or heparin levels ?

• PT- prothrombin time• PTT- activated partial thromboplastin time

Prothrombin time

• TF added tests factors- VII, X, V, II, I• TF + Factor => robust response• Vitamin K dependant factors (II,VII, IX , X)• Variability in thromboplastin potency

=>INR• Excessive amounts of heparin will alter the

prothrombin time

Partial Thromboplastin time

• Thromboplastin + phospholipid (Cephalin kaolin)

• TF absent• Intrinsic pathway• Not as robust a response (takes longer for

fibrin to form thrombus)• Measure of Heparin effect- II, X, IX , XI

• One advantage to selecting the ACT to monitor anticoagulation during cardiac surgery is that other clotting time methods (e.g., activated partial throm- boplastin time, thrombin time) become either incoa- gulable (infinite) or highly variable at heparin concentrations below those usually required for safe CPB(10,13-15).

Thrombin Time

• Plasma + thrombin => fibrin (10 sec)• Factors which affect

– Heparin– Fibrinogen– Fibrinogen degradation products

Activated clotting time• Point of care test introduced by Casthely in

1966• 1975 Bull – heparin monitoring protocol

ACT for cpb*• 2 cc of whole blood withdrawn from arterial

circulation• Mixed- with activator (celite or kaolin) in

test tube with magnet• Tube 370c and rotates• Clot holds magnet away from detector =>

end of test ( nl- 80-? sec)

Activated clotting time

• Celite– More sensitive to heparin (higher ACT)– More sensitive to hypothermia (higher ACT)– Aprotinin artificially prolongs ACT

• Kaolin– More resistant to heparin– Not prolonged by aprotinin– Binds aprotinin

Anticoagulation Protocols for Cardiopulmonary Bypass

• How much Heparin should we give for CPB?

• How do we know to give more heparin CPB ?

• Should we measure heparin effect or serum concentration?

Factors affecting the Activated Clotting Time

• Heparin• Hypothermia• Hemodilution• Thrombocytopenia

– <20,000– Severe Platelet inhibitors > 50%– GP IIb/IIIa inhibitors alone no, with yes

• Protamine– Gross protamine excess

Bull. Heparin therapy during extracorporeal circulation. 1975 J Thor

Card Surg

Bull 1975 J thorac Card Surg

• Looked at 6 heparin dosing protocols• Measured ACT’s• Found a 3 fold patient variation with

heparin dosing• Found in 4 of the dosing protocols ACTS

non therapeutic (<300)• Defined therapeutic range 300< TR<600

Bull. 1975 J thorac Card surg

• Suggested ACT > 480 before initiating CPB• Provide safety margin over an Act of 300

sec• “ it appears many practitioners assume a

needed ACT > 480 for cpb and that number represents minimum safe level ( not scientifically validated)”

Case Presentation

• 48 yr old obese male for CABG• Weight = 122 kg• Calculated heparin dose= 36.6 K units

heparin• ACT= 380• What to do?

Case

• Given 15 K of heparin• Repeat ACT = 410• Vein not ready patient temperature 35.3• Repeat ACT= 340• What to do?• How much heparin is to much?• Should we accept an ACT below 400 s?

Gravlee G. Variability of the activated clotting time. Anesth Analg 1988:,67

469-72• 46 pts undergoing CPB• Duplicate act• Baseline, 5 min post hep, 5 min post prot• Beef lung heparin- 300 unit/kg• Protamine administered by protamine

titration test

Variability Activated clotting time

Gravlee and Rogers Anesth & analg 1988

Variability of ACT. A&A 1988

Variability of ACT. A&A 1988

ACT variability

• Once prolonged beyond 300 seconds, one should not expect ACT to produce pinpoint accuracy in determining heparin or prota- mine doses.

• Maintaining ACT values over 400 seconds during CPB probably constitutes safe anticoagulation.

Metz and Keats. Low activated coagulation time during cpb does not increase bleeding. J

thorac & Cardiovasc surg 1990• 193 patients• Heparin single dose 300 units /kg (porcine)• Random ACT measurement, and heparin

levels• Measured clot in CPB circuit chest tube

drainage• Protamine reversal 1.5 mg/100 units of

heparin

Metz. J thorac Cardiovasc surg 1990

Metz Annal Thorac Surg

Metz. 1990• Ave pump time = 59 min• 51 patients Act < 400 , 4 <300 • Patients with low ACT values not bleed

more than those with higher values• Heparin level decreased markedly during

CPB (2-4 u/ml) did not correlate with ACT• Conclusion: No need to measure ACT for 1

hour of CPB

J thoracic Cardio 1990

• Gravlee- found maintaining higher CPB heparin concentrations better suppressed plasma coagulation but predisposed to increased postoperative blood loss

• Measure fibrinopeptide a

Studies

• Gravlee. Variability of the activated coagulation time. A&A

• Metz. . Low activated coagulation time during cpb does not increase bleeding. J thorac & Cardiovasc surg 1990

• Gravlee. Heparin Management protocol for CPB influences heparin rebound but not bleeding.Anesthesiology 1992

Studies

• Increased accuracy and precision of heparin and protamine dosing reduces blood loss and transfusion patients undergoing primary cardiac operations. Jobes 1995

• Heparin and protamine titration do not improve hemostasis in cardiac surgical patients Can Journal 1998 Shore lesserson

Studies

• The Impact of heparin concentration and activated clotting time monitoring on blood conservation. Despotis J thorac Surgery 1995

Gravlee. Heparin Management protocol for CPB influences heparin rebound but not

bleeding. Anesthesiology 1992• 63 patients• Randomized- 200 units/kg bovine heparin,

additional heparin to achieve ACT > 400 sec (Group A) N=30

• Or 400 units/kg to maintain heparin level of > 4 units/ml (group H) N=33

• Both groups same protamine neutralization protocol

Heparin Management protocols for cardiopulmonary bypass influences heparin

rebound but not bleeding • Heparin dose group A 28,000

– Prot 193

• Heparin dose group H 57,000 (prot 256)• 8 and 24 post no difference in chest tube

drainage• Group H > incidence in hep rebound, rx

aggressive• Antithrombin III levels lower in group H• Small dose vs large dose no diff in blood

loss or transfusion

Gravlee. Heparin protocols

Solid line= Group ADotted line= Group H

Increased accuracy and precision of heparin and protamine dosing reduces blood loss and transfusion in patients undergoing primary

cardiac operations. Jobes 1995• N= 52• Control group (24)- heparin 300 units/kg

(porcine)- protamine 1 mg/100 units of heparin (pump heparin not included)

• Test group(22)- heparin dose = 3(480-ACT)/ (HRT-ACT) X EBV– Protamine 0.02(ACT status-ACTbase)/

(ACTstatus-PRT) X EBV

Jobes. J thoracic Ccardiovasc 1995

Jobes. 1995

Heparin and protamine titration do not improve hemostasis in cardiac surgical patients Can Journal

1998 Shore Lesserson• 4 groups-

Results

Results

Why the difference?

• Initial heparin dose by Jobes not reported• Transfusion triggers by Jobes not reported

nor standardized by protocol• Different protamine management strategies

between the 2 groups• No mention of the duration of

cardiopulmonry bypass

The Impact of heparin concentration and activated clotting time monitoring on blood conservation. Despotis J thoracic Surgery

1995• N= 254• Control= heparin (porcine) 250 units/kg

additional 5k to achieve ACT > 480s.– Protamine 0.8 mg/100 units heparin

• Hepcon ACT= protamine titration method– Additional heparin if ACT< 480s– Protamine dose based on heparin concentration

Despotis et al

Despotis et al

ACT and Heparin concentrations

Despotis Results

Conclusions

• Patient variability exists with respect to ACT response when given heparin

• Empiric 300 units per kg appears as common practice in cardiac operating rooms

• Achieving ACT >400 sec for CPB is acceptable

Conclusions

• Studies investigating heparin concentration vary in conclusions

• Differences in methodology as well as duration of CPB remain important

• Lack of standardization for transfusion of PRBC and of blood products may also contribute to different conclusions reached

Conclusions

• A discordance exists between ACT measure and serum heparin concentrations

• This discordance may contribute microvascular bleeding 2ndary to using to high a protamine reversal

• This discordance is exacerbating as the duration of CPB increases

References

• Anticoagulation Monitoring during cardiac surgery. Anesthesiology 1999 91:1122-51

• Gravlee. Cardiopulmonary bypass principles and practice. Anticogulation for cardiopulmonary bypass

• Heparin sensitivity and Resistance: Management during cardiopulmonary bypass. Anesth Analg 2013:116:1210-22

Heparin Pharmacology• Polysaccharide contained in mast cells

– Acid, negative charge

• Unfractionated (beef lung vs porcine mucosa) – low molecular weight – high molecular weight (1k-50K da)

• High molecular weight attraction for anti thrombin III-thrombin complex- heparin cofactor II

• Low molecular weight (< 6K) heparin bind preferentially factor X no effect on anti thrombin III

Thrombin inhibition -simultaneous binding of heparin antithrombin III and thrombin

Must contain critical pentasaccharide sequence/ length 18oligosaccharide

Other affects of Heparin on coagulation

• Heparin may induce fibrinolysis => activate tissue plasminogen activator also releases TFPI

• Heparin affects platelet function– Suppresses alpha granule release– Increase platelet factor - 4 release– Gp IIb / IIIa– Gp Ib/ IIa

Heparin

• Only 1 in 3 heparins have critical sequence to bind to the antithrombin III complex

• Heparin also produces release of tissue factor pathway inhibitor and affects the extrinsic coagulation system (high dose)

• Possible initiation of the fibrinolytic pathway

Heparin dosing

Bolus 2 mg/ kg heparin ( Bull )- heparin response test

150 units / kg – 400 units / kg

- 150 u/kg for heparin bound circuit

- 200 u/kg with additional bolus

- 300 u/kg

Measure an ACT if > 300 s , if > 400 s, if > 480s

Heparin Pharmicokinetics

• Elimination half life varies with heparin dose (50 % eliminated by renal excretion)– 100 units => 60 min– 400 units => 150 min

• Substantial variability in heparin anticoagulant responsiveness- wide range of heparin dose response (patient specific)

Heparin Resistance

• Despite adequate dosing of heparin the ACT does not increase to the prescribed institutional value to initiate (safely) cardiopulmonary bypass

• The presumptive mechanism is Antithrombin III deficiency (possible VIII)

• Acquired liver disease, malnutrition, nephrotic syndrome, and heparin infusions

• Decrease antithrombin III levels

Heparin resistance

• The incidence of heparin resistance is higher in patients with low anti-thrombin III levels.

• ? Supplementation with AT III fails to increase the ACT to target levels in all patients (some other mechanism)

• Heparin anti III complex cleared by the reticuloendothelial system

• Nicholson=> no diference in AT III levels

• Heparin responsiveness is measured by ACT and just may be decreased in patients receiving preop heparin infusions

• Heparin resistance may be demonstrated by a decrease responsiveness in the ACT

Anticoagulation in patients undergoing cardiac surgery on heparin infusions. Anesth

Analg 2000• Patients receiving heparin H (n= 33) vs

patients not receiving heparin REF (n=32)• Measured ACT and high dose thrombin

time• ACT values increased less in the H group• HiTT values did not differ between groups• Thrombin/antithrombin III complex and

fibrin monomer not differ

Heparin Resistance

• > 600 units /kg with ACT no increase > 400 sec.– Case reports as large as 1200 units/kg– Larger doses associated with increased heparin

rebound

• RX-– More heparin– FFP– Antithrombin III concentrate– Accept lower ACT

Use of FFP

• Using FFP to prolong the ACT is based upon case reports

• 2 units of FFP increase AT III levels to 500 iu

• Aviden demonstrated 2 units FFP not increase heparin responsiveness in majority of patients

Anti thrombin III concentrate

• No study demonstrate a reduction in bleeding

• Anti thrombin III concentrate increases the ACT in heparin resistant patients

• 500 iu-1000 iu

Scenarios

Conclusions

• HMW vs LMW anti thrombin III complexes Factor X vs II

• Dosing affects elimination half life• Hep resistance rxed with FFP no scientific

basis• Hep resistance rxed with antithrombin III

concentrate expensive but effective• Accepting lower target ACT may be most

effective

Heparin Neutralization

• Protamine Pharmacology• Assessing Reversal of Anticoagulation• Protamine reactions• Protamine allergy• Who at risk for protamine allergy• Site of Administration

Protamine Pharmacology

Blood conservation strategy

• Increase preoperative hemoglobin• Implement Acute normovolumic

hemodilution• Reduce pump prime (mini CPB circuits)• Administer Antifibrinolytics

– Lysine analogues- Amicar or Tranexamic Acid

• Discontinue preop P2Y12 inhibitors– Plavix, effexor

The impact of blood conservation of cardiac surgery: Is it safe and effective.

Ann Thorac surg 2010;90:451-9• Englewood Hospital 2000-2004• Blood conservation program

– Permissive anemia Hgb < 6g/dl– Acute normovolemic hemodilution– Sug technique– antifibrinolytics

• New jersey department heath and senior services registry (32,000 CABG patients)

• 586 Englewood Hospital (EH) CABG• 586 Other hospital (OH) case matched• 10% of EH vs 46% OH received blood

transfusion• 5 EH vs 15 OH deaths p= .03• Complications ( Stroke, Myocardial

infarction, multisystem organ failure, prolonged ventilation,

Conclusion

• Permissive anemia can be tolerated for cardiac surgical procedures

• Blood conservation program reduces the incidence of Red blood cell transfusion

• By reducing Red blood cell transfusion reduce patient mortality and morbidity

Blood Conservation

• Acute normovolemic hemodilution

• Antifibrinolytics• Retrograde Autologous Priming• Decrease prime in CPB mini- circuit – Reduced diameter of CPB tubing

Acute normovolemic hemodilution

• From large bore central catheter remove 250-500 cc whole blood– Can use a-line

• Remove prior to heparinization• Replace volume 1:1 with colloid (5 % salt pure

albumin)• Reinfuse after CPB, after protamine

administration

Perioperative blood transfusion and blood conservation in cardiac

surgery: The Society of thoracic surgeons and the society of

cardiovascular anesthesiologists practice guideline series

• “Acute normovolemic hemodilution is not unreasonable for blood conservation but its usefulness is not well established.”

Acute Normovolemic Hemodilution

• Contraindications– Hemoglobin < 12 gm / dl or hematocrit < 36%– Ejection fraction < 30%– Creatinine > 2 mg/dl

Acute normovolemic Hemodilution

• From large bore central catheter remove 250-500 cc whole blood– Can use a-line

• Remove prior to heparinization• Replace volume 1:1 with colloid (25 % salt pure

albumin)• Reinfuse after CPB, after protamine

administration

Perioperative blood transfusion and blood conservation in cardiac

surgery: The Society of thoracic surgeons and the society of

cardiovascular anesthesiologists practice guideline series

“Acute normovolemic hemodilution is not unreasonable for blood conservation but its usefulness is not well established.”

Administration of Anti-fibrinolytic

• Synthetic lysine analogues - Amino-caproic acid

• Bolus, 150 mg/kg• Infusion, 10 mg/kg/hr • Continue 4-6 hours post CPB

Aprotinin administration associated with increased perioperativemortality

Perioperative blood transfusion and blood conservation in cardiac surgery: The Society of

thoracic surgeons and the society of cardiovascular anesthesiologists practice guideline series

• Lysine analogues limit total blood loss and the number of patients who require blood transfusion after cardiac procedures. These agents are slightly less potent blood-sparing drugs compared with aprotinin but may have a more favorable safety profile

Acute normovolemic Hemodilution

• Contraindications– Hemoglobin < 12 gm / dl or hematocrit < 36%– Ejection fraction < 30%– Creatinine > 2 mg/dl

Heparin Administration

• 300 units /kg of bovine heparin– After IMA dissection

• 400 units/ kg if on heparin infusion• Targeted Activated clotting time > 400 sec• Activated clotting times > 480 sec may be

associated with less postoperative bleeding

Cardiopulmonary Bypass

• Maintain muscle relaxation• Maintain volatile agent

– 1 MAC volatile agent• Maintain mean arterial pressure

– MAP > 60 mmHg• Maintain amnesia• Maintain ACT > 400 seconds if using

aprotinin need ACT > 480 seconds

Cardiopulmonary bypass

• Single clamp technique– Decrease incidence neuro injury

• Distal anastomosis• Proximal anastomosis• Cardioplegia q 15 min• Assess electrical activity• Open IMA decrease MAP

– Minimize reperfusion injury

Cardiopulmonary bypass

Maintain tight blood glucose control (< 180)

Maintain hemoglobin < 6-7 gms/ dl

Maintain hematocrit > 18 %

* some recommend Hct > 22%

* use cerebral oximetry guide treatment

Attempt to avoid transfusion

Separation from bypass• Resume full mechanical ventilation

– Reinflate lungs place on ventilator• Achieve target heart rate 90 bpm

– Atropine, isoproterenol, Beta-dose epi – Epicardial pacing ( AOO, DOO, DDD)

• Achieve target temperature– Bladder > 340 C, Esophageal > 370 C– When leave OR target temp > 350 C

• Maintain hemoglobin > 7 gm/dl– Reinfuse whole blood removed after protamine

• Maintain K+ > 4 but < 5.5

Emergence Bypass

• Determine cardiac function– Calculate cardiac index– Transesophageal echocardiogram

• Administer Vasoactive agents– If Cardiac Index < 2.0 or echo demonstrates poor

ventricular function• Reversal of Heparin

– Protamine Sulfate 250 mg – Act return to baseline– Protamine not benign

• 4 types reactions

Post bypass

• Maintain fast track protocol– Target extubation 4- 8 hours after emergence from CPB

• Maintain cardiac function– Continue inotropes

• Maintain muscle relaxation– Readminister vecuronium

• Redose amnestic and analgesic– Begin propofol (expensive, maintain volatile

anesthetic)– administer midaz or fentanyl

Problems post bypass

• Bleeding– Long bypass– Previous clopidorel– thrombin inhibitors, GP IIbIIIa inhibitors– other anticoagulants

• Poor cardiac function– Epinephrine, milrinone, norepinephrine, vasopressin,

intra-aortic balloon pump, ventricular assist device• Poor respiratory function

Affects of Inhalation agent of ischemic myocardium

• Ischemic preconditioning– Cath lab- inflate balloon for 5 min prior to

PTCA– Result reduction in myocardial damage– “ ischemic preconditioning”

• Inhalation agents exhibit myocardial protection– Activate same pathways as ischemic

preconditioning

Poor intraoperative blood glucose control is associated with a worsened hospital outcome after

cardiac surgery in diabetic patients. Ouattara Anesthesiology 2005;103:677-8

Which inhalation agents?

• Sevoflurane• Isoflurane• Desflurane

Coagulation Factors

• Bradykinin levels increase 10 fold with CPB

• Elevated bradykinins induce secretion of TPA

• 5 fold increase in TPA levels• 10-100 increase in plasmin generation with

CPB• Fibrin consumption occurs during cpb

• Contact activation• XII, XI, bradykinin, HMWK and

prekallikrein- rapidly degraded by kinins• XII auto-cleaves itself when in contact with

the CPB circuit• XII activates Kalllikreins which feedbacks

and cleaves XII• Binds to the circuit

Platelet Cascade

Platelets

Two Phase Model

Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass Anthony P.

Furnary, MDa,d, Guangqiang Gao, MDa, Gary L. Grunkemeier, PhDb, YingXing Wu, MDb, Kathryn J. Zerr, MBAb, Stephen O. Bookin, MDc, H.

Storm Floten, MDa,d, Albert Starr, MDa,d

• Staged trial 1st- subcutaneous administration of insulin- 2nd stage insulin infusion

• Glucose levels- 150- 200- then 125-175 then 100-150

CPB upsets Coagulation balance

• CPB circuit is foreign surface– Activates coagulation cascade and

inflammatory response (leukocytes host attacks)

– Platelet activation and coat the CPB circuit– First pass decreases antithrombin III levels

• Paralysis of the coagulation cascade by heparin -

• hemodilution• Hypothermia• Stimulus of coagulation and pro-

inflammatory mediators

Heparin

• Heparin binds to circulating antithrombin and causes a conformational change that accelerates its binding to and inactivation of three critical coagulation factors:

• Thrombin, Xa, and IXa• Heparin also has both direct and indirect

antiplatelet effects• heparin binds to vWf at a site critical for

binding to platelet GPIb

End result

• Prothrombin => thrombin • Fibrinogen cleaved to fibrin

– Basic structure of clot