Anticoagulation During Cardiopulmonary Bypass

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Heparin

Heparin is a naturally occurring polysaccharide secreted by basophils and mast cells, primarily in lung and liver tissues. The main role

Fig. 3 Modern membrane oxygenator.

of heparin is to prevent coagulation of blood in these slow flowing circulatory systems. Its molecular weight varies between 6000 and 22,000 Daltons depending on its source. Bovine lung heparins are thought to be more immunologically active than the porcine gut heparins. Heparin has a negatively charged molecule that is neutralised electrostatically by a positively charged protamine. The main advantage of heparin is that it can be infused parenterally in a more predictable fashion with its monitoring by the activated clotting time (ACT) on cardiopulmonary bypass and/or by activated partial thromboplastin time (APTT). It is quick in its onset of action and has a short half-life of around 4 to 6 hours. Heparin accentuates the action of anti-thrombin III by 10 s-100 s times. Anti-thrombin III mainly prevents conversion of prothrombin to thrombin. Heparin also acts on other steps of the coagulation cascade by inhibiting factors IX, X, XI, and XII.10,11 As heparin does not have a fibrinolytic action it does not act on the thrombus that is already formed in the circulation. It merely prevents the further propagation of clot.

One of the major, but uncommon side effects of heparin is heparin induced thrombocytopaenia (HIT). The platelet count can fall to below 100,000/ml in those who are on heparin treatment. Counts less than 20,000/ml have, however, been reported rarely with this condition, in which life-threatening bleeding can ensue. In this situation, heparin infusions should be stopped immediately and the blood collected for the analysis of heparin antibodies. If they are not found, then platelet transfusion can be given safely without the risk of thrombosis. If further anti-coagulation is required, as in patients who are on haemofiltration, then heparin should be replaced with an iloprost (prostacyclin) infusion, a powerful platelet inhibitory prostaglandin. This agent should not be used as the sole anti-coagulant in CPB as it can give rise to thrombosis in the extracorporeal circulation. Other heparin substitutes can also be used in cases where heparin cannot be used. Herudin, danaparoid, argatroban, and LMWH are examples. Cardiac surgery using these substitutes is, however, still in its infancy. LMWH is mainly used only in the areas of prophylaxis of DVT and in the management of unstable angina. Its main advantage is that it is less immunogenic and less likely to cause thrombocyto-penia. Its pharmacokinetics are more predictable, and there is no need to monitor APTT levels. It also can be given subcutaneously once or twice daily instead of the continuous infusion required in the case of unfractionated heparins.

Allergic reaction to heparin is rare, however, a condition called heparin resistance may develop in patients who have prior heparin exposure. The mechanism of this condition involves depletion of anti-thrombin III, leading to the failure of inhibition of formation of thrombin. The treatment of this condition paradoxically involves giving FFP transfusions to replenish the anti-thrombin III levels.

The phenomenon of heparin rebound is widely incriminated for postoperative bleeding. Various theories have been put forward for this phenomenon. The initial dose of protamine given for reversal may be inadequate, or it may be that heparin is released into the circulation from early break down of heparin-protamine complexes or from other tissue depots. It also may be due to the fact that protamine has a shorter half-life than that of heparin. Whatever the theory, it is a very difficult phenomenon to prove objectively in a clinical setting. In practice, a small additional dose ofprotamine may be given postoperatively in patients who are bleeding and have abnormal APTT, without causing any harmful effects.

The batch potency of heparin differs on the basis of its source, and patient sensitivity and metabolism vary between patients.12 Heparin monitoring is, therefore, strongly recommended in cardiopulmonary bypass. ACT is one of the methods used during cardiac surgery.13,14 The clotting time, which is prolonged due to heparin for up to 70 to 80 minutes, is measured by the process of activation with the use of diatomaceous earth. With celite-ACT it is recommended to be > 750 seconds and with kaolin-ACT it is recommended to be > 450 seconds in CPB. One milligram of heparin may contain potency of 80 to 130IU. Therefore, after the initial dose of 300 U/kg, ACT is measured, and if it is > 300 seconds then cannulation can be done and the pump suckers can be switched on. With an ACT > 400 seconds CPB can be established, otherwise an extra dose of heparin is given.15 The ACT is measured every 30 minutes and is kept around 450 seconds. The level of400 seconds is widely accepted, and research byJ.J. Verska16 has shown that at these levels, the microcirculation is free of thrombosis. The ACT is a less accurate measure in hypothermic patients and in cases where more than 5 mg/kg of heparin is required. Despite these drawbacks, currently available systems like Haemocron are widely used due to their user friendliness and compactness. Newer systems use the principle of direct assay of heparin activity. They are complex to use, but they overcome the drawbacks of the Haemocron as they are accurate both in the setting of hypothermia and with high heparin doses. Heparin requirements during pae-diatric cardiac surgery are more or less the same as in adults, except during cases of deep hypothermic circulatory arrest where the doses required are higher than those in normothermia.17 Hypothermia is thought to derange coagulation due to a decrease in enzymatic activity and in collagen induced platelet aggregation. Hypothermia also gives rise to a marked increase in fibrinolysis, thrombocytopenia, and hepatic dysfunction that further add to the causes ofbleeding.

At the end of cardiopulmonary bypass each 100 U of heparin is neutralised with 1 mg of protamine. On suspicion of heparin rebound, additional small doses of protamine may be given in intensive care unit. Protamine is thought to have anti-coagulant action only in large doses. This action is seen rarely in clinical practice.

Protamine

Protamine sulphate is a simple protein and is a strong base in characteristics, as against heparin which is acid. Therefore, it forms electrostatic complexes with the molecules of heparin and neutralises its action by inhibition of anti-thrombin III. It acts on all stages of the coagulation cascade. Protamine is extracted from a fish sperm and can show cross-immunity by giving a hypersensitivity reaction in patients who are allergic to fish protein. Protamine can also, by the same mechanism, give rise to allergic reactions in those who have a history of testicular trauma or procedures like vasectomy, in which there is a breach in the blood-sperm barrier. Patients, who are on protamine containing insulin preparations (PZI, NPH insulin), can also elicit strong reactions to protamine. Apart from minor reactions like skin rash, nausea, and lassitude it can give rise to some major reactions like hypotension, hypertension, bradycardia, and severe bronchospasm. Urticaria with severe angioedema and pulmonary hypertensive crises with right heart failure are other major reactions. The mechanism of this is thought to be due to the release of the contents of pulmonary mast cell granules, particularly histamine. To avoid this potential complication, some surgeons give protamine directly into the left atrium or into the aorta. Only in large doses can protamine give rise to severe bleeding. Therefore, protamine is given as a slow intravenous injection, at the rate of not more than 100 mg over 3 to 5 minutes. Pro-tamine reactions should be treated with steroids and anti-histaminics, and the general management of cardiac failure should be done with inotropes and optimal fluid infusion.

Role of Platelets in CPB and Anti-platelet Agents

In CPB, platelets decrease in numbers partially due to haemodilu-tion.18 They are also activated with the modification of membrane receptors. ADP induced platelet aggregation is markedly

Table 2. Drugs Giving Rise to Thrombocytopenia

Penicillins/Cephalosporins Diuretics/ACE inhibitors Unfractionated heparins Anti-metabolites/Alkylating agents

Table 3. Drugs Giving Rise to Thrombosthenia

Aspirin/Dipyridamol/Clopidogrel

Indomethacin/Other NSAIDs

Alcohol

Oestrogens

Diuretics

Ranitidine impaired from the onset of CPB and is eventually restored around five days postoperatively.19 Platelet factor IV, thrombospondin, and ^-thromboglobulin are released from a-granules.20,21 Thromoxane A2, which is a strong vasoconstrictor in the circulation, is also released.22

Various drugs can give rise to derangement ofeither platelet numbers or their function. The list is long, but some commonly used drugs are shown in Tables 2 and 3.

Platelet function can be objectively measured and evaluated by various methods. One of the simplest is the bleeding time measurement. Other methods include aggregometry with ADP, adrenaline and arachidonic acid, monoclonal antibody measurement, flow cytometry, and electron microscopic measurement of platelet granule contents.

Thromboelastograph (TEG)

This was originally described in 1948 by Professor Hartert in Germany. Till the 1980s its use was somewhat limited, but when liver transplantation became a worldwide phenomenon, its use greatly increased. Since then it has been used in diverse groups of clinical settings, such as, cardiac surgery, obstetrics, vascular surgery, and trauma. As against the conventional tests for blood coagulation, which look at the isolated stages of the coagulation, the thromboelastograph looks at the whole process of coagulation. The measurement is displayed as a graph from the clot formation to fibrinolysis. It also measures the kinetics of clot formation and the tensile strength of the clot by monitoring platelet function, fibrinogenesis, and vaso-elastic assessment of thrombin formation. Abnormal TEG profiles seen in the perioperative period may predict postoperative bleeding. Some studies have, however, failed to prove the usefulness of TEG in predicting postoperative bleeding.23 New versions of TEG have the ability to assess the effects of aspirin and clopidogrel. This may change the cardiac surgical usage of these machines. A normal TEG suggests that the postoperative bleeding is not caused by a coagulation factor deficiency, deranged platelet counts or function, or fibrinolysis. Many centres in the US run the TEG in an operating room satellite lab, and the TEG curve output is transmitted to the operating room, enabling everyone concerned to view it. TEG is the most useful indicator of excessive fibrinolysis, occurring due to the excessive production of tissue plasminogen activator (t-PA) from the vascular endothe-lium or the lack of its clearance. D-dimer is not a good surrogate for measuring fibrinolysis; it measures intravascular fibrin and not its lysis.

Management of Postoperative Bleeding

Understanding the mechanisms of coagulation/fibrinolysis and the role of platelets in CPB is essential in managing the postoperative bleeding following cardiac surgery. The management of postoperative bleeding starts in the preoperative period, with full optimisation of the patient. All medications that give rise to excessive bleeding should be discontinued in the preoperative period, if the clinical circumstances permit. In cases of tight left main disease, unstable angina, or critical coronary narrowings it may be deemed safer to balance the risk of bleeding against the risk of preoperative thrombosis. When there is clinical urgency, patients may still be taking medications including anti-platelet agents, warfarin, and LMWH, and there may not be an opportunity to stop them. Patients who have recently had thrombolytic therapy may also need intervention. In these scenarios one has to anticipate the possibility of postoperative bleeding and arrange for the blood products. One may consider the use of anti-fibrinolytic agents like aprotinin or tranexamic acid, intra-operatively. This strategy may also be followed in re-do operations, complex operations, and paediatric cases. In addition, patients with sepsis, renal impairment, or DM and elderly patients can benefit from such intervention.

Intravenous infusions of heparin should be discontinued 4 to 6 hours prior to the operation. Warfarin should be discontinued at least 48 to 72 hours before the planned operation, and the anti-platelet agents (aspirin, clopidogrel) that block platelets irreversibly by acetylation of platelet cyclo-oxygenase (thromboxane A2 induced aggregation is inhibited for the life of platelets), should be discontinued at least seven days prior to a planned operation. This provides adequate time for a new set of platelets to be released into the circulation.

Vitamin K

Vitamin K is a fat-soluble vitamin that is generated in the gut by the bacterial flora. It is also present in the normal diet (in dark green vegetables like spinach and broccoli and in oils, particularly soyabean oil). It is absorbed with the help ofbile salts in the liver to form clotting factors II, VII, IX, and X and proteins C, S, Z, and M. Activated protein C functions as an anti-coagulant by degrading the activated forms of factors V and VIII. Protein S is the co-factor for the activation of protein C. Neonates, where the gut flora is not yet developed and patients suffering from malnutrition or hepatic dysfunction are prone to vitamin K deficiency. Neonates can be given 1 mg of vitamin K before the operation. Adult patients falling in the above-mentioned category should receive 1 to 10 mg of vitamin K. The action of warfarin is reversed with the transfusion of fresh frozen plasma in the acute setting and with vitamin K in the elective setting if the prothrombin time persists above the normal level, despite stopping warfarin for 48 to 72 hours.

Sickle Cell Disease and Thalassemia in Cardiac Surgery Sickle cell haemoglobinopathy

The Hb-S gene may manifest in either homozygous form causing sickle cell disease or in the heterozygous form known as sickle cell trait. This type of haemoglobinopathy is prevalent in 8% of American Blacks and 20 to 50% of African Blacks. In sickle cell trait 38 to 45% of Hb-A is replaced by Hb-S, while in sickle cell disease 75 to 95% of haemoglobin is Hb-S. With different stimuli, Hb-S changes its conformation leading to sickling of the red cell. This sickled cell gives rise to thrombosis in peripheral tissues. Important stimuli precipitating sick-ling are hypoxia, dehydration, infection, and hypothermia. Patients with sickle cell disease are prone to different types of crises including aplastic, vasospastic, and thrombotic depending upon its pathogenesis. The diagnosis of this condition is made by screening the high-risk ethnic population by sickle test and by a haemoglobin solubility test. It can be confirmed by electrophoretic analysis. Sickle cell positive patients undergoing cardiac surgery pose a particular challenge to the anaesthetists due to the possibility of triggering sickle cell crises during CPB. In these patients, fluid balance is carefully managed to avoid the dehydration of peripheral tissues. Prevention of hypoxia is also vital. During cardiac surgery most patients are cooled below 37°C and, therefore, utmost care is taken to keep the patients well-oxygenated. Infections are controlled with appropriate antibiotics.

Thalassaemias

Thalassaemias are a heterogeneous group of disorders. They have a genetically determined reduction in the rate of synthesis of one or more types of normal haemoglobin polypeptide chains. Thalas-saemias were originally described in the people of Mediterranean origin. It is now, however, known that they are distributed geographically through the Middle East, India, and South-east Asia. Depending on the lack of a or f chain production, they are named as a or f thalas-saemias, respectively. They can be in a major or a minor form depending on the manifestation of the gene. The diagnosis is based on the electrophoresis or on the microcolumn chromatography. Patients with thalassaemias present with anaemia that requires repeated blood transfusions, massive hepato-splenomegaly, and hyperplastic bone marrow changes in the skull and in the other long bones. The patients are prone to congestive cardiac failure, cirrhosis, and diabetes mellitus due to haemosiderosis. The mortality of the major forms of thalassaemias is high, and patients do not often survive beyond the third decade of life. Patients with thalassaemias undergoing cardiac surgery are, therefore, likely to be in their first or second decade of life. For these patients, the focus of attention is on the management oftheir anaemia, infection, and other systemic problems seen in thalassaemias.

Intraoperatively, meticulous attention and maintaining respect for the tissues are cornerstones in any blood conservation programme. We have moved long away from the days when the surgeon had only mosquito clips and ligatures for attaining haemostasis. Today, surgeons have a wide choice of topical agents, drugs, and allo-graft and homograft tissues that can be used for good haemostasis. Ligaclips, bipolar diathermy, stapling devices, and artificial materials (for buttressing frail tissues) have all made a significant contribution along with major advances in the manufacturing technologies of needles, suture materials, and other equipment.

Materials like Teflon can be used as pledgets or as a strip to reinforce the delicate and frail tissues (in old age, aortic dissection) and the areas with excessive calcification. Natural tissues are thought to be better in resisting infection in cases of root abscesses. Pericardial autografts or allografts and homograft or autograft valves (Ross procedure) are used widely to limit infection and bleeding. Goretex (expanded PTFE) is thought to be better in limiting the bleeding from the needle holes, as it swells when it comes into contact with blood. Sutures made of Goretex are also available.

Skilled management of the heart-lung machine helps to minimise blood injury, haemolysis, and fibrinolysis. The use of membrane oxygenators, haemofilters in the circuit, cell savers, micro filters, centrifugal pumps, and thromboresistant materials are examples of the advances in perfusion technology. There is still controversy over the use of inline arterial filters. By avoiding large pressure gradients in the circuits, cooling and rewarming the patient without large gradients, and using pump suckers without churning of the air and blood mixture perfusionists and surgeons can reduce postoperative bleeding. Anaesthetists obviously play a significant part in maintaining optimal haemodynamics throughout the operation by avoiding extremes of the blood pressure.

One author, B. G., was taught many years ago as a registrar at the National Heart Hospital to remember the seven Ps of bleeding. They are pressure (BP control), prokne (surgical haemostasis), platelets, plasma (FFP), protamine, PEEP (to achive controlled tamponade), and prayer (as mentioned in Table 4). This aide-memoire can be a useful method for thinking through the various factors that may be contributing to a bleeding situation and provide a pointer to management. This simple checklist can act as a good bedside aide-memoire to ensure all reasonable measures are considered.

Topical Agents

Agents like Surgicel (cellulose) and Gelfoam (gelatine foam) have been in use in surgical practice for many decades. Tisseel contains two separate injections of fibrinogen and thrombin that rapidly form fibrin clot locally at the required site. As it contains biological materials, there is a potential risk of transmission of hepatitis B antigen. Areas like bleeding needle holes can be sprayed with this agent when the field is dry. Gelatin/Resorcinol/Formalin (GRF), also known as bioglue, has shown good results in friable tissues and in cases of aortic dissection.24

Table 4. An Aide-Memoire for Bleeding

Pressure

Prolene

Platelets

Plasma

Protamine

PEEP

Prayer

On transfer of the patient to the intensive therapy unit, optimal control of its haemodynamics can be enhanced by appropriate sedation. Emphasis is placed on avoiding the swings ofhypotension and hypertension that can exacerbate postoperative bleeding. A few centres follow a strategy of extubating the patients on the operating table immediately after the cardiac operation. In those centres, surgeons and anaesthetists make decisions in accordance with local protocols. It is a common practice to keep patients who have had long times in CPB, DHCA, or other complex procedures, sedated for a short time until it is clear that the patient is stable from all points ofview. Excessive agitation leads to excessive muscle activity of the patient that can increase the blood loss from the raw areas of the operative field. All patients should be actively rewarmed with the help ofa warming blanket to avoid the consequences ofderanged clotting in hypothermia. A low haemotocrit itself is a factor in the propagation of the cycle of bleeding, and patients with low haemoglobin should be transfused to maintain the haemoglobin at around 8.5g/dl. The presence of an acidosis can cause derangement of clotting enzymes and its serious action on the heart, leading to a state oflow cardiac contractility. Treatment depends on identifying the cause. Haemodynamics should be optimised to improve the peripheral tissue circulation. A diuresis can be achieved by optimal filling and by drugs like frusemide and mannitol. Renal function can be supported by haemofiltration of the patient. The blood sugar can be maintained within a tight range to avoid the possibility of acid production by anaerobic metabolism, which may occur in ischaemic areas of the body. Acidosis can also be treated with an infusion of 8.4% NaHCO3.

On arrival of the patient in the ITU, a clotting screen is sent. If the ACT is above the normal level of 120 seconds, then a small dose of protamine (50 mg over 2 to 3 minutes i.v.) can be given if the patient has excessive postoperative bleeding. A platelet transfusion should be considered in those who are bleeding with low platelet count (< 40,000/cu mm) or with abnormal TEG profile as discussed earlier. A single bag of platelets is created by pooling from the multiple donors. Therefore, there is an increased risk of transmission of CJD and hepatitis B/C. Blood banks, do all they can to minimise these risks, from testing programmes to donor selection.

A prolonged INR can be corrected with transfusion of FFPs. Excessive fibrinolytic activity can be demonstrated with low levels of fibrinogen and high levels of fibrin degradation products (FDPs). Cryoprecipitates and anti-fibrinolytic drugs like aprotinin and tranex-amic acid may be useful adjuncts in this situation.

Anti-fibrinolytic Agents Aprotinin

This drug has been in clinical use for the past three to four decades. It is a serine protease inhibitor that is extracted from bovine lung tissue. It has a number ofbiochemical effects on the coagulation system and, therefore, is likely to have several mechanisms of action. Aprotinin in high dose regimen is known to inhibit kallikrein and plasmin.25 Recent studies suggest that the most striking differences between aprotinin treated and untreated patients exist in the fibrinolytic systems. There is a reduction in the formation of FDPs,26 increased a2-anti-plasmine,27 and plasminogen activator inhibitory activities and decreased t-PA release from endothelial cells28 in treated patients. High dose aprotinin prevents the prolongation of the bleeding time seen after CPB, suggesting that the platelet function is preserved with this agent.29 The correlation between the intrinsic coagulation system and the complement system is reflected by the inhibitory effects of aprotinin on kallikrein, the common link between these systems. Complement amplification may be initiated by thrombin and plasmin, therefore, inhibition of the intrinsic pathway of coagulation as well as direct inhibition of plasmin by aprotinin would be expected to inhibit this process.30

Aprotinin (Trasylol) is given as a test dose of 1 ml before the loading dose is given. The preparations used prior to its use in cardiac surgery contained alcohol as a preservative, but the preparations made in Germany are free of any preservatives. Therefore, they can be given in higher doses without any toxicity issue. Hypersensitivity reactions are known and are more common in patients who have prior exposure to aprotinin (5% incidence in re-exposure within 6 months, 0.9% incidence in re-exposure after 6 months).31 Ana-phylaxis is known to occur sometimes even after negative test dose response, therefore, pump-prime is given 20 minutes after the full loading dose has gone in. A loading dose is given before the ster-notomy is performed. Two regimens commonly used are shown in Table 5. A range of operations are likely to benefit from aprotonin. These include re-do operations and operations for endocarditis and those with complex repairs. Patients, in whom a long bypass is anticipated, may also be benefited. A few studies32 have shown reduction in the blood loss and in the requirement for blood transfusions in paediatric cardiac surgery. The mix of patients in these studies was, however, heterogeneous. Therefore, it is difficult to draw any firm conclusions. Although aprotinin has demonstrated some clinical efficacy in a few trials of paediatric surgery, more studies are needed to firmly recommend aprotinin in this setting. Aprotonin is not indicated in the first time CABG patients that are otherwise low risk cases for postoperative bleeding. The prothrombotic effects of aprotinin may give rise to the graft blockages. Studies conducted in the early 1990s have, however, tried to refute such claims.33 Renal impairment and hypersensitivity to the drug are other contra-indications.

During CPB if aprotinin is given, then Celite-based ACT is maintained at 750 seconds and Kaolin-based ACT is maintained at 480 seconds. During DHCA the ACT is maintained at 1000 seconds and, therefore, an additional dose of heparin is given just before stopping circulation in this situation.

Table 5. Regimen of Trasylol Use in Cardiac Surgery

High dose regimen 2 million units (200 ml) 500,000 units/hr over bolus i.v. over

3 to 4 hours i.v. post-op till bleeding < 100ml/hr

30 minutes (after test dose of 1 ml) 2 million units in pump-prime

Low dose regimen 1 million (100 ml)

250,000 units/hr over 3 to 4 hours i.v. post-op till bleeding < 100ml/hr units bolus over 30 minutes (after test dose of 1 ml)

1 million units in pump-prime

Other anti-fibrinolytic agents like Tranexamic acid, EACA, and desmopressin (DDAVP) are also used in clinical practice of cardiac surgery. Tranexamic acid (Cyklocapron) is used more regularly due to its milder toxicity. Before the sternotomy 2 g is given, and 1 to 2 g may be given after cardiac surgery if the patient continues to bleed. It can be given along with Aprotinin.

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