【Hot Spots of Anesthesia】Application of Aprotinin and Antifibrinolytic Enzyme Drugs in Cardiac Surgery

The application of aprotinin and antifibrinolytic enzyme drugs in heart surgery.
Case form: stage case analysis patient, female, 79 years old, 62kg (body mass index 22), due to severe chest pain and new ST segment in inferior leads Elevated to the emergency room, emergency cardiac catheterization is recommended
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Angiography confirmed that the right coronary artery was completely blocked and the circumflex artery was obviously diseased
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Due to the indications of percu-taneous coronary intervention (PCI) for right coronary lesions, it is recommended that patients undergo emergency coronary artery bypass grafting
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Two years before this admission, the patient underwent percutaneous coronary intervention of the left anterior descending artery with a drug-eluting stent
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Other medical history includes high blood pressure and high blood lipids, for which she is taking metoprolol and simvastatin
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I have been taking clopidogrel and aspirin since PCI two years ago
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Body temperature: 36.
9℃; blood pressure: 135/76mmHg; heart rate: 65 beats/min; respiratory rate: 18 beats/min
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Preoperative hemoglobin: 126g/L; platelet count: 253x109/L; international normalized ratio: 1.
1; prothrombin time: 29 seconds
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Electrolytes, urea nitrogen and creatinine were all normal
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Why is heart surgery related to bleeding? Surgery that requires cardiopulmonary bypass is accompanied by complex changes in the coagulation system.
This is caused by the following reasons: low temperature, blood dilution of coagulation factors, continuous production of thrombin leading to consumption of coagulation factors, fibrinolysis, platelet consumption and dysfunction, and heparin Insufficient chemistry and heparin rebound after deheparinization with protamine
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In addition, new anticoagulants, such as low molecular weight heparin, direct thrombin inhibitors (such as hirudin, bivalirudin), and antiplatelet drugs (such as glycoprotein IIa/IIIb antagonists, clopidogrel) are increasingly used ) Etc.
will cause bleeding during heart surgery
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Does this patient have a higher risk of bleeding during the perioperative period? The patient's medical history indicated that he was at risk of perioperative bleeding
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Compared with patients who have not received antiplatelet drug treatment, continuous clopidogrel use makes the bleeding risk higher
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Several studies have attempted to determine the risk factors for non-surgical bleeding after cardiac surgery and the expected adverse consequences
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The identified risk factors include: advanced age, female, random cases, reoperation, complicated surgery, and small body mass index.
Prolonged CPB time and surgery and continued hypothermia after surgery are also important risk factors
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Before the operation, the heart surgeon, anesthesiologist, and perfusion physician discuss the operation plan and the patient's precautions together
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Everyone agrees that this patient has a high risk of bleeding during surgery, and because the patient has recently used antiplatelet drugs, it is very likely that the patient will need platelet transfusion after CPB
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The blood bank is required to ensure that there are sufficient available concentrated red blood cells, fresh frozen plasma and platelets
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Why is preventing bleeding important in heart surgery? Perioperative bleeding can lead to the risk of blood transfusion and re-exploration of the mediastinum due to continuous bleeding or pericardial tamponade
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Perioperative bleeding further leads to the infusion of stock red blood cells and clotting factors
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Blood transfusion is associated with infectious and non-infectious complications
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Due to improved screening methods, the risk of virus transmission due to massive blood transfusions has been significantly reduced, but the risk of infection with infectious diseases still exists (especially hepatitis C)
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The spread of bacterial pathogens caused by stock red blood cells, especially platelet transfusion, is more risky than virus transmission
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Other risks associated with blood transfusion include blood transfusion-related acute lung injury, excessive volume load, hemolytic and non-hemolytic transfusion reactions
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In addition, the supply of blood products is limited, so strategies to minimize blood transfusion are necessary
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What is the incidence of heart surgery again and what are its associated risks? Approximately 3% to 6% of patients undergoing cardiac surgery require reopening due to postoperative bleeding
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Emergency re-mediastinal exploration increases the patient’s stay in the intensive care unit, the need for intra-aortic balloon counterpulsation, and also increases the mortality rate
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Not surprisingly, most of the risk factors for reopening the chest after cardiac surgery are the same as the risk factors for increased bleeding
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The surgical team has discussed the patient's blood protection strategies, including the use of antifibrinolytic drugs
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What drugs can be used to reduce the need for bleeding and blood transfusions? Fibrinolysis is an important factor of non-surgical bleeding after heart surgery.
Fibrinolysis not only causes the thrombus to rupture and fall off, but also leads to a large consumption of coagulation factors
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Antifibrinolytic drugs are mainly used in cardiac surgery to prevent excessive blood loss, such as tranexamic acid (TXA), epsilon-aminocaproic acid (EACA) and aprotinin
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EACA and TXA are compounds derived from lysine
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Lysine analogs inhibit the process of fibrinolysis by binding to the lysine site on plasminogen
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Binding with lysine is an essential way for the conversion of plasminogen to plasmin
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Therefore, the binding of these lysine analogues to the lysine site on plasminogen inhibits the formation of plasmin
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Normally, plasmin produces fibrinolysis (dissolution of blood clots) by degrading fibrin and fibrinogen
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These lysine analogs can not only reduce the production of plasmin, but also inactivate the existing plasmin
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On the contrary, aprotinin is a protease inhibitor that can inhibit several important enzymes including plasmin and kallikrein
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However, the exact mechanism of aprotinin is not fully understood
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What is the evidence for the effectiveness of antifibrinolytic drugs? Multiple prospective randomized, double-blind, placebo-controlled trials to evaluate the effectiveness of antifibrinolytic drugs in reducing bleeding and blood transfusion during cardiac surgery have been completed
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Most studies are small-scale, especially studies evaluating three lysine analogs
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Aprotinin is the most studied drug
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Multiple multi-center studies with sufficient testing power have confirmed the effectiveness of aprotinin.
Compared with the placebo group, it can reduce bleeding, blood transfusion and the need for re-exploration of the mediastinum due to bleeding after heart surgery, especially for complex heart surgery Or surgery again
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These findings support that aprotinin can be used to reduce bleeding during heart surgery and has been approved by the US Food and Drug Administration
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Neither TXA nor EACA has similar research support
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However, multiple studies have reported the effectiveness of these drugs in reducing bleeding complications in heart surgery
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Through meta-analysis, the testing power of these small studies has increased
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Through a systematic review of 51 trials of fibrinolytic drugs, the use of aprotinin can reduce chest tube drainage, blood transfusion and the need for reoperation due to bleeding compared with the placebo group
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Studies comparing TXA with placebo have shown that TXA can reduce the use of blood products and mediastinal drainage, as well as reoperation due to bleeding
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The results show that compared with placebo, TXA can save about one unit of allogeneic blood transfusion, and blood loss is reduced by about 300ml
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But TXA does not affect the risk of reoperation
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Studies on the application of EACA in cardiac surgery have shown that EACA can reduce the need for allogeneic blood transfusion by 35%, and reduce blood loss by approximately 230ml (intraoperative) and 200ml (postoperative)
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Studies directly comparing EACA and TXA show that the effects of the two on blood transfusion and reoperation due to bleeding are almost the same
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Anesthesiologists worry about the safety of anti-fibrinolytic drugs, but recognize that high-risk patients use the drug, the benefits outweigh the risks
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What are the risks of using antifibrinolytic drugs in cardiac surgery? Although the efficacy of aprotinin and lysine analogues has been established, the safety of these drugs in high-risk patients is still controversial
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In particular, the safety of aprotinin has always been the focus of controversy
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Prospective randomized placebo-controlled studies have confirmed the safety of the drug
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These data prove that, compared with placebo, aprotinin can reduce the risk of perioperative stroke
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The use of aprotinin causes a transient increase in serum creatinine, possibly due to its effect on the renal proximal tubules
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Because aprotinin is a bovine serum protein, it has been determined that aprotinin can cause allergic reactions, including fatal allergic reactions, so the test dose is usually used first, but it can also cause severe reactions
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Recent use (within 1 year) will increase the possibility of hypersensitivity reactions in patients
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Therefore, it is recommended that aprotinin should be used where CPB can be quickly established
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Considering the mechanism of action of antifibrinolytic drugs, theoretically they may increase the risk of thrombosis
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The meta-analysis of the Cochrane Collaboration (which analyzed 211 randomized controlled trials) did not show that aprotinin, TXA or EACA increase the risk of mortality, stroke, myocardial infarction, and deep vein thrombosis
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The incidence of renal insufficiency in the aprotinin group showed an increasing trend, but it was not statistically significant
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Compared with its wide clinical application after approval, the use of the drug in a well-controlled clinical trial may not be sufficient to represent their safety, especially anticoagulant effect
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Regardless of whether heparinization is sufficient, aprotinin can prolong the activated clotting time (ACT) of diatomaceous earth
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Therefore, the use of kaolin ACT monitoring is necessary when the application of aprotinin or the high level of ACT during surgery (>750 seconds)
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In addition, the actual application of aprotinin to bleeding patients may also use other hemostatic drugs
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Combination of lysine analogues and aprotinin can strongly inhibit fibrinolytic reaction
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In addition, the simultaneous use of recombinant factor Vila and aprotinin may cause thrombotic complications
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A recent retrospective analysis of data obtained from a multi-center study questioned the safety of aprotinin
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This analysis showed that compared with lysine analogue antifibrinolytic drugs, patients had an increased risk of myocardial infarction, stroke, renal dysfunction, and death after receiving aprotinin during cardiac surgery
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Retrospective studies cannot eliminate the treatment bias, and patients who use aprotinin are at higher risk of adverse reactions regardless of whether antifibrinolytic drugs are used or not
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In addition, analysis of other large-scale single-center databases did not confirm this finding
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At this time, a large-scale prospective randomized double-blind multicenter study comparing aprotinin, TXA and EACA was suspended because of the higher incidence of adverse events in the aprotinin group
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The details of the test are yet to be determined
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However, according to recent developments and analysis of the results of the system management database, the US Food and Drug Administration has requested that the sales of aprotinin be suspended until the data analysis is completed
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After discussing all the options, the surgical team decided to use TXA during the procedure
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The patient successfully underwent the stripping of the two great saphenous veins, the circumflex artery and the right crown bypass
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CPB lasted 36 minutes and the aorta was blocked for 58 minutes
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Fully de-heparinized with protamine, the final ACT was 121 seconds
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After sufficient surgery to stop the bleeding, close the sternum, the patient was sent to the cardiac surgery intensive care unit
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Close monitoring for 24 hours, less chest tube drainage
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The patient was discharged without complications 5 days after surgery
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Summarize key information 1.
Drug treatments to prevent excessive bleeding during heart surgery are mainly anti-fibrinolytic drugs such as TXA, EACA and aprotinin
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2.
Lysine analogs inhibit the process of fibrinolysis by binding to the lysine binding site on plasminogen
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3.
Aprotinin is a serine protease inhibitor that inhibits several important enzymes including plasmin and kallikrein
.

4.
A recent retrospective analysis of data obtained from a multi-center study revealed that the safety of aprotinin was questioned
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This analysis showed that compared with the lysine analogue antifibrotic solvent, the incidence of myocardial infarction, stroke, renal dysfunction, and death was increased after the use of aprotinin during cardiac surgery
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Question 1.
What is the incidence of reoperation for cardiac surgery? Answer: Approximately 3%~6% of heart surgery require reopening of the chest due to postoperative bleeding
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2.
What is the main mechanism of EACA? Answer: EACA is a synthetic derivative of lysine
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Lysine analogs inhibit the process of fibrinolysis by binding to the lysine binding site on plasminogen
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3.
Is aprotinin nephrotoxic? Answer: The use of aprotinin is associated with a transient increase in serum creatinine, which reflects that it may have an effect on the renal proximal tubules
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Notes/Guan Yong Typesetting/Dingdong Balls, Ma Xiaohan, Only Plum Dumplings