【Anesthesia Hotspot】The application of aprotinin and antifibrinolytic drugs in cardiac surgery

Application of Aprotinin and Antifibrinolytic Drugs in Cardiac Surgery Case Form of Solar Terms in Xiaohan Elevated to the emergency room, emergency cardiac catheterization is recommended
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Angiography confirmed complete occlusion of the right coronary artery with obvious lesions in the circumflex branch
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Due to the indications of non-percutaneous coronary intervention (PCI) for right coronary lesions, it is recommended that patients undergo emergency coronary artery bypass grafting
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Two years prior to this admission, the patient underwent percutaneous coronary intervention in the left anterior descending artery with a drug-eluting stent
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Other medical history included hypertension, hyperlipidemia, for which she was taking metoprolol and simvastatin
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She has been taking clopidogrel and aspirin since PCI two years ago
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Body temperature: 36.
9°C; 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, blood urea nitrogen and creatinine were normal
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Why is heart surgery associated with bleeding? Surgery requiring cardiopulmonary bypass is accompanied by complex changes in the coagulation system caused by: hypothermia, hemodilution of coagulation factors, depletion of coagulation factors due to continuous thrombin generation, fibrinolysis, platelet consumption and dysfunction, deheparin Insufficient heparinization and heparin rebound after deheparinization with protamine
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In addition, newer anticoagulants such as low molecular weight heparins, direct thrombin inhibitors (eg, hirudin, bivalirudin) and antiplatelet agents (eg, glycoprotein IIa/IIIb antagonists, clopidogrel) are increasingly being used ), etc.
can cause bleeding during heart surgery
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Does this patient have a higher perioperative bleeding risk? The patient's medical history indicated a risk of perioperative bleeding
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Continued use of clopidogrel put him at a higher risk of bleeding than patients who had not received antiplatelet medication
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Several studies have attempted to determine the risk factor stratification of patients for non-surgical bleeding after cardiac surgery and the expected adverse outcomes
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Identified risk factors included: advanced age, female gender, random cases, reoperation, complex surgery, and smaller body mass index, prolonged CPB duration and surgery, and persistent postoperative hypothermia were also significant risk factors
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Before surgery, the cardiac surgeon, anesthesiologist, and perfusion physician discuss the surgical plan and the patient's considerations
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There was consensus that this patient was at high risk of bleeding during surgery, and because of the patient's recent use of antiplatelet drugs, there was a high likelihood that the patient would require platelet transfusions after CPB
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Ask the blood bank to ensure that there are sufficient packed red blood cells, fresh frozen plasma, and platelets available
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Why is bleeding prevention important in heart surgery? Perioperative bleeding leads to transfusion and the risk of mediastinal re-exploration due to persistent bleeding or cardiac tamponade
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Perioperative bleeding further leads to transfusion of banked red blood cells and coagulation factors
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Blood transfusions are associated with infectious and non-infectious complications
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Thanks to improved screening methods, the risk of viral transmission from massive blood transfusions has been significantly reduced, but the risk of infectious diseases (especially hepatitis C) remains
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Transfusion of bacterial pathogens from banked red blood cells, especially platelets, is a higher risk than viral transmission
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Other risks associated with transfusion include transfusion-related acute lung injury, excessive volume overload, and hemolytic and nonhemolytic transfusion reactions
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In addition, the limited supply of blood products necessitates strategies to minimize transfusions
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What is the incidence of repeat heart surgery and what are its associated risks? About 3% to 6% of cardiac surgery patients require re-opening of the chest due to postoperative bleeding
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Urgent re-exploration of the mediastinum increases the patient's stay in the intensive care unit, the need for intra-aortic balloon pumping, and increases mortality
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Not surprisingly, most of the risk factors for thoracotomy after cardiac surgery are the same as those for increased bleeding that have been demonstrated
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The surgical team has discussed blood conservation strategies for this patient, including the use of antifibrinolytics
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What medications can be used to reduce bleeding and the need for blood transfusions? Fibrinolysis is an important factor in non-surgical bleeding after cardiac surgery.
Fibrinolysis not only leads to thrombus rupture and shedding, but also leads to a large consumption of coagulation factors
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Antifibrinolytic drugs such as tranexamic acid (TXA), epsilon-aminocaproic acid (EACA) and aprotinin are mainly used in cardiac surgery to prevent excessive blood loss
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EACA and TXA are lysine-derived compounds
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Lysine analogs inhibit the process of fibrinolysis by binding to the lysine site on plasminogen
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Conjugation with lysine is an essential pathway for the conversion of plasminogen to plasmin
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Thus, binding of these lysine analogs to the lysine site on plasminogen inhibits plasmin formation
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Normally, plasmin produces fibrinolysis (dissolution of blood clots) by degrading fibrin and fibrinogen
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These lysine analogs not only reduce plasmin production, but also inactivate plasmin that is already present
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In contrast, aprotinin is a protease inhibitor that inhibits several important enzymes including plasmin and kallikrein
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However, the exact mechanism of action of aprotinin is not fully understood
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What is the evidence for the effectiveness of antifibrinolytics? Multiple prospective randomized, double-blind, placebo-controlled trials have been conducted to evaluate the effectiveness of antifibrinolytics in reducing bleeding and blood transfusion during cardiac surgery
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Most studies were small, especially those evaluating three lysine analogs
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Aprotinin is the most studied drug
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Multiple well-powered multicenter studies have established the effectiveness of aprotinin in reducing bleeding, blood transfusions, and the need for mediastinal re-exploration due to bleeding after cardiac surgery compared with placebo, especially for complex cardiac surgery or reoperation
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These findings support aprotinin for reducing bleeding in cardiac surgery and have been approved by the US Food and Drug Administration
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Neither TXA nor EACA are supported by similar studies
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But multiple studies have reported the effectiveness of these drugs in reducing bleeding complications from cardiac surgery
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The power of these small studies was increased by meta-analysis
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In a systematic review of 51 trials of fibrinolytic drugs, the use of aprotinin reduced chest tube drainage, blood transfusion, and bleeding-related reoperations compared with placebo
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Studies comparing TXA with placebo have shown that TXA reduces blood product use and mediastinal drainage, as well as reoperations due to bleeding
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The results showed that compared with placebo, TXA could save about one unit of allogeneic blood transfusion and reduce blood loss by about 300ml
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But TXA did 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 transfusions by 35%, reducing blood loss by approximately 230ml (intraoperative) and 200ml (postoperative)
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Studies that directly compared EACA and TXA showed similar effects on blood transfusion volume and reoperation due to bleeding
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Anesthesiologists are concerned about the safety of using antifibrinolytics, but agree that the benefits outweigh the risks in high-risk patients
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What are the risks of using antifibrinolytics in heart surgery? Although the efficacy of aprotinin and lysine analogs has been established, the safety of these drugs in high-risk patients remains controversial
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In particular, the safety of aprotinin has been the focus of debate
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Prospective randomized placebo-controlled studies confirmed the safety of the drug
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These data demonstrate that aprotinin reduces the risk of perioperative stroke compared with placebo
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Transient elevation of serum creatinine with aprotinin may be due to its effect on the proximal renal tubule
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Because aprotinin is a bovine serum protein, aprotinin has been established to cause allergic reactions, including fatal anaphylaxis, so test doses are usually used first, but serious reactions can also occur
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Recent use (within 1 year) increases the likelihood of hypersensitivity reactions in patients
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It is therefore recommended that aprotinin should be used where CPB can be rapidly established
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Considering the mechanism of action of antifibrinolytic drugs, they may theoretically increase the risk of thrombosis
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A meta-analysis by the Cochrane Collaboration (which analyzed 211 randomized controlled trials) did not show that aprotinin, TXA or EACA increased 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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The use of the drugs in well-controlled clinical trials may not be sufficient to represent their safety, especially the anticoagulant effect, compared to their widespread clinical use after approval
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Regardless of whether heparinization is sufficient, aprotinin can prolong the activated clotting time (ACT) of diatomite
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Therefore, kaolin ACT monitoring is necessary when aprotinin is applied or when ACT levels are high (>750 seconds) during surgery
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In addition, other hemostatic agents may have actually been administered concurrently with aprotinin in patients with bleeding
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Combination of lysine analogs and aprotinin strongly inhibits fibrinolysis
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In addition, concomitant use of recombinant factor VIIa with aprotinin may cause thrombotic complications
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A recent retrospective analysis of data from a multicenter study questioned the safety of aprotinin
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This analysis showed that patients who received aprotinin at the time of cardiac surgery had an increased risk of myocardial infarction, stroke, renal dysfunction, and death compared with lysine analog antifibrinolytic drugs
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Retrospective studies do not eliminate treatment bias, and patients using aprotinase have a higher risk of adverse effects with or without antifibrinolytics
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Furthermore, analysis of other large-scale single-center databases did not confirm this finding
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At this time, a large prospective, randomized, double-blind, multicenter study comparing aprotinin, TXA, and EACA was suspended because of a higher rate of adverse events in the aprotinin group
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Details of the trial are yet to be decided
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However, based on recent developments and an analysis of the results of the System Administration Database, the US Food and Drug Administration has requested a moratorium on aprotinin sales until the data analysis is complete
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After discussing all options, the surgical team decided to use TXA during the procedure
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The patient successfully underwent two great saphenous vein dissection and circumflex and right coronary bypass
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CPB lasted 36 minutes and aortic occlusion was performed for 58 minutes
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Sufficient deheparinization with protamine resulted in a final ACT of 121 sec
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After adequate surgical hemostasis, the sternum was closed, and the patient was admitted to the cardiac surgery intensive care unit
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24-hour close monitoring, chest tube drainage is low
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The patient was discharged 5 days postoperatively without complications
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Summarize key information 1 .
Medications to prevent excessive bleeding during cardiac surgery are primarily antifibrinolytics, 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
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4.
In a recent retrospective analysis of data obtained from a multicenter study, the safety of aprotinin was questioned
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This analysis showed that compared with the lysine analog antifibrinolytics, patients treated with aprotinin during cardiac surgery had increased rates of myocardial infarction, stroke, renal dysfunction, and death
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Question 1.
What is the incidence of reoperation for heart surgery? Answer: About 3% to 6% of cardiac surgeries require re-opening of the chest due to postoperative bleeding
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2.
What is the main mechanism of action 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, reflecting its possible effects on the proximal renal tubule
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Notes/Guan Yong's typography/Dingdang balls, Ma Xiaohan, only plum dumplings