Use of bivalirudin as an anticoagulant during cardiopulmonary bypass

Bivalirudin is a short-acting direct thrombin inhibitor that has been used in cardiac surgical patients with heparin-induced thrombocytopenia (HIT) or suspected HIT. Although no direct thrombin inhibitor is indicated for anticoagulation during cardiac surgery in patients with heparin-induced thrombocytopenia (HIT) or suspected HIT, use of heparin-alternatives are increasing as the awareness of HIT increases. Reports of anticoagulation with bivalirudin are sporadic, however, with variable dosing and management strategies. In this report, we describe our management techniques for cardiopulmonary bypass with bivalirudin based upon our personal experience. Although the reported clinical experience with bivalirudin in cardiac surgery is reviewed, operative techniques for the perfusionist/surgeon team are discussed in detail. We recognize that the use of bivalirudin during cardiopulmonary bypass is evolving and modifications of technique will undoubtedly occur as further data and experience accumulate.     

An assay to monitor bivalirudin levels on cardiopulmonary bypass

Anticoagulation therapy for cardiopulmonary bypass in patients with recently diagnosed heparin-induced thrombocytopenia can be particularly challenging. Although heparin is the standard of care, in these situations anticoagulation is achieved with alternative agents such as direct thrombin inhibitors. Therapeutic concentrations are difficult to assess with direct thrombin inhibitors, and their use is riddled with bleeding and thrombotic complications. We report the successful use of a specific chromogenic antifactor IIa assay in a patient with heparin-induced thrombocytopenia who received anticoagulation therapy with bivalirudin during cardiopulmonary bypass for coronary artery bypass graft surgery.     

Antithrombin III. Key factor in extracorporeal circulation

Antithrombin III plays many different roles during cardiac operations with cardiopulmonary bypass. Basically, it acts as the natural inhibitor of thrombin, which, in presence of heparin, blocks the thrombin action and avoids gross thrombus formation inside the extracorporeal circulation circuit. By acting as a "suicide substrate", antithrombin III is consumed during cardiopulmonary bypass; at the same time, thrombin is extensively formed during and after cardiopulmonary bypass. As a result, at the end of the operation there is a potential imbalance in the antithrombin III-thrombin interaction, leading to a prothrombotic status. Moreover, patients pre-treated with heparin reach the operating theater with reduced levels of circulating antithrombin III; this may lead to the heparin resistance phenomenon and may further increase the risk for postoperative thrombotic complications. Finally, the anti-inflammatory properties of antithrombin III in the setting of the "whole body inflammatory reaction" induced by the cardiopulmonary bypass represents a new and unexplored field of research.     

Use of ecarin clotting time (ECT) with lepirudin therapy in heparin-induced thrombocytopenia and cardiopulmonary bypass

Heparin-induced thrombocytopenia (HIT) is described as an allergy-like adverse reaction to heparin. It is a potentially severe complication of heparin therapy that can result in serious or life-threatening venous or arterial thromboembolic events. In the United States, lepirudin (Aventis Pharma AG, Strasbourg, France) is an approved therapy for anticoagulation in patients with HIT requiring anticoagulation. Lepirudin is a recombinant form of hirudin, a leech enzyme that is a highly specific direct inhibitor of thrombin. Lepirudin monitoring during surgery can be managed with ecarin clotting time (ECT) (Cardiovascular Diagnostics, Inc., Raleigh, NC), which has recently been approved as a humanitarian device exemption (HDE) for use in the United States in the management of HIT with cardiopulmonary bypass. This case report describes a patient with HIT who was managed successfully with lepirudin and ECT during coronary artery bypass grafting.     

Successful use of Argatroban as a heparin substitute during cardiopulmonary bypass: heparin-induced thrombocytopenia in a high-risk cardiac surgical patient

Whereas heparin is the most widely used intravenous anticoagulant in the US for the treatment of thromboembolic disease and is a seminal adjunct to many clinical procedures, its use can cause serious adverse events. Heparin-induced thrombocytopenia (HIT) has emerged as one of the most frequently seen complications of heparin therapy and can be a life-threatening immunohematological challenge for patients requiring cardiopulmonary bypass (CPB) with obligatory heparin exposure. Unfortunately, lack of convenient monitoring techniques and the presence of HIT and other comorbidities in the complex patient frequently limits or precludes the use of most alternatives to heparin anticoagulation during CPB. This case report describes the successful use of the celite activated clotting time and high-dose thrombin time, while using the direct thrombin inhibitor Argatroban as an alternative to heparin anticoagulation during CPB in a high-risk patient presenting with type II HIT, end-stage renal failure, and ischemic cardiomyopathy with ventricular fibrillatory arrest.     

Cardiopulmonary bypass for complex cardiac surgery using bivalirudin anticoagulation in a patient with heparin antibodies

BACKGROUND: The presence of antibodies directed against heparin necessitates the use of an alternative anticoagulant in patients undergoing cardiac surgery. Bivalirudin is a short-acting direct thrombin inhibitor that has been used successfully in routine cardiac surgical cases. Experience in complicated cases requiring extended cardiopulmonary bypass is limited, however. We report the successful use of bivalirudin in a patient who underwent complex cardiac surgery. METHOD: A 42-year-old patient with aortic regurgitation due to endocarditis who had heparin antibodies underwent a Ross procedure for aortic valve replacement using bivalirudin as anticoagulant during cardiopulmonary bypass (CPB). Bivalirudin was given with a bolus of 1 mg/kg and a continuous infusion of 2.5 mg/kg/hours during CPB. Monitoring of bivalirudin was performed using the ecarin clotting time (ECT). RESULTS: After 128 minutes of extracorporeal circulation, the patient was weaned from CPB without problems. After termination of CPB, modified ultrafiltration (MUF) was commenced. Perioperatively, six units of fresh frozen plasma were transfused. The 12-hour postoperative blood loss was 550 mL. The postoperative course was uneventful and the patient was discharged from hospital after 5 days. CONCLUSION: Bivalirudin can be safely used for anticoagulation during CPB even in complex cardiac surgery.     

Effect of temperature and cardiopulmonary bypass on the pharmacokinetics of remifentanil

Sixteen patients undergoing coronary revascularization requiring cardiopulmonary bypass received remifentanil 2 micrograms kg-1 or 5 micrograms kg-1 by infusion over 1 min after sternotomy but before commencing cardiopulmonary bypass, during hypothermic cardiopulmonary bypass and during cardiopulmonary bypass after rewarming. Hypothermic cardiopulmonary bypass reduced the clearance of remifentanil by an average of 20%, and this was attributed to the effect of temperature on blood and tissue esterase activity. Reductions in arterial pressure occurred with administration of both doses during normothermia only.      

Impact of bispectral index monitoring on propofol administration in patients undergoing cardiopulmonary bypass

Propofol anaesthesia using target control infusion during cardiac surgery has become more popular recently. However, without depth of anaesthesia monitoring, the standard target concentration used may be higher than necessary to maintain adequate hypnosis during hypothermic cardiopulmonary bypass. The purpose of this study was to evaluate the effect of bispectral index monitoring on propofol administration during hypothermic cardiopulmonary bypass. After ethics committee approval and written informed consent, 20 New York Heart Association class I-III patients scheduled for elective cardiac surgery requiring hypothermic cardiopulmonary bypass were studied in this prospective randomised controlled trial. In group C, routine anaesthesia was practised, where patients received propofol at target concentration between 1.5 to 2.5 microg/ml during cardiopulmonary bypass. In group B, the target concentration was titrated to a bispectral index value of 40 to 50. Mean arterial pressure and bispectral index were recorded at various time intervals. The use of propofol, phenylephrine, sodium nitroprusside and adrenaline were recorded. The median propofol administration in group B was significantly less than that in group C (2.9 mg/kg/h compared to 6.0 mg/kg/h). The bispectral index value during bypass was significantly lower in group C than in group B, reflecting a deeper state of anaesthesia. There was no difference in the use of inotropes, vasoconstrictors or vasodilators. Bispectral index monitoring enables a 50% reduction in propofol administration at this standard dose during hypothermic cardiopulmonary bypass.     

Anticoagulation with bivalirudin during cardiopulmonary bypass in cardiac surgery

Heparin is the standard agent used for systemic anticoagulation during cardiopulmonary bypass in cardiac operations. Alternatives are needed when patients with heparin-induced thrombocytopenia type II are encountered. We present a patient with a clinical picture of heparin-induced thrombocytopenia type II who was effectively anticoagulated with bivalirudin, a direct thrombin inhibitor, during cardiopulmonary bypass for a cardiac operation.     

Pharmacologic platelet anesthesia by glycoprotein IIb/IIIa complex antagonist and argatroban during in vitro extracorporeal circulation

OBJECTIVE: Contact between blood and the synthetic surfaces of a cardiopulmonary bypass circuit leads to platelet activation, and resultant platelet dysfunction contributes to postoperative bleeding. We compared the effects of various platelet inhibitors on preservation of platelet function during simulated cardiopulmonary bypass circulation. METHODS: Fresh human blood was recirculated in an in vitro cardiopulmonary bypass model circuit. We measured various platelet activation markers including expressions of PAC-1 and P-selectin, annexin V binding, and microparticle formations by means of whole-blood flow cytometry. RESULTS: Two types of glycoprotein IIb/IIIa complex antagonists, peptide-mimetic FK633 and abciximab and prostaglandin E(1), significantly prevented platelet loss and the increase in binding of PAC-1, an antibody specific for fibrinogen receptor on activated platelets, during extracorporeal circulation of heparinized blood. These antagonists significantly suppressed but did not abolish P-selectin expression, annexin V binding, and microparticle formation. Anti-von Willebrand factor monoclonal antibody and aurin tricarboxylic acid (an inhibitor of glycoprotein Ib) had no effect on platelet activation during simulated cardiopulmonary bypass circulation. These data suggest that inhibition of fibrinogen binding glycoprotein IIb/IIIa complex is partly effective in attenuating platelet activation in a heparinized cardiopulmonary bypass model circuit. The direct thrombin inhibitor argatroban prevented platelet loss and expression of P-selectin significantly more than did heparin. A combination of FK633 with argatroban as a substitute for heparin further prevented platelet loss and platelet secretion during simulated cardiopulmonary bypass circulation, although the inhibition of microparticle formation was less. CONCLUSION: The inhibition of both platelet adhesion and thrombin may be effective to preserve platelet number and function during cardiopulmonary bypass circulation.     

Complications related to off-pump bypass grafting

Surgical myocardial revascularization is a technique undergoing critical reevaluation in an attempt to reduce operative morbidity and mortality. As the age and number of comorbidities in the surgical population presenting for bypass increases, improved strategies to lessen operative risk have evolved. The use of off-pump bypass grafting to avoid the detrimental effects of extracorporeal circulation demonstrates great promise in reducing operative complications. However, with new techniques come new challenges. Avoidance of the cardiopulmonary bypass circuit has been linked to the development of a hypercoagulable state postoperatively. Complications related to the unique management of the ascending aorta and target vessels during the performance of beating heart surgery are also being reported. Moreover, despite increasing experience in a number of centers, hemodynamic collapse does occur during off-pump bypass, thereby requiring rapid institution of cardiopulmonary bypass. Continued scientific investigation and research should provide the tools to manage the unique obstacles encountered with off-pump coronary artery bypass.     

Anticoagulant monitoring techniques in a heparin-induced thrombocytopenia patient undergoing cardiopulmonary bypass using bivalirudin anticoagulant

Heparin is widely used as the anticoagulant of choice for cardiopulmonary bypass. However, some patients exposed to heparin therapies develop heparin-induced thrombocytopenia (HIT). Severe complications of HIT-induced thrombosis may lead to end-organ dysfunction and death. Bivalirudin, a hirudin analog, is an alternative anticoagulant that may be used in the patient with HIT without inducing thrombotic disorders. This case report provides a look at the successful use of bivalirudin as the sole anticoagulant in a patient diagnosed with HIT undergoing minimally invasive cardiothoracic surgery requiring cardiopulmonary bypass for severe mitral insufficiency. An 80-year-old male presented to the operating room for a minimally invasive mitral valve repair. Past medical history included mitral valve prolapse, atrial fibrillation, hypertension, and congestive heart failure. Preoperative evaluation noted the existence of HIT with heparin exposure 2 months prior. The decision was made to use bivalirudin as the sole anticoagulant for the operative procedure. Anticoagulation evaluation was performed with both high-does thrombin time (HiTT) and Celite activated clotting time tubes for comparison using a Hemochron device. Cardiopulmonary bypass was initiated, and the patient's mitral valve was repaired using a 34-mm annuloplasty ring. The patient was successfully weaned from bypass. No complications or evidence of HIT exacerbation were noted in the postoperative course.     

Acute mesenteric ischemia after cardiopulmonary bypass.

Acute mesenteric ischemia is an uncommon but catastrophic event after cardiopulmonary bypass. From 1980 to 1990, 16,951 cardiac procedures requiring cardiopulmonary bypass were performed at Emory University Hospital in Atlanta, Ga. Eighteen patients (0.1%) had acute mesenteric ischemia that resulted in intestinal infarction. Emergency cardiac surgery had been performed in 16 of the 18 patients, and all 18 patients were vasopressor dependent for hemodynamic support after surgery. Diagnostic difficulties resulted in the diagnosis of intestinal infarction an average of 9 1/2 days after cardiopulmonary bypass. Nonocclusive mesenteric arterial ischemia was the determined cause in all cases. Statistically significant risk factors associated with acute mesenteric ischemia after cardiopulmonary bypass surgery included (1) emergency cardiac surgery (p less than 0.0001), (2) the use of an intraaortic balloon pump (p less than 0.0001), (3) failed angioplasty requiring emergency surgery (p = 0.0074), (4) prolonged pump time (p = 0.0093), and (5) advanced age (p = 0.0016). A high index of suspicion for mesenteric ischemia after cardiopulmonary bypass in patients with identified risk factors may decrease the diagnostic delay and lead to an improvement in the 67% mortality rate seen in this series.     

Cardiopulmonary bypass in conscious patients undergoing cardiac surgery

This study was undertaken to evaluate the feasibility of thoracic epidural anesthesia as an alternative technique to general anesthesia in patients undergoing cardiac surgery under cardiopulmonary bypass. This prospective study was conducted in a tertiary referral hospital. Seventeen patients underwent cardiac surgical procedures requiring cardiopulmonary bypass without general anesthesia under thoracic epidural anesthesia from February to May 2004. An epidural catheter was inserted at any of intervertebral spaces from C7 to T2 on the day before surgery. Subsequently, cardiac surgery was performed under normothermic cardiopulmonary bypass, during which the patients remained conscious. The types of surgery included closure of atrial septal defects, valve replacements, and combined bypass surgery and valve replacements. Approach to the heart was obtained through midsternotomy. Anticoagulation was achieved with 300 units/kg of heparin. Normothermic cardiopulmonary bypass was initiated slowly during the course of 10 to 15 min. Nonpulsatile flow was administered using centrifugal pump and mean perfusion pressure was maintained in the range of 70-80 mmHg. The planned surgical procedure could be performed in all the patients. Soon after establishing cardiopulmonary bypass, the patients developed apnea, which reverted to normalcy a few minutes after disconnection of cardiopulmonary bypass. The mean time for cardiopulmonary bypass was 102 +/- 28 min, aortic cross clamp time was 58 +/- 28 min, and the total duration of surgery was 229 +/- 64 min. None of the patients required conversion to general anesthesia. There was no mortality or morbidity in this series and to our knowledge our series is the first such. Cardiac surgical procedures requiring cardiopulmonary bypass may be conducted under thoracic epidural anesthesia, without endotracheal general anesthesia.     

The antithrombotic and antiinflammatory mechanisms of action of aprotinin

Aprotinin (Trasylol) is generally regarded to be an effective hemostatic agent that prevents blood loss and preserves platelet function during cardiac surgery procedures requiring cardiopulmonary bypass (CBP). However, its clinical use has been limited by the concern that such a potent hemostatic agent might be prothrombotic, particularly in relation to coronary vein graft occlusion. In this review we present a mechanism of action that challenges such a viewpoint and explains how aprotinin can be simultaneously hemostatic and antithrombotic. Aprotinin achieves these two apparently disparate properties by selectively blocking the proteolytically activated thrombin receptor on platelets, the protease-activated receptor 1 (PAR1), while leaving other mechanisms of platelet aggregation unaffected. We also review recent research leading to the discovery of novel antiinflammatory targets for aprotinin. A better understanding of its mechanisms of action has led to the conclusion that aprotinin is a remarkable drug with the capacity to correct many of the imbalances that develop in the coagulation system and the inflammatory system after CPB. Nonetheless, it has been clinically underused for fear of causing thrombotic complications, a fear that in light of recent evidence may be unfounded.     

Aprotinin and hemostasis monitoring concerns during cardiac surgery

Aprotinin (Trasylol) is a serine protease inhibitor, isolated from bovine lung that initially was marketed for the treatment of pancreatitis. In the mid 1980s, reports of its ability to decrease hemorrhaging after cardiopulmonary bypass surgery introduced the drug to the realm of cardiac surgery. Unfortunately, its introduction into this arena was followed by the publication of multiple studies and case reports that blamed aprotinin for poor outcomes in the form of early graft closure. More than 17 years have passed since the initial article describing the use of aprotinin during cardiopulmonary bypass, and with time there has been a significant increase in scientific knowledge and clinical experience. Interestingly, modern literature does not support the dogma that aprotinin is a procoagulant. Aprotinin increases the activated partial thromboplastin time (aPTT), as well as the kaolin- and celite-activated clotting time (ACT), regardless of heparin. Aprotinin, because of its ability to inhibit kallikrein, has been found to decrease thrombin antithrombin III complexes, fibrin-split products, fibrinopeptide 1+2, prothrombin fragments, and all markers of thrombin formation. Some authors have suggested that it may have a synergistic effect with heparin to ensure graft patency. Anticoagulation monitoring during the use of aprotinin also has been developed based on early studies. Aprotinin administration does influence the results of various ACT tests, and consequently different methods of testing anticoagulation have been developed. Researchers have demonstrated that the celite ACT is not "artificially" prolonged in the presence of heparin and aprotinin, rather the kaolin ACT is "artificially" shortened. This article will review the scientific literature with regard to aprotinin's anticoagulatory effects and review the current recommendations for hemostasis monitoring during the use of aprotinin.     

Metabolic indices of pulmonary damage. Changes in angiotensin converting enzyme and alpha 1 anti-trypsin activity after cardiopulmonary bypass

The activity of angiotensin-converting enzyme was measured in patients undergoing cardiopulmonary bypass and in a control group requiring thoracotomy for pulmonary surgery. The activity of the enzyme was higher in patients with cardiac disease, fell during operations involving cardiopulmonary bypass, but did not change during thoracotomy for pulmonary surgery. Possible reasons for these differences are discussed. The activity of another enzyme, alpha 1 anti-trypsin, did not change during cardiopulmonary bypass and no arteriovenous difference could be detected during or after operation.     

Hemophilia A in cardiac operations: a model of reduced thrombin generation

Patients with hemophilia A have a congenital defect in thrombin generation. Only limited data are available on the substitution regimens in hemophilia A patients during and after cardiac operations. There are no data on heparinization of these patients during cardiopulmonary bypass. Whereas most case reports suggest factor VIII replacement in combination with standard heparinization to achieve near-normal physiologic factor VIII activity, we describe the successful management of a hemophilic A patient using a low-level factor VIII replacement combined with a reduced heparin dosage during cardiopulmonary bypass. This approach facilitated adequate anticoagulation and minimized the amount of factor VIII treatment necessary without compromising bleeding control.     

Undergoing cardiopulmonary bypass using enoxaparin only during a cardiac transplantation procedure

The use of enoxaparin as a replacement drug to standard heparin, for anticoagulation during extracorporeal circulation, in patients with heparin-induced thrombocytopenia, is still very limited. Enoxaparin significantly reduces thrombin formation and activity during cardiopulmonary bypass. The prolonged circulating rate, slow elimination rate and non-total reversion of enoxaparin by protamine can induce important postoperative bleeding. We are describing the first case of cardiac transplantation where enoxaparin was used as a replacement drug to standard heparin.     

An unusual cause of seizures after cardiopulmonary bypass

IMPLICATIONS: We present a case of a 34-yr-old woman who developed seizures after an open-heart procedure requiring cardiopulmonary bypass. The seizures were most likely caused by previously undiagnosed neurocysticercosis and may also have been contributed to by cardiopulmonary bypass.