John M. Alvarez

Avoidance of Bleeding During Surgery in Patients Receiving Anticoagulant and/or Antiplatelet Therapy: Pharmacokinetic and Pharmacodynamic Considerations

Perioperative management of chronically anticoagulated patients and/or patients treated with antiplatelet therapy is a complex medical problem. This review considers the pharmacokinetic and pharmacodynamic properties of commonly used antiplatelet and anticoagulant drugs with special emphasis on loss of effects after discontinuation and possible counteracting (or antidote) strategies. These drugs are aspirin (acetylsalicylic acid), ticlopidine/clopidogrel, abciximab, tirofiban and eptifibatide, heparin (unfractionated and low-molecular-weight), warfarin and direct thrombin inhibitors. Since the pharmacological mechanisms of some of these drugs are based on irreversible or slowly reversible effects, their pharmacokinetic profiles are not necessarily predictive for their pharmacodynamic profiles. A close and direct relationship between plasma concentrations and effects is seen only for the glycoprotein (GP) IIb/IIIa inhibitors tirofiban and eptifibatide with a fast off-rate for dissociation from the GPIIb/IIIa receptor, and for direct thrombin inhibitors (hirudin and argatroban). For other compounds, drug concentrations in plasma and pharmacodynamic effects are not closely correlated because of, for example, irreversible binding to their target (aspirin, Clopidogrel and abciximab), inhibition of the generation of a subset of clotting factors with differing regeneration and degradation rates (coumarins) or sustained binding to the vascular wall (heparins).Surgery in patients on anticoagulant and/or antiplatelet therapy may be categorised as: (i) elective versus urgent; and (ii) cardiopulmonary bypass (CPB) versus non-CPB. Monotherapy with Clopidogrel or aspirin need not be discontinued in elective non-CPB surgery, and temporary discontinuation of warfarin should be accompanied by preoperative intravenous heparin only in selected high-risk patients. Vitamin K as an antidote for warfarin should only be used subcutaneously and solely in urgent/emergency surgery. In elective surgery requiring CPB (coronary artery bypass grafting), it is recommended to discontinue aspirin 7 days preoperatively in patients with a low risk profile. Patients requiring urgent CPB surgery (e.g. after failure of a percutaneous coronary angioplasty with or without coronary stent deployment) are usually pretreated with several antiplatelet agents (e.g. aspirin and Clopidogrel, together with a GPIIb/IIIa inhibitor) together with unfractionated or low-molecular-weight heparin. With judicious planning, urgent/emergency cardiac surgery can be safely performed on these patients. Delaying surgery (e.g. for 12 hours in patients treated with abciximab) should be considered if possible. Standard heparin doses should be given to achieve optimal anticoagulation for CPB. Prophylactic use of aprotinin (intraand/or postoperatively), aminocaproic acid or tranexamic acid should be considered. Early (in the operating theatre prior to chest closure) and judicious use of replacement blood products (platelets) should be commenced when clinically indicated.

Emergency coronary bypass grafting for failed percutaneous coronary artery stenting: increased costs and platelet transfusion requirements after the use of abciximab

The adjunctive use of abciximab (ReoPro), a platelet glycoprotein IIb/IIIa receptor antagonist, with aspirin as pretreatment for percutaneous coronary artery stenting (PTCS) has risen dramatically. 2 Reports on the outcomes of patients who require emergency coronary bypass grafting (CABG) for unsuccessful PTCS are scarce. This report documents three cases. Table I outlines cardiopulmonary bypass (CPB), hematologic, and coagulation assays. All patients had received aspirin (300 mg) and abciximab (0.25 mg/kg/5 min bolus and 9 mg/500 ml normal saline solution at 10 mg/min intravenous infusion) before the operation. All had a profound bleeding diathesis evident from skin incision and persisting for 4 to 5 hours after the operation. Patients PATIENT 1. A 38-year-old man had acute stent thrombosis 14 days after PTCS to the left anterior descending coronary artery. Cardiogenic shock ensued, necessitating emergency CABG. Ticlopidine (Ticlid) at 250 mg twice a day had been continued since the original PTCS. CABG with a left internal thoracic artery graft to the left anterior descending coronary artery and a saphenous vein graft to a first diagonal was performed. After reversal of heparinization, 5 units of platelets were given and the chest was closed. By 60 minutes, the mediastinal blood loss was 1500 ml. At resternotomy, no specific surgical source was evident. A 1.5 mg dose of 1-deamino-8-Darginine vasopressin (Minirim) and a 4 3 10 kallikrein activation unit (KIU) dose of aprotinin (Trasylol) were given intravenously. An additional 1900 ml blood loss occurred during the next 24 hours. The patient was discharged on postoperative day 10. PATIENT 2. A 73-year-old man in cardiogenic shock with intraaortic balloon pump support was referred for operation with a postinfarct inferior ventricular septal rupture; PTCS to the proximal right coronary artery had been performed. The operation entailed polyethylene terephthalate (Dacron) patch closure of the ventricular septal defect and placement of four venous coronary bypass grafts. Because of the previous experience, intravenous aprotinin (“high” Hammersmith dose [7 3 10 KIU]) was given at induction, and after CPB 10 units of platelets were given. This patient died of low cardiac output syndrome 96 hours after the operation. PATIENT 3. A 39-year-old woman, in cardiogenic shock from an evolving anterolateral acute myocardial infarction after PTCS to the circumflex coronary artery required emergency CABG. A left internal thoracic artery graft to the left anterior descending coronary artery and two additional venous bypass grafts were performed. “High” Hammersmith dose aprotinin was used (total 5 3 10 KIU); after CPB, 10 units of platelets were also given. The patient was discharged home 6 days after the operation. Discussion. This limited experience focuses attention on the potential impact of abciximab on patients undergoing emergency CABG; the message is sharp. In all three cases, results of history, physical examination, and hematologic and coagulation assays were normal before the operation, yet perioperative blood loss was in excess of what was expected. Aprotinin in the “high” Hammersmith dose and immediate, repeated platelet transfusions after CPB appear necessary and effective in reducing mediastinal blood loss. Abciximab use is based on the reduction in the 30-day primary end point (death, acute myocardial infarction, revascularization) reported by the EPIC (placebo 12.8% vs treated 8.5%), EPILOG (placebo 11.7% vs treated 5.2%), and CAPTURE (placebo 15.9% vs treated 11.3%) trials. 2 Only the EPIC trial reported on patients requir-

Postpneumonectomy pulmonary edema.

The adult respiratory distress syndrome seen after pneumonectomy is an uncommon but usually lethal complication. Its etiology remains unknown, although several factors such as fluid overload, endothelial damage, lymphatic interruption, and hyperinflation are thought to be involved in its pathogenesis.

Cardiac surgery in Australian octogenarians: 1996−2001

Background:  The number of octogenarians receiving cardiac surgery is increasing. Concerns regarding the outcomes and significant expense required to provide this service have not been addressed because no prospective medium term outcomes of Australian octogenarians have been published.

Catastrophic presentation of atrial myxoma with total occlusion of abdominal aorta

Cardiac myxoma is a rare disease with protean manifestations. Embolic phenomena are well-known entities. However, total occlusion of the descending aorta by saddle embolism along with multi-organ embolism is very unusual. We report a patient with cardiac myxoma presenting with multi-organ embolism including saddle embolism of the aorta in a previously healthy female.

Bilateral thoracoscopy, mediastinoscopy and laparoscopy, in addition to CT, MRI and PET imaging, are essential to correctly stage and treat patients with mesothelioma prior to trimodality therapy*

Background:  Trimodality therapy (TMT; extrapleural pneumonectomy (EPP), chemotherapy and radiation therapy) offers the potential of optimal survival in selected patients with Brigham stage I–II epitheliod mesothelioma based on CT, MRI and PET scanning. We hypothesized that these scanning modalities were inadequate to accurately stage these patients.

Fatal intraoperative pulmonary thrombosis after graft replacement of an aneurysm of the arch and descending aorta in association with deep hypothermic circulatory arrest and aprotinin therapy

A 69-year-old woman had graft replacement of the distal aortic arch and proximal descending thoracic aorta for a 13 cm atherosclerotic aneurysm. Left ventricular function and coronary artery anatomy were normal, as were results of all preoperative hematologic and coagulation assays. Heparin administration was 300 units/kg plus 5000 units in the pump prime. Kaolin-based activated clotting time (ACT) was kept above 500 seconds during cardiopulmonary bypass (CPB) and above 750 seconds before circulatory arrest. Protamine was reversed on a 1 mg/100 units heparin ratio (Table I). Aprotinin (Trasylol) was given for a total dose of 6 3 10 kallikrein inactivation units (KIU; 2 3 10 KIU intravenously after anesthetic induction, 2 3 10 KIU in the pump prime, and 0.5 3 10 KIU/hr). After establishment of CPB, antegrade and retrograde blood cardioplegic arrest together at 18° C, with continuous retrograde cerebral sanguineous perfusion through the superior vena cava during the period of circulatory arrest, were employed. The aneurysm was resected and replaced with a woven polyethylene terephthalate fiber (Dacron) graft; the arch vessels were reimplanted as a Carrel patch. The patient was weaned from CPB unaided, with normal hemodynamic indexes, effective myocardial contractility, and a dry operative field. Ten minutes later, unheralded right ventricular failure with a normal electrocardiogram occurred. Protamine was discontinued and heparin was readministered to the patient. Despite inotropic support and intraaortic balloon counterpulsation, cardiac function was inadequate. CPB was recommenced, and right ventricular failure frustrated attempts to discontinue CPB. Transesophageal echocardiography revealed no valvular abnormality, with effective biventricular contraction in the decompressed heart. The pulmonary artery was opened, yet no evidence of pulmonary embolism was demonstrable. Right ventricular assistance was commenced. Unexplained intermittent inadequate venous return and raised pulmonary pressures hampered effective right ventricular assistance action, and the patient died 70 minutes later. Postmortem examination revealed extensive deposits of skeinlike, fibrinous material loosely adherent to the walls of the main and segmental pulmonary arteries, right ventricle, and within the venous cannulas. Histologic examination revealed extensive thrombosis within the small pulmonary artery branches. No evidence of thrombosis was detected in other organs. Aprotinin is highly effective in reducing blood loss after cardiac operations. However, safety concerns, initially raised by the Cleveland Clinic group, remain unanswered. The safety of aprotinin in the setting of aortic reconstruction with deep hypothermic circulatory arrest is currently unclear. Sundt and associates from St. Louis and Westaby’s group from Oxford have reported a detrimental effect of aprotinin in this setting of complex aortic operations with deep hypothermic circulatory arrest. The St. Louis group found a higher operative mortality rate, perioperative myocardial infarction rate, and renal failure rate in the aprotinin group than in a historical case-matched control group (15% vs 0%, 20% vs 0%, and 65% vs 5%, respectively). The Oxford group reported a greater incidence of bleeding and thrombosis-related deaths associated with aprotinin. These reports represent large series by experienced

Cardiac angiosarcoma: too little known, too late treatment or just too bad a tumour?

Cardiac angiosarcoma is a rare tumour. Current imaging techniques (magnetic resonance imaging, MRI; computed axial tomography, CAT; 2-D echocardiography), although useful in delineating the extent of tumour involvement, do not correlate well with intraoperative findings of resectability. We report a case were palliative surgical resection was technically possible, contrary to expectations from CAT and MRI findings. However, the patient was clinically in extremis, with advanced ventricular dysfunction, and died. Despite the short-term risk involved in surgery, if palliative resection is possible, a multidisciplinary approach with adjuvant chemotherapy and radiation can result in mid-term survival. (Heart, Lung and Circulation 2001; 10: 30–34)

Tension haemothorax: an uncommon life-threatening complication.

A 42-year-old woman was transferred from a peripheral hospital to the Emergency department of Sir Charles Gairdner Hospital (Perth, Australia) in profound shock. Nine days previously, a bilateral circumareolar reduction mammoplasty had been performed. A right breast haematoma occurred, requiring submammary drainage and placement of surgical drains under direct vision. The patient required transfusion of four units of packed cells as the haemoglobin (Hb) had fallen to 65 g/L. Her previous surgical history (laparoscopic cholecystectomy, three caesarean sections) was unremarkable. Following surgical evacuation, swelling of the right breast persisted. Five days later, the patient complained of acute dyspnoea and of severe right-sided chest pain. The electrocardiogram (ECG) demonstrated sinus tachycardia (ST) and was reported as exhibiting an ‘S1Q3T3’ pattern. The chest X-ray (CXR) revealed opacification of the entire right hemithorax. A clinical diagnosis of pulmonary embolism (PE) was made and the patient was anticoagulated with 65 mg subcutaneously of enoxaparin sodium (Clexane, Aventis Pharma, Lane Cove, Sydney). A helical computed tomography-scan of the thorax revealed a large right-sided pleural effusion consistent with a haemothorax, but no evidence of PE (Fig. 1). Despite an acute Hb fall to 78 g/L, her haemodynamics remained stable. Following the transfusion of fresh frozen plasma (2 units), cryoprecipitate (7 units) and packed cells (2 units), the coagulation screen was normal (platelets: 303 × 109/L; international normalized ratio (INR): 0.9; activated partial thromboplastin time (APTT): 28 s; D-dimer: 0.2 < mg/L). Twelve hours later, acute hypotension and systolic blood pressure (SBP) of 90 mmHg, unresponsive to volume replacement occurred, mandating an emergency transfer to our Accident and Emergency department. On arrival, the patient was in profound shock (SBP: 65/45 mmHg; ST: 150 b.p.m.; jugular venous pulse (JVP): 20 cm). Marked left-sided tracheal deviation was present, air entry and breath sounds were absent over the right hemithorax. Asymmetry of the breasts was noted with marked bruising of the right breast. Immediate insertion of a lateral intercostal tube (ICT) produced a marked haemodynamic improvement. Upon breaching the chest wall, blood gushed at high pressure from within the pleural cavity; approximately 700 mL drained within 5 min. The restoration of normal haemodynamics was immediate (BP: 120/75 mmHg; JVP: normal). A transthoracic echocardiogram CASE REPORT

Endoscopic ligation of intercostal arterial perforators to the latissimus dorsi muscle with a time delay improves collateral blood supply

Abstract Background: The latissimus dorsi muscle (LDM) derives its blood supply from the thoracodorsal (TDR) pedicle and from perforating branches (ICP) arising from the intercostal arteries. Current methods of surgical harvesting can cause significant ischaemic damage to this muscle. Objective: To show that by endoscopically dividing the perforating vessels of the in situ muscle and by allowing a delay of 2 weeks, angiographically detectable new collateral vascular channels develop between the terminal branches of the TDR pedicle and the vascular territories of the ICP. Methods: Six sheep underwent endoscopic ligation of the ICP of the LDM on one side. After 2 weeks, both LDMs were surgically dissected. By injecting dye into the thoracodorsal artery, angiograms were obtained. The opposite LDM served as the control. Histological sections were taken at 6 transverse levels along the length of these LDMs. Creatine kinase (CK) assays were taken before surgery and at days 1 and 2 after surgery. In 4 separate sheep which solely underwent formal surgical dissection, CK assays were also taken before surgery and days 1 and 2 after surgery. Results: In the endoscopically prepared LDMs, new vascular collaterals were convincingly demonstrated to have developed between the vascular networks of the TDR pedicle and the ICP vascular networks. Histological examination revealed minimal or no evidence of myocyte necrosis in the distal half of the LDMs of the endoscopically prepared group compared to extensive myocyte necrosis in the control LDMs of the same animal. The mean peak CK elevation of the endoscopically dissected LDM was 307±22 U/L versus a mean peak CK elevation of 910±38 U/L in the 4 sheep having surgical dissection only. In this surgically dissected group, gross muscle necrosis occurred in all animals. Conclusions: Endoscopic ligation of the ICP vessels followed by a 2-week delay allows the development of collateral channels such that the TDR can solely and adequately supply the entire LDM. Subsequent surgical dissection is then tolerated with minimal or no ischaemic myocyte necrosis.