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Ann Thorac Surg 2000;69:90-95
© 2000 The Society of Thoracic Surgeons

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Original Articles

Emergency coronary artery bypass graft surgery in abciximab-treated patients

^a Northwest Surgical Associates, Portland, Oregon, USA
^b Legacy Portland Hospitals, Portland, Oregon, USA
^c Southwest Washington Medical Center, Vancouver, Washington, USA

Address reprint requests to Dr Lemmer, 2222 NW Lovejoy, Suite 315, Portland, OR 97210
e-mail: jlemmerjr{at}aol.com

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Although the platelet antiaggregant abciximab is frequently used with percutaneous coronary interventions, results of emergency coronary artery bypass graft operations in patients recently treated with abciximab are poorly characterized.

Methods. During a 29-month period, 12 patients required emergency coronary artery bypass grafting within 12 hours (mean, 1.9 hours) of abciximab therapy. Our full standard heparin dose regimen was used (mean heparin dose, 53,000 U per patient). Each patient received a single platelet transfusion dose after protamine administration, and further blood products were transfused as necessary. Clinical outcome and transfusion requirements were compared with predicted results based on risk-adjusted historical patients.

Results. No patients died and none were returned to the operating room for coagulopathy-related bleeding. Per-patient transfusion requirements were as follows: red blood cells, 3.6 units; apheresis platelets, 1.4 units; and fresh frozen plasma, 1.5 units. As compared with predicted values, there was no excessive incidence of mortality, stroke, or red blood cell transfusion requirements.

Conclusions. Emergency coronary artery bypass graft operations using full-dose heparin can be performed successfully in acutely ischemic abciximab-treated patients. Prophylactic transfusion of platelets after protamine administration appears to be useful.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
Pharmacologic impairment of platelet membrane glycoprotein (GP) function to inhibit thrombosis is of benefit to patients undergoing percutaneous coronary interventions such as balloon angioplasty, atherectomy, and stent implantation. Abciximab (ReoPro, Centocor, Malvern, PA) is an intravenously administered antibody fragment that binds specifically to the platelet membrane GP IIb/IIIa receptor and profoundly inhibits platelet aggregation. Currently, abciximab is indicated for the prevention of ischemic complications in patients undergoing percutaneous coronary interventions and for patients with unstable angina not responding to medical therapy when a coronary intervention is planned within 24 hours. In these situations, abciximab administration has been associated with improved short- and long-term clinical outcomes, and the use of the drug has become widespread [1–3].

Despite these improved outcomes, occasional patients who have been treated with abciximab require emergency coronary artery bypass graft (CABG) procedures. Because of the drug-induced qualitative platelet defect, concern has arisen about the safety of such operations. A few reports of the results of surgery in this setting have been published, and they described variable rates of blood product transfusion and hemorrhagic complications [4–9]. Of note, bleeding problems are greater in patients who required CABG within 12 hours of receiving abciximab [7]. Suggestions for management of the abciximab-treated patients have included reducing the amount of heparin administered for cardiopulmonary bypass during the CABG procedure and the empirical transfusion of donor platelets [7, 8, 10, 11].

In our practice, 12 patients underwent emergency CABG procedures using cardiopulmonary bypass within 12 hours of the discontinuation of abciximab therapy. Our standard, and rather large, heparin dose regimen was used in all of these patients, and all patients received one prophylactic platelet dose after protamine administration. This report describes the results of surgery in these patients.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
Review of the medication administration records at our participating hospitals found 890 patients who had been treated with abciximab during a period of 29 months (July 1996 to December 1998). Twelve patients (1.3%) required emergency CABG for ongoing myocardial ischemia within 12 hours of the discontinuation of abciximab therapy. Of the 12 patients, 8 had experienced failed intervention procedures (angioplasty, stent implantation, or atherectomy), whereas 6 had presented with acute myocardial infarctions necessitating emergency angiography with unsuccessful angioplasty having been attempted in 2 patients. None of the operations were repeat sternotomy procedures. Demographic, surgical, and outcome data were recorded at the time of operation and at the end of each patient’s hospitalization and entered into the Patient Analysis and Tracking Systems database (PATS; Axis Clinical Software, Portland, OR).

All patients had received the abciximab loading dose of 0.25 mg/kg body weight followed by a continuous infusion of 10 µg/min that was continued until the decision to perform emergency CABG was made. The average time from the discontinuation of abciximab therapy to the beginning of surgery was 1.9 hours (range, 0.5 to 10 hours). Eight of the 12 patients were transferred directly from the cardiac catheterization laboratory to the operating room. Three required preoperative intraaortic balloon pump placement. Preoperative drug treatment included aspirin in all 12 patients, continuous heparin infusion in 11 patients, and ticlopidine (two doses) in 1 patient. All operations were conducted using cardiopulmonary bypass with moderate systemic hypothermia (32°C) and cold hyperkalemic blood cardioplegia. Seven patients received aprotinin during surgery; 6 received the high (full Hammersmith) dose and 1 was given low (half) dose aprotinin [12]. The other 5 patients received -aminocaproic acid at the following dose regimen: 10 g loading dose, 10 g in the pump prime solution, and 10 g after administration of protamine.

An average of 2.8 bypass grafts were constructed per patient (range, 1 to 5). The left internal mammary artery was used as the bypass conduit in 7 of the 11 patients who required grafts to the left anterior descending coronary artery. No other arterial grafts were used. Saphenous vein grafts were constructed to bypass the other arteries. Anticoagulation for cardiopulmonary bypass was accomplished with a (porcine) heparin loading dose of 450 U/kg body weight and 10,000 U of heparin added to the pump prime solution. Kaolin activated clotting times (ACTs) were maintained at greater than 600 seconds. For the aprotinin-treated patients, additional doses of heparin (100 U/kg) were administered every 60 minutes on cardiopulmonary bypass, irrespective of the ACT level, in accordance with our ACT-directed fixed-dose heparin regimen [13]. After separation from bypass, protamine was administered at the dose of 0.5 to 0.75 mg/100 U total heparin administered during the procedure.

After the reversal of heparin effect by protamine administration, each of the 12 patients received a transfusion of one apheresis platelet unit. Each apheresis platelet unit is derived from one donor and has the approximate volume and number of platelets that are equivalent to six random donor units [14]. Additional platelets and other blood products were transfused as judged necessary on the basis of clinical and laboratory criteria.

Outcome analysis was performed by comparing the results in our patients with predicted values using the Cardiac RiskMaster software (Health Data Research, Portland, OR). This program uses a Bayesian model and the Merged Cardiac Registry (a database containing the results of more than 188,000 cardiac operations) to predict, from preoperative risk factors, the expected incidences of death, stroke, and red blood cell (RBC) transfusions for specified groups of patients [15].

	Results

Top Abstract Introduction Material and methods Results Comment References

 
Demographic and surgical details are shown in Table 1. We limited this report to patients who underwent CABG within 12 hours of receiving abciximab, because published clinical experience has demonstrated that such patients have more severe bleeding complications than abciximab recipients for whom there is a greater delay before undergoing CABG [7]. In fact, in our 12 patients, the mean period between discontinuation of the abciximab infusion and the beginning of surgery was 1.9 hours. Of note, the mean baseline ACT on arrival in the operating room was 275 seconds, and the mean maximal ACT achieved during bypass was 1,190 seconds. The mean total heparin dose for the entire operative procedure was 53,000 U per patient or 625 U/kg.

Each of our 12 patients received a transfusion of one prophylactic apheresis platelet dose after the administration of protamine, to reverse the abciximab effect. Three of the patients required a second apheresis platelet dose, and 1 required three total platelet units. One patient was returned to the operating room 6 hours after surgery for exploration because of excessive chest tube drainage. He was found to be bleeding from an arterial branch on the internal mammary artery graft pedicle. A second patient was returned to the operating room 3 hours after surgery because of low cardiac output and possible tamponade. Tamponade was not present, and the patient was found to be experiencing a large acute anterior wall infarction related to the preoperative failed stent placement. An intraaortic balloon pump was placed, and the patient made a successful recovery. For the 12 patients, the average time of ventilator support was 15 hours, and the average duration of stay in the intensive care unit was 52 hours.

Chest tube drainage and blood product transfusion data are shown in Table 2. As a group, the abciximab-treated patients required a mean number of 6.5 total blood product (RBCs, apheresis platelets, and plasma) exposures during their hospitalization. Patients who were treated with aprotinin received 6.4 blood product units per patient versus 6.6 units per patient for those who were administered -aminocaproic acid. The average length of hospital stay from operation to discharge was 7.0 days (range, 5 to 10 days). Two diabetic patients required readmission to the hospital for late sternal wound complications (one infection, one sterile dehiscence), which were successfully treated. Telephone follow-up 1 to 28 months after the operation was possible in 10 patients; all 10 were alive, living at home, and free of angina pectoris.

	Comment

Top Abstract Introduction Material and methods Results Comment References

Reports of surgical results for emergency CABG shortly after abciximab treatment are limited in number and detail. In an abstract, Bracey and colleagues [4] described large increases in blood use in 24 abciximab-treated patients as compared with elective CABG patients. Boehrer and associates [5] described 32 patients who required urgent CABG after abciximab treatment in a large, multicenter trial (EPIC) comparing abciximab versus placebo in 2,099 patients. Five of the 32 abciximab-treated patients requiring surgery died within 30 days (16% mortality), although 4 of the deaths were not the result of hemorrhage. Red blood cell transfusions were administered to 88% of the patients, and 76% required platelet transfusions, higher levels than in the placebo group, although not to a statistically significant degree. It is noted, however, that in the EPIC trial the median duration from abciximab treatment to CABG was more than 24 hours, at which time significant normalization of platelet function would be expected to be present [17]. Similarly, Booth and co-workers [6], in abstract form, reported results in patients requiring urgent CABG in two large trials of abciximab administration with percutaneous intervention. Twenty patients randomized to receive abciximab required CABG within 7 days of percutaneous intervention, versus 22 in the placebo group. The investigators report similar transfusion and bleeding complication rates for the two groups, with the exception of higher platelet transfusion rates (75% versus 46%) for abciximab-treated patients versus controls. In this abstract the time interval between abciximab treatment and CABG was not specified. In the reports by both Boehrer and associates [5] and Booth and colleagues [6], the specific numbers of blood product units required per patient were not reported, thereby reducing the usefulness of this information [18].

Gammie and associates [7] detailed the results of CABG procedures in 6 patients who had received abciximab within 12 hours (mean, 1.7 hours) before undergoing operations. Substantial postoperative bleeding was observed (mean 24-hour drainage, 1,540 mL), and each patient required an average of 10.7 units RBCs (median, 6 units), 37.5 platelet packs (median, 20 units), and 7.2 units fresh frozen plasma (median, 4 units). There were no deaths. Because of the observed coagulopathy and large transfusion requirements seen in their patients, the authors suggest reducing the heparin dose for cardiopulmonary bypass in the abciximab-treated patient. Specifically, they state that they routinely give a low heparin dose (150 U/kg) to maintain the ACT between 400 and 500 seconds and that this regimen "may minimize perioperative bleeding while maintaining adequate levels of anticoagulation."

Juergens and colleagues [8] reported 4 patients who underwent surgery within 6 hours of failed angioplasty during which abciximab was used. All 4 patients received transfusions of platelets, and 2 patients received RBC transfusions, although the numbers of platelet and RBC units transfused were not specified. The authors concluded that routine platelet transfusion is reasonable when emergency surgery is required in abciximab-treated patients. Alvarez [9] reported 3 patients who underwent emergency CABG for failed stent implantation shortly after receiving abciximab. All 3 patients were described as havng a profound bleeding diathesis, and the transfusion requirements were large (mean, 28 units platelets, 4.7 units RBCs, and 8.3 units plasma); 1 patient died, although not of bleeding-related causes.

In contrast to these reports, our 12 patients, who received standard heparin doses and prophylactic platelet transfusion after cardiopulmonary bypass, did not demonstrate excessive postoperative bleeding or a greater than predicted number of RBC transfusions.

Abciximab treatment is associated with prolongation of the ACT of heparinized blood, although the magnitude of this prolongation is modest, approximately 35 to 85 seconds [19, 20]. This effect was also observed by Gammie and co-workers [7] and contributed to the suggestion that a smaller heparin dose should be used for abciximab-treated patients who require emergency operation. A similar suggestion was also made by Kereiakes [10] and by Ferguson and associates [11]. Like the patients described by Gammie and colleagues [7], our patients arrived at the operating room with above-normal ACT values, but this was likely the result of both abciximab treatment and the fact that most of the patients had received preoperative heparin infusions. Therefore, the relative contribution of abciximab to the ACT prolongation in our patients is not determinable.

Concern arises regarding the use of smaller-than-standard heparin doses for cardiopulmonary bypass in abciximab-treated patients [21]. Although abciximab does inhibit thrombus formation and prolongs the ACT, the effectiveness of using smaller heparin doses in reducing transfusion requirements in the setting of cardiopulmonary bypass has not been demonstrated. It is important to note that the safety of this approach with respect to thromboembolic complications has not been evaluated in a comparison trial. The ACT is notorious for being poorly reproducible under the conditions of hypothermic cardiopulmonary bypass, being a poor measure of serum heparin levels, and being sensitive to many factors, including the specific device used, temperature, platelet count, and the presence of drugs such as aprotinin [22]. Because of these potential sources for unreliability, it seems most reasonable to use doses of heparin that ensure high ACT values and a wide margin of safety. Although abciximab does prolong the ACT to some degree, it has not yet been demonstrated to be a "heparin-sparing" agent allowing for safe extracorporeal perfusion with lower-than-standard serum heparin levels. Furthermore, data reported by Despotis and associates [23] support the use of more, rather than less, heparin for cardiopulmonary bypass. In their study of 254 patients, larger heparin doses (612 U/kg per patient) were not associated with increased bleeding as compared with smaller heparin doses (462 U/kg). In fact, the use of larger heparin doses was associated with a lower incidence of transfusion of hemostatic blood products and a trend toward smaller RBC transfusion requirements, likely on the basis of less consumption of coagulation factors during bypass. In our experience with 12 abciximab-treated patients, the use of standard, rather large, heparin doses (625 U/kg per patient) was associated with very acceptable transfusion requirements and complication rates. Based on these considerations, we currently recommend the use of standard, full heparin doses for patients who have recently been treated with abciximab and who require emergency CABG using cardiopulmonary bypass.

Abciximab binds to the platelet membrane GP IIb/IIIa receptor and prevents the binding of both fibrinogen and von Willebrand factor to the receptor, thus preventing activated platelets from aggregating. Standard abciximab treatment is a bolus loading dose (0.25 mg/kg) followed by a continuous infusion (up to 10 µg/min). Mascelli and colleagues [24] found that after adminstering the abciximab loading dose, more than 90% of the platelet GP IIb/IIIa receptors are effectively blocked and, in most patients, 80% remain blocked at the end of the 12-hour infusion. This level of receptor blockade (greater than 80%) is associated with marked inhibition of platelet aggregation [25].

Unbound abciximab is rapidly cleared from circulation with little or no drug being present in serum or bound to tissues other than platelets. Subsequent transfusion of platelets leads to return of platelet aggregation because very little free abciximab is present to bind to the new platelets and the previously bound abciximab redistributes to the new platelets, thus decreasing the overall percentage of blocked GP IIb/IIIa. When the percentage of blocked receptors falls to less than approximately 80%, the ability for the platelets to aggregate and the bleeding time normalize. This is the basis for the recommendation that platelets be transfused to reverse the abciximab effect [26]. Some authors have suggested that platelet transfusion be performed before beginning the operation, even en route to the operating room [10,11]. Although this should improve clotting during opening of the chest, it does subject the transfused platelets to the adverse effects of cardiopulmonary bypass, resulting in subsequent impairment of platelet function. Furthermore, administration of donor platelets before arrival in the operating room could precipitate abrupt closure of a precariously stenotic coronary artery whose patency is dependent on the abciximab-induced platelet dysfunction, thereby possibly causing severe hemodynamic decompensation. In our experience, the degree of bleeding on opening the chest, although greater than usual, was manageable, and the transfusion of platelets before cardiopulmonary bypass was not necessary. We therefore recommend the routine infusion of one platelet dose (either a single apheresis platelets unit or six random donor units), after the administration of protamine, to dilute the abciximab effect and to promote effective hemostasis.

This report is a retrospective review of a small number of patients (representing only about 0.35% of our total surgical volume during the period described) who underwent emergency CABG for ongoing ischemia while under the influence of abciximab. It was not a prospective trial that rigorously tested the hypothesis that routine platelet transfusion under these circumstances prevents excessive bleeding. Abciximab is, however, a powerful antiplatelet agent, the effect of which is reversed by administration of platelets, just as the effect of heparin is reversed by the administration of protamine. The use of routine platelet transfusion for this infrequent circumstance appears to be both logical and effective.

Aprotinin was used in 7 of our 12 patients. Aprotinin is clearly efficacious in reducing blood product transfusion in patients undergoing CABG but, on the basis of current knowledge, it is not expected to be an antidote for the GP IIb/IIIa receptor blockade caused by abciximab. Other properties of aprotinin (such as its antifibrinolytic and potential antiinflammatory effects) may contribute to a beneficial result when used in patients undergoing emergency CABG while under the effect of abciximab. Although the number of patients in this report is too small for meaningful comparison, our aprotinin-treated patients did not require significantly fewer total blood product transfusions than our patients who were treated with -aminocaproic acid.

Our experience in 12 patients indicates that emergency CABG procedures may be performed in acutely ischemic patients who have recently been treated with abciximab without incurring excessive mortality, bleeding, or transfusion requirements. For that reason, emergency operations should not be withheld from the abciximab-treated patient when otherwise indicated. We currently recommend the administration of full, standard heparin doses for cardiopulmonary bypass despite the observation that abciximab prolongs the ACT to a modest degree. In many patients, the internal mammary artery may be used as a bypass conduit, although the decision to do so should be made on the basis of the amount of bleeding encountered on opening the chest and the hemodynamic status of the patient. The prophylactic transfusion of one platelet dose (either one apheresis platelet unit or six random donor units) after the administration of protamine is our recommended treatment for the qualitative platelet defect caused by abciximab. Additional platelets and other blood products should be transfused as indicated by usual clinical and laboratory measurements. The utility of aprotinin administration for this circumstance requires further study.

	Footnotes

 
Doctor John H Lemmer, Jr, is a paid consultant for Eli Lilly (distributor of abciximab) and Bayer (manufacturer of aprotinin).

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): John H. Lemmer, Jr Mark T. Metzdorff Albert H. Krause, Jr J. Edward Okies Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lemmer, J. H. Articles by Hill, J. G. Search for Related Content PubMed PubMed Citation Articles by Lemmer, J. H., Jr Articles by Hill, J. G.