- Email: [email protected]
Relation of preoperative use of aspirin to increased mediastinal blood loss after coronary artery bypass graft surgery
Relation of preoperative use of aspirin to increased mediastinal blood loss after coronary artery bypass graft surgery To evaluate the potential effect of aspirin, a platelet inhibitory agent, on postoperative bleeding complications after coronary artery bypass graft surgery, we compared each of nine patients who had taken aspirin within 7 days prior to operation to one or two control subjects (total 16 patients) matched for age, sex, extent of coronary disease, number of grafts placed, total operative time, bypass time, and preoperative use of propranolol. Preoperative prothrombin time, partial thromboplastin time, and platelet counts were normal for all patients. Mean mediastinal blood loss was significantly greater in the aspirin group (919 ± 164 ml., S.E.) than in the control group (437 ± 61 ml., p < 0.001). The degree of mediastinal blood loss did not correlate with patient age, total operative time, bypass time, number of vessels diseased, or grafts placed. In addition, compared to controls the aspirin group required prolonged chest tube drainage (33 ± 5 hours versus 19 ± 1 hour, p < 0.001). Eric L. Michelson, M . D . , * Joel Morganroth, M.D., Michael Torosian, B.A., and Horace MacVaugh III, M . D . , Philadelphia, Pa.
X. he potential for use of platelet inhibitory agents to prevent the progression of coronary artery disease and associated fatal coronary events is promising. 1 - 8 Many patients for whom these agents are prescribed subsequently undergo coronary artery bypass grafting (CABG) and, therefore, may be subject further to the abnormalities of hemostasis occurring after cardiopulmonary bypass. 9 ' 10 The present study was undertaken to determine if the preoperative use of one such platelet inhibitory agent, aspirin, contributes to clinically significant postoperative bleeding. Although aspirin is known to affect platelet function in vitro, 1 1 - 1 3 it has not been demonstrated that aspirin increases bleeding in otherwise normal patients without disorders of hemostasis. Mediastinal bleeding after coronary artery surgery can be quantitated accurately, and this provides an ideal model in which to evaluate the in vivo effects of antiplatelet agents on bleeding. From the Cardiovascular Section, Department of Medicine, and the Cardiothoracic Surgery Section, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pa. Received for publication May 9, 1978. Accepted for publication July 31, 1978. Address for reprints: Joel Morganroth, M.D., 2221 Medical Science Building, Lankenau Hospital, Philadelphia, Pa. 19151. *Research Fellow of the American Heart Association, Southeastern Pennsylvania Chapter. 694
Patients and methods For this study we selected nine consecutive patients who had taken aspirin within 7 days of undergoing CABG performed by one surgeon (H. M.), at the Hospital of the University of Pennsylvania, over a 4 month period. None of these nine patients had used any other medication known to affect platelet function in the 7 preoperative days. Prior to admission all patients had been taking aspirin as prescribed by their referring physicians: two for symptomatic arthritis and seven for prevention of coronary thrombotic events. In no case was aspirin administered specifically for the purpose of the study. Each of seven patients was matched with two control patients; the other two patients could be matched with only a single suitable control subject. Control patients, chosen retrospectively, were matched for age, sex, preoperative use of propranolol, number of diseased coronary vessels, number of grafts placed, total operating time and time on cardiopulmonary bypass (Table I). All patients had been using propranolol preoperatively. Again, none of the patients in this study had used any other drug known to affect platelet function in the 7 days before the CABG operation. No patient was included about whom there was any doubt concerning medication ingestion or history. The cardiothoracic surgeon (H. M.) was "blinded" to patients' ingestion of medications but he did know that preoperative platelet counts, prothrombin times, and partial thromboplastin times were normal in all
0022-5223/78/110694+04$00.40/0 © 1978 The C. V. Mosby Co.
Volume 76 Number 5 November, 1978
Effect of aspirin on blood loss after CABG
695
Table I Patient Age (yr.), race, sex No.
CT drain (ml.)
CT duration (hr.)
Total exog. units blood
Time bypass (hr.)
Time Oper. (hr.)
Hbg
HCT
Hbg
HCT
AHgb/ HCT
Aspirin 1 2 3 4 5 6 7 8 9
1,158 1,827 515 400 457 1,367 925 1,110 513
48 38 17 21 36 19 43 18 60
2 3 1 0 0 1 3 0 0
2.17 0.83 1.5 0.92 1.42 1.33 1.33 1.25 1.17
5.5 4.25 4.67 3.67 4.25 3.58 5.0 4.25 3.5
15.2 12.5 12.6 13.6 15.6 14.5 13.9 13.1 14.2
46 37 37 42 46 43 41 39 42
10.1 10.7 7.3 8.6 7.4 7.9 9.6 10.0 10.1
33 32 22 27 24 25 29 30 30
5.1/13 1.8/5 5.3/15 5.0/15 8.2/22 6.5/18 4.3/12 3.1/9 4.1/12
3 3 3 2 3 2 2 3 2
4 2 3 2 3 3 2 3 4
28 11 14 9 10 15 17 13 15
33.3 15.4 5
1.1 1.3 0.4
1.3 0.4 0.1
4.0 1.2 0.4
13.9 1.1 0.4
41.4 3.4 1.1
28 3.7 1.2
4.8/13.4 1.8/ 4.9 0.6/ 1.6
2.6 0.5 0.2
2.9 0.8 0.3
14.7 5.6 1.9
20 20 20 36 15 14 18 25 18 19 20 16 17 13 20 15
2 1 1 2 1 2 6 0 1 0 1 0 3 0 1 0
2.0 2.17 0.83 1.83 1.67 1.5 1.58 1.58 1.5 0.83 1.0 1.25 1.42 1.42 1.17 1.08
5.67 5.0 3.5 5.42 4.92 4.5 4.5 4.17 5.17 3.42 3.83 5.08 4.0 4.67 4.0 3.25
12.5 11.8 12.1 13.5 14.2 13.0 12.8 13.4 14.6 13.7 11.5 16.0 12.7 14.7 15.3 14.0
36 35 35 40 42 39 38 40 42 39 34 48 38 44 45 42
24 22 25 31 21 35 25 25 31 24 26 32 23 31 25 19
4.5/12 4.9/13 4.0/10 3.1/9 7.7/21 1.0/4 4.8/13 5.3/15 4.5/11 5.7/15 3.0/8 5.4/16 5.1/15 3.9/13 7.2/20 7.7/23
3 3 3 3 3 3 3 3 3 2 2 2 2 2 2 2
4 4 2 2 3 3 3 3 3 2 2 2 2 3 3 4
13 10 12 11 12 11 12 10 19 13 13 9 11 11 10 11
19.1 5.4 1.4
1.3 1.5 0.4
1.4 .4 0.1
4.4 0.7 0.2
13.5 1.3 0.3
39.8 3.9 1.0
26.2 4.5 1.1
4.7/13.6 2.0/4.9 0.5/1.6
2.6 0.5 0.1
2.8 0.8 0.2
11.8 2.3 0.5
66, 57, 45, 48, 40, 49, 59, 57, 60,
N= 9 Mean S.D. S.E.M. Controls 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 N = 16 Mean S.D. S.E.M.
W, W, W, W, W, W, W, W, W,
M M M M M M M M M
53.4 8.4 2.8
56, 56, 67, 57, 40, 49, 52, 63, 51, 56, 57, 48, 56, 53, 53, 60,
W, M W, M W, M W, M W, M W, M B, M W, M W, M W, M B, M W, M W, M W, M W, M W, M
54.6 6.2 1.6
919 491 164
125 610 390 213 540 304 1,211 434 380 425 348 430 333 250 600 400
437 244 61
Pre op.
On DIC
9.1 1.3 0.4
8.0 6.9 8.1 10.4 6.5 12.0 8.0 8.1 10.1 8.0 8.5 10.6 7.6 10.8 8.1 6.3
8.6 1.7 0.4
No. ves. dis.
No. grafts
Hosp. stay (days)
Legend: CT, Chest tube, exog.. Exogenous. Oper., Operation. Preop., Preoperative. D/C, Discharge. Hbg, Hemoglobin. HCT, Hematocnt. A, Change, ves. dis., Vessels diseased. Hosp., Hospital. WM, White male. BM, Black male.
patients. Similarly, control patients were chosen by a "blinded" observer (E. L. M.), not directly involved in the care of these patients, who had no knowledge of the patients' mediastinal blood losses or duration of chest tube drainage. Study patients used in this report were a subset of patients from an ongoing study to evaluate the potential effect of multiple agents on postoperative bleeding.14 CABG was the only surgical procedure performed on these patients, and.no patient has previously undergone thoracotomy. During this 4 month study period, the surgical technique remained constant. Prior to cardiopulmonary bypass, all patients were systemically
given 300 units of heparin per kilogram of body weight. Following cannulation for bypass, each patient was bled of an amount necessary to reduce the hematocrit value to 25 percent; the autologous blood was stored in bags containing acid-citrate-dextrose solution and was reinfused at the end of the operation, along with all blood from the heart-lung machine (including intraoperative blood losses returned to the heart-lung reservoir). Cardiopulmonary bypass was instituted with a Sarns Model 2000 pump (Sams, Inc., Ann Arbor, Mich.) equipped for the Travenol Variflow bubble oxygenator (Travenol Laboratories, Inc., Morton Grove, 111.) primed with an electrolyte and plasma pro-
The Journal of Thoracic and Cardiovascular Surgery
6 9 6 Michelson et al.
Table II. Kinetics of mediastinal blood loss Postoperative hours Groups
I
Aspirin (N = 9)
130 ± 30
Control (N = 16)
94 ± 13
2
4
3
5
6
148* ± 28 98* ± 28 69t ± 17 53* + 14
46 ± 8
30 ±
5
30 ±
7
24 ±
6
7
8
45 ± 9 4 2 + 1 3
26 ± 7 27 +
9
10
II
12
38 ± 13 31 ± 8 23 + 6 26 ± 10 19 + 6
8 21 ±
4 20 + 4
19 + 3 18 ±
3 18 ± 3
Legend: The data are expressed as mean mediastinal blood loss (in milliliters) ± standard error of mean as a function of postoperative time (hours). 'When compared to control values, differences are statistically significant, p < 0.001. tp < 0.01. tp < 0.02.
tein solution. Body temperature was maintained at 37° C. during bypass. After completion of all anastomoses, the heart was electrically defibrillated and cardiopulmonary bypass was stopped when the myocardium demonstrated adequate contractility. Protamine sulfate was then administered in a dose sufficient to reverse the effects of heparin used during the operation (initially, 1 mg. per 100 units of heparin). The pericardium was closed if allowed by the patient's hemodynamic status, and the mediastinum was drained with a No. 40 chest tube placed just behind the sternum, prior to sternal closure. The chest tube was manipulated frequently to ensure tube patency. Postoperative mediastinal blood loss was determined by chest tube drainage, which was monitored at hourly intervals while the patients were in the surgical intensive care unit. All patients received routine perioperative care independent of medication history. Statistics Data were analyzed by means of Student's t test, an analysis of variance, and Scheffe's multiple comparisons where appropriate. Data are expressed as means and as standard errors of the means. Results The age, sex preoperative hematologic status, extent of coronary artery disease, number of vessels bypassed, duration of cardiopulmonary bypass, the total operating time, duration of chest tube drainage, degree of mediastinal bleeding, and duration of hospitalization for each of the aspirin-treated and control patients are detailed in Table I. No patient had a history or clinical evidence of any coagulation disorder or platelet abnormality prior to operation; prothrombin times, partial thromboplastin times, and platelet counts were normal in all patients. In detailing the extent of coronary artery disease, the main left, left anterior descending, right coronary, and left circumflex coronary arteries were considered separate vessels. Because
grafts were often connected to more than one tributary (e.g., bypassing two diagonal branches of the left anterior descending artery), the number of grafts placed exceeded the number of vessels diseased in some cases. As detailed in Table I, both the degree of mediastinal bleeding (919 ± 164 ml. versus 437 ± 61 ml.) and the duration of chest tube drainage (33 ± 5 hours versus 19 ± 1 hour) were significantly greater (p < 0.001) in aspirin versus control patients. The hourly chest tube drainage for aspirin and control patients is detailed in Table II. Compared to the control group, chest tube drainage was significantly increased in the aspirin group for the second through fifth hours (p < 0.001 versus p < 0.02). There was no demonstrable relationship between the daily dose of aspirin or duration of use and the degree of chest tube drainage. Aspirin usage varied from 600 to 2,400 mg. per day. The range of duration of aspirin use was 2 weeks to 60 months and the range of termination of use before operation was 2 to 7 days. In this small group of patients, there was no difference in bleeding among those who had stopped using aspirin 5 to 7 days before operation compared to those who had discontinued use 1 to 4 days preoperatively. Also, there was no correlation between the preoperative propranolol dosage and postoperative bleeding. At the time of discharge from the hospital, there was no difference in either hemoglobin or hematocrit values between the aspirin-treated and control patients. Discussion The present study demonstrates that the preoperative use of aspirin within the 7 days' of CABG results in increased mediastinal blood loss as well as increased duration of chest tube drainage. Aspirin's antithrombotic activity is mediated via its inhibition of platelet function by irreversible acetylation of the active site of the platelet enzyme cyclooxygenase.7' u Inactivation of this enzyme prevents the formation of cyclic endoperoxides and thromboxane A2
Volume 76 Number 5 November, 1978
which are necessary for the platelet release reaction. 12 ' 13 Affected platelets function abnormally thereafter. Platelet half-life, normally about 5 days, is unchanged in patients who have taken aspirin. 7 ' 15 Therefore, patient use of aspirin within 7 days of operation was a criterion for inclusion in this study so that at least one platelet half-life was spanned and so as to allow for individual variation in platelet kinetics. There was a significant difference in aspirin-treated versus control patients when hourly mediastinal blood losses were compared in the immediate postoperative period (Table II). Such increased bleeding early in the postoperative course may have adverse hemodynamic consequences and may increase the risk of cardiac tamponade. 16 Aspirin-treated patients also had prolonged chest tube drainage. By the time of discharge, however, there were no statistically significant differences in the hemoglobin or hematocrit levels between aspirin and control groups. This can be accounted for by several factors, including the variability in actual determination of hemoglobin and hematocrit values, variations in patient response to iron therapy, and changing volume status of patients in the postoperative period. In addition, there was a trend toward additional days of hospitalization for the aspirin group during which time the therapy regimen included administration of and relative volume restriction. There was no difference in the number of units of heterologous blood transfused for the two groups (Table I). Presumably, if control patients had not been matched for total operating time, these differences would have been more marked. Because of the increased interest in use of aspirin to prevent thrombotic events, the results of this study should have impact upon those physicians who advocate such practice. Our data suggest that aspirin use should be discontinued at least 7 days prior to CABG. Such operations require the use of cardiopulmonary bypass which, in itself, can adversely affect hemostatic function. 9, 10 Similarly, other patients undergoing cardiovascular surgery who have used aspirin or other platelet inhibitory agents preoperatively may be at increased risk of postoperative bleeding complications. At this time these findings cannot be extrapolated to other types of operations. Also, it is not known whether the perioperative use of antiplatelet agents may affect long-term patency of grafts. In addition, our data demonstrate the limitations of routine preoperative hemostatic parameters and suggest the need to evaluate further the predictive value of in vitro platelet aggregation studies and determinations of bleeding time. We are grateful to Ms. Charlotte Drzewiecki and Mrs. Frances Laird for secretarial assistance.
Effect of aspirin on blood loss after CABG
69 7
REFERENCES 1 Hammond EC, Garfinkel L: Aspirin and coronary heart disease. Findings of a prospective study. Br Med J 2:269-271, 1975 2 Elwood PC, Cochrane AL, Burr ML, Sweetnam PM, Williams G, Welsby E, Hughes SJ, Renton R: A randomized controlled trial of acetyl salicylic acid in the secondary prevention of mortality from myocardial infarction. Br Med J 1:436-440, 1974 3 Boston Collaborative Drug Surveillance Group: Regular aspirin intake and acute myocardial infarction. Br Med J 1:440-443, 1974 4 Can aspirin prevent myocardial infarction? Med Lett Drugs Ther 17:25-26, 1975 5 The Aspirin Myocardial Infarction Study Group, editorial: Aspirin and myocardial infarction—A new national cooperative trial. JAMA 232:1359-1360, 1975 6 Folts JD, Crowell EB Jr, Rowe GG: Platelet aggregation in partially obstructed vessels and its elimination with aspirin. Circulation 54:365-370, 1976 7 Majerus PW, editorial: Why aspirin? Circulation 54: 357-359, 1976 8 The Anturane Reinfarction Research Group: Sulfinpyrazone in the prevention of cardiac death after myocardial infarction. N Engl J Med 298:289-295, 1978 9 Bachmann F, McKenna R, Cole ER, Najafi H: The hemostatic mechanism after open-heart surgery. I. Studies on plasma coagulation factors and fibrinolysis in 512 patients after extracorporeal circulation. J THORAC CARDIOVASC SURG 70:76-85, 1975
10 McKenna R, Bachmann F, Whittaker B, Gilson J, Weinberg M: The hemostatic mechanism after open-heart surgery. II. Frequency of abnormal platelet functions during and after extracorporeal circulation. J THORAC CARDIOVASC SURG 70:298-309, 1975
11 Roth GJ, Stanford N, Majerus PW: Acetylation of prostaglandin synthetase by aspirin. Proc Natl Acad Sci USA 72:3073-3076, 1975 12 Hamberg M, Swensson J, Samuelsson B: Prostaglandin endoperoxides. A new concept concerning the mode of action and release of prostaglandins. Proc Natl Acad Sci USA 71:3824-3828, 1974 13 Needleman P, Minkes M, Raz A: Thromboxanes. Selective biosynthesis and distinct biologic properties. Science 193:163-165, 1976 14 Torosian M, Michelson EL, Morganroth J, Mac Vaugh H: Aspirin-and Coumadin-related bleeding after coronary artery bypass graft surgery. Ann Intern Med 89:325329, 1978 15 Stuart MJ, Murphy S, Oski FA: A simple nonradioisotope technique for the determination of platelet life span. N Engl J Med 292:1310-1313, 1975 16 Gomes MM, McGoon DC: Bleeding patterns after openheart surgery. J THORAC CARDIOVASC SURG 60:87-97,
1970
X. he potential for use of platelet inhibitory agents to prevent the progression of coronary artery disease and associated fatal coronary events is promising. 1 - 8 Many patients for whom these agents are prescribed subsequently undergo coronary artery bypass grafting (CABG) and, therefore, may be subject further to the abnormalities of hemostasis occurring after cardiopulmonary bypass. 9 ' 10 The present study was undertaken to determine if the preoperative use of one such platelet inhibitory agent, aspirin, contributes to clinically significant postoperative bleeding. Although aspirin is known to affect platelet function in vitro, 1 1 - 1 3 it has not been demonstrated that aspirin increases bleeding in otherwise normal patients without disorders of hemostasis. Mediastinal bleeding after coronary artery surgery can be quantitated accurately, and this provides an ideal model in which to evaluate the in vivo effects of antiplatelet agents on bleeding. From the Cardiovascular Section, Department of Medicine, and the Cardiothoracic Surgery Section, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pa. Received for publication May 9, 1978. Accepted for publication July 31, 1978. Address for reprints: Joel Morganroth, M.D., 2221 Medical Science Building, Lankenau Hospital, Philadelphia, Pa. 19151. *Research Fellow of the American Heart Association, Southeastern Pennsylvania Chapter. 694
Patients and methods For this study we selected nine consecutive patients who had taken aspirin within 7 days of undergoing CABG performed by one surgeon (H. M.), at the Hospital of the University of Pennsylvania, over a 4 month period. None of these nine patients had used any other medication known to affect platelet function in the 7 preoperative days. Prior to admission all patients had been taking aspirin as prescribed by their referring physicians: two for symptomatic arthritis and seven for prevention of coronary thrombotic events. In no case was aspirin administered specifically for the purpose of the study. Each of seven patients was matched with two control patients; the other two patients could be matched with only a single suitable control subject. Control patients, chosen retrospectively, were matched for age, sex, preoperative use of propranolol, number of diseased coronary vessels, number of grafts placed, total operating time and time on cardiopulmonary bypass (Table I). All patients had been using propranolol preoperatively. Again, none of the patients in this study had used any other drug known to affect platelet function in the 7 days before the CABG operation. No patient was included about whom there was any doubt concerning medication ingestion or history. The cardiothoracic surgeon (H. M.) was "blinded" to patients' ingestion of medications but he did know that preoperative platelet counts, prothrombin times, and partial thromboplastin times were normal in all
0022-5223/78/110694+04$00.40/0 © 1978 The C. V. Mosby Co.
Volume 76 Number 5 November, 1978
Effect of aspirin on blood loss after CABG
695
Table I Patient Age (yr.), race, sex No.
CT drain (ml.)
CT duration (hr.)
Total exog. units blood
Time bypass (hr.)
Time Oper. (hr.)
Hbg
HCT
Hbg
HCT
AHgb/ HCT
Aspirin 1 2 3 4 5 6 7 8 9
1,158 1,827 515 400 457 1,367 925 1,110 513
48 38 17 21 36 19 43 18 60
2 3 1 0 0 1 3 0 0
2.17 0.83 1.5 0.92 1.42 1.33 1.33 1.25 1.17
5.5 4.25 4.67 3.67 4.25 3.58 5.0 4.25 3.5
15.2 12.5 12.6 13.6 15.6 14.5 13.9 13.1 14.2
46 37 37 42 46 43 41 39 42
10.1 10.7 7.3 8.6 7.4 7.9 9.6 10.0 10.1
33 32 22 27 24 25 29 30 30
5.1/13 1.8/5 5.3/15 5.0/15 8.2/22 6.5/18 4.3/12 3.1/9 4.1/12
3 3 3 2 3 2 2 3 2
4 2 3 2 3 3 2 3 4
28 11 14 9 10 15 17 13 15
33.3 15.4 5
1.1 1.3 0.4
1.3 0.4 0.1
4.0 1.2 0.4
13.9 1.1 0.4
41.4 3.4 1.1
28 3.7 1.2
4.8/13.4 1.8/ 4.9 0.6/ 1.6
2.6 0.5 0.2
2.9 0.8 0.3
14.7 5.6 1.9
20 20 20 36 15 14 18 25 18 19 20 16 17 13 20 15
2 1 1 2 1 2 6 0 1 0 1 0 3 0 1 0
2.0 2.17 0.83 1.83 1.67 1.5 1.58 1.58 1.5 0.83 1.0 1.25 1.42 1.42 1.17 1.08
5.67 5.0 3.5 5.42 4.92 4.5 4.5 4.17 5.17 3.42 3.83 5.08 4.0 4.67 4.0 3.25
12.5 11.8 12.1 13.5 14.2 13.0 12.8 13.4 14.6 13.7 11.5 16.0 12.7 14.7 15.3 14.0
36 35 35 40 42 39 38 40 42 39 34 48 38 44 45 42
24 22 25 31 21 35 25 25 31 24 26 32 23 31 25 19
4.5/12 4.9/13 4.0/10 3.1/9 7.7/21 1.0/4 4.8/13 5.3/15 4.5/11 5.7/15 3.0/8 5.4/16 5.1/15 3.9/13 7.2/20 7.7/23
3 3 3 3 3 3 3 3 3 2 2 2 2 2 2 2
4 4 2 2 3 3 3 3 3 2 2 2 2 3 3 4
13 10 12 11 12 11 12 10 19 13 13 9 11 11 10 11
19.1 5.4 1.4
1.3 1.5 0.4
1.4 .4 0.1
4.4 0.7 0.2
13.5 1.3 0.3
39.8 3.9 1.0
26.2 4.5 1.1
4.7/13.6 2.0/4.9 0.5/1.6
2.6 0.5 0.1
2.8 0.8 0.2
11.8 2.3 0.5
66, 57, 45, 48, 40, 49, 59, 57, 60,
N= 9 Mean S.D. S.E.M. Controls 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 N = 16 Mean S.D. S.E.M.
W, W, W, W, W, W, W, W, W,
M M M M M M M M M
53.4 8.4 2.8
56, 56, 67, 57, 40, 49, 52, 63, 51, 56, 57, 48, 56, 53, 53, 60,
W, M W, M W, M W, M W, M W, M B, M W, M W, M W, M B, M W, M W, M W, M W, M W, M
54.6 6.2 1.6
919 491 164
125 610 390 213 540 304 1,211 434 380 425 348 430 333 250 600 400
437 244 61
Pre op.
On DIC
9.1 1.3 0.4
8.0 6.9 8.1 10.4 6.5 12.0 8.0 8.1 10.1 8.0 8.5 10.6 7.6 10.8 8.1 6.3
8.6 1.7 0.4
No. ves. dis.
No. grafts
Hosp. stay (days)
Legend: CT, Chest tube, exog.. Exogenous. Oper., Operation. Preop., Preoperative. D/C, Discharge. Hbg, Hemoglobin. HCT, Hematocnt. A, Change, ves. dis., Vessels diseased. Hosp., Hospital. WM, White male. BM, Black male.
patients. Similarly, control patients were chosen by a "blinded" observer (E. L. M.), not directly involved in the care of these patients, who had no knowledge of the patients' mediastinal blood losses or duration of chest tube drainage. Study patients used in this report were a subset of patients from an ongoing study to evaluate the potential effect of multiple agents on postoperative bleeding.14 CABG was the only surgical procedure performed on these patients, and.no patient has previously undergone thoracotomy. During this 4 month study period, the surgical technique remained constant. Prior to cardiopulmonary bypass, all patients were systemically
given 300 units of heparin per kilogram of body weight. Following cannulation for bypass, each patient was bled of an amount necessary to reduce the hematocrit value to 25 percent; the autologous blood was stored in bags containing acid-citrate-dextrose solution and was reinfused at the end of the operation, along with all blood from the heart-lung machine (including intraoperative blood losses returned to the heart-lung reservoir). Cardiopulmonary bypass was instituted with a Sarns Model 2000 pump (Sams, Inc., Ann Arbor, Mich.) equipped for the Travenol Variflow bubble oxygenator (Travenol Laboratories, Inc., Morton Grove, 111.) primed with an electrolyte and plasma pro-
The Journal of Thoracic and Cardiovascular Surgery
6 9 6 Michelson et al.
Table II. Kinetics of mediastinal blood loss Postoperative hours Groups
I
Aspirin (N = 9)
130 ± 30
Control (N = 16)
94 ± 13
2
4
3
5
6
148* ± 28 98* ± 28 69t ± 17 53* + 14
46 ± 8
30 ±
5
30 ±
7
24 ±
6
7
8
45 ± 9 4 2 + 1 3
26 ± 7 27 +
9
10
II
12
38 ± 13 31 ± 8 23 + 6 26 ± 10 19 + 6
8 21 ±
4 20 + 4
19 + 3 18 ±
3 18 ± 3
Legend: The data are expressed as mean mediastinal blood loss (in milliliters) ± standard error of mean as a function of postoperative time (hours). 'When compared to control values, differences are statistically significant, p < 0.001. tp < 0.01. tp < 0.02.
tein solution. Body temperature was maintained at 37° C. during bypass. After completion of all anastomoses, the heart was electrically defibrillated and cardiopulmonary bypass was stopped when the myocardium demonstrated adequate contractility. Protamine sulfate was then administered in a dose sufficient to reverse the effects of heparin used during the operation (initially, 1 mg. per 100 units of heparin). The pericardium was closed if allowed by the patient's hemodynamic status, and the mediastinum was drained with a No. 40 chest tube placed just behind the sternum, prior to sternal closure. The chest tube was manipulated frequently to ensure tube patency. Postoperative mediastinal blood loss was determined by chest tube drainage, which was monitored at hourly intervals while the patients were in the surgical intensive care unit. All patients received routine perioperative care independent of medication history. Statistics Data were analyzed by means of Student's t test, an analysis of variance, and Scheffe's multiple comparisons where appropriate. Data are expressed as means and as standard errors of the means. Results The age, sex preoperative hematologic status, extent of coronary artery disease, number of vessels bypassed, duration of cardiopulmonary bypass, the total operating time, duration of chest tube drainage, degree of mediastinal bleeding, and duration of hospitalization for each of the aspirin-treated and control patients are detailed in Table I. No patient had a history or clinical evidence of any coagulation disorder or platelet abnormality prior to operation; prothrombin times, partial thromboplastin times, and platelet counts were normal in all patients. In detailing the extent of coronary artery disease, the main left, left anterior descending, right coronary, and left circumflex coronary arteries were considered separate vessels. Because
grafts were often connected to more than one tributary (e.g., bypassing two diagonal branches of the left anterior descending artery), the number of grafts placed exceeded the number of vessels diseased in some cases. As detailed in Table I, both the degree of mediastinal bleeding (919 ± 164 ml. versus 437 ± 61 ml.) and the duration of chest tube drainage (33 ± 5 hours versus 19 ± 1 hour) were significantly greater (p < 0.001) in aspirin versus control patients. The hourly chest tube drainage for aspirin and control patients is detailed in Table II. Compared to the control group, chest tube drainage was significantly increased in the aspirin group for the second through fifth hours (p < 0.001 versus p < 0.02). There was no demonstrable relationship between the daily dose of aspirin or duration of use and the degree of chest tube drainage. Aspirin usage varied from 600 to 2,400 mg. per day. The range of duration of aspirin use was 2 weeks to 60 months and the range of termination of use before operation was 2 to 7 days. In this small group of patients, there was no difference in bleeding among those who had stopped using aspirin 5 to 7 days before operation compared to those who had discontinued use 1 to 4 days preoperatively. Also, there was no correlation between the preoperative propranolol dosage and postoperative bleeding. At the time of discharge from the hospital, there was no difference in either hemoglobin or hematocrit values between the aspirin-treated and control patients. Discussion The present study demonstrates that the preoperative use of aspirin within the 7 days' of CABG results in increased mediastinal blood loss as well as increased duration of chest tube drainage. Aspirin's antithrombotic activity is mediated via its inhibition of platelet function by irreversible acetylation of the active site of the platelet enzyme cyclooxygenase.7' u Inactivation of this enzyme prevents the formation of cyclic endoperoxides and thromboxane A2
Volume 76 Number 5 November, 1978
which are necessary for the platelet release reaction. 12 ' 13 Affected platelets function abnormally thereafter. Platelet half-life, normally about 5 days, is unchanged in patients who have taken aspirin. 7 ' 15 Therefore, patient use of aspirin within 7 days of operation was a criterion for inclusion in this study so that at least one platelet half-life was spanned and so as to allow for individual variation in platelet kinetics. There was a significant difference in aspirin-treated versus control patients when hourly mediastinal blood losses were compared in the immediate postoperative period (Table II). Such increased bleeding early in the postoperative course may have adverse hemodynamic consequences and may increase the risk of cardiac tamponade. 16 Aspirin-treated patients also had prolonged chest tube drainage. By the time of discharge, however, there were no statistically significant differences in the hemoglobin or hematocrit levels between aspirin and control groups. This can be accounted for by several factors, including the variability in actual determination of hemoglobin and hematocrit values, variations in patient response to iron therapy, and changing volume status of patients in the postoperative period. In addition, there was a trend toward additional days of hospitalization for the aspirin group during which time the therapy regimen included administration of and relative volume restriction. There was no difference in the number of units of heterologous blood transfused for the two groups (Table I). Presumably, if control patients had not been matched for total operating time, these differences would have been more marked. Because of the increased interest in use of aspirin to prevent thrombotic events, the results of this study should have impact upon those physicians who advocate such practice. Our data suggest that aspirin use should be discontinued at least 7 days prior to CABG. Such operations require the use of cardiopulmonary bypass which, in itself, can adversely affect hemostatic function. 9, 10 Similarly, other patients undergoing cardiovascular surgery who have used aspirin or other platelet inhibitory agents preoperatively may be at increased risk of postoperative bleeding complications. At this time these findings cannot be extrapolated to other types of operations. Also, it is not known whether the perioperative use of antiplatelet agents may affect long-term patency of grafts. In addition, our data demonstrate the limitations of routine preoperative hemostatic parameters and suggest the need to evaluate further the predictive value of in vitro platelet aggregation studies and determinations of bleeding time. We are grateful to Ms. Charlotte Drzewiecki and Mrs. Frances Laird for secretarial assistance.
Effect of aspirin on blood loss after CABG
69 7
REFERENCES 1 Hammond EC, Garfinkel L: Aspirin and coronary heart disease. Findings of a prospective study. Br Med J 2:269-271, 1975 2 Elwood PC, Cochrane AL, Burr ML, Sweetnam PM, Williams G, Welsby E, Hughes SJ, Renton R: A randomized controlled trial of acetyl salicylic acid in the secondary prevention of mortality from myocardial infarction. Br Med J 1:436-440, 1974 3 Boston Collaborative Drug Surveillance Group: Regular aspirin intake and acute myocardial infarction. Br Med J 1:440-443, 1974 4 Can aspirin prevent myocardial infarction? Med Lett Drugs Ther 17:25-26, 1975 5 The Aspirin Myocardial Infarction Study Group, editorial: Aspirin and myocardial infarction—A new national cooperative trial. JAMA 232:1359-1360, 1975 6 Folts JD, Crowell EB Jr, Rowe GG: Platelet aggregation in partially obstructed vessels and its elimination with aspirin. Circulation 54:365-370, 1976 7 Majerus PW, editorial: Why aspirin? Circulation 54: 357-359, 1976 8 The Anturane Reinfarction Research Group: Sulfinpyrazone in the prevention of cardiac death after myocardial infarction. N Engl J Med 298:289-295, 1978 9 Bachmann F, McKenna R, Cole ER, Najafi H: The hemostatic mechanism after open-heart surgery. I. Studies on plasma coagulation factors and fibrinolysis in 512 patients after extracorporeal circulation. J THORAC CARDIOVASC SURG 70:76-85, 1975
10 McKenna R, Bachmann F, Whittaker B, Gilson J, Weinberg M: The hemostatic mechanism after open-heart surgery. II. Frequency of abnormal platelet functions during and after extracorporeal circulation. J THORAC CARDIOVASC SURG 70:298-309, 1975
11 Roth GJ, Stanford N, Majerus PW: Acetylation of prostaglandin synthetase by aspirin. Proc Natl Acad Sci USA 72:3073-3076, 1975 12 Hamberg M, Swensson J, Samuelsson B: Prostaglandin endoperoxides. A new concept concerning the mode of action and release of prostaglandins. Proc Natl Acad Sci USA 71:3824-3828, 1974 13 Needleman P, Minkes M, Raz A: Thromboxanes. Selective biosynthesis and distinct biologic properties. Science 193:163-165, 1976 14 Torosian M, Michelson EL, Morganroth J, Mac Vaugh H: Aspirin-and Coumadin-related bleeding after coronary artery bypass graft surgery. Ann Intern Med 89:325329, 1978 15 Stuart MJ, Murphy S, Oski FA: A simple nonradioisotope technique for the determination of platelet life span. N Engl J Med 292:1310-1313, 1975 16 Gomes MM, McGoon DC: Bleeding patterns after openheart surgery. J THORAC CARDIOVASC SURG 60:87-97,
1970