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1 Use of the Activated Coagulation Time in In traoperative Heparin Reversal for Cardiopulmonary Operations ' Kenneth L. Mattox, M.D., Gene A. Guinn, M.D., Pedro A. Rubio, M.D., and Arthur C. Beall, Jr., M.D. ABSTRACT Activated clotting time (ACT) was used in 300 consecutive patients undergoing cardiac operations to determine the adequacy of heparin reversal. Mean ACT prior to protamine sulfate administration was 9 minutes 40 seconds. A return to normal value (< 2 min 10 sec) occurred in three-fourths of our patients following administration of 1.5 mg of protamine sulfate for each 100 units of heparin. Additional protamine sulfate was administered in 50 mg doses to those having abnormal ACT until normal clotting was obtained. Normal values for ACT usually coincided with clotting in the operative field. ACT proved to be a reliable guide to protamine sulfate administration. H eparin is usually neutralized with protamine sulfate to control blood loss at the completion of cardiopulmonary bypass. Objective clotting tests to evaluate the efficacy of this neutralization have been the whole-blood coagulation time (WBCT)[ 17, 221; the activated partial thromboplastin time (APTT) [6, 181; the partial thromboplastin time (FTT)[21, 301; the heparin assay - rapid, easy method (HAREN)[4]; the ground-glass clotting time [ 191; and the thrombin clotting time [261. These tests have proved difficult to work with in the operating room, and their application in the assessment of heparin reversal has been limited. In 1966 Hattersley [ 161 described the activated coagulation time (ACT). In this test 2 ml of whole blood is added to a tube containing 12 mg of diatomaceous or siliceous earth.* The immediate activation of clotting in freshly drawn blood by the inert diatomite greatly shortens the coagulation time and produces a sensitive, reproducible test of coagulation. Favorable experience using the ACT in long-term heparin administration has been reported by Allison and associates [ 11. Hill and co-workers 1171 reported the simplicity and reliability of ACT in patients on prolonged extracorporeal circulation. Our paper reports the use of activated clotting time as a guide to evaluating heparin reversal at the termination of cardiopulmonary bypass. From the Cora and Webb Mading Department of Surgery, Baylor College of Medicine, and the Veterans Administration Hospital, Houston, Tex. Supported in part by U.S. Public Health Service Grants HE and HE We gratefully acknowledge the assistance of Mrs. Connie Harmon, M.T. (ASCP), who performed the activated clotting time tests. Presented at the Twenty-first Annual Meeting of the Southern Thoracic Surgical Association, Williamsburg, Va., Nov. 7-9, Address reprint requests to Dr. Mattox, 1502 Taub Loop, Houston, Tex *Tube no. 3865, Becton Dickinson, Inc., Columbus, Neb. 634 THE ANNALS OF THORACIC SURGERY

2 Activated Coagulation Time in Heparin Reversal TABLE 1. OPERATIONS PERFORMED IN 300 PATIENTS UNDERGOING ACT TESTING AFTER HEPARIN NEUTRALIZATION BY PROTAMINE SULFATE Operation No. of Patients Coronary artery bypass 214 Valve replacement 62 Coronary bypass with valve replacement 9 Aortic aneurysmectomy 7 Resection of ascending aortic aneurysm &valve replacement 6 Closure of septa1 defect 2 Clinical Material and Methods Activated clotting time was tested in 300 patients having open-heart operations at the Houston Veterans Administration Hospital between October, 197 1, and July, All patients were men, and the mean age was 53 years. Of the 300 open-heart operations performed, 2 14 were coronary artery bypass procedures, 62 were valve replacements, and 24 were other open-heart procedures (Table 1). Duration of cardiopulmonary bypass ranged from 45 to 180 minutes (average, 85 minutes). The anesthetic agent in all patients was a narcotic with supplemental analgesic drugs. Approximately one-third of the patients had 1,000 ml of 5% alcohol infused intrzgvenously to counteract the antidiuretic effect of morphine [24]. The operative results in the patients undergoing coronary bypass have been reported previously [25]. Patients received bovine lung heparin, 3 mg per kilogram of body weight, before cannulation. At the end of cardiopulmonary bypass, 1.5 mg of protamine sulfate was given for each 100 units of heparin. Seventy patients had moderate hypothermia (28 C) during the later part of the study. Activated clotting time was tested 15 minutes following completion of protamine sulfate administration. The average time from administration of heparin until protamine sulfate was given was 95 minutes. Fifteen minutes after the protamine sulfate had been given and after the pump reservoir blood had been returned to the patient, 1 ml of blood was withdrawn from the central venous pressure line and discarded. Two ml of blood was then drawn and placed in a prewarmed glass tube containing 12 mg of siliceous earth prewarmed to 37"C, and a timer was started. The tube was inverted three times to mix the contents and was placed in a Thermolyne dry bath* at 37 C for 60 seconds. It was then inverted every 5 seconds until the first definite clot formed. Clotting time was recorded to the nearest 5 seconds. The normal ACT is less than 2 minutes 10 seconds [16]. If the coagulation time was prolonged, additional protamine sulfate was administered in 50 mg doses until a normal ACT was obtained (Table 2). Results Seventy-five percent of the 300 patients had a normal ACT after heparin neutralization; the remaining 25% required one or more additional 50 mg aliquots of protamine sulfate. Because of the large quantity (3 mg/kg) of heparin given to ensure against any possibility of clotting in the extracorporeal circuit, the *Model DB-5915E, Sybron Corp., Dubuque, Ill. VOL. 19, NO. 6, JUNE,

3 MATTOX ET AL. TABLE 2. HEPARIN NEUTRALIZATION BY PROTAMINE SULFATE IN 300 PATIENTS Pump Time, Heparin + Protarnine* No. of (min) ACT < 2 1 ACT > 2 15 Patients t t 28 Total no. of patients *1.5 rng of protarnine sulfate to 1.0 rng heparin (1 rng = 100 U).?Received extra heparin due to long pump run. blood was relatively incoagulable before protamine administration in all patients tested (ACT, 9 min). When extra heparin was administered due to extended cardiopulmonary bypass (> 100 min), the reliability of ACT in detecting adequacy of heparin reversal was not altered. Ten patients required two or more additional 50 mg doses of protamine sulfate before a normal ACT was achieved. The appearance of clotting in the operative field usually coincided with normal ACT. Average blood replacement was 1,237 ml. Eleven of the 300 patients required reoperation for postoperative bleeding. In these 11 patients the platelets, prothrombin time, partial thromboplastin time, fibrinolysin activity, serum calcium, and ACT were normal. Specific bleeding sites that were controllable were found in 7 patients; the other 4 patients had only a generalized ooze. Comment Heparin as an anticoagulant for extracorporeal circulation is universally utilized 19, 11, 20, 293. While activity may vary from lot to lot, the half-life of heparin is reported to be from 1 to 1 Yi hours [2,9-1 1,201. The incoagulable state is extended as larger doses are given. Heparin neutralization with protamine sulfate at the end of cardiopulmonary bypass is used by most surgeons, although this concept has been questioned [5,11,12,20]. Protamine sulfate has been shown to produce blood coagulation defects and to exert a specific action on the cardiovascular system. When given in levels greater than 3 mg per kilogram, protamine sulfate acts as a true antithromboplastin by producing a deficiency in Factor VIII [13]. Studies by Ellison and associates [S] have demonstrated that this anticoagulant activity is transient and probably unimportant. Systemic effects of protamine sulfate include arterial hypotension, decreased cardiac output, decreased total-body vascular resistance, decreased blood flow, and increased resistance in the superior mesenteric artery For these reasons, proper dosage and slow administration are important considerations. The traditional test for monitoring the anticoagulant effects of heparin has been the whole-blood clotting time [17, 21, 22,301. Estes [9, 101 demonstrated a linear correlation between the whole-blood clotting time, the partial thromboplas- 636 THE ANNALS OF THORACIC SURGERY

4 Activated Coagulation Time in Heparin Reversal tin time, and the activated partial thromboplastin time and recommended use of the more rapidly performed test. The activated partial thromboplastin time is of value both for monitoring patients having continuous heparin infusion and in the control of heparin therapy in open-heart operations, but it must be done in the laboratory. Although initially.reported in 1966 by Hattersley [16], the ACT has not received wide use. It has been a reliable preoperative screening test, a guide to heparin reversal in patients undergoing heparinization for angiography, and a means of managing heparin administration in prolonged extracorporeal circulation up to 230 hours [ 17,281. It requires only one tube and 2 ml of whole blood. Its end-point is easily determined and reproducible. It can be performed in the operating suite, where its quick results make it practical as a guide to protamine administration. In instances of prolonged ACT and in patients with persistent postoperative bleeding, the ACT is utilized in conjunction with ongoing evaluation of more specific coagulation deficiencies. We have come to rely on the ACT in controlling blood loss due to residual heparin activity after cardiac operations. This simple test is useful both as an initial screening measure and as an adjunct to the standard battery of coagulation assays employed to evaluate bleeding. References 1. Allison, A., Clark, S., and Brown, F. Activated clotting time in the control of heparin therapy. Bull Geisinger Med Cent 21:199, Anderson, M. N., Mendelow, M., and Alfano, G. A. Experimental studies of heparin-protamine activity with special reference to protamine inhibition of clotting. Surgmy 46: 1060, Berger, R. L., Ramaswamy, K., and Ryan, T. J. Reduced protamine dosage for heparin neutralization in open-heart operations. Cardiovasc Surg (Suppl 11): 155, Blakeley, B. A. A rapid bedside method for control of heparin therapy. Can MedAssoc ' J 99:1072, Castaneda, A. R. Must heparin be neutralized following open heart surgery? J Thorac Cardwvasc Surg 52:716, Dilup, B., Gallus, A., Hirsh, J., and Cade, J. A prospective study of the value of activated partial thromboplastin time. N Engl J Med 287:324, Durie, N. D., Hansebout, R. R., Peterson, E. W., and Ringer, T. R. A unified method for regional anticoagulation of blood. Am J Surg 120:341, Ellison, N., Ominsky, A. J., and Wallman, H. Is protamine a clinically important anticoagulant? Anesthesiology 35:621, Estes, J. W. Kinetics of the anticoagulant effect of heparin. JAMA 212:1492, Estes, J. W. Heparin therapy. Intern Med Dig 6:33, Frick, P. G., and Brogli, H. The mechanism of heparin rebound after extracorporeal circulation for open cardiac surgery. Surgery 59:721, Gans, H., and Castaneda, A. R. Problems in hemostasis during open heart surgery: VII. Change in fibrinogen concentration during and after cardiopulmonary bypass with particular reference to the effect of heparin neutralization on fibrinogen. Ann Surg 165:551, Goldman, B. S., Joison, J., and Austen, W. G. Cardiovascular effects of protamine sulfate. Ann Thmm Surg 7:349, Comes, M. M. R., and McGoon, D. C. Bleeding patterns after open-heart surgery. J Thmm Cardiovasc Surg 60:87, Gourin, A., Streisand, R. L., Greineder, J. K., and Stuckey, J. H. Protamine sulfate administration and the cardiovascular system. J Thorac Cardiovasc Surg 62: 193, VOL. 19, NO. 6, JUNE,

5 MATTOX ET AL. 16. Hattersley, P. G. Activated coagulation time of whole blood. JAMA 196:436, Hill, J. D., Dontigny, L., de Leval, M., and Mielke, C. H., Jr. A simple method of heparin management during prolonged extracorporeal circulation. Ann Thorac Surg 17:129, Hill, N. O., Ridgway, H. J., and Speer, R. J. Coagulation testing in the surgical patient. Tex Med 66:43, Hoffman, G. C., and Snyder, A. The ground-glass clotting time. Cleue Clin Q 33: 107, Hurt, R., Perkins, H. A., Osborn, J. J., and Gerbode, F. The neutralization of heparin by protamine in extracorporeal circulation. J Thorac Cardiovasc Surg 32:612, Jaberi, M., Bell, W. R., and Benson, D. W. Control of heparin therapy in open heart surgery. J Thwac Cardiovasc Surg 67:133, Lenahan, J. G., Frye, S., Jr., and Phillips, G. E. Use of the activated partial thromboplastin time in the control of heparin administration. Clin Chem 12:263, Lolobow, T., Spragg, R. G., Pierce, J. E., and Zapol, W. M. Extended term (to 16 days) partial extracorporeal blood gas exchange with the spiral membrane lung in unanesthetized lambs. Trans Am SOC ArtqZntern Organs 17:350, Mannheimer, W. H. The use of morphine and intravenous alcohol in the anesthetic management of open-heart surgery. South Med J 54:1125, Mathur, V. A,, and Guinn, G. A. Prospective randomized study of coronary artery bypass surgery (BS): Preliminary report (abstract). Circulation 46 (Suppl. IV):224, Penner, J. A. Experience with a thrombin clotting time assay for measuring heparin activity. Am J Clin Pathol 61:645, Stahl, G. M., and Martin, B. G. The role of the laboratory in screening patients for open-heart surgery. Lab Med 2:29, Wallace, S., Medellin, H., DeJongh, D. S., and Gianturco, T. Systemic heparinization for angiography. Am J Roentgen01 Radium Ther Nucl Med 116:204, Wessler, S., and Gaston, L. W. Pharmacologic and clinical aspects of heparin therapy. Anesthesiology 27 : 475, Zucker, A., Cathey, M. H., and Wylie, R. L. Controlof heparin therapy: Sensitivity of the activated partial thromboplastin time for monitoring the antithrombotic effects of heparin. J Lab Clin Med 73:320, THE ANNALS OF THORACIC SURGERY