Heparin reversal in off-pump coronary artery bypass surgery: complete, partial, or no reversal?

PII: S0967-2109(01)00142-9

Cardiovascular Surgery, Vol. 10, No. 3, pp. 245–250, 2002  2002 The International Society for Cardiovascular Surgery Published by Elsevier Science Ltd. All rights reserved 0967-2109/02 $22.00

www.elsevier.com/locate/cardiosur

Heparin reversal in off-pump coronary artery bypass surgery: complete, partial, or no reversal? G. Gatti and P. Pugliese Cardiac Surgery Department, Casa di Cura ‘Villa Torri’-Clinica accreditata, viale Filopanti 12, 40126 Bologna, Italy Several clinical studies have reported that avoiding cardiopulmonary bypass reduces postoperative bleeding. The purpose of this study is to verify that protamine during off-pump coronary artery bypass surgery produces significant reduction of postoperative bleeding. Sixty consecutive patients undergoing off-pump coronary artery bypass surgery were prospectively randomized in three groups: Group A received 1 mg of protamine every 100 IU of heparin, Group B 0.5 mg of protamine every 100 IU of heparin, and Group C none. The three groups were analyzed for differences in preoperative cardiac function, pre-, intra-, and postoperative coagulation profile, intraoperative variables, and postoperative bleeding. In the three study groups, no statistically significant difference was found in preoperative cardiac function, pre- and intraoperative coagulation profile, and prothrombin time, activated partial thromboplastin time, platelet count in the first postoperative day. In Group A, total postoperative bleeding, use of packed red blood cells, and mild pericardial effusion prevalence at discharge were significantly lower only when compared to Group C, but they were not significantly different when compared to Group B. In off-pump coronary artery bypass surgery, heparin should be reverted with protamine, otherwise the postoperative bleeding risk might increase. Partial heparin reversal might not increase postoperative bleeding risk, but it may reduce dose-dependent protamine adverse effects.  2002 The International Society for Cardiovascular Surgery. Published by Elsevier Science Ltd. All rights reserved Keywords: heparin reversal, protamine, OPCAB surgery, postoperative bleeding

Introduction Cardiopulmonary bypass (CPB) has long been recognized as one of the main causes of a complex systemic inflammatory response, which may contribute to postoperative complications and to multiple organ dysfunctions [1]. Therefore, renewed interest in off-pump coronary artery bypass (OPCAB) surgery has arisen in the last few years [2–5]. Several clinical studies comparing outcomes of OPCAB surgery and coronary artery bypass grafting

Correspondence to: G. Gatti, via Pignolini 5, d/G–37019 Verona, Italy. Tel.: +39-51-243444; Fax: +39-51-251320; e-mail: giusep.gatti @tiscali.it

CARDIOVASCULAR SURGERY

JUNE 2002 VOL 10 NO 3

(CABG) with CPB have shown that patients undergoing OPCAB surgery have less blood loss and need for transfusions [6–8]. In OPCAB surgery, systemic anticoagulation with heparin is established using 100, 150, or 200 IU/kg to achieve a target activated clotting time from 200 to 350 s. Complete heparin reversal with protamine is generally used [4–6]. Nevertheless, it is well known that protamine can cause some adverse effects that range from mild hypotension to very rare but potentially fatal events, such as noncardiogenic pulmonary oedema and catastrophic pulmonary vasoconstriction [9–11]. This study considers the opportunity to reduce or avoid protamine at the end of OPCAB surgery, without increasing the postoperative bleeding risk. 245

Heparin reversal in off-pump coronary artery bypass surgery: G. Gatti and P. Pugliese

Material and methods

Heparin treatment

Patient population

All patients were heparinized, during harvesting of internal mammary artery, with a single starting heparin dose of 150 IU/kg (1 mg/kg). No additional heparin was given.

At our Department, between February 1999 and March 2001, after adequate informed consent, 60 consecutive patients undergoing OPCAB surgery with single- or double-vessel disease were prospectively randomized in three groups: Group A (complete heparin reversal, CHR) had 1 mg of protamine chloride (Protamina Roche, Roche S.p.A., Milano, Italy) every 100 IU of heparin (Eparina Vister, Parke-Davis S.p.A., Lainate (MI), Italy) (protamine to heparin ratio (mg/mg): 1.5), Group B (partial heparin reversal, PHR) had 0.5 mg of protamine every 100 IU of heparin (protamine to heparin ratio (mg/mg): 0.75), and Group C (no heparin reversal, NHR) had no protamine administering. Cardiac function was classified according to the New York Heart Association classification, angina was assessed using the Canadian Cardiovascular Society classification, and operative risk was estimated using the European SCORE (EuroSCORE) [12]. The three groups were analyzed for differences in age, cardiac function class, angina class, and operative risk. Left ventricular ejection fraction was quantified by preoperative echocardiography. Preoperative myocardial infarction was documented if it occurred within six months before operation. Number of grafts per patient, reoperation prevalence, anastomotic and operation time were recorded (anastomotic time is the total time of coronary occlusion to sew the anastomosis). Prothrombin time, activated partial thromboplastin time, and platelet count were examined preoperatively and in the first postoperative day. Activated clotting time was analyzed preoperatively, intraoperatively, and postoperatively every 2 h during the first 24 h. Use of acetylsalicylates within the seven days before operation was also recorded. Postoperative hourly drainage from chest tubes for 5 h, the first 12-h postoperative drainage, and total postoperative drainage were reported. Kirklin’s chest drainage criteria for reoperation were adopted [13]. Total number of packed red blood cells, fresh frozen plasma, and platelets units were recorded. Hemoglobin concentrations were recorded preoperatively, in the first postoperative day, and at discharge. In all patients, one predischarge echocardiography was performed and possible pericardial effusion quantified. Cardiac troponine T-peak, creatine-kinase enzyme-peak, creatine-kinase-MB enzyme-peak, and postoperative acute myocardial infarction prevalence were calculated. Intensive Care Unit and Hospital postoperative stay were determined. 246

Surgical technique All operations were performed by the same experienced cardiac surgeon (P.P.). A conventional median sternotomy was used and the pedicled internal mammary artery technique was adopted. Pericardial traction sutures were used to ease visibility and access and elevating gauze pads were used to rotate the heart if necessary to obtain an unobstructed view of the target coronary artery. Stabilization of the target arteries in the early phase of the study was accomplished with the CTS tissue stabilizer (Cardiothoracic Systems Inc, Cupertino, CA) and recently with the Octopus II stabilizer (Medtronic Inc, Minneapolis, MN). Tourniquetmounted two-pledgets 4-0 Prolene (Ethicon, Somerville, NJ) sutures were used to occlude temporarily the proximal vessel during ischemic preconditioning time (5 min) and anastomotic time. Visualization of anastomotic site was enhanced using a surgical blower-humidifier (Medtronic ClearView TM Misted Blower, Minneapolis, MN). Proximal anastomoses of vein grafts were carried out with the aid of a partially occluding aortic side clamp [4–7]. Postoperative antiplatelet and anticoagulant treatment Postoperative antiplatelet therapy included single intravenous lysine acetylsalicylate dose of 250 mg (Flectadol, Sanofi-Synthelabo S.p.A., Milano, Italy), 12 h after surgical procedure and every postoperative day until extubation; by the day after extubation, daily antiplatelet treatment included 150 mg of acetylsalicylate (Ascriptin, Rhoˆne-Poulenc Rorer S.p.A., Milano, Italy). Prevention of thromboembolic venous disease included single subcutaneous enoxaparin dose of 2000 IU (Clexane, Rhoˆ ne-Poulenc Rorer S.p.A., Milano, Italy) by the first postoperative day, until complete mobilization of the patient. Statistical analysis Data are presented as mean±standard deviation or percentage, and analyzed by Student’s t-test for continuous variables and the χ2 test for non-continuous variables. Statistical significance was assumed for a P value less than 0.05.

Results In the three study groups, there was no statistically significant difference in age, female sex prevalence, CARDIOVASCULAR SURGERY

JUNE 2002 VOL 10 NO 3

Heparin reversal in off-pump coronary artery bypass surgery: G. Gatti and P. Pugliese Table 1 Demographic data, cardiac function, and operative risk

Age (years) Female sex New York Heart Association class Canadian Cardiovascular Society class Left ventricular ejection fraction (%) Preoperative recent MIa EuroSCOREb

Group A (CHR) (n=20)

Group B (PHR) (n=20)

Group C (NHR) (n=20)

Group A vs. Group B Group A vs. Group C (P value) (P value)

65.0±11.9 5 (25.0%) 3.1±0.8 3.45±0.6

64.3±14.0 3 (15.0%) 3.05±0.7 3.5±0.7

67.9±11.8 4 (20.0%) 3.15±0.7 3.4±0.75

NS NS NS NS

NS NS NS NS

50.1±7.1 6 (30.0%) 5.92±4.96

51.0±8.7 7 (35.0%) 6.14±4.77

48.2±6.3 5 (25.0%) 5.43±4.42

NS NS NS

NS NS NS

CHR = complete heparin reversal, PHR = partial heparin reversal, NHR = no heparin reversal a Myocardial infarction occurred within six months before operation. b Ref. [12].

cardiac function class, angina class, operative risk, left ventricular ejection fraction, and recent preoperative myocardial infarction prevalence (Table 1). In Group A, the number of grafts per patient was the greatest (P = 0.03), anastomotic time the longest (P = 0.01), but operation time was longer only when compared to Group C (P = 0.02) (Table 2). Preoperative and first postoperative day prothrombin and activated partial thromboplastin time, use of acetylsalicylates within the seven days before operation, and preoperative and intraoperative activated clotting time were similar in the three groups. Activated clotting time was always above 200 s. Preoperative platelet count was greater in Group A than in Group C (P = 0.03), but not in the first postoperative day. Obviously, postoperative activated clotting time in Group A was the shortest (Group A versus Group B, P = 0.04; Group A versus Group C, P = 0.03) (Table 3). Patients of Group A had significant lower partial and total postoperative drainage from chest tubes (P = 0.04) and mild pericardial effusion prevalence at discharge (P = 0.02) than those of Group C; total postoperative drainage from chest tubes and mild pericardial effusion prevalence at discharge were not significantly lower in Group A than in Group B. Both in Group B and in Group C, one patient returned to the operating room because of increased postoperative bleeding, but no surgical cause was

observed (in the patient of Group B preoperative and first day postoperative activated partial thromboplastin time ratio were 1.52 and 1.38, respectively, and intraoperative and postoperative activated clotting time were 410 and 250 s, respectively). Additionally, in Group A blood products were rarely needed, but difference was significant only for packed red blood cells in Group A compared to Group C (P = 0.03). No significant difference was found in preoperative, first day, and discharge hemoglobin concentrations (Table 4). No protamine-dependent adverse effects occurred. Postoperative myocardial infarction prevalence and cardiac troponine T-peak, creatine-kinase enzyme-peak, and creatine-kinase-MB enzyme-peak were similar in the three study groups. There was no significant difference in Intensive Care Unit and Hospital postoperative stay (Table 5).

Comment From clinical and experimental observations, it is known that heparin reversal with protamine causes dose-dependent decreases in cardiac contractility and in myocardial oxygen extraction and consumption [15–18]. Furthermore, low-dose administration of protamine spares platelet function [19–21]. Several clinical studies have reported that avoiding

Table 2 Intraoperative variables

Number of grafts per patient Reoperation prevalence Anastomotic time (min)a Operation time (min)

Group A (CHR) (n=20)

Group B (PHR) (n=20)

Group C (NHR) (n=20)

Group A vs. Group B Group A vs. Group C (P value) (P value)

1.45±0.5 0 20.1±8.0 162.1±36.2

1.1±0.3 1 (5.0%) 14.6±5.2 155.5±49.0

1.1±0.3 3 (15.0%) 14.4±4.9 134.8±31.4

0.03 NS 0.01 NS

0.03 NS 0.01 0.02

CHR = complete heparin reversal, PHR = partial heparin reversal, NHR = no heparin reversal a The total time of coronary occlusion to sew the anastomosis.

CARDIOVASCULAR SURGERY

JUNE 2002 VOL 10 NO 3

247

Heparin reversal in off-pump coronary artery bypass surgery: G. Gatti and P. Pugliese Table 3 Preoperative, intraoperative, and postoperative coagulation profile

Preoperative coagulation profile Prothrombin time (INR) Activated partial thromboplastin time (aPTT ratio) Platelet count (×103/mm3) Use of aspirin within seven days before the operation Activated clotting time (s) Intraoperative activated clotting time (s) Postoperative coagulation profilea Prothrombin time (INR) Activated partial thromboplastin time (aPTT ratio) Platelet count (×103/mm3) Activated clotting time (s)

Group A (CHR) (n=20)

Group B (PHR) (n=20)

Group C (NHR) (n=20)

Group A vs. Group B Group A vs. Group C (P value) (P value)

1.07±0.13 1.46±1.29

1.03±0.03 0.94±0.06

1.04±0.29 1.59±1.54

NS NS

NS NS

236.9±68.6 9 (45.0%)

201.9±59.7 7 (35.0%)

183.5±44.9 9 (45.0%)

NS NS

0.03 NS

141.0±52.4 288.6±70.4

121.3±24.7 285.6±55.4

134.8±28.7 268.3±67.8

NS NS

NS NS

1.14±0.05 1.09±0.19

1.14±0.07 1.07±0.16

1.30±0.60 1.31±0.71

NS NS

NS NS

196.4±70.7 108.0±9.50

248.0±57.6 156.3±26.3

182.5±50.9 199.7±47.4

NS 0.04

NS 0.03

CHR = complete heparin reversal, PHR = partial heparin reversal, NHR = no heparin reversal a In the first postoperative day.

Table 4 Drainage from chest tubes, preoperative and postoperative hemoglobin concentrations, use of blood products, and prevalence of reoperation for bleeding and mild pericardial effusion at discharge

Drainage from chest tubes First hour (ml) Second hour (ml) Third hour (ml) First 4 h (ml) First 5 h (ml) First 12 h (ml) Total (ml) Hemoglobin (Hb) Preoperative Hb (g/l) Postoperative Hb g/l)a Hb at discharge (g/l) Blood products use Packed red blood cells(IU) Fresh frozen plasma (ml) Platelets units (IU) Reoperation for bleeding Mild pericardial effusion at discharge

Group A (CHR) (n=20)

Group B (PHR) (n=20)

Group C NHR) (n=20)

Group A vs. Group B Group A vs. Group C (P value) (P value)

110.0±149.4 44.4±37.2 26.1±12.7 205.0±196.9 221.7±202.5 326.1±219.9 538.3±247.4

192.3±107.5 105.9±113.6 80.9±80.3 445.4±236.6 560.9±439.2 619.5±232.7 736.4±207.6

175.6±168.1 182.0±174.7 77.0±48.9 522.0±312.8 558.0±318.1 675.9±366.5 951.6±550.1

NS NS NS 0.03 0.05 NS NS

NS 0.03 0.006 0.01 0.008 0.01 0.04

13.3±1.8 10.7±1.5 11.2±1.1

13.7±2.6 11.7±0.9 10.8±1.3

13.5±1.8 11.4±1.6 10.5±1.3

NS NS NS

NS NS NS

0.5±1.1 70.0±217.9 0.1±0.3 0 2 (10.0%)

0.9±1.5 130.0±431.8 0.1±0.4 1 (5.0%) 3 (15.0%)

1.9±2.6 360.0±888.8 0.4±1.2 1 (5.0%) 7 (35.0%)

NS NS NS NS NS

0.03 NS NS NS 0.02

CHR = complete heparin reversal, PHR = partial heparin reversal, NHR = no heparin reversal a In the first postoperative day.

CPB reduces postoperative bleeding and, consequently, use of blood products after CABG [6–8]. Late improvements in the OPCAB surgical technique (i.e. exposure, stabilization, and occlusion of the target vessel and visualization of the anastomotic site) and updated surgeon’s familiarity with this matter make the anastomoses more accurate and thus more secure [3–6,14,15]. In our prospective study, we therefore reduced protamine use in OPCAB surgery. Sixty consecutive 248

patients undergoing OPCAB surgery were randomly assigned to one of the three groups. All operations were performed by the same cardiac surgeon and with the same surgical technique so that all operator-dependent and technique-dependent variables were minimized. Demographic data, cardiac function, operative risk, and preoperative coagulation profile were similar in the three groups. Preoperative platelet count was greater in Group A than in Group C, but not CARDIOVASCULAR SURGERY

JUNE 2002 VOL 10 NO 3

Heparin reversal in off-pump coronary artery bypass surgery: G. Gatti and P. Pugliese Table 5 Postoperative myocardial infarction prevalence, serum markers-peaks of cardiac damage, and Intensive Care Unit and Hospital postoperative stay

Postoperative acute MIa Cardiac troponine T-peak (U/l) Creatine-kinase enzyme-peak (U/l) Creatine-kinase-MB enzyme-peak (U/l) Intensive Care Unit stay (days) Hospital postoperative stay (days)

Group A (CHR) (n=20)

Group B (PHR) (n=20)

Group C (NHR) (n=20)

Group A vs. Group B Group A vs. Group C (P value) (P value)

0 0.124±0.207 283.3±133.6 24.8±21.9

0 0.169±0.432 400.2±405.8 23.7±19.6

2 (10.0%) 0.773±1.546 716.4±896.6 80.3±168.1

NS NS NS NS

NS NS NS NS

1.5±0.6 7.4±2.3

1.9±1.1 7.6±3.1

2.2±1.6 8.2±3.4

NS NS

NS NS

CHR = complete heparin reversal, PHR = partial heparin reversal, NHR = no heparin reversal a Myocardial infarction.

in the first postoperative day and it was always within normal range in all the three study groups. All patients were heparinized with a single standard starting heparin dose normalized to body weight. Since intraoperative target activated clotting time was similar in the three groups and always longer than 200 s, no additional heparin dose was given. Heparin reversal was simplified with a single standard protamine dose: 1 mg every 100 IU of heparin (protamine to heparin ratio (mg/mg): 1.5) in Group A and 0.5 mg every 100 IU of heparin (protamine to heparin ratio (mg/mg): 0.75) in Group B. Partial and total postoperative bleeding, packed red blood cells use, and mild pericardial effusion prevalence at discharge of Group A were significantly lower than Group C. Total postoperative bleeding, packed red blood cells use, and mild pericardial effusion prevalence at discharge of Group A were not significantly different compared to Group B. In conclusion, in OPCAB surgery, heparin should be reverted with protamine because no heparin reversal might increase postoperative bleeding risk and packed red blood cells use. Partial heparin reversal might significantly raise neither postoperative bleeding risk nor packed red blood cells use, but it may reduce dose-dependent protamine adverse effects. Complete or partial heparin reversal with protamine does not increase myocardial ischemic risk, although it raises blood viscosity [22]. The main limitation of our study derives from the small number of patients in every group and from the few groups studied. Partial heparin reversal with different protamine doses should be tested to find the best protamine dose (the best protamine to heparin ratio) for heparin reversal in OPCAB surgery.

3. 4. 5. 6. 7. 8. 9. 10. 11.

12. 13.

14.

15.

16.

17.

References 1. Kirklin, J. W. and Barratt-Boyes, B. G. Cardiac surgery: morphology, diagnostic criteria, natural history, techniques, results, and

CARDIOVASCULAR SURGERY

2.

JUNE 2002 VOL 10 NO 3

18.

indications, part I Churchill Livingstone, New York, 1993(chapter 2, p. 61–127). Wan, S., Izzat, M. B. and Lee, T. W., Avoiding cardiopulmonary bypass in multivessel CABG reduces cytokine response and myocardial injury. Ann Thorac Surg, 1999, 68, 52–57. Ascione, R., Lloyd, C. T. and Underwood, M. J., Inflammatory response after coronary revascularization with or without cardiopulmonary bypass. Ann Thorac Surg, 2000, 69, 1198–1204. Penttila¨ , H. J., Lepoja¨ rvi, M. V. K. and Kiviluoma, K. T., Myocardial preservation during coronary surgery with and without cardiopulmonary bypass. Ann Thorac Surg, 2001, 71, 565–571. Baumgartner, F. J., Gheissari, A. and Capouya, E. R., Technical aspects of total revascularization in off-pump coronary bypass via sternotomy approach. Ann Thorac Surg, 1999, 67, 1653–1658. Nader, N. D., Khadra, W. Z. and Reich, N. T., Blood product use in cardiac revascularization: comparison of on- and off-pump techniques. Ann Thorac Surg, 1999, 68, 1640–1643. Ascione, R., Lloyd, C. T. and Underwood, M. J., Economic outcome of off-pump coronary artery bypass surgery: a prospective randomised study. Ann Thorac Surg, 1999, 68(6), 2237–2242. Kshettry, V. R., Flavin, T. F. and Emery, R. W., Does multivessel, off-pump coronary artery bypass reduce postoperative morbidity? Ann Thorac Surg, 2000, 69, 1725–1731. Carr, J. A. and Silvermann, N., The heparin-protamine interaction, A review. J Cardiovasc Surg (Torino), 1999, 40(5), 659–666. Porsche, R. and Brenner, Z. R., Allergy to protamine sulfate. Heart Lung, 1999, 28(6), 418–428. Urdaneta, F., Lobato, E. B. and Kirby, R. R., Noncardiogenic pulmonary edema associated with protamine administration during coronary artery bypass surgery. J Clin Anesth, 1999, 11(8), 675–681. Nashef, S. A. M., Roques, F., Michel, P. EuroSCORE study group, European System for Cardiac Operative Risk Evaluation (EuroSCORE). Eur J Cardio-thorac Surg, 1999, 16, 9–13. Kirklin, J. W. and Barratt-Boyes, B. G. Cardiac surgery: morphology, diagnostic criteria, natural history, techniques, results, and indications, part I Churchill Livingstone, New York, 1993(chapter 5, p. 195–248). Arom, K. V., Flavin, T. F. and Emery, R. W., Safety and efficacy of off-pump coronary artery bypass grafting. Ann Thorac Surg, 2000, 69, 704–710. Wakefield, T. W., Bies, L. E. and Wrobleski, S. K., Impaired myocardial function and oxygen utilization due to protamine sulfate in an isolated rabbit heart preparation. Ann Surg, 1990, 212(4), 387–393. Wakefield, T. W., Wrobleski, S. K. and Nichol, B. J., Heparinmediated reductions of the toxic effects of protamine sulfate on rabbit myocardium. J Vasc Surg, 1992, 16(1), 47–53. Katircioglu, S. F., Saritas, Z. and Ulus, A. T., Comparison of the effects of enoximone and isoproterenol on protamine cardiotoxicity in anesthetized dogs. Jpn Circ J, 1998, 62(2), 122–126. Katircioglu, S. F., Ulus, A. T. and Yamak, B., Experimental

249

Heparin reversal in off-pump coronary artery bypass surgery: G. Gatti and P. Pugliese inhibition of protamine cardiotoxicity by prostacyclin. Angiology, 1999, 50(11), 929–935. 19. Kresowik, T. F., Wakefield, T. W. and Fessler, R. D. II, Anticoagulant effects of protamine sulfate in a canine model. J Surg Res, 1988, 45(1), 8–14. 20. Mochizuki, T., Olson, P. J. and Szlam, F., Protamine reversal of heparin affects platelet aggregation and activated clotting time after cardiopulmonary bypass. Anesth Analg, 1998, 87(4), 781– 785.

250

21. Shigeta, O., Kojima, H. and Hiramatsu, Y., Low-dose protamine based on heparin-protamine titration method reduces platelet dysfunction after cardiopulmonary bypass. J Thorac Cardiovasc Surg, 1999, 118(2), 354–360. 22. Spiess, B. D., Ischemia—a coagulation problem? J Cardiovasc Pharmacol, 1996, 27(Suppl 1), S38–S41. Paper accepted 28 November 2001

CARDIOVASCULAR SURGERY

JUNE 2002 VOL 10 NO 3