- Email: [email protected]
Prostacyclin Reduces Incidence of Myocardial Damage After Coronary Endarterectomy
Z˘ivojin S. Jonjev, MD, Svetozar Nic´in, MD, Vujadin Mujovic´, MD, Ljuborad Petrovic´, MD, and Ninoslav Radovanovic´, MD Institute of Cardiovascular Diseases, University of Novi Sad, Sremska Kamenica, Yugoslavia, Institute of Physiology, University of Belgrade, Belgrade, Yugoslavia, and Division of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, Missouri
Background. After coronary endarterectomy, patients have an increased incidence of perioperative myocardial infarction. This study was undertaken to evaluate the possible reduction of perioperative myocardial damage after coronary endarterectomy by intravenous utilization of prostacyclin. Methods. Elective coronary artery bypass grafting was performed in 1,190 patients with diffuse and distal coronary artery disease, in whom endarterectomy of one or more vessels was used as a treatment. All procedures were done with cardiopulmonary bypass. There were 584 patients in the prostacyclin-treated group, and 606 patients in the control group. Prostacyclin (10 ng · kgⴚ1 · minⴚ1) was started 20 minutes before the cross-clamp removal, or at the time of rewarming, and was continued during the
first 24 hours after surgery. The incidence of perioperative myocardial damage was detected by creatine kinase-MB enzyme measurement, and electrocardiographic and left ventricular function changes. Results. A significant decrease in perioperative myocardial damage was detected in the group treated with prostacyclin with respect to the control group. Conclusions. Prostacyclin infusion initiated during revascularization and continued in the early postoperative course could be successfully employed for the prevention of thrombocyte aggregation and potentially decrease the overall incidence of significant myocardial damage after coronary endarterectomy. (Ann Thorac Surg 2004;78:1299 –303) © 2004 by The Society of Thoracic Surgeons
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niques for both right and left coronary artery [4], extensive and total endarterectomies become acceptable options for this group of patients. The worldwide reported incidence of perioperative myocardial infarction after coronary endarterectomy ranges from 4.9% to 13.1% [5–9]. Even our initial postoperative results were at a level similar to related reports, we believed that the incidence of overall postoperative myocardial damage after multiple coronary endarterectomy in our institution remained relatively high (11.61%). Prostacyclin (prostaglandin PGI2; epoprostenol) is a naturally occurring substance in all vascular tissues that have been examined. It is synthesized by the vascular endothelium from arachidonic acid and represents the most potent endogenous inhibitor of platelet aggregation thus far discovered [10, 11]. Prostacyclin has a very short biodegradation half time (t1⁄2 ⫽ 3 minutes at 37°C) [11, 12]. It has several physiologic functions (platelet inhibitory effect, cytoprotection, vasodilation, antiinflammation, and so forth), but many of them are still under investigation. Our previous study emphasized that PGI2 and thromboxane A2 imbalance might have a key role in the local control of vascular functions against vasospasm and unwanted coagulation of the blood [13]. In this study, we tested the hypothesis (based on prostacyclin’s cytoprotective and antiaggregatory effect) that intraoperative and perioperative administration of prostacyclin could be beneficial for patients who underwent CABG with coronary endarterectomy.
oronary arteries with diffuse and distal atherosclerotic plaques are traditionally described as “nongraftable arteries” [1]. Thus, when a patient presents in the advanced stages of coronary arteriosclerosis, cardiac surgeons have only two possible options. The first option is to declare the affected arteries inoperable, to continue with medical treatment, and to determine that patient’s candidacy for heart transplantation. The second option is to perform endarterectomy of the coronary arteries with or without coronary artery bypass grafting (CABG). The first option, heart transplantation, is wrought with many problems such as long waiting lists, very limited available donors, and associated high costs. Although CABG has long been a standard procedure, CABG with endarterectomy is one of the most controversial procedures in cardiac surgery. High technical demands, long duration of the procedure, and consequent increased perioperative morbidity and mortality are arguments that discourage the use of coronary endarterectomy [2]. The number of patients with diffuse and distal coronary artery disease is high, and despite improved primary health care is still increasing [3]. Encouraged with rapid progress in the development of operative techAccepted for publication Feb 23, 2004. Address reprint requests to Dr Jonjev, University of Novi Sad, School of Medicine, Institute of Cardiovascular Diseases, University Clinic of Cardiovascular Surgery, Institutski put 4, 21204 Sremska Kamenica, Serbia and Montenegro, Yugoslavia; e-mail: [email protected].
© 2004 by The Society of Thoracic Surgeons Published by Elsevier Inc
0003-4975/04/$30.00 doi:10.1016/j.athoracsur.2004.02.132
CARDIOVASCULAR
Prostacyclin Reduces Incidence of Myocardial Damage After Coronary Endarterectomy
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JONJEV ET AL PROSTACYCLIN AND CORONARY ENDARTERECTOMY
Ann Thorac Surg 2004;78:1299 –303
Table 1. Preoperative Characteristics of Patients With Endarterectomy
CARDIOVASCULAR
Variable
Patients Without Prostacyclin (n ⫽ 606)
Patients With Prostacyclin (n ⫽ 584)
55.8 ⫾ 6.2
58.1 ⫾ 5.8
515 (84.98%) 91 (15.02%)
485 (83.05%) 99 (16.95%)
338 (55.77%) 341 (56.27%) 410 (67.65%) 356 (58.74%) 262 (43.23%) 391 (64.52%) 421 (69.47%)
314 (53.76%) 321 (54.96%) 355 (60.78%) 348 (59.58%) 233 (39.89%) 368 (63.01%) 389 (66.61%)
40.3% 47 (7.76%) 215 (35.47%) 344 (56.77%) 52 (8.58%)
42.0% 56 (9.58%) 194 (33.21%) 334 (57.21%) 61 (10.44%)
Age (years) Sex Male Female Risk factors Diabetes Hypertension Hyperlipidemia Smoking history Family history Unstable angina Previous myocardial infarction Ejection fraction Single-vessel disease Double-vessel disease Triple-vessel disease Left-main disease
Material and Methods The study was approved by the Institutional Ethical and Scientific Committee. All patients included in this randomized, prospective study underwent elective surgery between March 30, 1994, and July 15, 1999. All procedures were done by the same surgical team. The inclusion criteria were presence of diffuse and distal coronary artery disease with at least one coronary endarterectomy at the time of surgery. A total of 1,190 patients was randomly assigned to one of the groups (PGI2 or control group) at the time of surgery by the research coordinator. His decision was strictly independent, and was based on the “coin toss” rule. There were 584 patients in the prostacyclin-treated group in which endarterectomy of one or multiple vessels was performed with prostacyclin treatment. Patients who underwent endarterectomy without prostacyclin treatment (n ⫽ 606) were used as a control group. Preoperative characteristics of the patients are described in Table 1.
Fig 1. Protocol for myocardial protection during open-heart surgical procedures. The procedure is based on the physiologic approach to cardioprotection, owing to adjustment of recovery of the “steady state” during cardiopulmonary bypass. In addition to catecholamine and nitroglycerin, prostacyclin was added to the protocol to achieve inotropic, vasodilatory, cytoprotective, and antiaggregatory effect. (Ao ⫽ aorta; BW ⫽ body weight; Ca ⫽ calcium; ECC ⫽ extracorporeal circulation; H ⫽ hours; Hc ⫽ hematocrit; min ⫽ minutes; POSTOP. ⫽ postoperative; T ⫽ temperature.)
dopamine and the vasodilatory effect of nitroglycerin, prostacyclin was added to the protocol for its cytoprotective and antiaggregatory effects [11, 14 –19]. In these CABG procedures where endarterectomy was used as a method, the protocol described in Figure 2 was used for antiaggregatory and anticoagulant therapy. Heparin was started after opening the pericardial sac (3 mg/kg), and was neutralized with protamine at the end of extracorporeal circulation in a 1:1 ratio. Sodium epoprostenol (prostacyclin) was dissolved in a glycin buffer (pH 10.2 to 10.8; Flolan-Glaxo Welcome, Research Triangle Park, NC), and initiated 10 to 15 minutes before the removal of the cross clamp, or at the time of rewarming. The dose of prostacyclin was 10 ng · kg⫺1 · min⫺1, and was continued as an intravenous infusion for the first 24 hours after surgery. Heparin was usually started 24 hours
Operative Technique Cardioplegic arrest, standard cardiopulmonary bypass, moderate systemic hypothermia (28°C to 30°C), and hemodilution, were used as a routine approach in this study. Myocardial protection was achieved using intermittent administration of cold (4°C) crystalloid St. Thomas no. 2 cardioplegia, and topical cooling of the heart. To achieve better myocardial recovery after cardioplegic arrest, the protocol described in Figure 1 was used for myocardial protection during surgery. This procedure is based on the physiologic approach to cardioprotection, owing to adjustment of recovery of the steady state during cardiopulmonary bypass. To supplement the inotropic effects of digoxin, catecholamines, and
Fig 2. Protocol for antiaggregatory and anticoagulation therapy for endarterectomized coronary patients. Heparin was started after opening the pericardial sac and was neutralized with protamine at the end of extracorporeal circulation in a 1:1 ratio. Prostacyclin infusion was started 10 to 15 minutes before the removal of the cross clamp, or at the time of rewarming. Prostacyclin infusion was continued for the first 24 hours after operation. Heparin was usually started 24 hours after the surgery, and was replaced with coumadin after the normalization of the thrombin and partial thromboplastin time. (BW ⫽ body weight; ECC ⫽ extracorporeal circulation; h ⫽ hours; min ⫽ minutes.)
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before surgery. Serum CK-MB enzyme levels were measured routinely every 4 hours during the first 24 hours after surgery. The criteria for defining postoperative myocardial infarction included the presence of new Q wave worsening of two grades (according to the Minnesota Code), elevation of serum CK-MB enzyme five times the upper limits of normal, or new left ventricular wall motion abnormalities diagnosed with postoperative nuclear ventriculography or echocardiography [5, 20 –22].
Statistics
Fig 3. Endarterectomized core after triple coronary endarterectomy.
after the operation, and was replaced with coumadin after the normalization of the thrombin and partial thromboplastin time. The endarterectomy was performed by closed and manual operative technique in all cases. The endarterectomized segments were between 3.5 and 15 cm in length, and were evacuated from the vessels by blunt dissection (Fig 3). If the distal portion of segment appeared incomplete, an additional small arteriotomy was made to complete coronary endarterectomy. Most of the anastomosis was closed without patching, and grafts were routinely flushed with cold crystalloid cardioplegic solution to evaluate distal runoff. In most cases, a skeletonized left internal thoracic artery was used for revascularization of the left anterior descending artery or first diagonal artery, and saphenous vein grafts were used for other coronary targets. The 12-lead electrocardiogram, creatine kinase-MB (CK-MB) enzyme, left ventricular wall motion, and left ventricular ejection fraction were measured at baseline,
All data are presented as means ⫾ SEM. Survival data were analyzed by the z test. The CK-MB data were analyzed by two-way analysis of variance (ANOVA). A p value less than 0.05 was considered significant for all comparisons.
Results Postoperative mortality during the immediate 30 postoperative days was 2.22% in the investigated group and 4.63% in the control group. Total postoperative mortality was 3.44%. The main cause of death was cardiac, followed by respiratory, renal, and cerebral causes (Table 2). Lower levels of serum CK-MB enzyme were detected in prostacyclin group. That phenomena was found to be significant during the first 24 hours after surgery in prostacyclin group, compared with the control group (Fig 4). Lower incidence of significant electrocardiogram changes and new left ventricular wall abnormalities were also detected in prostacyclin group. There were no major differences in the mean cross clamp time (PGI2 ⫽ 64.7 ⫾ 18 versus control ⫽ 67 ⫾ 11 minute), mean total bypass time (PGI2 ⫽ 92.4 ⫾ 16 versus control ⫽ 97 ⫾ 13 minutes), and mean number of grafts (PGI2 ⫽ 2.5 ⫾ 0.37 versus control ⫽ 2.6 ⫾ 0.29 per patient) between the PGI2 and the control groups.
Table 2. Postoperative Morbidity and Mortality Among Patients With Endarterectomy Variable Postoperative mortality (30 days) Causes of death Cardiac Respiratory Renal Cerebral Postoperative nonlethal complications Bleeding revision Presternal infection Rhythmic disturbances Perioperative myocardial infarction (MI) Single endarterectomy Double endaterectomy Triple endaterectomy Overall incidence of perioperative MI NS ⫽ not significant.
Patients Without Prostacyclin (n ⫽ 606)
Patients With Prostacyclin (n ⫽ 584)
p ⬍ Value
28 (4.63%)
13 (2.22%)
⬍0.001
20/28 (71.42%) 3/28 (10.72%) 3/28 (10.72%) 2/28 (7.14%)
8/13 (61.53%) 2/13 (15.38%) 1/13 (7.71%) 2/13 (15.38%)
⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001
24 (3.96%) 16 (2.64%) 57 (9.4%)
25 (4.28%) 17 (2.91%) 51 (8.73%)
NS NS NS
26/394 (6.59%) 10/81 (12.34%) 19/131 (14.50%) 55/606 (9.07%)
12/382 (3.14%) 5/73 (6.84%) 11/129 (8.52%) 28/584 (4.79%)
⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001
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CARDIOVASCULAR Fig 4. Release of creatine kinase-MB (CK-MB) isozyme over time in endarterectomized patients after surgery. Significantly lower levels of CK-MB isozyme in the prostacyclin group (triangles) suggested a possible lower level of myofilament degradation during cardioplegic arrest. Circles ⫽ control group. *Value of p for time (p ⬍ 0.001). †Value of p for group interaction (p ⬍ 0.001).
Comment Our perception of the role of eicosanoids in the cardiovascular system changed dramatically in the last 2 decades after the discovery of prostacyclin and thromboxane A2. Several studies indicated that intracoronary platelet aggregation and their release of thromboxane A2 may impede blood flow to the ischemic myocardium with extensive arteriosclerosis after cardioplegic arrest [16, 23]. Supporting the hypothesis that prostacyclin and thromboxane are on opposite sides of the same homeostatic system, it has been suggested that exogenous administration of prostacyclin might be useful in such conditions. The result of this study clearly indicates that prostacyclin infusion initiated 10 to 15 minutes before the removal of the cross clamp and continued during the early postoperative course (24 hours after surgery), could be beneficial for patients who had undergone coronary endarterectomy. In the dose of 10 ng · kg⫺1 · min⫺1, PGI2 significantly decreases postoperative levels of serum CK-MB enzyme between 4 and 20 hours after surgery with respect to the control group. Our data also indicate that lower level of CK-MB enzyme induced by prostacyclin might be associated with lower postoperative morbidity (expressed by the lower incidence of perioperative myocardial infarction) and lower immediate postoperative mortality (30 days) in the PGI2 group compared with the control group. The latest consensus document of the European Society of Cardiology and American College of Cardiology on the redefinition of perioperative myocardial infarction states that any degree of myocardial necrosis after revascularization procedures caused by myocardial ischemia and detected by serum markers should be recognized as an acute myocardial infarction [24]. Thus, elevated CK-MB enzyme turns out to be an early diagnostic indicator for myocardial damage after surgery, and was recently accepted as an independent predictor of early and late outcome after CABG procedures [21, 25]. Most
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patients after CABG surgery have elevation of serum cardiac markers, however, and more data are needed to determine the optimal enzyme cut-point to recognize new perioperative myocardial infarction. Even though the criteria for the definition of perioperative myocardial infarction used in this study are correlated with the criteria used in other relevant clinical trials (GUARDIAN, Minnesota Code), we believe that lower level of CK-MB after PGI2 administration represents a decrease in the extent of perioperative myocardial damage, rather than an indicator of overall perioperative myocardial infarction. Recent investigations indicate that PGI2 could be a useful drug not only after CABG but also for patients with ischemic heart failure, as it does not cause the “coronary steal” syndrome and myocardial ischemia [26, 27]. Prostacyclin has been rarely used as an antiaggregatory and cytoprotective drug postoperatively in cardiac surgery, however, and if used, it was predominantly for to its beneficial effect on pulmonary vasculature after uncomplicated CABG procedures [26, 27]. Arteriosclerosis, CABG procedures, and especially coronary endarterectomies are recognized as conditions with impaired platelet-vessel wall interactions, predisposed to thromboembolic events. Over the last 10 years a number of strategies with some stable prostacyclin analogues have been used to restore the loss of endogenous prostacyclin defense mechanisms in those conditions [12, 15–17, 28, 29]. We hypothesized that the in vivo effect of prostacyclin infusion is underestimated. Our preliminary study with endarterectomized patients suggested that the starting PGI2 dose of 10 ng · kg⫺1 · min⫺1 might be effective in PGI2/thromboxane A2 imbalance correction. We used the same PGI2 dose in this study, and that helped us to observe a significant reduction in postoperative serum CK-MB enzyme (Table 2). The level of CK-MB enzyme was 2 to 2.5 times lower compared with the control group, and was not influenced by the number of endarterectomies. Therefore, our results strongly support those of reports in which the number of endarterectomies is an independent predictor for early and longterm morbidity and mortality [5, 30]. Bergman and associates [17] indicated that infusion of PGI2 or analogues could provoke heart ischemia at rest. Ischemia was demonstrated as chest pain or ST-segment depression on the electrocardiogram. However, at the dose of 10 ng · kg⫺1 · min⫺1, we observed only the occasional side effects of facial flushing, headache, tachycardia, and rarely mild hypotension, but without signs of myocardial ischemia. It is important to say that these results apply to patients who had undergone previously described cardioplegic arrest and cardiopulmonary bypass. This clinical condition is unique, and the results herein cannot be projected to other conditions such as ischemic preconditioning, warm cardioplegic arrest, and off-pump surgery, in which the myocardial enzyme kinetics and distribution are different [31]. In conclusion, our study clearly demonstrated that prostacyclin reduces the level of postoperative CK-MB
enzyme and the incidence of postoperative myocardial damage in patients after coronary endarterectomy. Lower levels of CK-MB might be a result of the possible lower level of ischemic myofilament degradation caused by cardioplegic arrest or of the lower incidence of perioperative myocardial infarction. This phenomenon could be explained by prostacyclin’s cytoprotective effect as an oxygen free-radical scavenger, and PGI2 antiaggregatory effect followed by a lower incidence of postoperative myocardial damage [11, 27]. However, a prospective, randomized case-control study is needed to confirm our hypothesis that PGI2 might be effective for reducing the incidence of perioperative myocardial infarction and overall mortality after CABG procedures.
JONJEV ET AL PROSTACYCLIN AND CORONARY ENDARTERECTOMY
15. 16. 17.
18.
19.
The authors thank Prof Dr Rajko Igiæ, Dr Linda Teplitz, and Marci Bailey for assistance in preparing this manuscript.
20.
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Background. After coronary endarterectomy, patients have an increased incidence of perioperative myocardial infarction. This study was undertaken to evaluate the possible reduction of perioperative myocardial damage after coronary endarterectomy by intravenous utilization of prostacyclin. Methods. Elective coronary artery bypass grafting was performed in 1,190 patients with diffuse and distal coronary artery disease, in whom endarterectomy of one or more vessels was used as a treatment. All procedures were done with cardiopulmonary bypass. There were 584 patients in the prostacyclin-treated group, and 606 patients in the control group. Prostacyclin (10 ng · kgⴚ1 · minⴚ1) was started 20 minutes before the cross-clamp removal, or at the time of rewarming, and was continued during the
first 24 hours after surgery. The incidence of perioperative myocardial damage was detected by creatine kinase-MB enzyme measurement, and electrocardiographic and left ventricular function changes. Results. A significant decrease in perioperative myocardial damage was detected in the group treated with prostacyclin with respect to the control group. Conclusions. Prostacyclin infusion initiated during revascularization and continued in the early postoperative course could be successfully employed for the prevention of thrombocyte aggregation and potentially decrease the overall incidence of significant myocardial damage after coronary endarterectomy. (Ann Thorac Surg 2004;78:1299 –303) © 2004 by The Society of Thoracic Surgeons
C
niques for both right and left coronary artery [4], extensive and total endarterectomies become acceptable options for this group of patients. The worldwide reported incidence of perioperative myocardial infarction after coronary endarterectomy ranges from 4.9% to 13.1% [5–9]. Even our initial postoperative results were at a level similar to related reports, we believed that the incidence of overall postoperative myocardial damage after multiple coronary endarterectomy in our institution remained relatively high (11.61%). Prostacyclin (prostaglandin PGI2; epoprostenol) is a naturally occurring substance in all vascular tissues that have been examined. It is synthesized by the vascular endothelium from arachidonic acid and represents the most potent endogenous inhibitor of platelet aggregation thus far discovered [10, 11]. Prostacyclin has a very short biodegradation half time (t1⁄2 ⫽ 3 minutes at 37°C) [11, 12]. It has several physiologic functions (platelet inhibitory effect, cytoprotection, vasodilation, antiinflammation, and so forth), but many of them are still under investigation. Our previous study emphasized that PGI2 and thromboxane A2 imbalance might have a key role in the local control of vascular functions against vasospasm and unwanted coagulation of the blood [13]. In this study, we tested the hypothesis (based on prostacyclin’s cytoprotective and antiaggregatory effect) that intraoperative and perioperative administration of prostacyclin could be beneficial for patients who underwent CABG with coronary endarterectomy.
oronary arteries with diffuse and distal atherosclerotic plaques are traditionally described as “nongraftable arteries” [1]. Thus, when a patient presents in the advanced stages of coronary arteriosclerosis, cardiac surgeons have only two possible options. The first option is to declare the affected arteries inoperable, to continue with medical treatment, and to determine that patient’s candidacy for heart transplantation. The second option is to perform endarterectomy of the coronary arteries with or without coronary artery bypass grafting (CABG). The first option, heart transplantation, is wrought with many problems such as long waiting lists, very limited available donors, and associated high costs. Although CABG has long been a standard procedure, CABG with endarterectomy is one of the most controversial procedures in cardiac surgery. High technical demands, long duration of the procedure, and consequent increased perioperative morbidity and mortality are arguments that discourage the use of coronary endarterectomy [2]. The number of patients with diffuse and distal coronary artery disease is high, and despite improved primary health care is still increasing [3]. Encouraged with rapid progress in the development of operative techAccepted for publication Feb 23, 2004. Address reprint requests to Dr Jonjev, University of Novi Sad, School of Medicine, Institute of Cardiovascular Diseases, University Clinic of Cardiovascular Surgery, Institutski put 4, 21204 Sremska Kamenica, Serbia and Montenegro, Yugoslavia; e-mail: [email protected].
© 2004 by The Society of Thoracic Surgeons Published by Elsevier Inc
0003-4975/04/$30.00 doi:10.1016/j.athoracsur.2004.02.132
CARDIOVASCULAR
Prostacyclin Reduces Incidence of Myocardial Damage After Coronary Endarterectomy
1300
JONJEV ET AL PROSTACYCLIN AND CORONARY ENDARTERECTOMY
Ann Thorac Surg 2004;78:1299 –303
Table 1. Preoperative Characteristics of Patients With Endarterectomy
CARDIOVASCULAR
Variable
Patients Without Prostacyclin (n ⫽ 606)
Patients With Prostacyclin (n ⫽ 584)
55.8 ⫾ 6.2
58.1 ⫾ 5.8
515 (84.98%) 91 (15.02%)
485 (83.05%) 99 (16.95%)
338 (55.77%) 341 (56.27%) 410 (67.65%) 356 (58.74%) 262 (43.23%) 391 (64.52%) 421 (69.47%)
314 (53.76%) 321 (54.96%) 355 (60.78%) 348 (59.58%) 233 (39.89%) 368 (63.01%) 389 (66.61%)
40.3% 47 (7.76%) 215 (35.47%) 344 (56.77%) 52 (8.58%)
42.0% 56 (9.58%) 194 (33.21%) 334 (57.21%) 61 (10.44%)
Age (years) Sex Male Female Risk factors Diabetes Hypertension Hyperlipidemia Smoking history Family history Unstable angina Previous myocardial infarction Ejection fraction Single-vessel disease Double-vessel disease Triple-vessel disease Left-main disease
Material and Methods The study was approved by the Institutional Ethical and Scientific Committee. All patients included in this randomized, prospective study underwent elective surgery between March 30, 1994, and July 15, 1999. All procedures were done by the same surgical team. The inclusion criteria were presence of diffuse and distal coronary artery disease with at least one coronary endarterectomy at the time of surgery. A total of 1,190 patients was randomly assigned to one of the groups (PGI2 or control group) at the time of surgery by the research coordinator. His decision was strictly independent, and was based on the “coin toss” rule. There were 584 patients in the prostacyclin-treated group in which endarterectomy of one or multiple vessels was performed with prostacyclin treatment. Patients who underwent endarterectomy without prostacyclin treatment (n ⫽ 606) were used as a control group. Preoperative characteristics of the patients are described in Table 1.
Fig 1. Protocol for myocardial protection during open-heart surgical procedures. The procedure is based on the physiologic approach to cardioprotection, owing to adjustment of recovery of the “steady state” during cardiopulmonary bypass. In addition to catecholamine and nitroglycerin, prostacyclin was added to the protocol to achieve inotropic, vasodilatory, cytoprotective, and antiaggregatory effect. (Ao ⫽ aorta; BW ⫽ body weight; Ca ⫽ calcium; ECC ⫽ extracorporeal circulation; H ⫽ hours; Hc ⫽ hematocrit; min ⫽ minutes; POSTOP. ⫽ postoperative; T ⫽ temperature.)
dopamine and the vasodilatory effect of nitroglycerin, prostacyclin was added to the protocol for its cytoprotective and antiaggregatory effects [11, 14 –19]. In these CABG procedures where endarterectomy was used as a method, the protocol described in Figure 2 was used for antiaggregatory and anticoagulant therapy. Heparin was started after opening the pericardial sac (3 mg/kg), and was neutralized with protamine at the end of extracorporeal circulation in a 1:1 ratio. Sodium epoprostenol (prostacyclin) was dissolved in a glycin buffer (pH 10.2 to 10.8; Flolan-Glaxo Welcome, Research Triangle Park, NC), and initiated 10 to 15 minutes before the removal of the cross clamp, or at the time of rewarming. The dose of prostacyclin was 10 ng · kg⫺1 · min⫺1, and was continued as an intravenous infusion for the first 24 hours after surgery. Heparin was usually started 24 hours
Operative Technique Cardioplegic arrest, standard cardiopulmonary bypass, moderate systemic hypothermia (28°C to 30°C), and hemodilution, were used as a routine approach in this study. Myocardial protection was achieved using intermittent administration of cold (4°C) crystalloid St. Thomas no. 2 cardioplegia, and topical cooling of the heart. To achieve better myocardial recovery after cardioplegic arrest, the protocol described in Figure 1 was used for myocardial protection during surgery. This procedure is based on the physiologic approach to cardioprotection, owing to adjustment of recovery of the steady state during cardiopulmonary bypass. To supplement the inotropic effects of digoxin, catecholamines, and
Fig 2. Protocol for antiaggregatory and anticoagulation therapy for endarterectomized coronary patients. Heparin was started after opening the pericardial sac and was neutralized with protamine at the end of extracorporeal circulation in a 1:1 ratio. Prostacyclin infusion was started 10 to 15 minutes before the removal of the cross clamp, or at the time of rewarming. Prostacyclin infusion was continued for the first 24 hours after operation. Heparin was usually started 24 hours after the surgery, and was replaced with coumadin after the normalization of the thrombin and partial thromboplastin time. (BW ⫽ body weight; ECC ⫽ extracorporeal circulation; h ⫽ hours; min ⫽ minutes.)
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before surgery. Serum CK-MB enzyme levels were measured routinely every 4 hours during the first 24 hours after surgery. The criteria for defining postoperative myocardial infarction included the presence of new Q wave worsening of two grades (according to the Minnesota Code), elevation of serum CK-MB enzyme five times the upper limits of normal, or new left ventricular wall motion abnormalities diagnosed with postoperative nuclear ventriculography or echocardiography [5, 20 –22].
Statistics
Fig 3. Endarterectomized core after triple coronary endarterectomy.
after the operation, and was replaced with coumadin after the normalization of the thrombin and partial thromboplastin time. The endarterectomy was performed by closed and manual operative technique in all cases. The endarterectomized segments were between 3.5 and 15 cm in length, and were evacuated from the vessels by blunt dissection (Fig 3). If the distal portion of segment appeared incomplete, an additional small arteriotomy was made to complete coronary endarterectomy. Most of the anastomosis was closed without patching, and grafts were routinely flushed with cold crystalloid cardioplegic solution to evaluate distal runoff. In most cases, a skeletonized left internal thoracic artery was used for revascularization of the left anterior descending artery or first diagonal artery, and saphenous vein grafts were used for other coronary targets. The 12-lead electrocardiogram, creatine kinase-MB (CK-MB) enzyme, left ventricular wall motion, and left ventricular ejection fraction were measured at baseline,
All data are presented as means ⫾ SEM. Survival data were analyzed by the z test. The CK-MB data were analyzed by two-way analysis of variance (ANOVA). A p value less than 0.05 was considered significant for all comparisons.
Results Postoperative mortality during the immediate 30 postoperative days was 2.22% in the investigated group and 4.63% in the control group. Total postoperative mortality was 3.44%. The main cause of death was cardiac, followed by respiratory, renal, and cerebral causes (Table 2). Lower levels of serum CK-MB enzyme were detected in prostacyclin group. That phenomena was found to be significant during the first 24 hours after surgery in prostacyclin group, compared with the control group (Fig 4). Lower incidence of significant electrocardiogram changes and new left ventricular wall abnormalities were also detected in prostacyclin group. There were no major differences in the mean cross clamp time (PGI2 ⫽ 64.7 ⫾ 18 versus control ⫽ 67 ⫾ 11 minute), mean total bypass time (PGI2 ⫽ 92.4 ⫾ 16 versus control ⫽ 97 ⫾ 13 minutes), and mean number of grafts (PGI2 ⫽ 2.5 ⫾ 0.37 versus control ⫽ 2.6 ⫾ 0.29 per patient) between the PGI2 and the control groups.
Table 2. Postoperative Morbidity and Mortality Among Patients With Endarterectomy Variable Postoperative mortality (30 days) Causes of death Cardiac Respiratory Renal Cerebral Postoperative nonlethal complications Bleeding revision Presternal infection Rhythmic disturbances Perioperative myocardial infarction (MI) Single endarterectomy Double endaterectomy Triple endaterectomy Overall incidence of perioperative MI NS ⫽ not significant.
Patients Without Prostacyclin (n ⫽ 606)
Patients With Prostacyclin (n ⫽ 584)
p ⬍ Value
28 (4.63%)
13 (2.22%)
⬍0.001
20/28 (71.42%) 3/28 (10.72%) 3/28 (10.72%) 2/28 (7.14%)
8/13 (61.53%) 2/13 (15.38%) 1/13 (7.71%) 2/13 (15.38%)
⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001
24 (3.96%) 16 (2.64%) 57 (9.4%)
25 (4.28%) 17 (2.91%) 51 (8.73%)
NS NS NS
26/394 (6.59%) 10/81 (12.34%) 19/131 (14.50%) 55/606 (9.07%)
12/382 (3.14%) 5/73 (6.84%) 11/129 (8.52%) 28/584 (4.79%)
⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001
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CARDIOVASCULAR Fig 4. Release of creatine kinase-MB (CK-MB) isozyme over time in endarterectomized patients after surgery. Significantly lower levels of CK-MB isozyme in the prostacyclin group (triangles) suggested a possible lower level of myofilament degradation during cardioplegic arrest. Circles ⫽ control group. *Value of p for time (p ⬍ 0.001). †Value of p for group interaction (p ⬍ 0.001).
Comment Our perception of the role of eicosanoids in the cardiovascular system changed dramatically in the last 2 decades after the discovery of prostacyclin and thromboxane A2. Several studies indicated that intracoronary platelet aggregation and their release of thromboxane A2 may impede blood flow to the ischemic myocardium with extensive arteriosclerosis after cardioplegic arrest [16, 23]. Supporting the hypothesis that prostacyclin and thromboxane are on opposite sides of the same homeostatic system, it has been suggested that exogenous administration of prostacyclin might be useful in such conditions. The result of this study clearly indicates that prostacyclin infusion initiated 10 to 15 minutes before the removal of the cross clamp and continued during the early postoperative course (24 hours after surgery), could be beneficial for patients who had undergone coronary endarterectomy. In the dose of 10 ng · kg⫺1 · min⫺1, PGI2 significantly decreases postoperative levels of serum CK-MB enzyme between 4 and 20 hours after surgery with respect to the control group. Our data also indicate that lower level of CK-MB enzyme induced by prostacyclin might be associated with lower postoperative morbidity (expressed by the lower incidence of perioperative myocardial infarction) and lower immediate postoperative mortality (30 days) in the PGI2 group compared with the control group. The latest consensus document of the European Society of Cardiology and American College of Cardiology on the redefinition of perioperative myocardial infarction states that any degree of myocardial necrosis after revascularization procedures caused by myocardial ischemia and detected by serum markers should be recognized as an acute myocardial infarction [24]. Thus, elevated CK-MB enzyme turns out to be an early diagnostic indicator for myocardial damage after surgery, and was recently accepted as an independent predictor of early and late outcome after CABG procedures [21, 25]. Most
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patients after CABG surgery have elevation of serum cardiac markers, however, and more data are needed to determine the optimal enzyme cut-point to recognize new perioperative myocardial infarction. Even though the criteria for the definition of perioperative myocardial infarction used in this study are correlated with the criteria used in other relevant clinical trials (GUARDIAN, Minnesota Code), we believe that lower level of CK-MB after PGI2 administration represents a decrease in the extent of perioperative myocardial damage, rather than an indicator of overall perioperative myocardial infarction. Recent investigations indicate that PGI2 could be a useful drug not only after CABG but also for patients with ischemic heart failure, as it does not cause the “coronary steal” syndrome and myocardial ischemia [26, 27]. Prostacyclin has been rarely used as an antiaggregatory and cytoprotective drug postoperatively in cardiac surgery, however, and if used, it was predominantly for to its beneficial effect on pulmonary vasculature after uncomplicated CABG procedures [26, 27]. Arteriosclerosis, CABG procedures, and especially coronary endarterectomies are recognized as conditions with impaired platelet-vessel wall interactions, predisposed to thromboembolic events. Over the last 10 years a number of strategies with some stable prostacyclin analogues have been used to restore the loss of endogenous prostacyclin defense mechanisms in those conditions [12, 15–17, 28, 29]. We hypothesized that the in vivo effect of prostacyclin infusion is underestimated. Our preliminary study with endarterectomized patients suggested that the starting PGI2 dose of 10 ng · kg⫺1 · min⫺1 might be effective in PGI2/thromboxane A2 imbalance correction. We used the same PGI2 dose in this study, and that helped us to observe a significant reduction in postoperative serum CK-MB enzyme (Table 2). The level of CK-MB enzyme was 2 to 2.5 times lower compared with the control group, and was not influenced by the number of endarterectomies. Therefore, our results strongly support those of reports in which the number of endarterectomies is an independent predictor for early and longterm morbidity and mortality [5, 30]. Bergman and associates [17] indicated that infusion of PGI2 or analogues could provoke heart ischemia at rest. Ischemia was demonstrated as chest pain or ST-segment depression on the electrocardiogram. However, at the dose of 10 ng · kg⫺1 · min⫺1, we observed only the occasional side effects of facial flushing, headache, tachycardia, and rarely mild hypotension, but without signs of myocardial ischemia. It is important to say that these results apply to patients who had undergone previously described cardioplegic arrest and cardiopulmonary bypass. This clinical condition is unique, and the results herein cannot be projected to other conditions such as ischemic preconditioning, warm cardioplegic arrest, and off-pump surgery, in which the myocardial enzyme kinetics and distribution are different [31]. In conclusion, our study clearly demonstrated that prostacyclin reduces the level of postoperative CK-MB
enzyme and the incidence of postoperative myocardial damage in patients after coronary endarterectomy. Lower levels of CK-MB might be a result of the possible lower level of ischemic myofilament degradation caused by cardioplegic arrest or of the lower incidence of perioperative myocardial infarction. This phenomenon could be explained by prostacyclin’s cytoprotective effect as an oxygen free-radical scavenger, and PGI2 antiaggregatory effect followed by a lower incidence of postoperative myocardial damage [11, 27]. However, a prospective, randomized case-control study is needed to confirm our hypothesis that PGI2 might be effective for reducing the incidence of perioperative myocardial infarction and overall mortality after CABG procedures.
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15. 16. 17.
18.
19.
The authors thank Prof Dr Rajko Igiæ, Dr Linda Teplitz, and Marci Bailey for assistance in preparing this manuscript.
20.
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