Asian Cardiovasc Thorac Ann 2008;16:396-400
© 2008 Asia Publishing EXchange Ltd
Verapamil and Nitroglycerin Improves the Patency Rate of Radial Artery Grafts
Tomoya Yoshizaki, MD,
Noriyuki Tabuchi, MD,
Masaaki Toyama, MD1
Department of Cardiovascular Surgery, Yokohama City Minato Red Cross Hospital, Yokohama
1 Department of Cardiovascular Surgery, Kameda Medical Center, Chiba, Japan
For reprint information contact: Tomoya Yoshizaki, MD, Tel: 81 45 628 6100, Fax: 81 45 628 6101, Email: yoshizaki.tsrg{at}yokohama.jrc.or.jp, Department of Cardiovascular Surgery, Yokohama City Minato Red Cross Hospital, 3-12-1 Shinyamashita, Naka-ku, Yokohama 231-8682, Japan.
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ABSTRACT
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The best way to prevent spasm of the radial artery is still under investigation. We retrospectively compared the effectiveness of topical verapamil-nitroglycerin with papaverine in preventing graft spasm in 215 patients who underwent isolated conventional coronary artery bypass using a radial artery. Postoperative angiographic data were successfully collected in 116 patients. Perioperative radial artery graft spasm was observed in 2 patients in the papaverine group and 1 in the verapamil-nitroglycerin group; this difference was not considered significant. Complete or functional occlusion was detected by postoperative angiography in 13 grafts (10 in the papaverine group and 3 in the verapamil-nitroglycerin group). Multivariate regression analysis revealed that topical papaverine and grafting to the right coronary artery significantly increased the rate of occlusion of radial artery grafts. Although further studies are needed, our data support the view that topical verapamil-nitroglycerin reduces the incidence of radial artery graft occlusion.
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INTRODUCTION
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The radial artery (RA) has become the most popular arterial graft after the internal mammary artery.1 The successful revival of RA grafting by Acar and colleagues2 has been attributed to improvements in harvesting techniques and antispasmodic agents. Prevention of perioperative graft spasm is crucial for good patency. Not only a spastic property of the thick muscular wall but also enhanced reactivity to vasoactive mediators are important factors in RA graft spasm.3,4 Initially, the antispasmodic treatment used most often was a combination of systemic diltiazem and topical papaverine. However, the superiority of verapamil-nitroglycerin (VG) as a topical vasorelaxing agent was shown in an ex-vivo model by He and Yang5, where rapid and long-lasting relaxation of the artery was achieved, as well as preservation of endothelial function.6 Thus we modified our protocol to include VG solution. The purpose of this study was to retrospectively analyze our experience with patients who had undergone conventional coronary artery bypass grafting (CABG) to determine whether topical VG solution increased the patency rate of RA grafts compared to papaverine.
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PATIENTS AND METHODS
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There were 215 patients who underwent isolated conventional CABG using the RA between 1996 and 2001 at Kameda Medical Center; 6 who had off-pump CABG were excluded. The RA was not used if the patient had renal dysfunction or a positive Allen test. In 97 consecutive patients (group P), papaverine was applied to the RA as a topical vasodilator in combination with systemic diltiazem (0.8 µg·kg–1·min–1). In another 118 consecutive patients (group VG), topical VG solution combined with a systemic drip of verapamil (0.5 mg·h–1) was used. The preoperative characteristics were similar in both groups, except for the incidence of emergency cases and hyperlipidemia (Table 1
). VG solution contained verapamil hydrochloride 5 mg, nitroglycerin 2.5 mg, heparin 500 units, and 0.2 mL of 8.4% NaHCO3 in 300 mL Ringer’s solution.5 No blood was used to dilute or buffer papaverine or VG solution. The operation was carried out by the same group of surgeons using the same techniques, and no other technical modifications occurred during this period. Operative procedures were identical in both groups (Table 2). The distribution and severity of stenosis in native target arteries were also similar in both groups (Table 3).
The RA was removed immediately after dissection and after giving 3,000 IU of heparin. A skin incision was made from the wrist to the mid antecubital fossa. The RA was carefully mobilized with its accompanying veins and connective tissue, using a combination of low-power electrocautery and sharp dissection. The RA branches were identified, clamped with small hemoclips, and divided just distal to the accompanying veins. Papaverine or VG solution was used topically during harvesting to bathe the RA. After harvesting, the RA graft was gently irrigated and immersed in papaverine or VG solution until used for grafting. All CABG operations were performed under cardiopulmonary bypass. Grafting varied according to the surgeon’s preference, but the most common patterns were left internal mammary artery to left anterior descending artery, gastroepiploic artery to distal right coronary artery, and RA to branches of the circumflex artery or main trunk of the right coronary artery (RCA); RA targets were primarily the circumflex artery and RCA. The most proximal RA graft anastomosis was performed directly to the ascending aorta. When patients were transferred to the intensive care unit after the operation, diltiazem was substituted for verapamil. For 4 days immediately after the operation, diltiazem (1 µg·kg–1·min–1) was given systemically to both groups. Systematic use of verapamil after the operation could not be maintained because of frequent episodes of bradycardia. From the 5th postoperative day, oral diltiazem (240 mg daily) was given.
All data were collected retrospectively. Patients were followed up at the outpatient clinic or by their cardiologists. Any additional information pertinent to this research was obtained by telephoning the patients or their referring cardiologists. The mean follow-up period was 4.2 ± 1.1 years in group P and 2.3 ± 1.0 years in group VG. All patients were advised to have coronary angiography 1 year after the operation; however, angiograms were performed in only 55 patients in group P within 17.2 ± 13.3 months postoperatively, and in 61 in group VG within 13.1 ± 10.0 months of the operation.
Results are expressed as mean ± standard deviation. Statistical analysis was performed with Mann-Whitney’s nonparametric test and multivariate regression analysis. A p value < 0.05 was considered significant. Statistical analysis was performed using SPSS 11.5 software (SPSS Inc, Chicago, IL, USA).
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RESULTS
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There was 1 case of perioperative myocardial infarction (new Q waves in 2 or more contiguous electrocardiograph leads or peak creatine kinase-MB > 100 U·L–1) in group VG, despite patent grafts on postoperative coronary angiography. Perioperative RA spasm was identified in 3 patients (2 in group P, 1 in group VG). Otherwise, good graft flow with a good flow pattern was observed just after completing the anastomoses. In 1 patient in group P, temporary spasm of the RA was observed shortly after terminating cardiopulmonary bypass, with accompanying hemodynamic deterioration. Radial artery spasm was recognized by a sudden change of flow measured by an electromagnetic flowmeter and loss of arterial pulsation in the graft. After insertion of an intraaortic balloon pump, the RA spasm disappeared and hemodynamics stabilized. In another 2 patients, sudden hemodynamic collapse occurred 2 hours after the operation; emergency coronary angiography revealed graft spasm over the whole length of the RA graft. Hemodynamics were stabilized with an intraaortic balloon pump. Of these 3 patients, occlusion of the RA graft was observed at follow-up angiography in only 1 in group P, whereas the RA grafts were fully patent in the other 2. The prevalence of RA spasm was analyzed by multivariate regression analysis of 8 factors: use of topical medication (papaverine), site of grafting (RCA area), severity of stenosis (< 75%) in the native coronary artery, heart failure (NYHA 
2), diabetes mellitus, hypertension, hyperlipidemia and smoking; none had a significant influence on the prevalence of RA graft spasm.
Of 189 (88%) patients who were followed up for more than 2 years, 8 died, but none of the deaths was related to a cardiac event. Coronary angiography was performed in 116 patients (55 in group P, 61 in group VG) as part of the routine follow-up, except for 1 in group P who experienced a new onset of angina. Radial artery graft occlusion was observed in 13 grafts (11.2%; 10 in group P, 3 in group VG). Nonfunctioning grafts, defined as showing severe narrowing along the total length of the graft (string sign), were categorized as occluded. The prevalence of RA graft occlusion was analyzed by multivariate regression analysis including: use of topical medication (papaverine), site of graft (RCA area), severity of stenosis (< 75%) in the native coronary artery, heart failure (NYHA 2), diabetes mellitus, hypertension, hyperlipidemia and smoking. Two factors, topical papaverine (odds ratio, 4.55; p = 0.037) and RCA grafting (odds ratio, 3.71; p = 0.041), significantly increased the rate of RA graft occlusion.
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DISCUSSION
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Better patency of RA grafts was achieved with topical use of verapamil and nitroglycerin than with papaverine. This was confirmed by angiography more than a year after the operation, although clinical recognition of RA graft spasm during the perioperative period was not statistically different between the 2 drug combinations. In our experience, RA graft spasm in the perioperative period was often temporary and reversible. It is not clear from the results when occlusion took place in the 13 occluded grafts, but it has been suggested that RA reactivity is maximal within days of the operation, so it can be speculated that graft spasm might take place shortly after the operation, without any clinical signs.7 During this period, injury to endothelial cells in RA graft by papaverine might promote thrombosis of the graft.8,9 It is important to note that reversible spasm could take place more frequently than thought, and only spasms in important grafts carrying blood to critical areas might be recognized by unstable hemodynamics.
The RA is a thick-walled and predominantly muscular artery, in contrast to the internal mammary artery that is composed of more elastic components.10 The spastic character of the RA can also be attributed to its enhanced reactivity to vasoactive mediators such as endothelin I, angiotensin II, norepinephrine, serotonin and thromboxane A2.3 Although the most commonly used vasodilator for arterial grafts is papaverine, its limitations include an insufficient anti-spastic property and potential injury to the endothelium.7,8 Consequently, impaired endothelium due to papaverine could promote thrombosis and reduce endothelial-dependent relaxation. Several topical preparations designed to reduce RA graft vasospasm have been investigated. Calcium channel blockers, VG solution, phenoxybenzamine, and a phosphodiesterase inhibitor are all in clinical use as topical RA antispasmodic agents.2,5,11–14
An ex-vivo study has clearly shown the character and duration of action of each anti-spastic agent.15 The antispasmodic effect of papaverine was found to be limited to approximately 1 hour, whereas VG solution prevented vasoconstriction mediated by most contractile agonists and was effective for 5 hours. An in-vivo study has shown that phenoxybenzamine has a much longer vasorelaxing effect, up to 16 hours; but it has little action on vasoconstriction caused by noncatecholamine vasoactive mediaters.16 In the clinical setting, phenoxybenzamine reduced myocardial injury and perioperative adverse cardiac events more than VG solution, although an angiographic study was not conducted.17 Further investigation is needed in this regard. Because repeated application is not possible after chest closure and the vasoreactiviness of the RA is maximal early after the operation, the antispasmodic property of this agent and its duration are important.18 The best combination treatment remains to be established. Papaverine used instead of VG solution as a topical vasodilator was one factor that may have led to RA graft occlusion in this study. Papaverine is an acidic solution, so it damages endothelium and causes loss of viability of endothelial cells.6,8,9 When endothelium is impaired, it promotes clot formation and induces abnormal proliferation of endothelial cells, leading to graft occlusion. These drawbacks may account for the superior results with VG solution.
As shown in this study, grafting to the RCA area may promote RA graft occlusion. Competitive flow through abundant collateral arteries via the circumflex coronary system has been suggested as a cause of spasm in this muscular arterial conduit.19 Alternatively, competitive flow through a native coronary artery with moderate stenosis is more frequently reported as a cause of RA graft occlusion.19,20 Although we could not detect any influence of native competitive flow, VG treatment of the RA graft might have protected it from spasm, and further studies are needed in this regard.
This was a nonrandomized retrospective study and limitations include the lack of follow-up angiography in nearly half of the patients. In the clinical setting, it is quite difficult to study the efficacy of antispasmodic agents because RA spasm is often reversible, temporary, and possibly subclinical. No factor associated with RA graft spasm was identified in this study, possibly due to the small number (3) of perioperative RA spasms in our patients. Therefore, analysis of data from a larger population is important. Although it warrants further investigation, the superiority of verapamil-nitroglycerin over papaverine is suggested by these results.
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ABSTRACT
INTRODUCTION
