Effects of Papaverine and Glycerilnitrate-Verapamil Solution as Topical and Intraluminal Vasodilators for Internal Thoracic Artery

Transcription

1 Effects of Papaverine and Glycerilnitrate-Verapamil Solution as Topical and Intraluminal Vasodilators for Internal Thoracic Artery Francesco Formica, MD, Orazio Ferro, MD, Matteo Brustia, MD, Fabrizio Corti, MD, Luisa Colagrande, MD, PhD, Enrica Bosisio, MD, and Giovanni Paolini, MD, PhD Cardiac Surgery Clinic, Department of Surgical Science and Intensive Care, University of Milan-Bicocca, San Gerardo Hospital, Monza (Milan), Italy Background. Arterial spasm is described as an event occurring after left internal thoracic artery (LITA) harvesting. Many vasodilators have been used to treat or prevent LITA spasm. The aim of this study is to compare the effects between glyceril-trinitrate/verapamil (GV) solution and papaverine to treat LITA spasm and to determine the best delivery method. Methods. One hundred consecutive ischemic patients were randomly assigned to three groups: group GV (n 34, GV solution), group P (n 33, papaverine), or group C(n 33, normal saline). In each patient, pedicled LITA was harvested, thereafter sprayed with the randomized solution, and covered with a sponge. Fifteen minutes after heparin administration, LITA was distally divided; flow per minute was calculated after measuring the free flow for over 15 seconds; this is named topical free flow. Then, the vasodilator was injected intraluminally and free flow per minute was measured; this is called intraluminal free flow. Results. Analysis of variance was applied to detect differences among groups; paired-sample t test was used for LITA topical free flow versus intraluminal free flow within single groups. Mean LITA free flows were as follows: group GV, topical free flow ml/min versus intraluminal free flow ml/ min (p < ); group P, topical free flow ml/min versus intraluminal free flow ml/min (p < ); group C, topical free flow ml/min versus intraluminal free flow ml/min (p 0.14). Topical free flow difference among the three groups was not statistically significant (p 0.1); intraluminal free flow difference was statistically significant (p 0.001). Intraluminal free flow in group GV and in group P were higher than intraluminal free flow in group C (p and 0.001, respectively). Intraluminal free flow of group P was higher than that of group GV; this difference did not reach statistical significance (p 1.00). Conclusions. Glyceril-trinitrate/verapamil solution and papaverine are able to treat the spasm and increase the flow of the LITA, when they are used intraluminally. When used topically, these vasodilator agents do not ensure an optimal free flow. (Ann Thorac Surg 2006;81:120 4) 2006 by The Society of Thoracic Surgeons The internal thoracic artery (ITA) is considered worldwide the first conduit of choice for coronary artery bypass grafting (CABG). Many reports describe its superior patency compared with saphenous vein graft [1 4]. This has encouraged many surgeons to use other arterial conduits, such as radial artery [5 8], right gastroepiploic artery [9 11], inferior epigastric artery [12, 13], and descending branch of lateral femoral artery [14, 15]. Left ITA (LITA) graft on the left anterior descending artery is now the gold standard of CABG operation. Nevertheless, perioperative spasm of ITA, with consequent low free flow, has been described [16, 17] and held responsible for perioperative and postoperative morbidity. It is reported that surgical harvesting of the ITA leads to arterial spasm [18, 19]; therefore, several antispasmodic agents, such as Accepted for publication June 10, Address correspondence to Dr Formica, Clinica Cardiochirurgia, Ospedale San Gerardo, Via Donizetti 106, Monza (Milan) 20052, Italy; francesco_formica@fastwebnet.it. papaverine [20 23], calcium-channel blockers [24, 25] sodium nitroprusside [26], nitroglycerine [24, 27], milrinone [27, 28], and phenoxibenzamine [25, 29], have been studied, compared, and used both topically and intraluminally to treat the perioperative spasm of the arterial conduits. Papaverine is a phosphodiesterase inhibitor with a half-life of 100 minutes, and it is widely used during or after ITA harvesting to reverse spasm; nitroglycerin is a nitrosovasodilator (nitric oxide donor) with a vasodilator effect on native coronary arteries; verapamil, a selective voltage-dependent calcium-channel antagonist, prevents spasm on coronary and arterial vessels. All those three drugs are widely used in clinical practice to treat angina and hypertension as well as topical antispasmodic agents. For these reasons, we have carried out the present prospective randomized controlled trial first to compare the effects of glyceril-trinitrate/verapamil solution and papaverine in releasing the LITA spasm and finally to determine what should be the best modality of drug delivery by The Society of Thoracic Surgeons /06/$32.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg FORMICA ET AL 2006;81:120 4 PAPAVERINE AND GLYCERILNITRATE-VERAPAMIL FOR ITA VASODILATION Table 1. Preoperative Data Variables Group GV (n 34) Group P (n 33) Group C (n 33) p Value Age (years) Sex (male) 77.8% 78.8% 71% Diabetes mellitus 16.7% 27.3% 32.3% Diet 0% 24% 40% Oral 43.7% 31.5% 20% Insulin 56.3% 44.5% 20% Smoker 44.4% 69.7% 54.8% Previous 66.6% 60.8% 29.4% Current 33.3% 39.2% 70.6% Hypertension 61.1% 72.7% 77.4% Dislipidemia 41.7% 45.5% 45.2% Familiarity 16.7% 24.2% 29% Cerebrovasculopathy 2.8% 6.1% 0% Carotid disease 33.3% 30.3% 25.8% Peripheral disease 5.6% 18.2% 16.1% COPD 8.3% 9.1% 6.5% BSA (m 2 ) Ejection fraction (%) Data presented are mean standard deviation or number (percentages) of patients. All p values are calculated with the use of analysis of variance. BSA body surface area; C control; COPD chronic obstructive pulmonary disease; GV glycerilnitrate-verampil; P papaverine. Material and Methods Patient Selection and Data Collection Since 2000 in our institution, we have routinely used a glycerilnitrate-verapamil (GV) solution as an antispasmodic agent for the ITAs, vein, radial artery, and gastroepiploic artery. Between October 2004 and February 2005, 180 patients underwent adult cardiac surgery operations. One hundred twenty-eight of them had CABG operation. Of this series, 100 consecutive patients were enrolled if they met the following criteria: (1) elective operation, and (2) isolated and primary CABG. Patients were excluded from this study when rapid onset of ischemic events occurred during the elective operation. All patients were randomly assigned to one of three categories: group GV (n 34), treatment with GV solution; group P (n 33), treatment with papaverine; or group C (n 33), treatment with normal saline as the control group. The local Ethics Research Committee approved of the study on September 6, 2004, and each patient included in the study gave a written consent. Demographic and clinical data are listed in Table 1. Operative Technique All patients received preanesthesia treatment with morphine 0.1 to 0.15 mg/kg and diazepam 6 mg, 30 minutes before going into the operating room. Radial or femoral blood systemic pressure, heart rate, and central venous pressure was constantly monitored. Anesthesia was induced with fentenyl to 0.01 mg/kg, midazolam 0.08 to 0.2 mg/kg, and pancuronium 0.1 mg/kg. Anesthesia was maintained with propofol 3 to 6 mg kg 1 h 1, and fentenyl, sevoflorane, and pancuronium as needed. After sternal incision, LITA was harvested with its own pedicle (about 2 cm wide) from the subclavian vein to beyond ITA bifurcation. Three resident cardiac surgeons harvested the vessel with low-power electrocautetery. Major collaterals were ligated with hemoclips. Considering that one spasm stimulus is the artery harvesting, LITA dissection time was recorded starting after opening the pleural space and tracing the LITA pedicle; time was stopped after the artery dissection was completed. Afterward, following the randomization scheme, LITA was sprayed with the appropriate solution and then covered with a soaked sponge containing the same solution used to spray the vessel. The solutions used in this study were prepared in the following mixtures: the GV solution consisted of gliceryltrinitate 2.5 mg; verapamil 5 mg; 8.4% NaHCO 3, 0.2 ml; heparin, 500 units; and Ringer s lactate solution, 300 ml. Ten milliters of this solution were sprayed periarterially with an olive-tipped needle and 1 ml was gently injected intraluminally, using an olive-tipped needle and a 1-mL insulin syringe (glyceril-trinitrate mg/ml; verapamil mg/ml). The papaverine solution contained 10 ml of drug (1 mg/ml 0.9% normal saline) and was delivered periarterially with an olive-tipped needle; after transection of the LITA, 1 ml was gently injected intraluminal using an olive-tipped needle and an insulin syringe. The normal saline 0.9% solution was sprayed, 10 ml periarterially and 1 ml intraluminally, as described earlier. The temperature of each solution during delivery was the same as the temperature of the operating room (18 to 20 C). Fifteen minutes after systemic heparin administration (300 units/kg for an activated clotting time target of 480 seconds), the LITA was transected and trimmed 2 to 3 cm proximally to its bifurcation, and the free flow was collected for 15 seconds; free flow per minute was calculated accordingly. A 50-mL syringe without plunger was used as container. The flow calculated Table 2. Hemodynamic Data Variables Group GV Group P Group C p Value MAP-T MAP-I HR-T HR-I CVP-T CVP-I Time (min) All p values are calculated with the use of analysis of variance. C control; CVP-I central venous pressure during intraluminal injection; CVP-T central venous pressure during topical injection; GV glycerilnitrate-verampil; HR-I heart rate during intraluminal injection; HR-T heart rate during topical injection; MAP-I mean arterial pressure during intraluminal injection; MAP-T mean arterial pressure during topical injection; P papaverine; Time dissection time of left thoracic artery. CARDIOVASCULAR

3 122 FORMICA ET AL Ann Thorac Surg PAPAVERINE AND GLYCERILNITRATE-VERAPAMIL FOR ITA VASODILATION 2006;81:120 4 Table 3. Flow and Resistance Variables After Topical and Intraluminal Injection of Vasodilators Variables Group GV Group P Group C p Value T-Flow (ml/min) I-Flow (ml/min) a TR (mm Hg min/ml) IR (mm Hg min/ml) a According to Bonferroni s post hoc test no statistical difference, was detected between I-flow in group P and group GV (p 1). Data presented are mean standard deviation. All p values are calculated with the use of analysis of variance. C control; GV glycerilnitrate-verampil; I-Flow free flow after intraluminal delivery; IR resistance after intraluminal delivery; P papaverine; T-Flow free flow after topical delivery; TR resistance after topical delivery. after topical drug administration was called topical free flow (T flow). Then the solution was gently injected into the vessel, keeping it occluded proximally with a small plastic bulldog clamp. After 1 minute, the free flow per minute was calculated with the same method. This flow was called intraluminal free flow (I flow). Mean arterial pressure during both T flow and I flow collections, was maintained between 70 and 90 mm Hg, the heart rate between 70 and 100 beats per minute, and the central venous pressure between 6 and 13 mm Hg. During free flow collection, no vasoconstrictors or inotropic drugs were administered. Then, according to Poiseuille s law, using the formula that resistance is equal to pressure divided by flow, blood vessel resistance (R) was derived after topical delivery (TR) and intraluminal delivery (IR) of the solutions. Statistical Analysis Patients were randomly assigned to three groups applying the method of block randomization to obtain approximately the same number of patients in each group. Data are expressed as the mean SD for continuous variables. The Kruskal-Wallis one-way analysis of variance (ANOVA) and 2 test were applied to compare categorical variables. The paired t test was used for comparison between T flow and I flow and between topical delivery and intraluminal delivery in each group. A p value of less than 0.05 was considered to be statistically significant. Analysis of variance was used to detect differences among the three groups. In case of significance, the Bonferroni post hoc test was then used to compare LIMA flow after the topical and intraluminal administration of papaverine, of GV solution, and of normal saline. A p value of less than 0.05 was considered to be statistically significant. Changes between topical and intraluminal flow and variation between TR and IR were expressed in percentage. Results There were no statistical differences both in demographic and in hemodynamic parameters among the three groups (Table 1 and 2). In group GV, mean I flow increased by 50.5% compared with mean T flow. Moreover, GV treatment showed a significant reduction of R ( 42.5%) after intraluminal injection. In group P, mean I flow increased by 46.5%, and blood vessel resistance had a significant reduction after intraluminal injection ( 45%). In group C, no significant changes were recorded in free flow measurements and resistance after topical and intraluminal solution delivery. The I flow increased only by 6.5% compared with the T flow. By ANOVA, there was no significant difference among groups, when each solution was topically delivered (p 0.17). When each solution was injected intraluminally, a significant difference was observed among groups. According to Bonferroni test, I flow in group GV and in group P was significantly higher than I flow in group C (p ), whereas I flow in group P was higher than I flow in group GV, but they did not reach statistical significance (Table 3). Comment Almost 4 decades have passed since the advent of myocardial revascularization by CABG and yet spasm of conduits is still a debated issue by cardiac surgeons and pharmacologists. By the mid 1980s, when surgeons observed that regular use of LITA and other arterial conduits could lead to better long-term results, at the same time the arterial conduit spasm started being closely investigated, with the aim to find the ideal antispasmodic drug to overcome the problem. Actually, there is not a perfect vasodilator drug, because arterial spasm is often a multifactor phenomenon modulated by different mechanism, such as mechanical stimuli, drugs, temperature, and endogenous catecholamine. Green [20] introduced papaverine in surgery in Since then, many cardiac surgeons have used this drug to treat the spasm both of ITA and vein grafts. This vasodilator can be used topically and intraluminally, but its solution is acid (ph 4.4 to 4.8) [22] when used in surgery. Acid solutions are sometimes responsible for creating damage to endothelium [23, 30]. However, several reasons have induced us to use this solution. First, the GV solution has a ph of 7.4, because of NaHCO 3 in the mixture. That should create less endothelial damage when it is gently injected into the lumen. Second, the GV solution is suitable for all arterial conduits, and we use it to treat arterial spasm of radial artery and right gastroepiploic artery [11]. Third, the glyceril-trinitrate has a more rapid onset and verapamil has a longer action than papaverine [22, 24, 25, 30]. That should prevent spasm conduit in the early postoperative hours [25]. The results of our study show the difference of two vasodilators in term of type of solution and way of administration. Table 3 illustrates the difference of free flow before and after intraluminally injection of solution

4 Ann Thorac Surg FORMICA ET AL 2006;81:120 4 PAPAVERINE AND GLYCERILNITRATE-VERAPAMIL FOR ITA VASODILATION in each group: it is stated that, although the group treated with papaverine has the highest mean T flow and I flow, there is no statistical difference compared with the GV group (p 1.00). Therefore, keeping in mind that the papaverine poses a potential risk of damaging the endothelium and considering that the I flow and T flow differences between GV group and P group are not significant, we are encouraged to continue to use the GV solution. Moreover, also the differences between intraluminal delivery and topical delivery are not significant. Another issue to be focused on in this study is the drug administration method. As previously described, mechanical spasm during ITA harvesting represents one of the most important constrictor stimuli. In accordance with our results, we can show that when the antispasmodic agent is topically delivered there is not any significant difference among the three groups. Moreover, T flow remained low and probably not ideal to support blood flow in the left anterior descending artery system; on the other hand, when the antispasmodic agent was administered intraluminally, we observed a dramatic improvement of I flow in both the GV group and the P group, while no change was observed in the C group. The blood vessel resistance after intraluminal injection had a significant reduction in the groups treated with the antispasmodic agents. The major reason that could explain the low ITA flow, after topical application of vasodilator, is the LITA harvesting with its own pedicle (about 2 cm wide). Probably, both papaverine and GV solution did not work as topical vasodilators in the presence of a thick tissue around the LITA. We routinely harvest the LITA with its pedicle, and we have never tried to compare the flow with skeletonized LITA. Probably, owing to the absence of surrounding tissue in the skeletonized LITA, the topical application of vasodilator could guarantee a flow as good as the intraluminal injection. On the basis of our results, papaverine and GV solutions could be used indifferently to treat arterial conduit spasm. Nevertheless, in two recent reports, Mayranpaa and colleagues [23] and Gao and coworkers [31] have described two different types of damage induced by papaverine. Mayranpaa describes the evidence of endothelial damage of human radial graft in terms of endothelial denudation or porosity. This damage could be caused by low ph of papaverine. Gao and colleagues have demonstrated that papaverine could induce apoptosis in porcine coronary endothelial cells and in rat aortic smooth cells. They have concluded that papaverine itself and not its acidity is responsible for apoptosis. Those features have induced us to avoid the use of papaverine in all grafts, even if we have observed a slightly higher mean I flow in the P group than mean I flow in the GV group. Our study suffers from a few limitations. First, a diffused simple system to collect the free flow was adopted as described by many authors: blood free flow in a 50-mL syringe in 15 seconds and flow per minute calculated accordingly. By using more sophisticated systems, better measurements could be obtained. Second, we enrolled patients with low ejection fraction, and we did not calculate the cardiac index during each free flow measurement. That could be justified in that the ITA free flow is dependent on the mean arterial pressure rather than on the contractility. Third, arterial spasm is a multifactor phenomenon; we studied the indications to treat the mechanical spasm, but factors such as preoperative medications, endogenous catecholamine, and body temperature could modify the response of the arterial conduit to the tested vasodilators. In conclusion, the papaverine is the oldest vasodilator used in cardiac surgery to treat the internal thoracic spasm. Nevertheless, in the last years, data about its potential damage to endothelium have encouraged many surgeons to utilize other vasodilators to reduce the risks of intimal damage and early graft closure. The mixture with glicerylnitrate and verapamil should represent a valid alternative to papaverine. Moreover, when used topically, neither vasodilator agents ensures an optimal LITA free flow; therefore, careful intraluminal administration is an important tool to prevent and to treat the arterial spasm as well as to increase the arterial graft free flow. The authors wish to thank Dr Giorgia Pavan and Dr Gabriella Giannini for their help in the preparation and correction of the manuscript. References Lytle BW, Blackstone EH, Loop FD, et al. Two internal thoracic artery grafts are better than one. J Thorac Cardiovasc Surg 1999;117: Sabik JF, Lytle BW, Blackstone EH, Houghtaling PL, Cosgrove DM. Comparison of saphenous vein and internal thoracic artery graft patency by coronary system. Ann Thorac Surg 2005;79: Stevens LM, Carrier M, Perrault LP, et al. Single versus bilateral internal thoracic artery grafts with concomitant saphenous vein grafts for multivessels coronary artery bypass grafting: effects on mortality and event-free survival. J Thorac Cardiovasc Surg 2004;127: Domanski MJ, Borkow CB, Campeau L, et al. Prognostic factors for atherosclerosis progression in saphenous vein grafts. J Am Coll Cardiol 2000;36: Acar C, Farge A, Chardigny C, et al. Use of the radial artery for coronary artery bypass. A new experience after 20 years. Arch Mal Coeur Vaiss 1993;86: Barner HB. The continuing evolution of arterial conduits. Ann Thorac Surg 1999;68(3 Suppl):S Caputo M, Reeves B, Marchetto G, Mahesh B, Lim K, Angelini GD. Radial artery versus right internal thoracic artery as a second arterial conduit for coronary artery surgery: early and midterm outcomes. J Thorac Cardiovasc Surg 2003;126: Modine T, Al-Ruzzeh S, Mazrani W, et al. Use of radial artery graft reduces the morbidity of coronary artery bypass graft surgery in patients aged 65 years and older. Ann Thorac Surg 2002;74: Suma H, Takeuchi A, Hirota Y. Myocardial revascularization with combined arterial grafts utilizing the internal mammary and the gastroepiploic arteries. Ann Thorac Surg 1989;47: Lytle BW, Cosgrove DM, Ratliff NB, Loop FD. Coronary artery bypass with the right gastroepiploic artery. J Thorac Cardiovasc Surg 1989;97: CARDIOVASCULAR

5 124 FORMICA ET AL Ann Thorac Surg PAPAVERINE AND GLYCERILNITRATE-VERAPAMIL FOR ITA VASODILATION 2006;81: Formica F, Ferro O, Greco P, Martino A, Gastaldi D, Paolini G. Long-term follow-up of total arterial myocardial revascularization using exclusively pedicle bilateral internal thoracic artery and right gastroepiploic artery. Eur J Cardiothorac Surg 2004;26: Manapat AE, McCarthy PM, Lytle BW, et al. Gastroepiploic and inferior epigastric arteries for coronary artery bypass. Early results and evolving applications. Circulation 1994;90(5 Pt 2):II Paolini G, Mariani MA, Benussi S, et al. Total arterial myocardial revascularization. Eur J Cardiothorac Surg 1993; 7: Tatsumi TO, Tanaka YT, Kondok K, Minohara S, et al. Descending branch of lateral femoral circumflex artery as a free graft for myocardial revascularization: a case report. J Thorac Cardiovasc Surg 1996;112: Fabbrocini M, Fattouch K, Camporini G, et al. The descending branch of lateral femoral circumflex artery in arterial CABG: early and midterm results. Ann Thorac Surg 2003;75: Sarabu MR, McClung JA, Fass A, Reed GE. Early postoperative spasm in left internal mammary artery bypass grafts. Ann Thorac Surg 1987;44: Von Segesser L, Simonet F, Meier B, Finci L, Faidutti B. Inadeguate flow internal mammary-coronary artery anastomoses. Thorac Cardiovasc Surg 1987;35: Barner HB. Blood flow in the internal mammary artery. Am Heart J 1973;86: Jones EL, Lattouf OM, Wintraub WS. Catastrophic consequences of internal mammary artery hypoperfusion. J Thorac Cardiovasc Surg 1989;98: Green GE. Rate of blood flow from internal mammary artery. Surgery 1971;70: Cooper GJ, Wilkinson GAL, Angelini GD. Overcoming perioperative spasm of the internal mammary artery: which is the best vasodilator? J Thorac Cardiovasc Surg 1992;104: He GW, Buxton B, Rosenfieldt F, Angus JA, Tatoulis J. Pharmacological dilatation of the internal thoracic artery during coronary artery bypass surgery. J Thorac Cardiovasc Surg 1994;107: Mayranpaa M, Simpanen J, Hess MW, Werkalla K, Kovanen PT. Arterial endothelial denudation by intraluminal use of papaverine-nacl solution in coronary bypass surgery. Eur J Cardiothorac Surg 2004;25: He GW, Yang CQ. Use of verapamil and nitroglycerin solution in preparation of radial artery for coronary grafting. Ann Thorac Surg 1996;61: Mussa S, Guzik TJ, Black E, Dip MA, Cannon KM, Taggart DP. Comparative efficacies and durations of action of phenoxybenzamine, verapamil/nitroglycerin solution, and papaverine as topical antispasmodics for radial coronary bypass grafting. J Thorac Cardiovasc Surg 2003;126: Sassoon L, Cohen AJ, Hauptman E, Schanchner A. Effect of topical vasodilators on internal mammary arteries. Ann Thorac Surg 1995;59: Zabeeda D, Medalion B, Jackobshvilli S, Ezra S, Schachner A, Cohen AJ. Comparison of systemic vasodilators: effects on flow in internal mammary and radial arteries. Ann Thorac Surg 2001;71: Lobato E, Janelle GM, Urdaneta F, Martin TD. Comparison of milrinone versus nitroglycerin, alone and in combination, on grafted internal mammary artery flow after cardiopulmonary bypass: effect of -adrenergic stimulation. J Cardiothorac Vasc Anesth 2001;15: Dipp MA, Nye PCG, Taggart DP. Phenoxybenzamine is more effective and less harmful than papaverine in the prevention of radial artery vasospasm. Eur J Cardiothorac Surg 2001;19: Rosenfeldt FL, He GW, Buxton B, Angus JA. Pharmacology of coronary artery bypass. Ann Thorac Surg 1999;67: Gao YJ, Stead S, Lee RMKW. Papaverine induces apoptosis in vascular endothelial and smooth muscle cells. Life Sci 2002;70: