Comparison of the effects on the flow in the left internal thoracic artery using nimodipine and papaverine as vasodilators

Edhino Santos Junior Gil Vicente Lico Cividanes Rosangela Cristina Marchiori Francisco de Andrade Souto About the authors

Abstracts

OBJETIVO: O objetivo do presente estudo é comparar o fluxo da artéria torácica interna esquerda sob o efeito local farmacológico por embebição e o efeito intraluminal de bloqueador do canal de cálcio com um grupo controle com papaverina. MÉTODO: Foi realizado estudo prospectivo de 73 pacientes submetidos a revascularização do miocárdio, no período de quatro meses, nos quais se utilizou a artéria torácica interna esquerda como parte do grupo de enxertos, operados no período de julho de 2004 e novembro de 2004, para análise de fluxo comparativo entre dois fármacos. Os pacientes foram aleatorizados para receberem os vasodilatadores nimodipina ou papaverina. Foram determinados dois fluxos: o fluxo no Tempo 1, o qual representou o período de ação farmacológica por embebição (extraluminal), e o fluxo no Tempo 2, este representou a ação farmacológica intraluminal. A comparação das médias de fluxo entre os dois grupos de fármacos foi realizada através do teste não paramétrico de Mann-Whitney. RESULTADOS: Não há evidências de que os fluxos médios dos dois fármacos sejam diferentes no Tempo 1 (p=0,534). Os fluxos médios dos dois fármacos são semelhantes no Tempo 2 (p=0,063). CONCLUSÃO: Não há evidências de que os fluxos médios dos dois fármacos sejam diferentes sob ação por embebição (extraluminal), assim como os fluxos médios dos dois fármacos são semelhantes quando por ação farmacológica intraluminal, tornando a nimodipina uma opção como vasodilatador de ação local comparável à papaverina.

Papaverina; Nimodipino; Artéria torácica interna; Vasodilatadores


OBJECTIVE: To compare the flow of the left internal thoracic artery under a local pharmacological effect caused by the topical action on the arterial pedicle and the intraluminal effect of a calcium channel blocker with a control group using papaverine. METHODS: Over a period from July to November 2004, a prospective study was performed involving 73 patients who were submitted to coronary artery bypass surgery utilizing the left internal thoracic artery as one of a group of grafts. A comparative analysis of the flow was made when using two different pharmacological agents. The patients were randomized to receive either nimodipine or papaverine as vasodilators. Two types of flow were determined: the flow at Time 1 representing the period of topical action of the drug on the arterial pedicle (extraluminal) and the flow at Time 2 representing the intraluminal action of the drug. A comparison of the means of the two types of flow between the two groups of pharmacological agents was carried out using the non-parametric Mann-Whitney test. RESULTS: There is no evidence that the mean flow using the two pharmacological agents is different at Time 1 (p = 0.534) or at Time 2 (p = 0.063). CONCLUSIONS: There is no evidence that the mean flow varies due to the topical action of one or other drug or that the mean flow is different due to the intraluminal action, proving that nimodipine as a locally acting vasodilator is similar to papaverine.

Papaverine; Nimodipine; Mammary arteries; Vasodilator agents


ORIGINAL ARTICLE

Comparison of the effects on the flow in the left internal thoracic artery using nimodipine and papaverine as vasodilators

Edhino Santos JuniorI; Gil Vicente Lico CividanesII; Rosangela Cristina MarchioriII; Francisco de Andrade SoutoIII

IBSCVS and AMIB, Cardiovascular Surgeon / Intensive care

IICardiovascular Surgeon of the Hospital da Beneficência in São Paulo

IIICardiologist of SBC, Cardiologist of the Hospital da Beneficência in São Paulo

Correspondence address

ABSTRACT

OBJECTIVE: To compare the flow of the left internal thoracic artery under a local pharmacological effect caused by the topical action on the arterial pedicle and the intraluminal effect of a calcium channel blocker with a control group using papaverine.

METHODS: Over a period from July to November 2004, a prospective study was performed involving 73 patients who were submitted to coronary artery bypass surgery utilizing the left internal thoracic artery as one of a group of grafts. A comparative analysis of the flow was made when using two different pharmacological agents. The patients were randomized to receive either nimodipine or papaverine as vasodilators. Two types of flow were determined: the flow at Time 1 representing the period of topical action of the drug on the arterial pedicle (extraluminal) and the flow at Time 2 representing the intraluminal action of the drug. A comparison of the means of the two types of flow between the two groups of pharmacological agents was carried out using the non-parametric Mann-Whitney test.

RESULTS: There is no evidence that the mean flow using the two pharmacological agents is different at Time 1 (p = 0.534) or at Time 2 (p = 0.063).

CONCLUSIONS: There is no evidence that the mean flow varies due to the topical action of one or other drug or that the mean flow is different due to the intraluminal action, proving that nimodipine as a locally acting vasodilator is similar to papaverine.

Descriptors: Papaverine. Nimodipine. Mammary arteries. Vasodilator agents.

INTRODUCTION

The use of left internal thoracic artery (LITA) grafts to the anterior interventricular artery is associated with greater survival of patients submitted to coronary artery bypass graft surgery (CABG) [1-4] when compared to venous grafts [5-9]. However, perioperative spasms of the LITA, causing an early reduction in flow, have been associated to an increased morbidity rate in the perioperative period [8-16].

The reduction in flow of the LITA in the perioperative period has been attributed to the dissection and preparation of the internal thoracic artery (ITA) graft [10,17,18]. Handling and movement of the graft during dissection cause spasms that may be minimized by the local action of vasodilatory agents [8,19-21].

Nevertheless, we know that the beneficial effect of this is temporary and may not prevent LITA spasms in the postoperative period [22], so our investigation focused on the perioperative period assessing the capacity of a calcium channel blocker, nimodipine, to maintain an adequate blood flow in recently dissected anterior interventricular artery grafts compared to the use of papaverine.

Few clinical trials have studied the utilization of vasodilators applied to the LITA in an attempt to minimize the spasms [14,23,24] and promote a greater blood flow during the perioperative period. Among the groups of pharmacological agents studied are papaverine [25], calcium channel blockers [26,27], sodium nitroprusside [28], nitroglycerine [26,29], milrinone [29,30] and phenoxybenzamine [27,31], which were used either topically or in a intraluminal manner with the aim of treating vasospasms of arterial grafts. Papaverine is a phosphodiesterases inhibitor with a half-life of 100 minutes [9] which is very commonly utilized in ITA grafts after dissection. The pharmacological group of calcium channel blockers is empirically recommended for the control of vasospasms [32-40]. Among calcium channel blockers, the one that has the most intense vasodilation action promoting a high coronary blood flow is nimodipine [41]. This agent does not require a minimum effective concentration nor does it have a toxic concentration [41] however it should be used with caution to avoid systemic arterial hypertension.

METHOD

This study enrolled hemodynamically stable patients electively submitted to CABG. The patients were randomized into two groups using the method of sealed envelopes which were opened at the time of surgery; the first group of patients, denominated Group A, was a control group in which papaverine at a concentration of 1 mg/mL was used as a vasodilator for the ITA graft; for the second group of patients, Group B, nimodipine at a concentration of 0.0012 mg/mL was used as the vasodilator. Two one-minute periods were determined to measure the blood flow.

To compare the two groups, a protocol of these measurements was established:

a) The length of the LITA was considered from its origin to its end at the bifurcation or trifurcation;

b) The graft was not skeletalized;

c) The mean arterial pressure (PAM) at the time of blood flow measurement was 70 mmHg (± 5 mmHg);

d) The heart rate at blood flow measurement was 80 beats per minute (± 5 beats per minute);

e) The temperature of the topic vasodilation solution was heated to 37ºC to prevent vasoconstriction due to hypothermia.

After total dissection of the LITA, it was soaked using gauzes drenched in the vasodilator solution. To perform the quantitative analysis of the blood flow, we chose the internationally accepted method described in publications [9,42]. After heparinization of the patient, the graft was sectioned at its end as mentioned in item 'a' above and its flow determined with the blood collected in a surgical flask over a 60-second period for future measurement and return to the blood system of the patient by the cardiopulmonary bypass. The time of pharmacological action from soaking to sectioning of the graft was denominated Time 1.

The one-minute blood flow measurement was denominated Flow 1. Subsequently, the lumen of the graft was inspected using a 1.5-mm Garrett vascular dilator followed by intraluminal infusion of the pharmacological agent with occlusion of the distal end using a metallic clip. After a determined period of intraluminal action, the distal portion was sectioned and the blood flow was again measured (denominated Flow 2) with this period denominated Time 2. The time of soaking (Time 1) and the time of intraluminal action (Time 2) were identical.

Comparison of the measurements between the two groups was made using the Mann-Whitney non-parametric test.

RESULTS

Over a period of four months, a total of 73 patients were included in the study the grafts of whom were randomly treated with either nimodipine or papaverine satisfying the conditions of the study protocol independently of gender, age, body mass index and co-morbidities.

Two flow rates were determined: flow at Time 1 (extraluminal action) and at Time 2 (intraluminal action).

Other variables included absolute differences and percentages between flows at Times 2 and 1 denominated "T2 – T1" and "T2/T1" respectively.

Table 1 shows the sample sizes for both groups.

Tables 2 and 3 describe the means and standard deviations of flows at Times 1 and 2 as well as the absolute differences and percentages.

Figure 1 illustrates the mean flows and standard errors obtained at Times 1 and 2 for the two groups.


The mean extraluminal (soaked in gauze) and intraluminal times of action of the nimodipine were both 10.24 minutes and the mean extraluminal and intraluminal times of action of the papaverine were both 10.60 minutes. There were no significant differences in respect to the times of action for the two groups.

The supposition of a normal distribution for student t-test was rejected for the four variables by the Kolmogorov-Smirnov test. Thus, comparison between the two groups was made using the Mann-Whitney non-parametric test.

There was no evidence of significant differences in flow rates at Time 1 between the two groups (p-value = 0.534). The flow rates of the two groups were also similar at Time 2 (p-value = 0.063). The absolute and relative differences between Time 2 and Time 1 were greater for papaverine than for nimodipine (p-value = 0.006 and p-value = 0.034, respectively).

A level of significance of 5% was adopted for statistical conclusions.

DISCUSSION

Dilation of the LITA, not only for anastomosis to the native coronary artery, but also for the blood flow of the graft, is a basic necessity during surgery in order to significantly reduce the morbidity in the perioperative period [10-15].

As papaverine is a well-known internationally accepted arterial vasodilator used by soaking the post-dissection graft, we chose to utilize it in the Control Group and analyze whether on soaking there is a significant difference between the two groups. There is no evidence that the flow rates are significantly different at Time 1 between the two groups (p-value = 0.534).

In this investigation, using identical periods of extraluminal and intraluminal action, the flow rates after intraluminal action of the vasodilators were also compared giving a more objective and reliable evaluation of the flow.

The mean flows in the two groups were also similar at Time 2 (p-value = 0.063) with a greater vasodilator action of the papaverine.

Similar results were obtained in a comparative study of flows between papaverine and a selective voltage-dependent calcium channel antagonist, analyzing the flows after soaking and intraluminal action [9]. These authors believe that the advantage of verapamil over papaverine is related to the greater lesions caused by the acidic pH of the papaverine (pH between 4.4 and 4.8) compared to verapamil (pH 7.4).

CONCLUSION

Based on this study, there were no significant differences in mean flow rates using the two pharmacological agents after soaking or after intraluminal action. Hence, nimodipine can be considered an option as a locally acting vasodilator similar to papaverine. The study opens the possibility of further studies with the aim of utilizing the drugs during the operation and also in the postoperative period as an endovenous infusion to prevent vasospasms of arterial grafts.

REFERENCES

  • Correspondence address:
    Edhino Santos Junior
    Rua Serra de Juréia, 727/112 - Tatuapé
    São Paulo, SP - CEP: 03323-020
    Tel: (11) 8244-5937
    E-mail:
  • Article received in January, 2006

    Article accepted in September, 2006

    Work carried out in the Cardiovascular Surgery Service of Dr. Gil Vicente Lico Cividanes, in Hospital da Real e Benemérita Sociedade Portuguesa de Beneficência de São Paulo - Hospital São Joaquim.

    • 1. Sasson L, Cohem AJ, Hauptman E, Schachner A. Effect of topical vasodilators on internal mammary arteries. Ann Thorac Surg. 1995;59(2):494-6.
    • 2. Loop FD, Lytle BW, Cosgrove DM, Stewart RW, Goormastic M, Williams GW, et al. Influence of the internal-mammary-artery graft on 10 year survival and other cardiac events. N Engl J Med. 1986;314(1):1-6.
    • 3. Olearchyk AS, Magovern GJ. Internal mammary artery grafting: clinical results, patency rates, and long-term survival in 833 patients. J Thorac Cardiovasc Surg. 1986;92(6):1082-7.
    • 4. Dion R, Verhelst R, Rousseau M, Goenen M, Ponlot R, Kesten-Servaye Y et al. Sequential mammary artery grafting. Clinical, functional and angiographic assessment 6 months postoperatively in 231 consecutive patients. J Thorac Cardiovasc Surg. 1989;98(1):80-8.
    • 5. Henriquez-Pino JA, Gomes WJ, Prates JC, Buffolo E. Estudo anatômico da artéria torácica interna aplicado à cirurgia cardiovascular. Rev Bras Cir Cardiovasc. 1997;12(1):83-8.
    • 6. Zeff RH, Kongtahworn C, Iannone LA, Gordon DF, Brown TM, Philips SJ, et al. Internal mammary artery versus saphenous vein graft to the left anterior descending coronary artery:prospective randomized study with 10-year follow-up. Ann Thorac Surg. 1988;45(5):533-6.
    • 7. Cameron A, Davis KB, Green G, Schaff HV. Coronary bypass surgery with internal thoracic artery grafts-effects on survival over a 15-year period. N Engl J Med. 1996;334(4):216-9.
    • 8. Takeuchi K, Sakamoto S, Nagayoshi Y, Nishizawa H, Matsubara J. Reactivity of the human internal thoracic artery to vasodilators in coronary artery bypass grafting. Eur J Cardiothorac Surg 2004;26(5):956-9.
    • 9. Formica F, Ferro A, Brustia M, Corti F, Colagrande L, Bosisio E, et al. Effects of papaverine and glycerylnitrate-verapamil solution as topical and intraluminal vasodilators for internal thoracic artery. Ann Thorac Surg. 2006;81(1):120-4.
    • 10. Sarabu MR, McClung JA, Fass A, Reed GE. Early postoperative spasm in left internal mammary artery bypass grafts. Ann Thorac Surg. 1987;44(2):199-200.
    • 11. Von Segesser L, Simonet F, Meier B, Finci L, Faidutti B. Inadequate flow after internal mammary-coronary artery anastomoses. Thorac Cardiovasc Surg. 1987;35(6):352-4.
    • 12. Blanche C, Chaux A. Spasm in mammary artery grafts. Ann Thorac Surg. 1988;45(5):586.
    • 13. von Segesser LK, Lehmann K, Turina M. Deleterious effects of shock in internal mammary artery anastomoses. Ann Thorac Surg. 1989;47(4):575-9.
    • 14. Mills NL, Bringase WL. Preparation of the internal mammary artery graft: which is the best method? J Thorac Cardiovasc Surg. 1989;98(1):73-9.
    • 15. Koike R, Suma H, Kondo K, Oku T, Saton H, Fukuda S, et al. Pharmacological response of internal mammary artery and gastroepiploic artery. Ann Thorac Surg. 1990;50(3):384-6.
    • 16. Wendler O, Tscholl D, Huang Q, Schafers HJ. Free flow capacity of skeletonized versus pedicled internal thoracic artery grafts in coronary artery bypass grafts. Eur J Cardiothorac Surg. 1999;15(3):247-50.
    • 17. Barner HB. Blood flow in the internal mammary artery. Am Heart J. 1973;86(4):570-1.
    • 18. Jones EL, Lattouf OM, Weintraub WS. Catastrophic consequences of internal mammary artery hypoperfusion. J Thorac Cardiovasc Surg. 1989;98(5 pt 2):902-7.
    • 19. Hendrick BB. Blood flow in the internal mammary artery. Am Heart J. 1973;86(4):570-1.
    • 20. Hillier C, Watt PA, Spyt TJ, Thurston H. Contraction and relaxation of human internal mammary artery after intraluminal administration of papaverine. Ann Thorac Surg. 1992;53(6):1033-7.
    • 21. 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(1):138-41.
    • 22. Izzat MB, West RR, Ragoonanan C, Angelini GD. Effect of systemic vasodilators on internal mammary artery flow: implications for postoperative treatment after myocardial revascularization. J Thorac Cardiovasc Surg. 1994;108(1):82-5.
    • 23. Cooper GJ, Wilkinson GA, Angelini GD. Overcoming perioperative spasm of the internal mammary artery:which is the best vasodilator? J Thorac Cardiovasc Surg. 1992;104(2):465-8.
    • 24. Vilandt J, Kjaergard H, Aggestrup S, Andreasen JJ, Olesen A. Intraluminal papaverine with pH 3 doubles blood flow in the internal mammary artery. Scand Cardiovasc J. 1999;33(6):330-2.
    • 25. Mayranpaa M, Simpanen J, Hess MW, Werkkala K, Kovanen PT. Arterial endothelial denudation by intraluminal use of papaverine-NaCl solution in coronary bypass surgery. Eur J Cardiothorac Surg. 2004;25(4):560-6.
    • 26. He GW, Yang CQ. Use of verapamil and nitroglycerin solution in preparation of radial artery for coronary grafting. Ann Thorac Surg. 1996;61(2):610-4.
    • 27. Mussa S, Guzik TJ, Black E, Dipp MA, Chanon 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(6):1798-805.
    • 28. Sasson L, Cohen AJ, Hamptman E, Schanchner A. Effect of topical vasodilators on internal mammary arteries. Ann Thorac Surg 1995;59(2):494-6.
    • 29. 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(1):138-41.
    • 30. 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: effects of alpha-adrenergic stimulation. J Cardiothorac Vasc Anesth. 2001;15(6):723-7.
    • 31. Dipp MA, Nye PC, Taggart DP. Phenoxybenzamine is more effective and less harmful than papaverine in the prevention of radial artery vasospasm. Eur J Cardiothorac Surg. 2001;19(4):482-6.
    • 32. Brodman RF, Frame R, Camacho M, Hu E, Chen A, Hollinger I. Routine use of unilateral and bilateral radial arteries for coronary artery bypass graft surgery. J Am Coll Cardiol. 1996;28(4):959-63.
    • 33. Acar C, Jebara VA, Portoghese M, Viesen B, Pogny JY, Grare P, et al. Revival of the radial artery for coronary artery bypass grafting. Ann Thorac Surg. 1992;54(4):652-60.
    • 34. Weinschelbaum EE, Gabe ED, Macchia A, Smimmo R, Suárez LD. Total myocardial revascularization with arterial conduits: radial artery combined with internal thoracic arteries. J Thorac Cardiovasc Surg. 1997;114(6):911-6.
    • 35. Borger MA, Cohen G, Buth KJ, Rao V, Bozinovski J, Liaghati-Nasseri N, et al. Multiple arterial grafts: radial versus right internal thoracic arteries. Circulation. 1998;98(19 suppl):II7-14.
    • 36. Calafiore AM, Teodori G, Di Giammarco G, D'Annunzio E, Angelini R, Vitolla G, et al. Coronary revascularization with the radial artery:new interest for an old conduit. J Card Surg. 1995;10(2):140-6.
    • 37. Dietl CA, Benoit CH. Radial artery graft for coronary revascularization: technical considerations. Ann Thorac Surg. 1995;60(2):102-10.
    • 38. Costa FD, Costa IA, Poffo R, Abuchaim D, Gaspar R, Garcia L et al. Myocardial revascularization with the radial artery:a clinical and angiographic study. Ann Thorac Surg. 1996;62(2):475-80.
    • 39. Barlem AB, Saadi EK, Gib MC, Manfroi WC. Enxertos arteriais na cirurgia de revascularização do miocardio: papel da artéria radial. Rev Bras Cir Cardiovasc. 2001;16(1):53-7.
    • 40. He GW, Buxton BF, Rosenfeldt FL, Angus JA, Tatoulis J. Pharmacologic dilatation of the internal mammary artery during coronary bypass grafting. J Thorac Cardiovasc Surg. 1994;107(6):1440-4.
    • 41. Brunton L, Lazo J, Parker K. Goodman and Gilman's: the pharmacological basis of therapeutics. 9th ed. McGraw-Hill. p.769.
    • 42. Takeuchi K, Sakamoto S, Nagayoshi Y, Nishizawa H, Matsubara J. Reactivity of the human internal thoracic artery to vasodilators in coronary artery bypass grafting. Eur J Cardiothorac Surg. 2004;26(5):956-9.

    Correspondence address: Edhino Santos Junior Rua Serra de Juréia, 727/112 - Tatuapé São Paulo, SP - CEP: 03323-020 Tel: (11) 8244-5937 E-mail: edhino7@hotmail.com, edhino@sti-hspe.com.br

    Publication Dates

    • Publication in this collection
      11 Sept 2007
    • Date of issue
      Dec 2006

    History

    • Accepted
      Sept 2006
    • Received
      Jan 2006
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