What is the optimal vasodilator for preventing spasm in the left internal mammary artery during coronary arterial bypass grafting
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a Department of Cardiothoracic Surgery, North Staffordshire Royal Infirmary, Stoke, UK
b Department of Cardiothoracic Surgery, James Cook University Hospital, Middlesbrough, UK
Abstract
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was which (if any) vasodilator prevents spasm of the internal mammary artery in patients undergoing coronary artery bypass grafting. Two hundred papers were found using the reported search, of which 13 represented the best evidence to answer the clinical question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses were tabulated. We conclude that mammary arteries often have low flow initially, but invariably will double their flow after 15–20 min even with no treatment. The strongest evidence for safe prevention of spasm is for papaverine given topically and periarterially, however many studies have also shown no benefit and thus no treatment at all is an entirely acceptable strategy.
Key Words: Evidence-based medicine; Thoracic surgery; Mammary arteries; Spasm
1. Introduction
A best evidence topic was constructed according to a structured protocol. This protocol is fully described in the ICVTS [1].
2. Clinical scenario
You have just started working with a consultant in a new firm. The consultant you had previously worked with uses topical papaverine to prevent vasospasm of the left internal mammary artery. Your new consultant never does this. On the first theatre day in your new firm you have completed harvesting the internal mammary and noted the flow to be poor. You are contemplating using topical papavarine to improve the vasospasm of the mammary artery. However, your consultant stops you and asks you to show him the evidence that topical vasodilators significantly improve mammary arterial flow before using any vasodilators in his cases.
2.1. Three-part question
In [patients undergoing CABG using the left internal mammary artery] do [vasodilators] improve [graft flow].
2.2. Search strategy
Medline 1966–March 2005 using the Ovid interface [exp Mammary Arteries/OR LIMA.mp. OR Mammary art$.mp OR thoracic art$.mp.] AND [protection.mp or spasm.mp OR flow.mp OR dilation.mp OR dilatation.mp] AND [SNP.mp or sodium nitroprusside.mp OR nitroglycerine.mp or GTN.mp OR exp Nitroglycerin/OR papaverine.mp OR exp Papaverine/OR phosphodiesterase.mp OR exp Phosphoric Diester Hydrolases/OR vasodilator.mp OR exp Vasodilator Agents/].
2.3. Search outcome
A total of 200 papers were found from the above search. Case reports and in vitro studies were excluded. Studies investigating systemic vasodilators were also excluded. Thirteen studies represented the best evidence to answer our question. These papers are listed in Table 1 [2–14].
3. Discussion
Eleven Randomized Controlled Trials and 2 multi-arm prospective cohort studies were found investigating the effects of topical, intraluminal and periarterial vasodilators. These studies compared the mode of administration the concentration of the drug administered and the temperature in which they have been administered for papaverine, sodium nitroprusside, nitroglycerine and phosphodiesterase inhibitors.
Among the studies papaverine has been used in all studies except one [9]. Papaverine has been shown to increase blood flow compared to control in some studies [2,5,10,14] but not others [3,4,6,8]. Flow prior to bypass in control groups varies from 36 ml per min to 85 ml per min among all studies reporting a control group. Positive papaverine studies demonstrate a mean flow from 100 to 229 ml/min with the highest pre-anastomosis flow rate being from intraluminal application followed by hydrostatic pressure dilatation [2]. Perivascular and intraluminal instillation of papaverine significantly increased blood flow compared to topical papaverine [7,10,13]. However, the microscopic analysis by Dregelid [12] showed that intraluminal instillation caused mechanical injury to the lumen of the mammary artery, with 5 dissections, 1 medial disruption and 2 medial invaginations into the lumen in their study. In addition Yavuz [7] identified 6 patients (4%) who were noted to have poor flow in the mammary artery after intraluminal injection and 3 were found to have suffered a dissection.
Sodium nitroprusside has also been widely investigated [3,6,8,9]. Two studies failed to show a significant improvement compared to control [3,6]. Cooper et al. [8] was the only study to show a significant improvement to controls and also the only study to demonstrate a benefit in comparison to other topical vasodilators, although the finding did not reach significance. Sasson et al. [3] found that topical application brought about systemic hypotension in 8 of the 10 patients receiving topical SNP requiring withdrawal of these patients from the study. Yorgancioglu et al. [9] found that periarterial injection of sodium nitroprusside brought about a greater increase in mammary flow in comparison to topical spraying although they had no control group.
Topical nitroglycerine was not shown to significantly increase blood flow in 3 studies [3,4,6], but was shown to increase blood flow compared to controls in one study [8]. No studies have shown nitroglycerine to be superior to any other vasodilators. Takeuchi et al. [4] is the only study to show that topical phosphodiesterase III inhibitors also increase mammary artery flow although the improvements compared to control were small.
In summary there is surprisingly little strong evidence that vasodilators significantly improve LIMA graft flow compared to no treatment. All studies that use a control show that the flow can often initially be low but the flow invariably doubles after 15–20 min. Only one study has demonstrated a significant benefit using SNP or GTN. The strongest evidence for benefit is for Papaverine with 4 studies showing a significant benefit. This benefit is greatest if periarterial or intraluminal injection is performed although there have been several reports of damage to the mammary artery with intraluminal injection.
4. Conclusion
Mammary arteries often have low flow initially, but invariably will double their flow after 15–20 min even with no treatment. The strongest evidence for safe prevention of spasm is for papaverine given topically and periarterially, however, many studies have also shown no benefit and thus no treatment at all is an entirely acceptable strategy.
Appendix A. ICVTS on-line discussion
Author: Hendrick B. Barner (Forest Park Hospital, St Louis, MO, USA)
eComment: Papaverine is an effective vasodilator [A1] but is usually unnecessary as the authors conclude. Because spasm varies in severity, some patients will have low free flow due to persistent spasm and others due to injury and pharmacologic vasodilation will help sort this out. With Y or T grafting, it is more important to have a dilated conduit and if one limb is the radial which requires drug dilation, in my experience then, it is reasonable to apply it to the ITA as well, at least the proximal segment.
I believe intraluminal use is more effective but carries the downside of ITA injury, usually dissection, which is localized to the distal segment and recognizable if one is careful and vigilant and at 1% does not deter me from this approach.
This report begs for a randomized controlled study guided by the ‘study weaknesses’ column.
Thanks for this effort!
References
A1 He GW, Yang CQ. Use of verapamil and nitroglycerin solution in preparation of radial artery for coronary grafting. Ann Thorac Surg 1996;61:610–614.
References
Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact CardioVasc Thorac Surg 2003;2:405–409.
Mills NL, Bringaze WL 3rd. Preparation of the internal mammary artery graft. Which is the best method J Thorac Cardiovasc Surg 1989;98:73–79.
Sasson L, Cohen A, Hauptmann E, Schachner A. Effect of topical vasodilators on Internal mammary arteries. Ann Thorac Surg 1995;59:494–496.
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;26:956–959.
Girard DS, Sutton JP III, Williams TH, Crumbley AJ III, Zellner JL, Kratz JM, Crawford FA. Papaverine delivery to the internal mammary artery pedicle effectively treats spasm. Ann Thorac Surg 2004;78:1295–1298.
Nili M, Stamler A, Sulkes J, Vidne B. Preparation of the internal thoracic artery by vasodilator drugs: is it really necessary A randomized double-blind placebo-controlled clinical study. Eur J Cardiothoracic Surg 1999;16:560–563.
Yavuz S, Celkan A, Goncu T, Turk T, Ozdemir A. Effect of papaverine applications on blood flow of the internal mammary artery. Ann Thorac Cardiovasc Surg 2001;7:84–88.
Cooper GJ, Wilkinson GA, Angelini GD. Overcoming perioperative spasm of the internal mammary artery: Which is the best vasodilator J Thorac Cardiovasc Surg 1992;104:465–468.
Yorgancioglu C, Tokmakoglu H, Gunaydin S, Catav Z, Suzer K. An alternative application of sodium nitroprusside to overcome perioperative spasm of the internal thoracic artery. Cardiovasc Surg 2001;9:64–67.
Vilandt J, Kjaergard H, Aggestrup S, Andreasen J, Olesen A. Intraluminal papaverine with pH 3 doubles blood flow in the internal mammary artery. Scand Cardiovasc J 1999;33:330–332.
Dregelid E, Heldal K, Andersen K, Stangeland L, Svendsen E. Dilation of the internal mammary artery by external papaverine application to the pedicle: an improved method. Eur J Cardiothorac Surg 1993;7:158–163.
Dregelid E, Heldal K, Resch F, Stangeland L, Breivik K, Svendsen E. Dilation of the internal mammary artery by external and intraluminal papaverine application. 1995;110:697–703.
Hausmann H, Photiadis J, Hetzer R. Blood flow in the internal mammary artery after the administraion of papaverine during coronary artery bypass grafting. Texas Heart Institute J 1996;23:279–283.
Bilgen F, Yapici F, Serbetcioglu A, Tarhan A, Coruh T, Ozler A. Effect of Normothermic papaverine to relieve intraoperative spasm of the internal thoracic artery. Ann Thorac Surg 1996;62:769–771.(Sivakumar Sivalingam, Adr)
b Department of Cardiothoracic Surgery, James Cook University Hospital, Middlesbrough, UK
Abstract
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was which (if any) vasodilator prevents spasm of the internal mammary artery in patients undergoing coronary artery bypass grafting. Two hundred papers were found using the reported search, of which 13 represented the best evidence to answer the clinical question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses were tabulated. We conclude that mammary arteries often have low flow initially, but invariably will double their flow after 15–20 min even with no treatment. The strongest evidence for safe prevention of spasm is for papaverine given topically and periarterially, however many studies have also shown no benefit and thus no treatment at all is an entirely acceptable strategy.
Key Words: Evidence-based medicine; Thoracic surgery; Mammary arteries; Spasm
1. Introduction
A best evidence topic was constructed according to a structured protocol. This protocol is fully described in the ICVTS [1].
2. Clinical scenario
You have just started working with a consultant in a new firm. The consultant you had previously worked with uses topical papaverine to prevent vasospasm of the left internal mammary artery. Your new consultant never does this. On the first theatre day in your new firm you have completed harvesting the internal mammary and noted the flow to be poor. You are contemplating using topical papavarine to improve the vasospasm of the mammary artery. However, your consultant stops you and asks you to show him the evidence that topical vasodilators significantly improve mammary arterial flow before using any vasodilators in his cases.
2.1. Three-part question
In [patients undergoing CABG using the left internal mammary artery] do [vasodilators] improve [graft flow].
2.2. Search strategy
Medline 1966–March 2005 using the Ovid interface [exp Mammary Arteries/OR LIMA.mp. OR Mammary art$.mp OR thoracic art$.mp.] AND [protection.mp or spasm.mp OR flow.mp OR dilation.mp OR dilatation.mp] AND [SNP.mp or sodium nitroprusside.mp OR nitroglycerine.mp or GTN.mp OR exp Nitroglycerin/OR papaverine.mp OR exp Papaverine/OR phosphodiesterase.mp OR exp Phosphoric Diester Hydrolases/OR vasodilator.mp OR exp Vasodilator Agents/].
2.3. Search outcome
A total of 200 papers were found from the above search. Case reports and in vitro studies were excluded. Studies investigating systemic vasodilators were also excluded. Thirteen studies represented the best evidence to answer our question. These papers are listed in Table 1 [2–14].
3. Discussion
Eleven Randomized Controlled Trials and 2 multi-arm prospective cohort studies were found investigating the effects of topical, intraluminal and periarterial vasodilators. These studies compared the mode of administration the concentration of the drug administered and the temperature in which they have been administered for papaverine, sodium nitroprusside, nitroglycerine and phosphodiesterase inhibitors.
Among the studies papaverine has been used in all studies except one [9]. Papaverine has been shown to increase blood flow compared to control in some studies [2,5,10,14] but not others [3,4,6,8]. Flow prior to bypass in control groups varies from 36 ml per min to 85 ml per min among all studies reporting a control group. Positive papaverine studies demonstrate a mean flow from 100 to 229 ml/min with the highest pre-anastomosis flow rate being from intraluminal application followed by hydrostatic pressure dilatation [2]. Perivascular and intraluminal instillation of papaverine significantly increased blood flow compared to topical papaverine [7,10,13]. However, the microscopic analysis by Dregelid [12] showed that intraluminal instillation caused mechanical injury to the lumen of the mammary artery, with 5 dissections, 1 medial disruption and 2 medial invaginations into the lumen in their study. In addition Yavuz [7] identified 6 patients (4%) who were noted to have poor flow in the mammary artery after intraluminal injection and 3 were found to have suffered a dissection.
Sodium nitroprusside has also been widely investigated [3,6,8,9]. Two studies failed to show a significant improvement compared to control [3,6]. Cooper et al. [8] was the only study to show a significant improvement to controls and also the only study to demonstrate a benefit in comparison to other topical vasodilators, although the finding did not reach significance. Sasson et al. [3] found that topical application brought about systemic hypotension in 8 of the 10 patients receiving topical SNP requiring withdrawal of these patients from the study. Yorgancioglu et al. [9] found that periarterial injection of sodium nitroprusside brought about a greater increase in mammary flow in comparison to topical spraying although they had no control group.
Topical nitroglycerine was not shown to significantly increase blood flow in 3 studies [3,4,6], but was shown to increase blood flow compared to controls in one study [8]. No studies have shown nitroglycerine to be superior to any other vasodilators. Takeuchi et al. [4] is the only study to show that topical phosphodiesterase III inhibitors also increase mammary artery flow although the improvements compared to control were small.
In summary there is surprisingly little strong evidence that vasodilators significantly improve LIMA graft flow compared to no treatment. All studies that use a control show that the flow can often initially be low but the flow invariably doubles after 15–20 min. Only one study has demonstrated a significant benefit using SNP or GTN. The strongest evidence for benefit is for Papaverine with 4 studies showing a significant benefit. This benefit is greatest if periarterial or intraluminal injection is performed although there have been several reports of damage to the mammary artery with intraluminal injection.
4. Conclusion
Mammary arteries often have low flow initially, but invariably will double their flow after 15–20 min even with no treatment. The strongest evidence for safe prevention of spasm is for papaverine given topically and periarterially, however, many studies have also shown no benefit and thus no treatment at all is an entirely acceptable strategy.
Appendix A. ICVTS on-line discussion
Author: Hendrick B. Barner (Forest Park Hospital, St Louis, MO, USA)
eComment: Papaverine is an effective vasodilator [A1] but is usually unnecessary as the authors conclude. Because spasm varies in severity, some patients will have low free flow due to persistent spasm and others due to injury and pharmacologic vasodilation will help sort this out. With Y or T grafting, it is more important to have a dilated conduit and if one limb is the radial which requires drug dilation, in my experience then, it is reasonable to apply it to the ITA as well, at least the proximal segment.
I believe intraluminal use is more effective but carries the downside of ITA injury, usually dissection, which is localized to the distal segment and recognizable if one is careful and vigilant and at 1% does not deter me from this approach.
This report begs for a randomized controlled study guided by the ‘study weaknesses’ column.
Thanks for this effort!
References
A1 He GW, Yang CQ. Use of verapamil and nitroglycerin solution in preparation of radial artery for coronary grafting. Ann Thorac Surg 1996;61:610–614.
References
Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact CardioVasc Thorac Surg 2003;2:405–409.
Mills NL, Bringaze WL 3rd. Preparation of the internal mammary artery graft. Which is the best method J Thorac Cardiovasc Surg 1989;98:73–79.
Sasson L, Cohen A, Hauptmann E, Schachner A. Effect of topical vasodilators on Internal mammary arteries. Ann Thorac Surg 1995;59:494–496.
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;26:956–959.
Girard DS, Sutton JP III, Williams TH, Crumbley AJ III, Zellner JL, Kratz JM, Crawford FA. Papaverine delivery to the internal mammary artery pedicle effectively treats spasm. Ann Thorac Surg 2004;78:1295–1298.
Nili M, Stamler A, Sulkes J, Vidne B. Preparation of the internal thoracic artery by vasodilator drugs: is it really necessary A randomized double-blind placebo-controlled clinical study. Eur J Cardiothoracic Surg 1999;16:560–563.
Yavuz S, Celkan A, Goncu T, Turk T, Ozdemir A. Effect of papaverine applications on blood flow of the internal mammary artery. Ann Thorac Cardiovasc Surg 2001;7:84–88.
Cooper GJ, Wilkinson GA, Angelini GD. Overcoming perioperative spasm of the internal mammary artery: Which is the best vasodilator J Thorac Cardiovasc Surg 1992;104:465–468.
Yorgancioglu C, Tokmakoglu H, Gunaydin S, Catav Z, Suzer K. An alternative application of sodium nitroprusside to overcome perioperative spasm of the internal thoracic artery. Cardiovasc Surg 2001;9:64–67.
Vilandt J, Kjaergard H, Aggestrup S, Andreasen J, Olesen A. Intraluminal papaverine with pH 3 doubles blood flow in the internal mammary artery. Scand Cardiovasc J 1999;33:330–332.
Dregelid E, Heldal K, Andersen K, Stangeland L, Svendsen E. Dilation of the internal mammary artery by external papaverine application to the pedicle: an improved method. Eur J Cardiothorac Surg 1993;7:158–163.
Dregelid E, Heldal K, Resch F, Stangeland L, Breivik K, Svendsen E. Dilation of the internal mammary artery by external and intraluminal papaverine application. 1995;110:697–703.
Hausmann H, Photiadis J, Hetzer R. Blood flow in the internal mammary artery after the administraion of papaverine during coronary artery bypass grafting. Texas Heart Institute J 1996;23:279–283.
Bilgen F, Yapici F, Serbetcioglu A, Tarhan A, Coruh T, Ozler A. Effect of Normothermic papaverine to relieve intraoperative spasm of the internal thoracic artery. Ann Thorac Surg 1996;62:769–771.(Sivakumar Sivalingam, Adr)