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Adenosine–lidocaine–magnesium non-depolarizing cardioplegia: Moving forward from bench to bedside. Reply to Vinten-Johansen
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Letters to the Editor
Adenosine–lidocaine–magnesium non-depolarizing cardioplegia: Moving forward from bench to bedside. Reply to Vinten-Johansen Francesco Onorati ⁎, Giuseppe Faggian Division of Cardiac Surgery, University of Verona, Italy
a r t i c l e
i n f o
Article history: Received 4 October 2012 Accepted 1 November 2012 Available online 23 November 2012 Keywords: Microplegia Adenosine Lidocaine Adenocaine Coronary artery bypass grafting Ischemia reperfusion injury
Dear Editor, We have greatly appreciated the interest by Dr Vinten-Johansen [1] in our paper investigating the beneficial impact of polarizing microplegia on biochemical, hemodynamic, echocardiographic and clinical outcomes of patients undergoing CABG for unstable angina [2]. We are really intrigued about his comments, related to the potential underestimation of the beneficial effects of our microplegia in terms of postoperative clinical outcome. Indeed, we were really impressed by our biochemical results, showing a significantly attenuated perioperative release of troponin I — which was our primary endpoint [2]. Accordingly, we have underscored also the significant amelioration of the entire “hemodynamic pattern” of patients treated with microplegia during the postoperative course, because of the better systo-diastolic left ventricular function at echocardiography, and the better hemodynamic indices of cardiac function, myocardial oxygen consumption, and ventricular–arterial coupling at PRAM monitoring [2]. However, when clinical outcome was considered, we were able to demonstrate only a significant reduction of blood products usage and a significantly shortened hospitalization. However, the level of statistical significance of our secondary clinical outcome “proxies” was significantly augmented by the Bonferroni correction, so that only a “trend” towards a shorter/lower need of inotropic support and a shorter ICU-length of stay could be detected. Whether these “preliminary” beneficial effects will translate in statistical significant differences need to be ascertained on higher number of patients and future clinical studies. However, we agree with Dr Vinten-Johansen that improvements in length of hospitalization and usage of blood products are still sufficient to ameliorate patient's outcome and hospital costs [3]. When the risk for potential bias related to the complex combinations of substrates in both groups (Buckberg and Microplegia) was considered, we completely agree that it is difficult at the moment to attribute the overall beneficial effect of microplegia to one or other substrate composing our “microplegic milieu”. However, we have tried to avoid all the potential biases by either strict enrollment criteria or standardized perioperative care. As example, tight glycemic control was always guaranteed by the application of Portland protocol either intraoperatively and postoperatively [4], so that only slight oscillations in glycemia could happen. Furthermore, the role of insulin in myocardial protection can be ⁎ Corresponding author. Tel.: +39 45 8121945; fax: +39 45 8123307. E-mail address: [email protected] (F. Onorati). 0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2012.11.022
considered a “never-ending story” which has actually no data demonstrating its beneficial effect [5,6]. Furthermore, when microplegia is routinely used in clinical practice (as we do in our institution following that experimental study), the first “impressive” result – compared to other cardioplegic solutions – is the extremely rare need for internal cardioversion after aortic declamping, a well-known sign of adequacy of myocardial protection for cardiac surgeons. According to the pioneering studies by Dobson et al. proving the anti-ischemic, antiinflammatory and pre-conditioning effects of adenosine–lidocaine– magnesium (ALM) solutions [7,8], we think that our data can only be attributed to a better myocardial protection achieved with the entire “ALM” milieu. According to that, our results – although achieved with a lower concentration of ALM reported in other preliminary clinical experiences [1] and animal studies [7,8] – can only be the consequence of an attenuated ischemia–reperfusion injury (IRI) in a cohort of patients at high risk, because of unstable angina, for severe IRI following aortic declamping [2]. Similarly, we cannot exclude that our blood product saving can be related either to the lower hemodilution (all-blood cardioplegia vs 4:1 crystalloid dilution of our Buckberg solutions) and the higher anti-inflammatory/anti-fibrinolytic effect (a direct consequence of IRI-attenuation) of microplegia. Certainly future studies on the topic are needed for definitive conclusions. Finally, we perfectly agree with Dr Vinten-Johansen on the urgent need for future clinical and laboratory investigations on the potential multiorgan effects of ALM in cardiac surgery. As examples, other intriguing issues needing future clinical investigations are the comparison between continuous and intermittent ALM administrations [9] and between “warm” and “cold” ALM administrations [10]. Certainly, the time to move from bench to bed has come! References [1] Vinte-Johansen J. Adenosine–lidocaine–magnesium non-depolarizing cardioplegia: moving forward from bench to bedside. Int J Cardiol 2013;166:537–8. [2] Onorati F, Santini F, Dandale R, et al. “Polarizing” microplegia improves cardiac cycle efficiency after CABG for unstable angina. Int J Cardiol Jul 12 2012 [Epub ahead of print]. [3] Society of Thoracic Surgeons Blood Conservation Guideline Task Force, Ferraris VA, Brown JR, et al. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg 2011;91:944–82. [4] Furnary AP, Gao G, Grunkemeier GL, et al. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg 2003;125:1007–21. [5] Rao V, Borger MA, Weisel RD, et al. Insulin cardioplegia for elective coronary bypass surgery. J Thorac Cardiovasc Surg 2000;119:1176–84. [6] Rao V, Christakis GT, Weisel RD, et al. The Insulin Cardioplegia Trial: myocardial protection for urgent coronary artery bypass grafting. J Thorac Cardiovasc Surg 2002;123:928–35. [7] Dobson GP, Jones MW. Adenosine and lidocaine: a new concept in nondepolarizing surgical myocardial arrest, protection and preservation. J Thorac Cardiovasc Surg 2004;127:794–805. [8] Shi W, Jiang R, Dobson GP, Granfeldt A, Vinten-Johansen J. The nondepolarizing, normokalemic cardioplegia formulation adenosine–lidocaine (adenocaine) exerts anti-neutrophil effects by synergistic actions of its components. J Thorac Cardiovasc Surg 2012;143:1167–75. [9] Sloots KL, Vinten-Johansen J, Dobson GP. Warm nondepolarizing adenosine and lidocaine cardioplegia: continuous versus intermittent delivery. J Thorac Cardiovasc Surg 2007;133:1171–8. [10] Corvera JS, Kin H, Dobson GP, et al. Polarized arrest with warm or cold adenosine/ lidocaine blood cardioplegia is equivalent to potassium blood cardioplegia. J Thorac Cardiovasc Surg 2005;129:599–606.
Letters to the Editor
Adenosine–lidocaine–magnesium non-depolarizing cardioplegia: Moving forward from bench to bedside. Reply to Vinten-Johansen Francesco Onorati ⁎, Giuseppe Faggian Division of Cardiac Surgery, University of Verona, Italy
a r t i c l e
i n f o
Article history: Received 4 October 2012 Accepted 1 November 2012 Available online 23 November 2012 Keywords: Microplegia Adenosine Lidocaine Adenocaine Coronary artery bypass grafting Ischemia reperfusion injury
Dear Editor, We have greatly appreciated the interest by Dr Vinten-Johansen [1] in our paper investigating the beneficial impact of polarizing microplegia on biochemical, hemodynamic, echocardiographic and clinical outcomes of patients undergoing CABG for unstable angina [2]. We are really intrigued about his comments, related to the potential underestimation of the beneficial effects of our microplegia in terms of postoperative clinical outcome. Indeed, we were really impressed by our biochemical results, showing a significantly attenuated perioperative release of troponin I — which was our primary endpoint [2]. Accordingly, we have underscored also the significant amelioration of the entire “hemodynamic pattern” of patients treated with microplegia during the postoperative course, because of the better systo-diastolic left ventricular function at echocardiography, and the better hemodynamic indices of cardiac function, myocardial oxygen consumption, and ventricular–arterial coupling at PRAM monitoring [2]. However, when clinical outcome was considered, we were able to demonstrate only a significant reduction of blood products usage and a significantly shortened hospitalization. However, the level of statistical significance of our secondary clinical outcome “proxies” was significantly augmented by the Bonferroni correction, so that only a “trend” towards a shorter/lower need of inotropic support and a shorter ICU-length of stay could be detected. Whether these “preliminary” beneficial effects will translate in statistical significant differences need to be ascertained on higher number of patients and future clinical studies. However, we agree with Dr Vinten-Johansen that improvements in length of hospitalization and usage of blood products are still sufficient to ameliorate patient's outcome and hospital costs [3]. When the risk for potential bias related to the complex combinations of substrates in both groups (Buckberg and Microplegia) was considered, we completely agree that it is difficult at the moment to attribute the overall beneficial effect of microplegia to one or other substrate composing our “microplegic milieu”. However, we have tried to avoid all the potential biases by either strict enrollment criteria or standardized perioperative care. As example, tight glycemic control was always guaranteed by the application of Portland protocol either intraoperatively and postoperatively [4], so that only slight oscillations in glycemia could happen. Furthermore, the role of insulin in myocardial protection can be ⁎ Corresponding author. Tel.: +39 45 8121945; fax: +39 45 8123307. E-mail address: [email protected] (F. Onorati). 0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2012.11.022
considered a “never-ending story” which has actually no data demonstrating its beneficial effect [5,6]. Furthermore, when microplegia is routinely used in clinical practice (as we do in our institution following that experimental study), the first “impressive” result – compared to other cardioplegic solutions – is the extremely rare need for internal cardioversion after aortic declamping, a well-known sign of adequacy of myocardial protection for cardiac surgeons. According to the pioneering studies by Dobson et al. proving the anti-ischemic, antiinflammatory and pre-conditioning effects of adenosine–lidocaine– magnesium (ALM) solutions [7,8], we think that our data can only be attributed to a better myocardial protection achieved with the entire “ALM” milieu. According to that, our results – although achieved with a lower concentration of ALM reported in other preliminary clinical experiences [1] and animal studies [7,8] – can only be the consequence of an attenuated ischemia–reperfusion injury (IRI) in a cohort of patients at high risk, because of unstable angina, for severe IRI following aortic declamping [2]. Similarly, we cannot exclude that our blood product saving can be related either to the lower hemodilution (all-blood cardioplegia vs 4:1 crystalloid dilution of our Buckberg solutions) and the higher anti-inflammatory/anti-fibrinolytic effect (a direct consequence of IRI-attenuation) of microplegia. Certainly future studies on the topic are needed for definitive conclusions. Finally, we perfectly agree with Dr Vinten-Johansen on the urgent need for future clinical and laboratory investigations on the potential multiorgan effects of ALM in cardiac surgery. As examples, other intriguing issues needing future clinical investigations are the comparison between continuous and intermittent ALM administrations [9] and between “warm” and “cold” ALM administrations [10]. Certainly, the time to move from bench to bed has come! References [1] Vinte-Johansen J. Adenosine–lidocaine–magnesium non-depolarizing cardioplegia: moving forward from bench to bedside. Int J Cardiol 2013;166:537–8. [2] Onorati F, Santini F, Dandale R, et al. “Polarizing” microplegia improves cardiac cycle efficiency after CABG for unstable angina. Int J Cardiol Jul 12 2012 [Epub ahead of print]. [3] Society of Thoracic Surgeons Blood Conservation Guideline Task Force, Ferraris VA, Brown JR, et al. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg 2011;91:944–82. [4] Furnary AP, Gao G, Grunkemeier GL, et al. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg 2003;125:1007–21. [5] Rao V, Borger MA, Weisel RD, et al. Insulin cardioplegia for elective coronary bypass surgery. J Thorac Cardiovasc Surg 2000;119:1176–84. [6] Rao V, Christakis GT, Weisel RD, et al. The Insulin Cardioplegia Trial: myocardial protection for urgent coronary artery bypass grafting. J Thorac Cardiovasc Surg 2002;123:928–35. [7] Dobson GP, Jones MW. Adenosine and lidocaine: a new concept in nondepolarizing surgical myocardial arrest, protection and preservation. J Thorac Cardiovasc Surg 2004;127:794–805. [8] Shi W, Jiang R, Dobson GP, Granfeldt A, Vinten-Johansen J. The nondepolarizing, normokalemic cardioplegia formulation adenosine–lidocaine (adenocaine) exerts anti-neutrophil effects by synergistic actions of its components. J Thorac Cardiovasc Surg 2012;143:1167–75. [9] Sloots KL, Vinten-Johansen J, Dobson GP. Warm nondepolarizing adenosine and lidocaine cardioplegia: continuous versus intermittent delivery. J Thorac Cardiovasc Surg 2007;133:1171–8. [10] Corvera JS, Kin H, Dobson GP, et al. Polarized arrest with warm or cold adenosine/ lidocaine blood cardioplegia is equivalent to potassium blood cardioplegia. J Thorac Cardiovasc Surg 2005;129:599–606.