Influence of Milrinone and Norepinephrine on Blood Flow in Canine Internal Mammary Artery Grafts

Transcription

1 Influence of Milrinone and Norepinephrine on Blood Flow in Canine Internal Mammary Artery Grafts Richard Gitter, MD, Jerry M. Anderson, Jr, BA, and G. Kimble Jett, MD Department of Cardiothoracic Surgery, Baylor University Medical Center, Dallas, Texas Background. Vasoactive agents are frequently needed in patients undergoing myocardial revascularization. The purpose of this study was to examine blood flow in the internal mammary artery (IMA) during infusion of drugs that are commonly used after myocardial revascularization. Methods. A canine right heart bypass preparation allowed precise control of cardiac output and blood pressure, which were maintained constant during drug infusion to isolate the effect of the drug on the IMA conduit. The IMA was anastomosed to a ligated left anterior descending coronary artery. Electromagnetic flow probes measured IMA graft flow. Results. Norepinephrine (0.1 /~g kg -1 min -1) alone and when combined with phentolamine (8:5 ratio) did not alter IMA flow. Milrinone increased IMA flow 33% -+ 9%, from to ml/min. All hemodynamic variables were unchanged. Conclusions. The results suggest that: (1) norepinephfine did not have a deleterious effect on IMA flow and (2) milrinone may be a useful drug in patients undergoing myocardial revascularization by increasing IMA blood flow. (Ann Thorac Surg 1996;61: ) he internal mammary artery (IMA) has clearly been T demonstrated to be a better conduit than reversed saphenous vein grafts in coronary artery bypass grafting I1]. In the past, the saphenous vein graft was preferred due to its availability and because of studies demonstrating the relatively poor immediate flow with IMA grafting [2]. Current reports, however, demonstrate superior long-term patient survival as well as significantly improved patency rates when the IMA is used [1, 3, 41. In addition to being less prone to arteriosclerosis, the IMA graft is able to enlarge in response to demands from its coronary vascular bed [5, 6]. Accordingly, the IMA is currently the preferred conduit for myocardial revascularization. New techniques have become available recently to help revascularize the heart completely with IMAs. These include bilateral, sequential and free IMA grafting [5]. Other arterial conduits also are being used [7, 8]. Graft flow immediately after myocardial revascularization has received less attention than long-term patency. It is during this immediate postbypass transition period that most hemodynamic instability occurs. Logically, this is the time most vasoactive drugs are given. Therefore, the purpose of this study was to compare the effects of commonly used vasoactive drugs on blood flow in the IMA in an experimental model holding all other variables constant. Accepted for publication Jan 9, Address reprint requests to Dr Jett, Mechanical Circulatory Assistance, Baylor University Medical Center, 1151 N Buckner Blvd, #205, Dallas, TX Material and Methods Adult mongrel dogs were used. All animals received humane care in compliance with the "Principles of Laboratory Animal Care" set forth by the National Society for Medical Research and the "'Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication 85-23, revised 1985). The dogs were sedated and then anesthetized with isoflurane 2%. A cuffed endotracheal tube was inserted, and ventilation was provided with a volume respirator. A canine right heart bypass preparation was established through a median sternotomy with cannulation of the right atrial appendage and right femoral vein for venous return. Arterial flow was provided through the pulmonary artery for right heart bypass and through the left subclavian artery for total heart bypass. The right IMA was dissected from the chest wall as a pedicle graft, and its side branches were secured with metal clips. Graft flow was measured with an electromagnetic flow probe (Carolina Medical Electronics, King, NC) placed around the proximal aspect of an area of partially skeletonized IMA. The probe was calibrated before each baseline reading using the autocalibration feature. Previous studies have demonstrated the probe accuracy, after autocalibration, to be within I to 2 ml/min [9]. Total bypass was established, and the animal was kept normothermic. The heart was then arrested with cold cardioplegic solution, 10 ml/kg (potassium concentration 20 meq/l, ph 7.80), after the application of an aortic crossclamp. An end-to-side anastomosis was then constructed 1996 by The Society of Thoracic Surgeons /$15.00 Published by Elsevier Science Inc PII S (96)

2 1368 G1TTER ET AL Ann Thorac Surg DRUG EFFECTS ON CANINE GRAFTS 1996;61: Table 1. Internal Mammary Artery Blood Flow (ml/min)" Dose Percentage Drug (~g kg -1 min 1) Control Drug Change Norepinephrine (n = 8) b Norepinephrine + phentolamine (n = 8) 0.1/ (8:5 ratio) 39 _ b Milrinone (n = 8) 50 p.g/kg loading, then _ _+ 9 ~ a Values are mean standard error of the mean. b p < 0.05 compared with milrinone, c p < 0.02 compared with control. from the right IMA to the proximal left anterior descending coronary artery with a continuous 7-0 monofilament suture. The cross-clamp was released and a 15-minute recovery period was allowed. The left anterior descending coronary artery was then ligated distal to the first diagonal branch and proximal to the coronary anastomosis. At this time, right heart bypass was resumed. Measurements Aortic and left atrial pressures were measured through fluid-filled catheters inserted through the common carotid artery and the right superior pulmonary vein, respectively. The left ventricular pressure was monitored with a Mikro-Tip pressure transducer (Millar Instruments, Inc, Houston, TX) inserted through the ventricular apex and secured with a pursestring suture. All pressures were recorded on a monitor (Marquette Electronics, Milwaukee, WI). Cardiac output was kept constant at 100 ml kg 1. min -1 by right heart bypass with infusion of blood into the pulmonary artery. Blood pressure was kept constant by systemic arterial blood infusion or withdrawal from the femoral artery. Heart rate remained constant throughout the experiment. Experimental Protocol Eight mongrel dogs were used for the experiment. The average weight of the dogs was 26.5 kg. Six animals were male and 2 were female. Pharmacologic agents were given in order of their half-lives so that the longest-acting drug was infused last. Norepinephrine (0.1 /~g. kg 1. min 1) or norepinephrine plus phentolamine was given in random order, followed by milrinone (50/~g/kg loading dose, followed by 0.5 /~g kg -1 min 1). Norepinephrine and phentolamine are cleared relatively rapidly (2 minutes and 19 minutes, respectively), whereas milrinone has a half-life of 2.3 hours. Control blood flow and hemodynamic indices were determined before each drug administration. Each pharmacologic intervention was effected at least 15 minutes before measurement. Ample time was allowed for each animal's indices to return to baseline before infusion of the new drug (approximately 30 minutes). All hemodynamic indices were held constant to isolate the effect of the drug on graft flow. Statistical Analysis The hemodynamic indices for each pharmacologic intervention were compared with control levels. The significance of hemodynamic changes and percentage changes from control flow were tested using a two-tailed, paired Student's t test. Probability values less than 0.05 were considered statistically significant. Results Control blood flow in each graft varied with time; therefore, control flow was measured just before each drug administration. Because the control flow in each graft was variable, expression and comparison of the data were done in percentage change from control flow as well as absolute flow. The vasoactive drug effects on percentage change in blood flow in each graft are shown in Table 1. Hemodynamic effects of drug administration are given in Table 2. Norepinephrine administration at a rate of 0.1/~g' kg 1 Table 2. Hemodynamic Variables a AoP AoP LVP LA--P HR Measurement (mm Hg) (ram Hg) (ram Hg) (mm Hg) (beats/min) Control 124/51 ~ 8/7 75 _ _ _+ 10 Norepinephrine (n = 8) 135/50 _+ 8/8 75 _ _ _ Control 128/55 ± 7/7 76 _ _ _ Norepinephrine + phentolamine 137/47 _+ 8/9 75 +_ _ (n = 8) Control 128/52 ~ 8/7 75 _ _ 5 10 _ _+ 10 Milrinone (n - 8) 139/47 ~ 11/ _ a Values are mean -+ standard error of the mean. AoP = phasic aortic pressure; AoP = mean aortic pressure; pressure. HR = heart rate; LAP = mean left atrial pressure; LVP = left ventricular

3 Ann Thorac Surg GITTER ET AL ;61: DRUG EFFECTS ON CANINE GRAFTS min ~ caused a nonsignificant decrease in the IMA flow (-9% -+ 7%), from 41 _+ 8 ml/min to 39 +_ 9 ml/min. Hemodynamic variables remained unchanged from baseline levels. The norepinephrine and phentolamine combination was administered at a rate of 0.1 /J,g kg -1 min -~ norepinephrine with phentolamine added in an 8:5 ratio. Control versus drug showed a nonsignificant increase in IMA flow, although there were marked variations in IMA flows among animals. Significant changes measured between the control and norepinephrine plus phentolamine infusion included a rise in aortic systolic pressure (10% 2%) from 128 +_ 7 mm Hg to 137 _+ 8 mm Hg (p = 0.05) and a fall in aortic diastolic pressure (-19% -+ 7%) from 55 ± 7 mm Hg to mm Hg (p = 0.02). However, the mean aortic blood pressure and all other hemodynamic indices were unchanged. Milrinone was administered at a loading close of 50/~g/kg followed by an infusion of 0.5 p~g kg -1 min -~. The IMA showed a significant increase in blood flow (33% +_ 9%; p = 0.02), from ml/min to ml/min. Milrinone caused no significant changes in hemodynamic variables. Norepinephrine percentage change compared with norepinephrine plus phentolamine percentage change did not show any significant hemodynamic differences. Norepinephrine alone and combined with phentolamine, when compared with milrinone, produced a significantly lower IMA flow rate (p ~ 0.01). Comment Methods of using the IMA have paralleled the evolution of techniques for myocardial revascularization. Direct implantation of the IMA into the myocardium was accomplished 40 years ago and resulted in good patency, but revascularized only a small amount of myocardium [10, 11]. Since Vineberg's original operation in 1950, the art of coronary artery bypass grafting has emerged with great success both macroscopically, as evident in overall patient survival and operation success, and microscopically, with the higher resolution of today's insight into graft physiology and graft patency. A variety of vasoactive substances are released during cardiopulmonary bypass [12]. It is also frequently necessary to use vasoactive agents in the immediate postcardiopulmonary bypass period for hemodynamic support in patients who have undergone coronary revascularization [13]. Because the IMA has emerged as the ideal conduit in the past several years, we studied the effects of three commonly used drugs on blood flow in the IMA after anastomosis to the left anterior descending coronary artery. A canine model was chosen to compare our results with those using other drugs in this model [14]. These drugs are used clinically to restore hemodynamic stability, but these agents may alter not only hemodynamic indices, but also graft flow. Obviously, any reduction in caliber or flow would be undesirable and could have catastrophic consequences, depending on the area revascularized by the IMA [15]. This study, similar to our previous work, effectively isolated the influence of vasoactive drugs on the graft by maintaining constant systemic hemodynamic indices [16-18]. In this sense, the study is not a clinical analogue, but the hemodynamic variables were kept constant to isolate the effects of the drug on IMA blood flow. Graft flow is dependent not only on the effect of the drug on the conduit, but also on the effect of the drug on the regional vasculature. Alterations in graft flow may be due to the effect of the drug on the conduit, the coronary vasculature, or both. Norepinephrine tended to decrease blood flow through the IMA. Although previous studies have shown a significant increase in IMA blood flow caused by norepinephrine, there was an associated increase in rate of left ventricular pressure increase, representing an increase in myocardial oxygen consumption and thus probably accounting for the increase in IMA flow [14]. Our present study demonstrated no significant changes in any hemodynamic index with norepinephrine and no significant alteration in IMA graft blood flow. Recent studies in humans support our results [9]. Norepinephrine is a potent c~-adrenergic vasoconstrictor and a relatively mild /3-adrenergic agonist that has positive inotropic and chronotropic effects. Its marked pressor effects are primarily due to increased peripheral vascular resistance mediated through both ~1 and ~2 postsynaptic receptors. Recent studies have shown that the human IMA is devoid of o~ 2 postsynaptic receptors in comparison with the saphenous vein, which contains both ~1 and o~ 2 postsynaptic receptors [19]. This is a possible explanation for the significant flow reduction effects of norepinephrine on the saphenous vein graft as opposed to the nonsignificant effect on the IMA [19]. Phentolamine combined with norepinephrine also had no significant influence on graft flow. Phentolamine, an ~-adrenergic blocking agent, is clinically used with norepinephrine to isolate the /3 effect of norepinephrine, thus reducing afterload while increasing contractility in patients with postcardiotomy ventricular dysfunction. The lack of effect on IMA flow is probably due to the scarcity of ~-adrenoceptors in the IMA [20]. Milrinone is a potent analogue of the cardiac bipyridine amrinone. Milrinone acts by inhibiting cyclic adenosine monophosphate phosphodiesterase, thereby increasing the intracellular concentration of cyclic adenosine monophosphate [21], which increases calcium uptake in myocardial and smooth muscle cells. The increased cyclic adenosine monophosphate results in increased inotropy and vasodilation [22]. Clinically, this results in increased cardiac output, reduction of left ventricular filling pressure, and reduction in peripheral vascular resistance [23, 24]. In addition, the phosphodiesterase inhibitors have been demonstrated to have an oxygen-sparing effect on the failing myocardium, with a decrease in myocardial oxygen consumption accompanying an improved inotropic state [25]. Milrinone significantly increased IMA flow in our

4 1370 GITTER ET AL Ann Thorac Surg DRUG EFFECTS ON CANINE GRAFTS 1996;61: study. This increase in IMA flow alone would be beneficial clinically, but milrinone has the added benefit of improving the inotropic state of the heart without an increase in oxygen consumption. Although we have previously demonstrated that nitroglycerin increases IMA flow [14], it lacks the favorable effect on inotropy of the heart. Recent studies have shown that amrinone, with the same mechanism of action as milrinone, can be used effectively as a primary and solo agent in the treatment of low cardiac output syndrome after myocardial revascularization [26]. In addition, amrinone-induced hemodynamic benefits compare favorably with those of dobutamine, except that postoperative myocardial infarctions are significantly reduced with the phosphodiesterase inhibitors [26]. The phosphodiesterase inhibitors would also have the added benefit of increasing IMA blood flow. Epinephrine also significantly increases IMA flow [14], but in addition it increases the inotropy of the heart and would adversely affect the heart by increasing myocardial oxygen consumption. There has been little work done with milrinone to study its effect in vivo on blood flow or in vitro on arterial contraction. There have been investigations on the effects of other phosphodiesterase inhibitors in vitro on arterial contraction/relaxation. Papaverine, also a phosphodiesterase inhibitor, has been shown to prevent mammary artery contraction or spasm [27]. Therefore, another potential benefit of milrinone would be to prevent postoperative IMA spasm through its phosphodiesterase inhibitor mechanism. Although nitroglycerin can cause IMA relaxation, it will not prevent IMA contraction or spasm [27, 28]. Although milrinone tended to increase heart rate, it has been demonstrated that the chronotropic activity of milrinone is less than its inotropic activity [22]. Even with an increased inotropic state, the myocardial oxygen consumption is unchanged [25]. In conclusion, our results demonstrate that although different inotropic and chronotropic agents are commonly used after IMA grafting, their individual effects on the IMA must be taken into account. In our study, IMA graft flow was dependent not only on the effect of the drug on the conduit, but also on the effect of the drug on the regional vasculature. Norepinephrine, alone or when combined with phentolamine, had no significant effect on IMA flow. Milrinone, however, significantly increased IMA flow. In addition to improving IMA flow, milrinone can improve the inotropy of the heart, thus making it an advantageous agent. The IMA is a dynamic and pharmacologically sensitive vessel. Proper drug selection in the postcardiopulmonary bypass period may greatly influence IMA blood flow and subserved myocardial oxygenation. References 1. Loop FD, Lytle BW, Cosgrove DM, et al. 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5 Ann Thorac Surg GITTER ET AL ;61: DRUG EFFECTS ON CANINE GRAFTS cardiac bipyridine, on isolated tissues from several animal species. J Cardiovasc Pharmacol 1983;5: Anderson JL. Hemodynamic and clinical benefits with intravenous milrinone in severe chronic heart failure: results of a multicenter study in the United States. Am Heart J 1991;121: Feneck RO. Intravenous milrinone following cardiac surgery: II. Influence of baseline hemodynamics and patient factors on therapeutic response. J Cardiothorac Vasc Anesth 1992;6: Benotti JR, Grossman W, Braunwald E, Carabello BA. Effects of amrinone on myocardial energy metabolism and hemodynamics in patients with severe congestive heart failure due to coronary artery disease. Circulation 1980; 62: Dupuis JY, Bondy R, Cattran C, Nathan HJ, Wynards JE. Amrinone and dobutamine as primary treatment of low cardiac output syndrome following coronary artery surgery: a comparison of their effects on hemodynamics and outcome. J Cardiothorac Vasc Anesth 1992;6: Jett GK, Guyton RA, Hatcher CR, Abel PW. Inhibition of human internal mammary artery contractions. J Thorac Cardiovasc Surg 1992;104: He GW, Rosenfeldt PC, Buxton BF, Angus JA. Reactivity of isolated human internal mammary artery to constrictor and dilator agents. Circulation 1989;80(Suppl 1): The Society of Thoracic Surgeons: Thirty-third Annual Meeting Mark your calendars for the Thirty-third Annual Meeting of The Society of Thoracic Surgeons, which will be held at the San Diego Convention Center in San Diego, California, February 3-5, Members may register for the Scientific Sessions at no charge. There will be a $250 registration fee for nonmember physicians except for Scientific and Poster Session presenters and residents. Registration for the Postgraduate Course is separate from the Annual Meeting. There will be a $70 registration fee for attendees of the Postgraduate Program, which will be held Sunday, February 2. The Postgraduate Course will provide in-depth coverage of thoracic surgical topics selected to enhance and broaden the knowledge of practicing thoracic and cardiac surgeons. Advance registration forms, hotel reservation forms, and details regarding transportation arrangements, as well as the complete meeting program, will be mailed to Society members this fall (1996). Nonmembers wishing to receive information on attending the meeting should write to the Society's Secretary, Peter C. Pairolero. Peter C. Pairolero, MD Secretary The Society of Thoracic Surgeons 401 N Michigan Ave Chicago, IL (312)