- Email: [email protected]
Safety, Tolerance, and Efficacy of Adenosine as an Additive to Blood Cardioplegia in Humans During Coronary Artery Bypass Surgery
Safety, Tolerance, and Efficacy of Adenosine as an Additive to Blood Cardioplegia in Humans During Coronary Artery Bypass Surgery Robert M. Mentzer, Jr., MD, Peter S. Rahko, MD, Victor Molina-Viamonte, MD, Charles C. Canver, MD, Paramjeet S. Chopra, MD, Robert B. Love, MD, Thomas D. Cook, PhD, Julia O. Hegge, BS, and Robert D. Lasley, PhD Myocardial stunning after heart surgery is associated with increased morbidity and mortality in patients with severe multivessel disease and reduced myocardial function. The purpose of this study was to evaluate the safety, tolerance, and efficacy of adenosine as a cardioprotective agent when added to blood cardioplegia in patients undergoing coronary artery bypass surgery. Sixty-one patients were randomized to standard coldblood cardioplegia, or cold-blood cardioplegia containing 1 of 5 adenosine doses (100 mM, 500 mM, 1 mM, 2 mM, and 2 mM with a preischemic infusion of 140 mg/kg/min of adenosine). Invasive and noninvasive measurements of ventricular performance and rhythm were obtained preoperatively, prebypass, and then at 1, 2, 4, 8, 16, and 24 hours postbypass. Use of inotropic agents and vasoactive drugs postoperatively was recorded; blood samples were collected for measurement of nucleoside levels. High-dose adenosine treatment was
associated with a 249-fold increase in the plasma adenosine concentration and a 69-fold increase in the combined levels of adenosine, inosine, and hypoxanthine (p õ0.05). Increasing doses of the adenosine additive were also associated with lower requirements of dopamine (p Å 0.003) and nitroglycerine (p Å 0.001). The 24-hour average doses for dopamine and nitroglycerine in the placebo group were 28-fold and 2.6-fold greater than their respective high-dose adenosine treatment cohorts. Finally, the placebo- and 100 mM-adenosine group was associated with a lower ejection fraction when compared to patients receiving the intermediate dose or high-dose treatment. These findings are consistent with the hypothesis that adenosine is effective in attenuating myocardial stunning in humans. Q1997 by Excerpta Medica, Inc. Am J Cardiol 1997;79(12A):38–43
yocardial stunning after heart surgery is not an uncommon problem despite marked improveM ment in surgical techniques and the development of
One cardioprotective agent to be considered in the development of new cardioplegic solutions is the nucleoside adenosine. This agent is a potent coronary vasodilator with known negative chronotropic, dromotropic, and anti-adrenergic properties.1 More recently, the nucleoside has been identified as one of the mediators of ischemic preconditioning, a phenomenon associated with reduction in myocardial infarct size.2 Because adenosine has been shown to reduce experimental myocardial stunning in numerous species,3 – 5 the purpose of this study was to evaluate the safety and tolerance of adenosine as an additive to blood cardioplegia during cardiac surgery in humans.
strategies designed to protect the heart during intraoperative cardiac arrest. Considerable controversy persists, however, regarding the ideal cardioplegic solution. This is partly due to the observation that myocardial stunning is frequently observed and associated with increased morbidity and mortality, especially in patients with acute disease, advanced age, and decreased myocardial reserve. The limitations of currently employed cardioplegic solutions are particularly evident in heart surgery candidates with poor ventricular function. As many as 20–25% of these individuals require major inotropic support to wean from cardiopulmonary bypass or to maintain adequate cardiac outputs in the immediate postoperative period. Thus, there is a need to develop cardioprotective strategies that significantly modify the components of existing cardioplegic solutions. From the University of Wisconsin, Division of Cardiothoracic Surgery, Section of Cardiology, Department of Biostatistics, Milwaukee, Wisconsin and Department of Internal Medicine, Duke University, Durham, North Carolina. Supported by grants NIH RO1 NL-34579, NIH PO1 HL-47053, and Medco Research, Inc. Address for reprints: Robert M. Mentzer, Jr., MD, University of Kentucky Medical Center, Department of Surgery, Room MN 264, 800 Rose Street, Lexington, KY 40536-0084.
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METHODS The protocol for this prospective, open-label, placebo-controlled study was approved by the Institutional Review Board of the University of Wisconsin. Study patients were in overall good health with an ejection fraction ú0.30. Exclusion criteria included females of known or suspected pregnancy, lactating females, presence of high-grade atrioventricular (AV) block or presence of sinus node dysfunction, presence of bronchospasm or bronchoconstrictive disease, and known hypersensitivity to adenosine. Inclusion criteria included males or females ú18 years of age who were scheduled for elective heart
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surgery and had the willingness and ability to give signed informed consent.
STUDY DESIGN The study was a single-center 7-day investigation of adenosine as an additive to cold-blood cardioplegia in patients undergoing coronary artery bypass surgery. Sixty-one patients were randomized to standard cold-blood cardioplegia or cold-blood cardioplegia containing 1 of 5 adenonine doses (100 mM, 500 mM, 1 mM, 2 mM, and 2 mM with a preischemic infusion of 140 mg/kg/min of adenosine). The preischemic adenosine treatment consisted of continuously infusing the agent for 10 minutes into the venous reservoir, at which time the aortic crossclamp was applied. The first dose of cardioplegia was then administered. Subsequent cardioplegic infusions and the duration of the infusion including the method of delivery were left to the surgeon’s discretion. Multiple measurements of ventricular performance and rhythm were obtained preoperatively, prebypass, and then at 1, 2, 4, 8, 16, and 24 hours after cessation of cardiopulmonary bypass. The electrocardiogram (ECG) was monitored continuously throughout the operation and for the first 24 hours postoperatively. Hemodynamic measurements included arterial blood pressure (BP), heart rate (HR), and central venous pressure (CVP). An Edwards Laboratory SwanGanz catheter was used to measure pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), and thermodilution cardiac output (CO). The cardiac index (CI), stroke volume (SV), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), right ventricular stroke work index (RVSWI), and left ventricular stroke work index (LVSWI) were derived from standard equations using a computer. Noninvasive evaluations of cardiac function included transesophageal echocardiography and transthoracic echocardiography. The transesophageal echocardiography was performed intraoperatively during the prebypass period, after the patient was stabilized after induction (but before the chest was opened), immediately postbypass after the patient was fully rewarmed and hemodynamics stabilized, and before the patient left the operating room. The transthoracic echocardiography was obtained the day before surgery and 7 days postoperatively. Regional wall motion was scored using the American Society of Echocardiography 16-segment model. Normal or hyperkinetic segments were assigned a score of 1/; hypokinetic segments 2/; akinetic segments 3/; dyskinetic segments 4/; and an aneurysm 5/. A wall motion score index was calculated by dividing the sum of segmental point scores by the number of segments analyzed. Left ventricular volume in the apical 2-chamber and 4-chamber views at end systole and end diastole was quantified by an on-line analysis package in the ultrasound system using the biplane method of discs. The left ventricular ejection fraction was calculated from these data. The use of inotropic agents (dopamine, dobutamine, norepinephrine, epinephrine, and
amrinone) and vasoactive drugs (nitroglycerine, nitroprusside, phenylephrine, ephedrine) was recorded for 24 hours after cessation of cardiopulmonary bypass. The institutional preference was to use dopamine to treat low cardiac output (cardiac index õ2.0) and nitroglycerine to treat ischemia and/or hypertension. In this Phase I study, trigger points for initiating the administration of specific vasoactive agents and doses were not specified. Each patient’s average drug dose over 24 hours was estimated as the area under the dose–response curve (AUC). Finally, plasma levels of adenosine and its degradation products, inosine and hypoxanthine, were measured during bypass and immediately postbypass. During bypass, 4ml blood samples were drawn immediately before and after the first, second, and last dose of cardioplegia. Postbypass central venous samples were drawn at 1 hour and 24 hours. In the pretreatment adenosine/cardioplegia group, blood samples were collected before pretreatment and after the first dose of cardioplegia. Due to the short half-life of adenosine in blood (õ10 seconds), all blood samples were placed immediately in an ice-cold stop solution containing dipyridamole (0.4 mmol/L), sodium ethylene diaminetetraacetic acid (EDTA; 8.4 mmol/L), 5-a, b-methylene adenosine 5*-diphosphate (AOPCP, 159 mmol/L), and (erythro-9)-2-hydroxy-3-nonyl adenine (EHNA, 10 mM/L) to prevent degradation of the nucleoside. Purine concentrations in plasma samples were determined by high performance liquid chromatography (HPLC) using previously described methods.6
STATISTICAL ANALYSIS The statistical analysis was based on the intention-to-treat principle. Results for all patients for whom follow-up data were available were included in analysis of the treatment groups. Demographic and plasma purine concentration data were analyzed by 1-way analysis of variance followed by the post hoc test. The effects of increasing doses of adenosine in the cardioplegic solution on cardiopulmonary bypass variables, drug use, regional wall motion, and global function were analyzed using Kendall’s statistic for dose–response trends. A p-value õ0.05 was considered statistically significant. RESULTS Patient demographics and the relationship between cardiopulmonary bypass perioperative variables, postoperative hemodynamics, ECG changes, and the treatment groups: The distribution of gender, age, weight,
preoperative ejection fraction, bypass time, and grafts per patients were the same in all treatment groups. The addition of adenosine to blood cardioplegia had no effect on cardiopulmonary bypass time, aortic crossclamp time, or postbypass BP, HR, CVP, PAP, PCWP, CO, CI, SV, SVR, PVR, RVSWI, and LVSWI. Similarly, there were no significant changes in regional wall motion detected by transesophageal echocardiography or intraoperative
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FIGURE 1. The relation between concentration of adenosine in cold-blood cardioplegia and venous adenosine levels. Blood samples were taken from the venous tubing of the bypass circuit. n Å number of patients; ADO Å adenosine.
ECG changes throughout the 24-hour time period among the various treatment groups. The effect of the adenosine addition on plasma adenosine, inosine, and hypoxanthine levels: The relation
between the treatment groups and venous plasma adenosine levels is shown in Figures 1 and 2. In the untreated group baseline adenosine and the summation of adenosine and its degradation products, inosine and hypoxanthine, were 0.17 { 0.09 mmol/ L and 1.70 { 0.19 mmol/L, respectively. These values are consistent with levels reported elsewhere for humans and other animal species. Increasing the dose of adenosine in blood cardioplegia resulted in marked increases in plasma levels. For example, high-dose adenosine treatment was associated with a 249-fold increase in the plasma adenosine concentration and a 69-fold increase in the combined levels of adenosine, inosine, and hypoxanthine. In all treatment groups, the venous plasma adenosine levels returned to control levels before the infusion of the next dose of cardioplegia. The 1-hour and 24-hour postbypass levels of adenosine and the combined adenosine, inosine, and hypoxanthine levels were the same as the control values. The effect of the adenosine addition on postbypass drug usage: The relation between adenosine treat-
ment and drug use is shown in Tables I and II. Adenosine treatment had no effect on dobutamine, amrinone, nitroprusside, or phenylephrine use. Data for epinephrine and ephedrine are not shown because only 4 and 6 patients received these drugs in the postbypass period, respectively. In contrast, 67% (41/61) and 88% (54/61) of all patients received dopamine and nitroglycerine within the first 24 hours of surgery. In these patients, increasing doses of adenosine were associated with a 65% (p Å 0.003) and 67% (p Å 0.001) probability of receiving less dopamine and nitroglycerine, respectively. Also, the number of patients who received dopamine and ni40
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FIGURE 2. The effect of increasing the concentration of adenosine in cold-blood cardioplegia on venous total adenosine, inosine, and hypoxanthine levels. n Å number of patients; Ado Å adenosine; INO Å inosine; HYPO Å hypoxanthine.
troglycerine (n ú0) in the postoperative period decreased as the adenosine concentration increased. The 24-hour average doses for dopamine and nitroglycerine in the placebo group were 28-fold and 2.6fold greater than their respective high-dose adenosine treatment cohorts. The effect of the adenosine additive on regional wall motion and global function assessed by transthoracic echocardiography: The relation between the dose of aden-
osine in the blood cardioplegia and changes in regional wall motion is shown in Figure 3. No changes in regional wall motion were noted in the septal (p Å 0.16), lateral region (p Å 0.59), and anteroseptal regions (p Å 0.12). In contrast, trend analysis revealed that the posterior region (p Å 0.001), the anterior region (p Å 0.007), and the inferior region (p Å 0.015) all showed significant improvement in function when compared to the preoperative values. Moreover, there was no significant deterioration in regional wall function in any of the regions studied postoperatively in patients receiving the additive. When the data were analyzed in the context of global function 7 days postoperatively and the treatment groups were collated into 3 groups (Figure 4), the placebo plus 100 mM adenosine group was associated with a lower ejection fraction when compared to the patients receiving the intermediate-dose or high-dose adenosine treatment.
DISCUSSION The results of this single-center, adenosine myocardial protection trial indicate that (1) the addition of adenosine to blood cardioplegia in patients undergoing coronary artery bypass surgery is safe and well tolerated; (2) increasing the concentration of the adenosine additive is associated with increased circulating plasma adenosine and its degradation products, inosine and hypoxanthine; and (3) high-dose adenosine treatment is associated with
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TABLE I Effect of Adenosine Additive on 24-Hour Dopamine, Dobutamine, and Amrinone Use Dobutamine† (AUC units/min)
Dopamine* (AUC units/min)
Amrinone‡ (AUC units/min)
Treatment
n
n ú0
Mean
SEM
n ú0
Mean
SEM
n ú0
Mean
SEM
Placebo 100 mM 500 mM 1 mM 2 mM Pre / 2 mM
13 11 9 10 9 9
12 9 6 6 6 2
1.69 2.40 0.72 0.94 2.18 0.06
0.39 0.62 0.36 0.46 0.81 0.04
2 2 2 1 0 1
0.28 1.25 0.64 0.17 0.00 0.10
0.19 1.16 0.45 0.17 0.00 0.10
2 3 1 1 0 0
0.32 0.87 0.14 0.31 0.00 0.00
0.22 0.58 0.14 0.31 0.00 0.00
AUC Å area under the curve; n Å number of patients; n ú0 Å number of patients who received drug; SEM Å standard error of the mean. *p Å 0.003, †p Å 0.347, ‡p Å 0.070, using Kendall’s t statistic for dose–response trend.
TABLE II Effect of Adenosine Additive on 24-Hour Nitroglycerin, Sodium Nitroprusside, and Phenylephrine Use Nitroprusside SNP† (AUC units/min)
Nitroglycerin* (AUC units/min)
Phenylephrine‡ (AUC units/min)
Treatment
n
n ú0
Mean
SEM
n ú0
Mean
SEM
n ú0
Mean
SEM
Placebo 100 mM 500 mM 1 mM 2 mM Pre / 2 mM
13 11 9 10 9 9
13 11 7 10 7 6
0.72 0.92 0.45 0.44 0.32 0.28
0.14 0.26 0.11 0.09 0.09 0.10
8 4 4 7 5 1
0.55 0.47 0.24 0.45 0.27 0.06
0.23 0.34 0.12 0.15 0.17 0.06
3 5 3 2 5 4
0.15 8.49 0.80 16.60 0.23 0.42
0.10 7.69 0.44 15.40 0.10 0.26
AUC Å area under the curve; n Å number of patients; n ú0 Å number of patients who received drug; SEM Å standard error of the mean; SNP Å sodium nitroprusside. *p õ0.001, †p Å 0.149, ‡p Å 0.424, using Kendall’s t statistic for dose–response trend.
decreases in use of dopamine and nitroglycerine as well as improved regional wall motion and global function 7 days postoperatively. These findings are consistent with the hypothesis that adenosine is effective in attenuating myocardial stunning in humans. Considerable experimental evidence indicates that adenosine is a cardioprotective agent. While several mechanisms have been implicated, the cardioprotective effect appears to be mediated, in part, by activation of the adenosine A1 receptor coupled
to the inhibitory guanosine (Gi) proteins.7,8 Adenosine also has a direct metabolic effect (i.e., it enhances the myocardial phosphorylation potential) and thereby improves myocardial energetics in the stunned heart.8,9 Others have reported that adenosine decreases oxygen-derived free radical production by neutrophils,10 an effect that could minimize the free-radical – induced damage believed to occur during reperfusion. Finally, increases in coronary blood flow during reperfusion could be beneficial both from the standpoint of increased oxygen and
FIGURE 3. Preoperative to postoperative changes in regional wall motion in the placebo and treatment groups. Regional wall motion was determined by transthoracic echocardiography obtained preoperatively and 7 days postoperatively. *p Å 0.060, **p Å 0.048, ***p Å 0.036.
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FIGURE 4. The effect of adenosine treatment on left ventricular ejection fraction assessed by transthoracic echo obtained 7 days after coronary bypass surgery (Post-op, º) compared to preoperative (Pre-op, j) function *p õ0.06.
substrate delivery and enhanced wash-out of toxic ischemic products. Thus, adenosine alters fundamental processes that occur in the myocyte before, during, and after ischemia such that postischemic damage is significantly attenuated. Despite many animal studies that support the hypothesis that adenosine is a cardioprotective agent, little is known about its anti-ischemic effects in humans. Intravenous adenosine infusions have been used after cardiac surgery to control postoperative systemic and pulmonary hypertension.11,12 However, the results of experimental studies indicate that adenosine’s cardioprotective effect is dependent on preischemic administration.4,5 In addition to the results of the present study, there are only 2 full reports of adenosine’s cardioprotective effects during heart surgery in humans. In 1995, Lee et al13 tested whether adenosine infusion in patients prior to undergoing coronary artery bypass grafting would improve postbypass myocardial hemodynamics. Seven patients were pretreated with adenosine and 7 served as controls. Adenosine was infused incrementally before the initiation of cardiopulmonary bypass at a rate of 50 mg/kg/min every minute until a dose of 350 mg/kg/min was reached. The total duration of the adenosine infusion lasted for 10 minutes or until the patient developed systemic arterial pressures õ70 mm Hg, at which time the infusion was discontinued. Five minutes after the completion of adenosine or the saline solution control infusion, patients were placed on cardiopulmonary bypass, and then underwent the standard bypass operation using cold-blood cardioplegia to facilitate arrest. The investigators concluded that adenosine treatment before the initiation of bypass was associated with improved postoperative myocardial function. Fremes et al14 reported the results of an openlabel, non-randomized Phase I adenosine dose-ranging study in patients scheduled for elective coronary artery bypass surgery. Anterograde warm-blood potassium cardioplegia was administered in routine 42
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fashion with adenosine added to the initial 1000-mL dose and final 500-mL dose. Adenosine concentrations of 0, 15, 20, and 25 mmol/L were tested. Although the investigators reported that hypotension during cardioplegic induction was more prevalent with higher doses, they concluded that adenosine can be safely administered as a supplement to cardioplegic formulations when used in the range of 15– 25 mmol/L. One concern with the use of intravenous adenosine infusions is the potential for systemic hypotension due to adenosine’s vasodilatory properties. However, in the present study and that by Lee et al,13 the high doses of adenosine during the pretreatment infusions and as an additive to the cardioplegic solutions were well tolerated. Fremes et al14 reported that at adenosine concentrations of ú25 mmol/L patients developed more conduction disturbances, hypotension, and phenylephrine requirements than with lower doses. We were unable, however, to document a significant trend in the use of phenylephrine in any of the patients receiving adenosine. The side effects associated with the lower doses of adenosine in the study by Fremes et al14 may be due to the use of normothermic cardioplegia and not to actively lowering the core body temperature. Although our findings of the safety and efficacy of high-dose adenosine are similar to those of Lee et al,13 there is 1 major difference between the 2 protocols. Lee et al treated patients with an intravenous adenosine infusion that was terminated 5 minutes before the initiation of cardiopulmonary bypass—a treatment referred to as adenosine preconditioning. In contrast, in the present study, 4 groups of patients received adenosine only as an additive to the cardioplegic solution. In the fifth group, patients were administered a pretreatment adenosine infusion that was not terminated until the time of aortic crossclamping. The infusion protocol was based on experimental findings that (1) adenosine preconditioning reduces myocardial infarct size,2,15,16 and (2) uninterrupted infusions before the onset of ischemia attenuate myocardial stunning.5,16 While the results of Lee et al13 suggest that adenosine preconditioning may attenuate stunning in humans, limitations of this study include the small sample size and the variability in the total dose of adenosine administered. The concept of adenosine preconditioning is based on the hypothesis that adenosine mediates, in part, the cardioprotective effects of ischemic preconditioning. The protective effects of ischemic preconditioning in experimental ischemia models have generated much excitement over their use in clinical settings. Similar to the few reports on adenosine cardioprotection in humans, there is a lack of data on ischemic preconditioning during cardiac surgery. Yellon et al17 reported that ischemic preconditioning in humans during coronary bypass surgery was associated with a slower rate of ATP depletion—an observation consistent with findings reported in animals subjected to ischemic preconditioning.18 In this study, 7
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patients underwent ischemic preconditioning with two 3-minute periods of crossclamping, interspersed with 2 minutes of reperfusion before application of the aortic crossclamp and subsequent grafting of a coronary artery. In the control group, 7 patients received only the ischemic insult of 10 minutes of aortic crossclamp fibrillation. The impact of this protocol on regional or global ventricular function, however, was not assessed. Perrault et al19 recently reported that 3 minutes aortic crossclamping and 2 minutes reperfusion before warm-blood cardioplegic arrest in patients during coronary bypass surgery did not enhance myocardial protection. As in the study by Yellon et al,17 ventricular function was not assessed. Because ischemic preconditioning is not associated with enhanced postischemic recovery of function in animal models,16,20 it remains to be determined whether ischemic preconditioning will benefit patients undergoing open heart surgery. The major limitations of our adenosine myocardial protection trial include the relatively small number of patients, the absence of specific trigger points for the administration of inotropic agents and vasodilators, and the lack of specific endpoints that define myocardial stunning. Because the primary endpoint, however, was safety and tolerance, it is interesting that the findings strongly suggest a dose–response efficacy. Certainly the next step is to proceed with a multicenter clinical trial, perhaps in high risk patients with more defined endpoints, to determine the clinical relevancy of the experimental findings to date. 1. Belardinelli L, Shryock JC, Song Y, Wang D, Srinivas M. Ionic basis of the
electrophysiological actions of adenosine on cardiomyocytes. FASEB J 1995; 9:359–65. 2. Liu GS, Thornton J, Van Winkle D, Stanley AWH, Olsson RA, Downey JM. Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart. Circulation 1991;84:350–356.
3. Lasley RD, Mentzer RM Jr. Adenosine improves recovery of postischemic myocardial function via an adenosine A1 receptor mechanism. Am J Physiol 1992;263: H1460–5. 4. Randhawa MPS Jr, Lasley RD, Mentzer RM Jr. Salutary effects of exogenous adenosine on canine myocardial stunning in vivo. J Thorac Cardiovasc Surg 1995;110:63–74. 5. Sekili S, Jeroudi MO, Tang XL, Zughaib M, Sun JZ, Bolli R. Effect of adenosine on myocardial ‘‘stunning’’ in the dog. Circ Res 1995;76:82–94. 6. Mentzer RM Jr, Rahko PS, Canver CC, Chopra PS, Love RB, Cook TD, Hegge JO, Lasley RD. Adenosine reduces postbypass transfusion requirements in humans after heart surgery. Ann Surgery 1996;224:523–529. 7. Lasley RD, Mentzer RM Jr. Pertussis toxin blocks adenosine A1 receptor mediated protection of the ischemic rat heart. J Mol Cell Cardiol 1993;25:815– 21. 8. Mentzer RM Jr, Bunger R, Lasley RD. Adenosine enhanced preservation of myocardial function and energetics. Possible involvement of the adenosine A1 receptor system. Cardiovasc Res 1993;27:28–35. 9. Zhou Z, Bu¨nger R, Lasley RD, Hegge JO, Mentzer RM Jr. Adenosine pretreatment increases cytosolic phosphorylation potential and attenuates postischemic cardiac dysfunction in swine. Surg Forum 1993;44:249–52. 10. Cronstein BN, Kramer SB, Weissmann G, Hirschhorn R. Adenosine: a physiological modulator of superoxide anion generation by human neutrophils. J Exper Med 1983; 158:1160–77. 11. Owall A, Ehrenberg J, Brodin LA, Juhlin-Dannfelt A, Sollevi A. Effects of low-dose adenosine on myocardial performance after coronary artery bypass surgery. Acta Anaesthesiol Scand 1993;37:140–148. 12. Fullerton DA, Jones SD, Grover FL, McIntyre RC Jr. Adenosine effectively controls pulmonary hypertension after cardiac operations. Ann Thorac Surg 1996;61:1118–1123. 13. Lee HT, Lafaro RJ, Reed GE. Pretreatment of human myocardium with adenosine during open heart surgery. J Cardiac Surg 1995;10:665–676. 14. Fremes SE, Levy SL, Christakis GT, Walker SE, Iazetta J, Mallidi HR, Federelituv R, Deemar KA, Cohen EA, Wong BI, Goldman BS. Phase 1 human trial of adenosine-potassium cardiolplegia. Circulation 1996;94(suppl II):II– 370–375. 15. Lasley RD, Konyn PJ, Hegge JO, Mentzer RM Jr. The effects of ischemic and adenosine preconditioning on interstitial fluid adenosine and myocardial infarct size. Am J Physiol 1995;269:H1460–H1466. 16. Lasley RD, Noble MA, Konyn PJ, Mentzer RM Jr. Different effects of an adenosine A(1) analogue and ischemic preconditioning in isolated rabbit hearts. Ann Thorac Surg 1995;60:1698–1703. 17. Yellon DM, Alkhulaifi AM, Pugsley WB. Preconditioning the human myocardium. Lancet 1993;342:276–7. 18. Murry CE, Richard VJ, Reimer KA, Jennings RB. Ischemic preconditioning slows energy metabolism and delays ultrastructural damage during a sustained ischemic episode. Circ Res 1990;66:913–31. 19. Perrault LP, Menasche P, Bel A, Dechaumaray T, Peynet J, Mondry A, Olivero P, Emanoilravier R, Moalic JM. Ischemic preconditioning in cardiac surgery—a word of caution. J Thorac Cardiovasc Surg 1996;112:1378–1386. 20. Ovize M, Przyklenk K, Hale SL, Kloner RA. Preconditioning does not attenuate myocardial stunning. Circulation 1992;85:2247–54.
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associated with a 249-fold increase in the plasma adenosine concentration and a 69-fold increase in the combined levels of adenosine, inosine, and hypoxanthine (p õ0.05). Increasing doses of the adenosine additive were also associated with lower requirements of dopamine (p Å 0.003) and nitroglycerine (p Å 0.001). The 24-hour average doses for dopamine and nitroglycerine in the placebo group were 28-fold and 2.6-fold greater than their respective high-dose adenosine treatment cohorts. Finally, the placebo- and 100 mM-adenosine group was associated with a lower ejection fraction when compared to patients receiving the intermediate dose or high-dose treatment. These findings are consistent with the hypothesis that adenosine is effective in attenuating myocardial stunning in humans. Q1997 by Excerpta Medica, Inc. Am J Cardiol 1997;79(12A):38–43
yocardial stunning after heart surgery is not an uncommon problem despite marked improveM ment in surgical techniques and the development of
One cardioprotective agent to be considered in the development of new cardioplegic solutions is the nucleoside adenosine. This agent is a potent coronary vasodilator with known negative chronotropic, dromotropic, and anti-adrenergic properties.1 More recently, the nucleoside has been identified as one of the mediators of ischemic preconditioning, a phenomenon associated with reduction in myocardial infarct size.2 Because adenosine has been shown to reduce experimental myocardial stunning in numerous species,3 – 5 the purpose of this study was to evaluate the safety and tolerance of adenosine as an additive to blood cardioplegia during cardiac surgery in humans.
strategies designed to protect the heart during intraoperative cardiac arrest. Considerable controversy persists, however, regarding the ideal cardioplegic solution. This is partly due to the observation that myocardial stunning is frequently observed and associated with increased morbidity and mortality, especially in patients with acute disease, advanced age, and decreased myocardial reserve. The limitations of currently employed cardioplegic solutions are particularly evident in heart surgery candidates with poor ventricular function. As many as 20–25% of these individuals require major inotropic support to wean from cardiopulmonary bypass or to maintain adequate cardiac outputs in the immediate postoperative period. Thus, there is a need to develop cardioprotective strategies that significantly modify the components of existing cardioplegic solutions. From the University of Wisconsin, Division of Cardiothoracic Surgery, Section of Cardiology, Department of Biostatistics, Milwaukee, Wisconsin and Department of Internal Medicine, Duke University, Durham, North Carolina. Supported by grants NIH RO1 NL-34579, NIH PO1 HL-47053, and Medco Research, Inc. Address for reprints: Robert M. Mentzer, Jr., MD, University of Kentucky Medical Center, Department of Surgery, Room MN 264, 800 Rose Street, Lexington, KY 40536-0084.
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METHODS The protocol for this prospective, open-label, placebo-controlled study was approved by the Institutional Review Board of the University of Wisconsin. Study patients were in overall good health with an ejection fraction ú0.30. Exclusion criteria included females of known or suspected pregnancy, lactating females, presence of high-grade atrioventricular (AV) block or presence of sinus node dysfunction, presence of bronchospasm or bronchoconstrictive disease, and known hypersensitivity to adenosine. Inclusion criteria included males or females ú18 years of age who were scheduled for elective heart
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surgery and had the willingness and ability to give signed informed consent.
STUDY DESIGN The study was a single-center 7-day investigation of adenosine as an additive to cold-blood cardioplegia in patients undergoing coronary artery bypass surgery. Sixty-one patients were randomized to standard cold-blood cardioplegia or cold-blood cardioplegia containing 1 of 5 adenonine doses (100 mM, 500 mM, 1 mM, 2 mM, and 2 mM with a preischemic infusion of 140 mg/kg/min of adenosine). The preischemic adenosine treatment consisted of continuously infusing the agent for 10 minutes into the venous reservoir, at which time the aortic crossclamp was applied. The first dose of cardioplegia was then administered. Subsequent cardioplegic infusions and the duration of the infusion including the method of delivery were left to the surgeon’s discretion. Multiple measurements of ventricular performance and rhythm were obtained preoperatively, prebypass, and then at 1, 2, 4, 8, 16, and 24 hours after cessation of cardiopulmonary bypass. The electrocardiogram (ECG) was monitored continuously throughout the operation and for the first 24 hours postoperatively. Hemodynamic measurements included arterial blood pressure (BP), heart rate (HR), and central venous pressure (CVP). An Edwards Laboratory SwanGanz catheter was used to measure pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), and thermodilution cardiac output (CO). The cardiac index (CI), stroke volume (SV), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), right ventricular stroke work index (RVSWI), and left ventricular stroke work index (LVSWI) were derived from standard equations using a computer. Noninvasive evaluations of cardiac function included transesophageal echocardiography and transthoracic echocardiography. The transesophageal echocardiography was performed intraoperatively during the prebypass period, after the patient was stabilized after induction (but before the chest was opened), immediately postbypass after the patient was fully rewarmed and hemodynamics stabilized, and before the patient left the operating room. The transthoracic echocardiography was obtained the day before surgery and 7 days postoperatively. Regional wall motion was scored using the American Society of Echocardiography 16-segment model. Normal or hyperkinetic segments were assigned a score of 1/; hypokinetic segments 2/; akinetic segments 3/; dyskinetic segments 4/; and an aneurysm 5/. A wall motion score index was calculated by dividing the sum of segmental point scores by the number of segments analyzed. Left ventricular volume in the apical 2-chamber and 4-chamber views at end systole and end diastole was quantified by an on-line analysis package in the ultrasound system using the biplane method of discs. The left ventricular ejection fraction was calculated from these data. The use of inotropic agents (dopamine, dobutamine, norepinephrine, epinephrine, and
amrinone) and vasoactive drugs (nitroglycerine, nitroprusside, phenylephrine, ephedrine) was recorded for 24 hours after cessation of cardiopulmonary bypass. The institutional preference was to use dopamine to treat low cardiac output (cardiac index õ2.0) and nitroglycerine to treat ischemia and/or hypertension. In this Phase I study, trigger points for initiating the administration of specific vasoactive agents and doses were not specified. Each patient’s average drug dose over 24 hours was estimated as the area under the dose–response curve (AUC). Finally, plasma levels of adenosine and its degradation products, inosine and hypoxanthine, were measured during bypass and immediately postbypass. During bypass, 4ml blood samples were drawn immediately before and after the first, second, and last dose of cardioplegia. Postbypass central venous samples were drawn at 1 hour and 24 hours. In the pretreatment adenosine/cardioplegia group, blood samples were collected before pretreatment and after the first dose of cardioplegia. Due to the short half-life of adenosine in blood (õ10 seconds), all blood samples were placed immediately in an ice-cold stop solution containing dipyridamole (0.4 mmol/L), sodium ethylene diaminetetraacetic acid (EDTA; 8.4 mmol/L), 5-a, b-methylene adenosine 5*-diphosphate (AOPCP, 159 mmol/L), and (erythro-9)-2-hydroxy-3-nonyl adenine (EHNA, 10 mM/L) to prevent degradation of the nucleoside. Purine concentrations in plasma samples were determined by high performance liquid chromatography (HPLC) using previously described methods.6
STATISTICAL ANALYSIS The statistical analysis was based on the intention-to-treat principle. Results for all patients for whom follow-up data were available were included in analysis of the treatment groups. Demographic and plasma purine concentration data were analyzed by 1-way analysis of variance followed by the post hoc test. The effects of increasing doses of adenosine in the cardioplegic solution on cardiopulmonary bypass variables, drug use, regional wall motion, and global function were analyzed using Kendall’s statistic for dose–response trends. A p-value õ0.05 was considered statistically significant. RESULTS Patient demographics and the relationship between cardiopulmonary bypass perioperative variables, postoperative hemodynamics, ECG changes, and the treatment groups: The distribution of gender, age, weight,
preoperative ejection fraction, bypass time, and grafts per patients were the same in all treatment groups. The addition of adenosine to blood cardioplegia had no effect on cardiopulmonary bypass time, aortic crossclamp time, or postbypass BP, HR, CVP, PAP, PCWP, CO, CI, SV, SVR, PVR, RVSWI, and LVSWI. Similarly, there were no significant changes in regional wall motion detected by transesophageal echocardiography or intraoperative
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FIGURE 1. The relation between concentration of adenosine in cold-blood cardioplegia and venous adenosine levels. Blood samples were taken from the venous tubing of the bypass circuit. n Å number of patients; ADO Å adenosine.
ECG changes throughout the 24-hour time period among the various treatment groups. The effect of the adenosine addition on plasma adenosine, inosine, and hypoxanthine levels: The relation
between the treatment groups and venous plasma adenosine levels is shown in Figures 1 and 2. In the untreated group baseline adenosine and the summation of adenosine and its degradation products, inosine and hypoxanthine, were 0.17 { 0.09 mmol/ L and 1.70 { 0.19 mmol/L, respectively. These values are consistent with levels reported elsewhere for humans and other animal species. Increasing the dose of adenosine in blood cardioplegia resulted in marked increases in plasma levels. For example, high-dose adenosine treatment was associated with a 249-fold increase in the plasma adenosine concentration and a 69-fold increase in the combined levels of adenosine, inosine, and hypoxanthine. In all treatment groups, the venous plasma adenosine levels returned to control levels before the infusion of the next dose of cardioplegia. The 1-hour and 24-hour postbypass levels of adenosine and the combined adenosine, inosine, and hypoxanthine levels were the same as the control values. The effect of the adenosine addition on postbypass drug usage: The relation between adenosine treat-
ment and drug use is shown in Tables I and II. Adenosine treatment had no effect on dobutamine, amrinone, nitroprusside, or phenylephrine use. Data for epinephrine and ephedrine are not shown because only 4 and 6 patients received these drugs in the postbypass period, respectively. In contrast, 67% (41/61) and 88% (54/61) of all patients received dopamine and nitroglycerine within the first 24 hours of surgery. In these patients, increasing doses of adenosine were associated with a 65% (p Å 0.003) and 67% (p Å 0.001) probability of receiving less dopamine and nitroglycerine, respectively. Also, the number of patients who received dopamine and ni40
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FIGURE 2. The effect of increasing the concentration of adenosine in cold-blood cardioplegia on venous total adenosine, inosine, and hypoxanthine levels. n Å number of patients; Ado Å adenosine; INO Å inosine; HYPO Å hypoxanthine.
troglycerine (n ú0) in the postoperative period decreased as the adenosine concentration increased. The 24-hour average doses for dopamine and nitroglycerine in the placebo group were 28-fold and 2.6fold greater than their respective high-dose adenosine treatment cohorts. The effect of the adenosine additive on regional wall motion and global function assessed by transthoracic echocardiography: The relation between the dose of aden-
osine in the blood cardioplegia and changes in regional wall motion is shown in Figure 3. No changes in regional wall motion were noted in the septal (p Å 0.16), lateral region (p Å 0.59), and anteroseptal regions (p Å 0.12). In contrast, trend analysis revealed that the posterior region (p Å 0.001), the anterior region (p Å 0.007), and the inferior region (p Å 0.015) all showed significant improvement in function when compared to the preoperative values. Moreover, there was no significant deterioration in regional wall function in any of the regions studied postoperatively in patients receiving the additive. When the data were analyzed in the context of global function 7 days postoperatively and the treatment groups were collated into 3 groups (Figure 4), the placebo plus 100 mM adenosine group was associated with a lower ejection fraction when compared to the patients receiving the intermediate-dose or high-dose adenosine treatment.
DISCUSSION The results of this single-center, adenosine myocardial protection trial indicate that (1) the addition of adenosine to blood cardioplegia in patients undergoing coronary artery bypass surgery is safe and well tolerated; (2) increasing the concentration of the adenosine additive is associated with increased circulating plasma adenosine and its degradation products, inosine and hypoxanthine; and (3) high-dose adenosine treatment is associated with
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TABLE I Effect of Adenosine Additive on 24-Hour Dopamine, Dobutamine, and Amrinone Use Dobutamine† (AUC units/min)
Dopamine* (AUC units/min)
Amrinone‡ (AUC units/min)
Treatment
n
n ú0
Mean
SEM
n ú0
Mean
SEM
n ú0
Mean
SEM
Placebo 100 mM 500 mM 1 mM 2 mM Pre / 2 mM
13 11 9 10 9 9
12 9 6 6 6 2
1.69 2.40 0.72 0.94 2.18 0.06
0.39 0.62 0.36 0.46 0.81 0.04
2 2 2 1 0 1
0.28 1.25 0.64 0.17 0.00 0.10
0.19 1.16 0.45 0.17 0.00 0.10
2 3 1 1 0 0
0.32 0.87 0.14 0.31 0.00 0.00
0.22 0.58 0.14 0.31 0.00 0.00
AUC Å area under the curve; n Å number of patients; n ú0 Å number of patients who received drug; SEM Å standard error of the mean. *p Å 0.003, †p Å 0.347, ‡p Å 0.070, using Kendall’s t statistic for dose–response trend.
TABLE II Effect of Adenosine Additive on 24-Hour Nitroglycerin, Sodium Nitroprusside, and Phenylephrine Use Nitroprusside SNP† (AUC units/min)
Nitroglycerin* (AUC units/min)
Phenylephrine‡ (AUC units/min)
Treatment
n
n ú0
Mean
SEM
n ú0
Mean
SEM
n ú0
Mean
SEM
Placebo 100 mM 500 mM 1 mM 2 mM Pre / 2 mM
13 11 9 10 9 9
13 11 7 10 7 6
0.72 0.92 0.45 0.44 0.32 0.28
0.14 0.26 0.11 0.09 0.09 0.10
8 4 4 7 5 1
0.55 0.47 0.24 0.45 0.27 0.06
0.23 0.34 0.12 0.15 0.17 0.06
3 5 3 2 5 4
0.15 8.49 0.80 16.60 0.23 0.42
0.10 7.69 0.44 15.40 0.10 0.26
AUC Å area under the curve; n Å number of patients; n ú0 Å number of patients who received drug; SEM Å standard error of the mean; SNP Å sodium nitroprusside. *p õ0.001, †p Å 0.149, ‡p Å 0.424, using Kendall’s t statistic for dose–response trend.
decreases in use of dopamine and nitroglycerine as well as improved regional wall motion and global function 7 days postoperatively. These findings are consistent with the hypothesis that adenosine is effective in attenuating myocardial stunning in humans. Considerable experimental evidence indicates that adenosine is a cardioprotective agent. While several mechanisms have been implicated, the cardioprotective effect appears to be mediated, in part, by activation of the adenosine A1 receptor coupled
to the inhibitory guanosine (Gi) proteins.7,8 Adenosine also has a direct metabolic effect (i.e., it enhances the myocardial phosphorylation potential) and thereby improves myocardial energetics in the stunned heart.8,9 Others have reported that adenosine decreases oxygen-derived free radical production by neutrophils,10 an effect that could minimize the free-radical – induced damage believed to occur during reperfusion. Finally, increases in coronary blood flow during reperfusion could be beneficial both from the standpoint of increased oxygen and
FIGURE 3. Preoperative to postoperative changes in regional wall motion in the placebo and treatment groups. Regional wall motion was determined by transthoracic echocardiography obtained preoperatively and 7 days postoperatively. *p Å 0.060, **p Å 0.048, ***p Å 0.036.
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FIGURE 4. The effect of adenosine treatment on left ventricular ejection fraction assessed by transthoracic echo obtained 7 days after coronary bypass surgery (Post-op, º) compared to preoperative (Pre-op, j) function *p õ0.06.
substrate delivery and enhanced wash-out of toxic ischemic products. Thus, adenosine alters fundamental processes that occur in the myocyte before, during, and after ischemia such that postischemic damage is significantly attenuated. Despite many animal studies that support the hypothesis that adenosine is a cardioprotective agent, little is known about its anti-ischemic effects in humans. Intravenous adenosine infusions have been used after cardiac surgery to control postoperative systemic and pulmonary hypertension.11,12 However, the results of experimental studies indicate that adenosine’s cardioprotective effect is dependent on preischemic administration.4,5 In addition to the results of the present study, there are only 2 full reports of adenosine’s cardioprotective effects during heart surgery in humans. In 1995, Lee et al13 tested whether adenosine infusion in patients prior to undergoing coronary artery bypass grafting would improve postbypass myocardial hemodynamics. Seven patients were pretreated with adenosine and 7 served as controls. Adenosine was infused incrementally before the initiation of cardiopulmonary bypass at a rate of 50 mg/kg/min every minute until a dose of 350 mg/kg/min was reached. The total duration of the adenosine infusion lasted for 10 minutes or until the patient developed systemic arterial pressures õ70 mm Hg, at which time the infusion was discontinued. Five minutes after the completion of adenosine or the saline solution control infusion, patients were placed on cardiopulmonary bypass, and then underwent the standard bypass operation using cold-blood cardioplegia to facilitate arrest. The investigators concluded that adenosine treatment before the initiation of bypass was associated with improved postoperative myocardial function. Fremes et al14 reported the results of an openlabel, non-randomized Phase I adenosine dose-ranging study in patients scheduled for elective coronary artery bypass surgery. Anterograde warm-blood potassium cardioplegia was administered in routine 42
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fashion with adenosine added to the initial 1000-mL dose and final 500-mL dose. Adenosine concentrations of 0, 15, 20, and 25 mmol/L were tested. Although the investigators reported that hypotension during cardioplegic induction was more prevalent with higher doses, they concluded that adenosine can be safely administered as a supplement to cardioplegic formulations when used in the range of 15– 25 mmol/L. One concern with the use of intravenous adenosine infusions is the potential for systemic hypotension due to adenosine’s vasodilatory properties. However, in the present study and that by Lee et al,13 the high doses of adenosine during the pretreatment infusions and as an additive to the cardioplegic solutions were well tolerated. Fremes et al14 reported that at adenosine concentrations of ú25 mmol/L patients developed more conduction disturbances, hypotension, and phenylephrine requirements than with lower doses. We were unable, however, to document a significant trend in the use of phenylephrine in any of the patients receiving adenosine. The side effects associated with the lower doses of adenosine in the study by Fremes et al14 may be due to the use of normothermic cardioplegia and not to actively lowering the core body temperature. Although our findings of the safety and efficacy of high-dose adenosine are similar to those of Lee et al,13 there is 1 major difference between the 2 protocols. Lee et al treated patients with an intravenous adenosine infusion that was terminated 5 minutes before the initiation of cardiopulmonary bypass—a treatment referred to as adenosine preconditioning. In contrast, in the present study, 4 groups of patients received adenosine only as an additive to the cardioplegic solution. In the fifth group, patients were administered a pretreatment adenosine infusion that was not terminated until the time of aortic crossclamping. The infusion protocol was based on experimental findings that (1) adenosine preconditioning reduces myocardial infarct size,2,15,16 and (2) uninterrupted infusions before the onset of ischemia attenuate myocardial stunning.5,16 While the results of Lee et al13 suggest that adenosine preconditioning may attenuate stunning in humans, limitations of this study include the small sample size and the variability in the total dose of adenosine administered. The concept of adenosine preconditioning is based on the hypothesis that adenosine mediates, in part, the cardioprotective effects of ischemic preconditioning. The protective effects of ischemic preconditioning in experimental ischemia models have generated much excitement over their use in clinical settings. Similar to the few reports on adenosine cardioprotection in humans, there is a lack of data on ischemic preconditioning during cardiac surgery. Yellon et al17 reported that ischemic preconditioning in humans during coronary bypass surgery was associated with a slower rate of ATP depletion—an observation consistent with findings reported in animals subjected to ischemic preconditioning.18 In this study, 7
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patients underwent ischemic preconditioning with two 3-minute periods of crossclamping, interspersed with 2 minutes of reperfusion before application of the aortic crossclamp and subsequent grafting of a coronary artery. In the control group, 7 patients received only the ischemic insult of 10 minutes of aortic crossclamp fibrillation. The impact of this protocol on regional or global ventricular function, however, was not assessed. Perrault et al19 recently reported that 3 minutes aortic crossclamping and 2 minutes reperfusion before warm-blood cardioplegic arrest in patients during coronary bypass surgery did not enhance myocardial protection. As in the study by Yellon et al,17 ventricular function was not assessed. Because ischemic preconditioning is not associated with enhanced postischemic recovery of function in animal models,16,20 it remains to be determined whether ischemic preconditioning will benefit patients undergoing open heart surgery. The major limitations of our adenosine myocardial protection trial include the relatively small number of patients, the absence of specific trigger points for the administration of inotropic agents and vasodilators, and the lack of specific endpoints that define myocardial stunning. Because the primary endpoint, however, was safety and tolerance, it is interesting that the findings strongly suggest a dose–response efficacy. Certainly the next step is to proceed with a multicenter clinical trial, perhaps in high risk patients with more defined endpoints, to determine the clinical relevancy of the experimental findings to date. 1. Belardinelli L, Shryock JC, Song Y, Wang D, Srinivas M. Ionic basis of the
electrophysiological actions of adenosine on cardiomyocytes. FASEB J 1995; 9:359–65. 2. Liu GS, Thornton J, Van Winkle D, Stanley AWH, Olsson RA, Downey JM. Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart. Circulation 1991;84:350–356.
3. Lasley RD, Mentzer RM Jr. Adenosine improves recovery of postischemic myocardial function via an adenosine A1 receptor mechanism. Am J Physiol 1992;263: H1460–5. 4. Randhawa MPS Jr, Lasley RD, Mentzer RM Jr. Salutary effects of exogenous adenosine on canine myocardial stunning in vivo. J Thorac Cardiovasc Surg 1995;110:63–74. 5. Sekili S, Jeroudi MO, Tang XL, Zughaib M, Sun JZ, Bolli R. Effect of adenosine on myocardial ‘‘stunning’’ in the dog. Circ Res 1995;76:82–94. 6. Mentzer RM Jr, Rahko PS, Canver CC, Chopra PS, Love RB, Cook TD, Hegge JO, Lasley RD. Adenosine reduces postbypass transfusion requirements in humans after heart surgery. Ann Surgery 1996;224:523–529. 7. Lasley RD, Mentzer RM Jr. Pertussis toxin blocks adenosine A1 receptor mediated protection of the ischemic rat heart. J Mol Cell Cardiol 1993;25:815– 21. 8. Mentzer RM Jr, Bunger R, Lasley RD. Adenosine enhanced preservation of myocardial function and energetics. Possible involvement of the adenosine A1 receptor system. Cardiovasc Res 1993;27:28–35. 9. Zhou Z, Bu¨nger R, Lasley RD, Hegge JO, Mentzer RM Jr. Adenosine pretreatment increases cytosolic phosphorylation potential and attenuates postischemic cardiac dysfunction in swine. Surg Forum 1993;44:249–52. 10. Cronstein BN, Kramer SB, Weissmann G, Hirschhorn R. Adenosine: a physiological modulator of superoxide anion generation by human neutrophils. J Exper Med 1983; 158:1160–77. 11. Owall A, Ehrenberg J, Brodin LA, Juhlin-Dannfelt A, Sollevi A. Effects of low-dose adenosine on myocardial performance after coronary artery bypass surgery. Acta Anaesthesiol Scand 1993;37:140–148. 12. Fullerton DA, Jones SD, Grover FL, McIntyre RC Jr. Adenosine effectively controls pulmonary hypertension after cardiac operations. Ann Thorac Surg 1996;61:1118–1123. 13. Lee HT, Lafaro RJ, Reed GE. Pretreatment of human myocardium with adenosine during open heart surgery. J Cardiac Surg 1995;10:665–676. 14. Fremes SE, Levy SL, Christakis GT, Walker SE, Iazetta J, Mallidi HR, Federelituv R, Deemar KA, Cohen EA, Wong BI, Goldman BS. Phase 1 human trial of adenosine-potassium cardiolplegia. Circulation 1996;94(suppl II):II– 370–375. 15. Lasley RD, Konyn PJ, Hegge JO, Mentzer RM Jr. The effects of ischemic and adenosine preconditioning on interstitial fluid adenosine and myocardial infarct size. Am J Physiol 1995;269:H1460–H1466. 16. Lasley RD, Noble MA, Konyn PJ, Mentzer RM Jr. Different effects of an adenosine A(1) analogue and ischemic preconditioning in isolated rabbit hearts. Ann Thorac Surg 1995;60:1698–1703. 17. Yellon DM, Alkhulaifi AM, Pugsley WB. Preconditioning the human myocardium. Lancet 1993;342:276–7. 18. Murry CE, Richard VJ, Reimer KA, Jennings RB. Ischemic preconditioning slows energy metabolism and delays ultrastructural damage during a sustained ischemic episode. Circ Res 1990;66:913–31. 19. Perrault LP, Menasche P, Bel A, Dechaumaray T, Peynet J, Mondry A, Olivero P, Emanoilravier R, Moalic JM. Ischemic preconditioning in cardiac surgery—a word of caution. J Thorac Cardiovasc Surg 1996;112:1378–1386. 20. Ovize M, Przyklenk K, Hale SL, Kloner RA. Preconditioning does not attenuate myocardial stunning. Circulation 1992;85:2247–54.
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