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Ann Thorac Surg 2007;83:2066-2072
© 2007 The Society of Thoracic Surgeons
a Institute of Cardiovascular Surgery, Xijing Hospital, Xi’an, China
c Department of Clinical Laboratory, Xijing Hospital, Xi’an, China
b Department of Physiology, the Fourth Military Medical University, Xi’an, China
Accepted for publication December 18, 2006.
* Address correspondence to Dr Yi, Institute of Cardiovascular Surgery, Xijing Hospital, the Fourth Military Medical University, 17 Changle West Rd, Xi’an 710032, China (Email: yidinghua{at}yahoo.com.cn).
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Abstract |
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Methods: Sixty patients with rheumatic heart valve disease undergoing heart valve replacement operations were randomized to an adenosine (1.5 mg/kg) or saline (as control) bolus injection through an arterial catheter immediately after the aorta cross-clamp was removed. The surgical indications were similar in both groups, and heart valve replacement was successful in all patients.
Results: The extubation time and postoperative hospital time were similar in both groups. Compared with the control group, however, the inotrope scores in the intensive care unit (ICU) were much lower (p < 0.01), and the ICU time was significantly shorter (p < 0.05) in adenosine group. More important, cardiac troponin I release was less in the adenosine group, especially at 12 and 24 hours after reperfusion (p < 0.01), and total cardiac troponin I release estimated with the area under curve was also significantly reduced during the first 24 hours after reperfusion (p < 0.01).
Conclusions: A 1.5-mg/kg bolus administration of adenosine through an arterial catheter immediately after the aorta cross-clamp is removed is feasible and well tolerated in patients undergoing heart valve replacement. An adenosine postconditioning adjunct to high potassium cold blood myocardial protection is related to less troponin I release, less inotropic drug use, and shorter ICU stay.
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Introduction |
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The current strategy for myocardial protection during cardiac procedures combines the two methods of hypothermia and cardioplegia arrest. The use of blood was introduced as a method to increase myocardial oxygen delivery during arrest [2]. Cardiac surgeons quickly adopted blood cardioplegia as their myocardial protective strategy of choice, and this strategy remains the mainstay of myocardial protection. Cardioplegia protects the myocardium by providing continuous or intermittent oxygen while simultaneously reducing cardiomyocyte oxygen demand through both hypothermia and cardiac arrest. Although an effective strategy, cardioplegia does not inherently increase the ischemic–reperfusion injury tolerance of the cardiomyocytes.
Postconditioning involves a series of brief mechanical interruptions of reperfusion that follow a specific prescribed algorithm applied at the very onset of reperfusion [3]. Zhao and colleagues [4] and Halkos and colleagues [5] showed that interruptive reperfusion after a 1-hour coronary artery occlusion in the canine model—with an algorithm of 30 seconds of reperfusion followed by 30 seconds of reocclusion repeated 3 times, followed by full reperfusion for 3 hours—reduced myocardial infarct size [4, 5]. A primary finding of these studies was that postconditioning offered the same protection as ischemic preconditioning, which Murry and colleagues [6] described more than 20 years ago.
Two pilot studies published in 2005 reported that conventional postconditioning is an effective treatment in a selected patient population with coronary artery disease:
Cardiac surgeons can also exploit this benefit. Unlike preconditioning, postconditioning does not require initiation before the ischemic event. This aspect offers several interesting opportunities for cardiac surgeons. Postconditioning can be used in situations where preconditioning is difficult or impossible to achieve. Theoretically, the optimal postconditioning strategy would be pharmacologic, which would avoid the adverse consequences associated with intermittent cross-clamping and provide a simple method for myocardial protection after all cardiac procedures.
Adenosine is a primary mediator of postconditioning effects. Studies performed in animal models indicate that adenosine receptor activation is involved in the cardioprotection conferred by postconditioning. The underlying mechanism may involve delaying the washout of endogenously released adenosine during the early minutes of reperfusion [9].
The protective effects could be blocked by the nonselective adenosine receptor antagonist, 8-(p-sulfophenyl) theophylline (8-SPT) [10], and by A2A and A3 selective antagonists given before postconditioning. Activation of the A2A and A3 receptors has been associated with infarct size reduction, attenuation of endothelial activation, and neutrophil activation and adherence [11–14], which are consistent with the in vivo changes observed after postconditioning.
Adenosine has also been implicated in the cardioprotection exerted by remote postconditioning [15]. In this concept, coronary artery reperfusion after myocardial ischemia is preceded by a 5-minute occlusion of one renal artery. The renal artery occlusion is released 1 minute before release of the coronary artery occlusion. This remote postconditioning significantly reduced infarct size. The infarct-sparing effect was abrogated by 8-SPT given only 5 minutes before release of the coronary artery occlusion. Permanent renal artery occlusion did not reduce myocardial infarct size, nor did a delay in the renal artery occlusion–reperfusion by 1 minute.
It is reasonable to postulate that endogenous adenosine, released at renal reperfusion and transmitted directly through the circulation or through neural pathways, can protect the reperfused myocardium from reperfusion injury [16]. It is theoretically possible that the clinical benefit of adenosine during reperfusion in humans is an example of the clinical use of postconditioning mimetic drugs. The objective of the present study was to determine whether adenosine, administered during the first minutes of reperfusion after removal of the aorta cross-clamp in patients undergoing valve replacement, could improve the effect of cold blood cardioplegia myocardial protection.
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Material and Methods |
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Study Population
Men and women aged older than 30 years who were diagnosed with rheumatic heart disease with severe valve impairment, and for whom the clinical decision had been made to perform valve replacement operation, were eligible for enrollment. Excluded were patients with the comorbidities of coronary heart disease, hypertension, diabetes mellitus, or congenital heart disease, or who were undergoing reoperation.
Experimental Design
This was a prospective, single-center, randomized controlled study. After the patients gave informed consent, they were randomly allocated to either the control or the adenosine postconditioning group. The randomization was realized by messages sealed in envelopes passed to the perfusionist just before the operation, and the surgeons and intensive care physicians were unaware of the allocation. After 15 control patients and 15 postconditioning patients were enrolled in the study, statistical analysis found that the cardiac troponin I (cTnI) release of the postconditioning group was less than that of the control group. This difference did not reach a statistically significant level, so we enrolled 15 more patients into each group. With 30 patients per group, the cTnI release at different postreperfusion time points was statistically significant between the two groups.
Anesthesia and Cardiopulmonary Bypass
Anesthesia was induced and maintained by intravenous propofol (target-controlled infusion), sufentanil citrate, and atracurium. Patients received 300 UI/kg of heparin before cardiopulmonary bypass (CPB). During CPB, the activated clotting time, using kaolin as the activating agent (Medtronic, ACT II HemoTec, Rueil Malmaison, France), was maintained at a value exceeding 480 seconds, with additional doses of heparin as required.
The extracorporeal circuit was primed with 1000 mL of a balanced acetate solution and 1000 mL of a polygeline solution containing 6000 U of heparin and 3 x 106 KIU aprotinin. A membrane oxygenator was used, and flows of 1.8 to 2.2 L/(min · m2) were obtained with a roller pump (Stockert Instrumente, Munich, Germany) under mild hypothermia (31° to 33°C).
After discontinuation of CPB, anticoagulation was reversed with protamine sulfate. Blood remaining in the CPB circuit was collected and infused to the patient before transfer to the intensive care unit (ICU).
Myocardial Protection Strategy
The crystalloid portion of the cardioplegia solution, which was supplied by the hospital pharmacy department, contained (in mM) 140 Na+, 75 K+, 16 Mg2+, 1.2 Ca2+, 104 Cl–, 20 HCO3
–, 10 glucose, and 0.7 lidocaine (pH 7.6 to 7.7). If there was no aortic valve regurgitation, cardioplegia was infused through a double-lumen needle in the ascending aorta for antegrade administration. After aortic cross-clamping, cardioplegic arrest was obtained with a 4:1 blood/crystalloid high-potassium solution antegrade infusion at 4°C, with a flow rate of 300 to 330 mL/min for 4 minutes. For patients with aortic regurgitation, the aorta was opened promptly after the cross-clamp was applied, the left and right coronary artery ostia were cannulated, and the cold-blood cardioplegia was delivered though a Y bifurcated catheter.
Diastolic arrest was maintained every 25 to 30 minutes by 2 minutes of cold antegrade infusion of the same cardioplegia. With aorta cross-clamp removal, the adenosine postconditioning group received a dose of adenosine (1.5 mg/kg) injected through the artery catheter within 1 minute. The control group received the same volume of saline instead.
Measurement of Plasma Cardiac Troponin I Concentrations
For each patient, 2-mL blood samples were taken at six time points: at the induction of anesthesia and at 1, 3, 6, 12, and 24 hours after the aorta cross-clamp removal. The blood was transferred into dry glass tubes and stored at 4° to 8°C before centrifugation. Plasma separated after centrifugation was frozen at –70°C until assayed. The plasma cTnI concentration was measured in the clinical laboratory of our hospital in duplicate by an Access AccuTnI assay system (Beckman-Coulter, Fullerton, CA) by individuals unaware of the group allocation.
The total cTnI release of the control and postconditioned patients is represented as the area under curve (AUC) from preoperation (C0) and the last sampling time (C24). It was calculated with the equation of trapezoid area: {AUC0–24 = [(C0 + C1) x 1 + (C1 + C3) x 2 + (C3 + C6) x 3 + (C6 + C12) x 6 + (C12 + C24) x 12]/2}. The total cTnI release from C0 to C6 and C6 to C24, which are represented as AUC0–6 and AUC6–24, were also calculated accordingly.
Data Collection
Preoperative and postoperative data for the study population were collected prospectively by the study team from the day of surgery until hospital discharge. The preoperative data included age, sex, body mass index, diastolic left ventricular volume, left ventricular ejection fraction, and the occurrence of chronic atrial fibrillation. The operative data include valve replacement operation type, CPB time, aorta cross-clamp time, total volume of cardioplegia, frequency of cardioplegia delivery, and type of rhythm recovery (spontaneous or electric defibrillation). Because adenosine administration could severely affect the systemic perfusion pressure, the lowest mean arterial pressure and the duration of low mean arterial pressure after cross-clamp removal were also recorded.
The postoperative data include the hours of mechanical ventilation in the ICU, urine volume during the first 24 hours in the ICU, and the length of stay in the ICU and the hospital. Serial data such as serum cTnI concentration at different time points were measured as described. The inotrope scores [17, 18] at different time points in ICU were calculated as dopamine (x1) + dobutamine (x1) + amrinone (x1) + milrinone (x15) + epinephrine (x100) + norepinephrine (x100) + isoprenaline (x100).
Statistical Analysis
All continuous variables are expressed as mean ± standard deviation, and discrete variables are presented as frequencies and percentages. Analysis of categoric variables was performed with the 
2 test. Analysis of continuous variables was performed with Student t tests. The serum cTnI concentrations and the postoperative inotrope scores were analyzed with a two-way analysis of variance, and multiple comparisons were made with post hoc least significant difference comparisons. A value of p 
0.05 was considered statistically significant.
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Results |
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We investigated the patients’ urine output during their first 24 hours in the ICU and found no significant difference between the groups, with 2387 ± 595 mL in the control group and 2296 ± 545 mL in the postconditioning group (Table 2). There was no significant difference between the two groups in extubation time, postoperation hospital stay, or survival rate (Table 2). However, the ICU length of stay for the postconditioned group was significantly shorter than that of the control group (3.1 ± 0.9 days versus 4.4 ± 3.1 days; p < 0.05, Table 2).
Serum Cardiac Troponin I Release
The concentrations of serum cTnI before surgery were very low in both groups and surged to high levels after the aorta cross-clamp was removed. The cTnI levels remained high during the first 24 hours after reperfusion in the control group but decreased 12 hours after reperfusion in the postconditioning group (Table 3
and Fig 1). At the time points of 12 and 24 hours after reperfusion, the levels of serum cTnI were significantly decreased in the postconditioning group (12.2 ± 6.9 and 11.3 ± 6.6 ng/mL) compared with the control group (19.7 ± 8.8 and 23.3±15.9 ng/mL; p < 0.01). The AUC0–24 and AUC6–24 of cTnI release for the adenosine postconditioned group (318 ± 200 and 229 ± 138, respectively) were significantly reduced compared with the control group (465 ± 178 and 370 ± 169, respectively), although the AUC0–6 of the two groups were alike (89 ± 64 versus 96 ± 38, p = 0.59; Fig 1).
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Comment |
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Cardiologists have introduced the therapeutic use of adenosine as a postconditioning drug to protect the human heart during acute myocardial infarct reperfusion therapy. In a pilot study, Mahaffey and colleagues [19] examined the effect of an intravenous adenosine infusion of 70 µg/(kg · min) for 3 hours during acute myocardial infarction. The adenosine group had a significant reduction in the infarct size. Quintana and colleagues [20] reported that an intravenous adenosine infusion reduced cardiac complications in patients with acute anterior wall myocardial infarction.
These studies paved the way for a more definitive study, the Acute Myocardial Infarction Study of Adenosine (AMISTAD) II [21]. This study randomized 2084 patients with acute myocardial infarction to a 3-hour infusion with adenosine or placebo within 15 minutes of reperfusion. Adenosine therapy was associated with smaller infarct sizes and a nonsignificant trend toward a lower incidence of congestive heart failure or death.
Preliminary studies with intracoronary adenosine suggested promise for this treatment for early intervention for myocardial infarction [22]. In a randomized study, Marzilli and colleagues [23] administered either adenosine (4 mg in 2 mL saline) or saline (2 mL) into the distal vascular bed just after the angioplasty balloon was inflated. The injection was completed in 1 minute. Adenosine administration was associated with improved flow in the infarct-affected artery and a lower incidence of no-reflow phenomenon at the end of the dilation procedure. The intracoronary injection of adenosine was also associated with lower creatine kinase release, less Q-wave myocardial infarction development, more dyssynergic segment improvement, and fewer adverse cardiac events after percutaneous coronary intervention.
Claeys and colleagues [24] assessed the myocardial reperfusion in patients receiving a 20-minute intracoronary infusion of adenosine during percutaneous coronary interventions. Myocardial reperfusion injury was present in only 19% of patients receiving adenosine versus 35% of control patients. Infarct size did not expand over time in patients receiving adenosine but expanded significantly in the control group, which indicates that adjunctive therapy with an intracoronary infusion of adenosine during percutaneous coronary interventions prevents the occurrence of severe myocardial reperfusion injury and is associated with lower infarct expansion.
In this study, serum cTnI concentration was adopted as a sensitive biomarker to evaluate the severity of myocardial injury, which was different from the studies described. Information about the clinical significance of cTnI dates back to the 1990s, when the role of cTnI was first studied in the context of ischemic coronary syndromes. Researchers at the time considered cTnI a sensitive biomarker for myocardial injury, because after the first year of life, cTnI is expressed exclusively in the myocardium, with uniform distribution between atria and ventricles [25]; therefore, elevated serum cTnI is exclusive for myocardial injury [26, 27].
Because most cTnI is eliminated through urine excretion, urine output might significantly affect its serum level. We investigated the patients’ urine output during their first 24 hours in ICU and found no significant difference between the groups. Therefore, the differences of serum cTnI levels between the groups in our study, particularly the cTnI AUC levels, were not affected by their urine outputs and mainly reflected that the two groups released different amounts of cTnI. The significant reduction of cTnI levels at the time points of 12 and 24 hours, especially the AUC calculation over the first 24 hours after cross-clamp removal in the postconditioning group compared with the control group, might imply that the myocardium injury in the postconditioning group would be much less than the control group, which indicated that the method used in this study was able to relieve myocardial injury during heart valve replacement in patients with rheumatic heart valve disease.
The two types of myocardial injury during open heart procedures are ischemic injury and reperfusion injury. As shown in the results, the cTnI release surged to very high levels after the removal of the aortic clamp. In the control group, these levels remained high for at least 24 hours, suggesting that myocardial injury could occur over more than 24 hours. At the postreperfusion time points of 1, 3, and 6 hours, the cTnI release in the postconditioned group was similar to the control group, which might indicate that the degree of the injury induced by the ischemia was similar and that adenosine postconditioning had failed to prevent the ischemic injury. However, cTnI release at 6 and 12 hours postreperfusion rapidly decreased in the postconditioned group relative to the control group, suggesting that adenosine administered at the onset of reperfusion may help to prevent further injury induced by reperfusion.
The approach used here is somewhat similar to the methods used by Marzilli and colleagues [23] and Claeys and colleagues [24], who administered adenosine directly into the coronary artery during the primary coronary angioplasty in patients with acute myocardial infarct. Our methods, however, differ from the traditional methods used. First, the CPB used in cardiac operations facilitates adenosine administration through the ascending aorta and guarantees the delivery of adenosine directly into both coronary arterial and systemic arterial beds. Second, with the support of CPB, adenosine can be administered at high doses without worrying about the transient hypotension induced by direct infusion of high-dose adenosine into the arterial beds.
This study does not add more information to the vast literature of experimental studies on the mechanisms of adenosine postconditioning benefit. The half-life of adenosine in human blood is less than 1 second; however, the half-life may underestimate the duration of the biologic effects of adenosine. One study found that coronary flow remains elevated for several minutes after a bolus injection of adenosine [28]. In this study, the duration of adenosine administration lasted only 1 minute, but its effect on the myocardium might last for minutes. From another view, the short half-life of adenosine provides an intrinsic protection from possible side effects. This contributed to our decision to select adenosine as a postconditioning treatment.
Adenosine can induce coronary artery vasodilation, reverse coronary spasm, keep the myocardial microvasculature open during reperfusion, and replenish high-energy phosphates. Adenosine has negative chronotropic and negative inotropic effects. It can also reduce afterload and heart rate, thus decreasing myocardial oxygen demand. In addition, it has antiplatelet and antineutrophil activity that may help prevent no-reflow phenomenon after reperfusion. The transient severe hypotension during the first minutes after the cross-clamp removal in the postconditioned group might have a beneficial effect to the heart. Whether adenosine had a direct biochemical effect on the cardiomyocytes or had a beneficial effect through its actions as described cannot be determined from the present results.
One possible limitation of the present study was that the recruited patients had relatively normal left ventricle function. There have been numerous reports of myoprotective strategies without great clinical significance for normal hearts. Whether this postconditioning technique would be beneficial or harmful to the more severely dysfunctional heart remains to be investigated.
The protective effects of adenosine in this study could not be translated into more obvious clinical benefits such as lower mortality rates or shorter postoperative hospital lengths of stay. However, the inotrope scores in the ICU were much lower in the postconditioning group than in the control group, which might imply that adenosine postconditioning is related to better postoperative heart function. It coincided with the cTnI level difference between the two groups and might contribute to the shorter stay in the ICU of the postconditioning group.
The present study demonstrated that pharmacologic postconditioning with adenosine administered through an arterial catheter during CPB produces protective effects against myocardial reperfusion injury in cardiac operations. In summary, the present study demonstrated that a that bolus injection of high-dose adenosine directly into the arterial catheter immediately at the removal of the aortic clamp was related to less cTnI release 24 hours after reperfusion, less inotropic drug use during the ICU stay, and a shorter stay in the ICU. A larger study on adenosine postconditioning at reperfusion in cardiac surgery is therefore warranted.
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