Effect of intermittent delivery of warm blood cardioplegia on myocardial recovery

Effect of Intermittent Deliverv of Warm Blood Cardioplegia on Myocardial Recovery J

Roderick W. Landymore, MD, Alan E. Marble, PhD(Eng), and John Fris, RRT Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada

Continuous warm blood cardioplegia is often temporarily interrupted during coronary artery operations to provide the surgeon with a bloodless operating field. To determine the effects of intermittent warm ischemia on myocardial recovery, we randomized 15 adult mongrel dogs to receive either multidose cold or warm blood cardioplegia during a 90-minute arrest. Myocardial metabolic and functional recovery was assessed before clamping of the aorta and after 30 and 60 minutes of reperfusion. Systolic function was well preserved, whereas diastolic function decreased slightly in both groups after arrest. Myocardial oxygen consumption in-

creased during reperfusion after cold heart protection but was unchanged after warm blood cardioplegia. Highenergy phosphates decreased significantly in both groups during reperfusion. Two conclusions were reached. (1) Myocardial functional recovery was well preserved, whereas metabolic recovery was impaired after either technique of myocardial preservation. (2) Preserved functional recovery after multidose warm blood cardioplegia suggests that repetitive episodes of ischemia may condition the myocardium, thus preventing injury during prolonged aortic cross-clamping. (Ann Thorac Surg 1994;57:1267-72)

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compared myocardial metabolic recovery after coronary artery bypass in 74 patients receiving either antegrade continuous warm, retrograde continuous warm, or multidose antegrade cold blood cardioplegia. The continuous infusion of warm blood frequently obscured the operating field and led to the interruption of cardioplegia for 39% of the total cross-clamp time in patients receiving antegrade warm blood and 25% of the cross-clamp time in patients receiving retrograde warm blood. Although the myocardium is known to tolerate short periods of ischemia during hypothermic arrest, it may be less tolerant of warm ischemia. We have employed warm heart protection at our institution for the past 2 years and although we attempt to maintain a continuous infusion of warm blood, in reality, warm blood is most often delivered in a multidose fashion. We therefore decided to examine the effects of intermittent ischemia during warm blood cardioplegia on myocardial recovery after elective cardiac arrest.

ontinuous warm blood cardioplegia for myocardial preservation was described 5 years ago by Lichtenstein and colleagues [l].Relying solely on a continuous infusion of warm hyperkalemic blood, this technique of myocardial preservation differs radically from more traditional methods of myocardial protection. Warm blood cardioplegia evolved from the knowledge that hypothermia impairs aerobic metabolism and mitochondrial function [2, 31, that secondary warm blood cardioplegia or terminal warm blood cardioplegia (socalled hot shot) improves myocardial recovery [4, 51, and that cardiac arrest alone without hypothermia will lower myocardial oxygen demands by as much as 85% [6]. The concept of warm heart protection is attractive because the continuous infusion of warm hyperkalemic blood not only maintains cardiac arrest but supports aerobic metabolism. In contrast, temporary techniques of myocardial protection that employ multidose cardioplegia are associated with intermittent ischemia. In practice, however, the continuous infusion of warm blood frequently obscures the operating field and is particularly cumbersome during coronary artery operations. Although Teoh and associates [7] have employed a highvelocity air jet to remove blood from the operating field, the majority of surgeons interrupt warm blood cardioplegia when visualization of the operating field becomes problematic. In fact, Lichtenstein and co-workers [8], who originally described the technique, admit to temporarily interrupting the infusion of warm blood for periods of up to 15 minutes. Yau and colleagues [9] have also used warm blood cardioplegia in a multidose fashion. They Accepted for publication Sep 13, 1993. Address reprint requests to Dr Landymore, R.C. Dickson Centre, Victoria General Hospital, Room 3065, Halifax, NS B3H 2Y9, Canada.

0 1994 by The Society of Thoracic Surgeons

Material and Methods Fifteen adult mongrel dogs weighing between 20 and 25 kg were randomized to receive multidose warm or cold blood cardioplegia. The animals were cared for using the guidelines set forth by the Canadian Council on Animal Care.

Surgical Preparation Anesthesia was induced and maintained with sodium pentobarbital. Ventilation was provided with a volumeregulated ventilator. An 8F USCI catheter (C.R. Bard, Inc, Billerica, MA) was inserted into the right femoral artery for continuous blood pressure monitoring. Heparin sodium was administered in a dose of 4 mgkg after the 0003-4975/94/$7.00

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chest was opened through a median sternotomy incision. A 16F USCI arterial catheter was then passed into the left femoral artery in preparation for cardiopulmonary bypass. A 5F Millar microtransducer-tipped catheter (Millar Instruments, Inc, Houston, TX) and a specially designed 7F conductance catheter were passed through the apex of the left ventricle through separate pursestring sutures. Two 34 USCI cannulas were inserted into the superior and inferior venae cavae to provide venous return for cardiopulmonary bypass. A 16F USCI catheter was passed through the wall of the right atrium and positioned in the coronary sinus for measurements of myocardial oxygen consumption. The flanged catheter fit snugly into the coronary sinus, thus permitting complete assessment of all coronary flow. Extracorporeal circulation was established with a Medtronic impeller pump (model 1835; Medtronic Inc, Cardiovascular Systems Division, Roseville, MA) that would deliver nonpulsatile flow at a rate of 2.5 L min-' m-'. During cardioplegic arrest, the cavae were snared and the left and right ventricles vented. Blood gases were monitored, and sodium bicarbonate was administered as necessary to correct mild metabolic acidosis.

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Myocardial Preservation Core temperature and myocardial temperature were maintained at 37°C. Transmural myocardial temperature was monitored with a specially designed plunge electrode that was positioned over the interventricular septum. The thermistor was calibrated prior to each experiment with a mercury thermometer, and temperature was recorded on a Gould-Brush model 260 six-channel recorder. Cardiac arrest was initiated by administering antegrade warm or cold blood cardioplegia delivered with a ShileyBuckberg blood cardioplegia administration set (Shiley Corp, Irvine, CA). The blood cardioplegia contained 22 mEqL of potassium delivered in a ratio of 4 parts blood to 1part crystalloid. Warm blood cardioplegia was administered at 37°C and cold blood cardioplegia, at 8°C. The heart was arrested by administering blood cardioplegia, 30 mL/kg, delivered at a rate of 150 mL/min. Subsequent infusions of cardioplegia were administered every 15 minutes during the 90-minute arrest in a dose of 10 mL/kg and at a rate of 150 mL/min.

Myocardial Hemodynamic Function The systolic elastance and the end-diastolic elastance of the left ventricle were determined from simultaneous measurements of left ventricular pressure and volume as previously described [lo, 111. Pressure was measured using a 5F Millar microtransducer-tipped catheter (frequency response, 0 to 24 kHz). Volume was measured using a specially constructed 7F conductance catheter containing eight electrodes. The proximal and distal electrodes were excited from a 24-V, 20-kHz source, which delivered a constant current of 100 PA. The other six electrodes were used as sensing electrodes to monitor the voltages created when the 100-PA current flowed through the blood in proximity to each pair of adjacent electrodes.

Ann Thorac Surg 1994:5712.67-72

The simultaneous volume and pressure measurements were processed with 'a PC 40-3 computer, which created pressurevolume loops for each set of measurements. Specially designed software computed the systolic and diastolic elastance of the left ventricle from the pressurevolume data., The maximum rate of rise of left ventricular pressure was also measured with the Millar catheter. Measurements of left ventricular function were made after volume loading to an end-diastolic pressure of 10 mm Hg. The heart rate was controlled by pacing the atrium at 150 beatdmin. Measurements were made before bypass and at 30 and 60 minutes after the 90-minute arrest.

Myocardial Metabolism Myocardial metabolism was assessed by measuring myocardial oxygen consumption and high-energy phosphates. Myocardial oxygen consumption was computed from coronary sinus flows and oxygen saturations by standard formulas [12]. At least three measuremenis of coronary sinus flow were used for each calculatioin of myocardial oxygen consumption. Transmural biopsy specimens were taken with a Travenol biopsy needle and immediately placed in liquid nitrogen. The specimens were analyzed for adenosine triphosphate (ATP) as previously described [131. Myocardial oxygen consumption and high-energy phosphates were assessed after each measurement of left ventricular function.

Statistical Methods Results were reported as the arithmetic mean 2 the standard error of the mean. Analysis of variance and the unpaired Student's t test were used for statistical comparisons.

Results Eight animals were randomized to receive multidose cold blood cardioplegia, and the remaining 7 animals were designated to receive warm blood cardioplegia. Hemolglobin levels were similar in both groups before bypass at 113 0.5 g/L in the group receiving cold blood cardioplegia and 122 f 0.5 g/L in the animals receiving warm blood cardioplegia. Hemodilution for bypass decreased the hemoglobin concentration similarly in both groups after bypass to 77 2 0.5 glL in the cold group and 78 2 0.4 g/L in the warm group. Myocardial temperature was recorded just prior to each reinfusion of cardioplegia. Myocardial temperature was 36" 1°C before cardioplegia reinfusion in those animals receiving warm blood cardioplegia. In contrast, during cold blood cardioplegia the temperature was significantly lower, measuring 24" f 2°C before reinfusion ( p < 0.001). Spontaneous electromechanical activity, which oclcurs frequently during the clinical use of warm blood cardioplegia, was infrequent in this experimental animal model. Only 3 of 7 animals receiving warm blood cardioplegia had spontaneous activity, which was limited to one episode per animal.

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Table 1. Surnmaru of Data on Sustolic and Diastolic Functional Recovenf Reperfusion 30 Minutes

Before Bypass 3.8 f 0.5 0.33 f 0.03 1,725 f 94

3.4 f 0.4 0.27 f 0.01 1,671 f 71

Warm

Variable

Systolic elastance (mm Hg/cm3) 3.8 f 0.4 End-diastolic elastance (mm Hg/cm3) 0.32 2 0.03 1,814 f 122 ddd, (mm Hg/s) a

Cold

Warm

Data are shown as the mean 2 the standard error of the mean.

60 Minutes

Cold

Warm

Cold

3.6 f 0.4 3.9 f 0.6 0.23 f 0.02b 0.26 2 0.02 1,762 f 91 1,700 f 53

4.3 f 0.7 0.25 2 0.03 1,727 ? 55

Significance: p < 0.02.

ddd, = maximum rate of rise of left ventricular pressure.

Systolic and Diastolic Functional Recovery Systolic and diastolic function are illustrated in Table 1. The systolic elastance of the left ventricle was well preserved after cardioplegic arrest. Systolic function, however, was decreased slightly but not significantly in both groups at 30 minutes and recovered fully by 60 minutes. End-diastolic elastance decreased in both groups after arrest but was significantly lower only at 30 minutes after cold blood cardioplegia. The maximum rate of rise of left ventricular pressure was not significantly different at 30 and 60 minutes after arrest in either group. However, it tended to be lower at 30 and 60 minutes with warm heart protection.

Myocardial Metabolic Recovery Myocardial oxygen consumption and measurement of high-energy phosphates are illustrated in Table 2. Myocardial oxygen consumption was significantly increased when measured after 30 minutes of reperfusion in animals that received cold heart protection but was unchanged after warm blood cardioplegia. Levels of ATP in the warm group decreased significantly after 30 and 60 minutes of reperfusion and were significantly lower at 60 minutes after cold heart protection.

Comment Warm heart protection has been employed by an increasing number of centers in both Europe and North America [14-181. Although the champions of warm heart surgery have extolled the benefits of this method of myocardial protection, the majority of the earlier reports either lacked controls or compared the results of warm heart protection

with an historical cohort of patients [8, 181. Regardless of whether warm blood cardioplegia is superior to multidose cold blood cardioplegia, the fact remains that warm blood cardioplegia is often delivered in a multidose fashion rather than in a continuous infusion as originally described [8]. Not only is the cardioplegia interrupted, but the length of ischemia may last as long as 15 minutes [8], which can represent almost half of the entire cross-clamp time (91. The practice of using warm blood cardioplegia in an intermittent or multidose fashion emphasizes the importance of determining the tolerance of the left ventricle to warm ischemia during cardioplegic arrest.

Tolerance of Myocardium to Warm Ischemia Although the effects of normothermic ischemia on the working, beating heart have been described [19-22 J, there was no literature until recently that focused on the effects of warm ischemia during cardioplegic arrest. We [23] interrupted antegrade warm blood cardioplegia for intervals of 1 minute to 10 minutes after arresting the heart with warm blood cardioplegia. Oxygen debt occurred after 4 minutes of normothermic ischemia, but lactate increased linearly during the duration of ischemia. KO and colleagues [24] arrested three groups of 7 dogs with antegrade warm blood cardioplegia. The control group received continuous warm blood cardioplegia, and the other two groups received multidose warm blood cardioplegia administered every 5 or 10 minutes during a 30-minute arrest. Systolic and diastolic recovery was impaired after arrest in animals that had received intermittent warm blood every 10 minutes, and mild stunning was observed when warm blood was administered every 5 minutes.

Table 2. Surnrnaru of Data on Muocardial Metabolic RecovenPb Reperfusion Before Bypass Variable

MVO, (mL * min-' * 100 g-' myocardium) ATP (pm/g dry weight)

30 Minutes

60 Minutes

Warm

Cold

Warm

Cold

Warm

Cold

3.2 2 0.4 18.9 f 1.2

3.7 2 0.3 18.0 f 1.0

3.1 2 0.3 13.2 t 1.5'

4.4 2 0.4' 15.5 f 0.8

3.1 f 0.5 13.4 f 1.4d

3.8 t 0.5 14.4 2 0.3d

Data are shown as the mean -+ the standard error of the mean. For ATP, there was no significant difference between groups at 30 and 60 minutes (unpaired Student's t test). However, ATP levels decreased significantly compared with preoperative levels (paired Student's t test]: ' p < 0.02, y < 0.03. a

ATP = adenosine triphosphate;

MVO,

=

myocardial oxygen consumption.

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In contrast, we [25] have shown that functional recovery is impaired only when the duration of ischemia exceeds 10 minutes. Adult dogs were subjected to 5, 10, and 15 minutes of ischemia during antegrade warm blood cardioplegia. Systolic and diastolic function was assessed after each period of ischemia and 10 minutes of reperfusion. Systolic and diastolic function was preserved after 10 minutes of warm ischemia but depressed after 15 minutes of warm ischemia. Ikonomidas and co-workers [26] examined the effects of warm ischemia during antegrade or retrograde warm blood cardioplegia in 56 patients undergoing coronary bypass. Lactate production increased proportionately with the length of ischemia during retrograde warm blood cardioplegia, and oxygen debt occurred only when the length of ischemia exceeded 7 minutes. Our experimental investigations indicate that myocardial metabolic recovery and functional recovery were similar after multidose antegrade warm or cold blood cardioplegia. Temporary stunning of the myocardium was observed with both techniques of preservation as evidenced by a transient decrease in systolic function at 30 minutes; function returned to normal after 60 minutes of reperfusion. The change in systolic function during the first 30 minutes of reperfusion after warm blood cardioplegia in all probability represents the effects of warm ischemia on myocardial recovery [23-251, whereas the reduction in systolic function after cold heart protection is more likely secondary to the adverse effects of hypothermia on aerobic metabolism and mitochondrial recovery [2, 3, 271. Diastolic function deteriorated slightly with both techniques of myocardial preservation and was manifested by a decrease in end-diastolic elastance of the left ventricle. These observations have been corroborated by more recent investigations in our laboratory that have confirmed that diastolic dysfunction increases proportionately with the duration of warm ischemia [25] and that hypothermia contributes directly to diastolic dysfunction after cardioplegic arrest [27]. There was evidence of metabolic dysfunction in both groups after arrest. Myocardial oxygen consumption was accelerated after arrest in animals that had received cold blood cardioplegia, a finding indicating the presence of hyperemia and increased metabolism that is often observed after ischemia. In contrast, myocardial oxygen consumption was not elevated at 30 or 60 minutes after arrest in animals that had received warm blood cardioplegia, despite the fact that this group had been subjected to repetitive episodes of intermittent ischemia and reperfusion during arrest. Either the myocardium was incapable of increased metabolism during reperfusion because of ischemia-induced injury, or more likely, oxygen consumption increased immediately after release of the aortic cross-clamp and normalized when first assessed at the 30-minute interval. This premise is supported by an earlier experiment by us [25] that demonstrated elevated myocardial oxygen consumption immediately after intermittent warm ischemia. The observations of Misare and associates [28] also support this hypothesis. They compared myocardial metabolic recovery after antegrade cold

Ann Thorac Surg 1994;571267-72

and warm blood cardioplegia. Myocardial oxygen consumption increased by 28% during the first 20 minutes of reperfusion after warm blood cardioplegia but had normalized within 40 minutes after release of the aortic cross-clamp. High-energy phosphates were lower during reperfusion after both techniques of myocardial preservation. The decrease in ATP after warm blood cardioplegia suggests not only that high-energy phosphates were utilized during normothermic arrest but that ischemic injury prevented the myocardium from resynthesizing ATP during reperfusion. The decrease in ATP after cold blood cairdioplegia is most likely related to the adverse effects of hypothermia on mitochondrial function and recovery. These conclusions are supported by Yau and colleagues [9], who measured adenine nucleotides and degradation products after both warm and cold heart protection. 'Their findings indicated that ATP is broken down to adenosine diphosphate, adenosine monophosphate, and adenosine after cold blood cardioplegia, that these molecules accumulate because of cold-induced inhibition of dephosphorylation and deamination enzymes, and that ATP is not regenerated during reperfusion because of cold-induced mitochondrial dysfunction. Warm ischemia in their study produced similar effects on ATP but by different mechanisms. Warm ischemia during cardioplegic arrest resulted in increased anaerobic metabolism as evidenced by excessive lactate production. Lactic acidosis, in turn, resulted in mitochondrial dysfunction, which inhibited oxidative phosphorylation and the regeneration of ATP, not only during cardioplegic arrest but also during reperfusion.

Preconditioning of Myocardium to Warm lschemia That we did not observe more marked functional imipairment in those animals receiving intermittent warm ischemia during multidose warm blood cardioplegia may have been related to a variant of the ischemic preconditioning concept. The term ischemic preconditioning has been used classically to describe an increased tolerance of the myocardium to prolonged ischemia when the ischemic insult is preceded by repetitive episodes of ischemia of short duration [19-221. Although the initial ischemic insult impairs functional recovery and depletes high-energy phosphates, subsequent episodes of ischemia do not necessarily halve a cumulative effect on myocardial recovery. Heyndrickx and colleagues [19] demonstrated that 5 minutes of normothermic regional ischemia in the working, beating heart results in myocardial stunning, evidenced by transient global dysfunction and regional wall abnormailities that can last up to 3 hours. Lange and co-workers [20], however, have shown that temporary occlusion of the left anterior descending coronary artery for three consecutive 5-minute intervals interspersed with 30 minutes of rieperfusion preconditioned the myocardium to further injury. Segmental wall abnormalities resulted from the first 5 minutes of warm ischemia, but there was no further deterioration in myocardial function with repetitive episodes of ischemia. Swain and colleagues [21] occluded the left anterior

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Ann Thorac Surg 1994:57 1267-72

descending coronary artery in open-chest dogs for three periods of 12 minutes. High-energy phosphates decreased by as much as 30% after the first occlusion but did not decrease further with repetitive episodes of ischemia. Murray and associates [22] have shown that four 5-minute periods of coronary occlusion will precondition the myocardium to tolerate prolonged normothermic ischemia, thus resulting in a decrease in infarct size of 25% compared with nonconditioned control animals. More recently, Mitchell and colleagues [29] demonstrated in an isolated rat heart model that preconditioning can be induced with very transient periods of ischemia that are of insufficient length to cause impaired myocardial functional recovery. Although our experiment does not comply precisely with the definition of preconditioning, the multiple episodes of ischemia that occurred during multidose warm blood cardioplegia may have conditioned the myocardium, thereby preventing myocardial dysfunction after arrest.

Limitations of Experimental Protocol Although our data suggest that there was no difference in the recovery of the myocardium after either technique of multidose antegrade blood cardioplegia, there are definite limitations to the experimental protocol. The animals used for the experiment were healthy mongrel dogs without coronary disease or myocardial hypertrophy, both factors that most likely would have magnified the adverse effects of warm ischemia on myocardial recovery. Further, the first measurements of myocardial recovery were made after 30 minutes of reperfusion, which may have masked more profound change in systolic and diastolic function had the measurements been made earlier. This premise is supported by the data from a more recent experiment [25] that demonstrated the presence of important systolic and diastolic dysfunction after 15 minutes of warm ischemia when recovery was assessed after 10 minutes of reperfusion. Despite these limitations, our data are unusual because our experimental design eliminated many of the confounding variables that have plagued earlier reports. We did not employ core cooling or topical hypothermia in animals randomized to cold heart protection and therefore, the only major variable affecting recovery of both groups was the temperature of the cardioplegia. Conclusion Our data indicate that myocardial metabolic and functional recovery was similar after either multidose warm or cold heart protection. Our observations suggest that repetitive episodes of ischemia may have conditioned the myocardium, thus preventing serious injury in the animals randomized to warm heart protection. The concept of myocardial conditioning may also explain in part the excellent clinical results that have been reported after the use of intermittent warm blood cardioplegia [S, 9, 261. Despite the recent interest in this new technique of myocardial protection, we have failed to demonstrate the superiority of warm blood cardioplegia and therefore

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have reverted to the use of multidose cold blood cardioplegia, which not only provides a bloodless operating field for the surgeon but also has provided safe myocardial protection for countless patients since its original description.

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21. Swain J, Sabina R, Hines J, Greenfield J Jr, Holmes E. Repetitive episodes of brief ischemia (12 min) do not produce a cumulative depletion of high energy phosphate compounds. Cardiovasc Res 1984;18:264-9. 22. Murray C, Jennings R, Reimer K. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:112636. 23. Landymore R, Marble A, MacAulay M, Fris J. Myocardial oxygen consumption and lactate production during warm antegrade blood cardioplegia. Eur J Cardio-thorac Surg 1992; 6:372-6. 24. KO W, Zelano J, Fahey L, et al. Warm ischemic tolerance of the arrested heart [Abstract]. Presented at the Sixth Annual Meeting of The European Association for Cardio-Thoracic Surgery, Geneva, Switzerland, Sep 14-16, 1992. 25. Landymore R, Marble A, Fris J. Warm blood cardioplegia: tolerance of the myocardium to intermittent ischemia during cardioplegia arrest [Abstract]. Presented at the Third World

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Congress of the International Society of Cardio-Thoracic Surgeons, Salzburg, Austria, Jan 25-27, 1993. Ikonomidis J, Yau T, Weisel R, et al. Warm blood cardioplegia: what happens when you turn it off? Circulation 1992; 86(Suppl 1):103. Landymore R, Marble A, Fris J. Myocardial recovery is more dependent upon the core temperature during bypass; than the temperature of the cardioplegia [Abstract]. Presented at the Seventh Annual Meeting of The European Association for Cardio-Thoracic Surgery, Barcelona, Spain, Sep 20-22, 1993. Misare B, Krukenkamp I, Lazer Z, Levitski S. Recovery of postischemic contractile function is depressed by antegrade warm continuous blood cardioplegia. J Thorac Cardiiovasc Surg 1993;105:37-44. Mitchell MB, Winter CB, Locke-Winter CR, Banejee A, Harken AH. Cardiac preconditioning does not require myocardial stunning. Ann Thorac Surg 1993;55:395-400.

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