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Ann Thorac Surg 1995;59:723-729
© 1995 The Society of Thoracic Surgeons

Tepid Antegrade and Retrograde Cardioplegia

Division of Cardiovascular Surgery, Department of Clinical Biochemistry, and Center for Cardiovascular Research, The Toronto Hospital and the University of Toronto, Toronto, Ontario, Canada

Accepted for publication December 7, 1994.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
To determine the optimal temperature for the combination of antegrade and retrograde cardioplegia, 42 patients undergoing coronary artery bypass grafting were randomized to receive cold (9°C; n = 14), tepid (29°C; n = 14), or warm (37°C; n = 14) blood cardioplegia delivered continuously retrograde and intermittently antegrade. Myocardial oxygen utilization, lactate and acid metabolism, and coronary vascular resistance were measured during the operation and cardiac function was assessed postoperatively. Myocardial oxygen consumption, lactate release and acid release were greatest with warm, intermediate with tepid, and least with cold cardioplegia (p = 0.0001). However, washout of lactate and acid at the time of cross-clamp release was reduced (p = 0.022) with tepid or cold compared with warm cardioplegia. Early postoperative left ventricular function was best preserved (p = 0.01) after tepid than after cold or warm combination cardioplegia. These results suggest that tepid combination cardioplegia reduced metabolic demands but permitted immediate recovery of cardiac function. This technique may provide better myocardial protection than cold or warm combination cardioplegia.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Normothermic blood cardioplegia offers the promise to resuscitate the ischemic myocardium and reduce the morbidity and mortality of coronary bypass operations [1]. Warm cardioplegia improved early postoperative end-systolic elastance, preload recruitable stroke work, and postoperative early diastolic relaxation compared with cold cardioplegia [2]. However, inadequate distribution or interruption of normothermic cardioplegia may induce anaerobic metabolism and warm ischemic injury. Therefore normothermic cardioplegia must be delivered continuously and homogeneously. We previously demonstrated that a combination of antegrade and retrograde warm cardioplegia reduced the accumulation of anaerobic metabolites and preserved adenosine triphosphate and ventricular function better than either antegrade or retrograde warm cardioplegia alone [3]. In addition, we found that reducing cardioplegic temperature from 37°C to 29°C did not alter myocardial oxygen consumption but reduced myocardial lactate and acid release and preserved cardiac function [4]. Therefore we investigated a combination of intermittent antegrade and continuous retrograde cardioplegia to determine the optimal temperature for this cardioplegic technique.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Patient Population
Forty-two patients scheduled for isolated coronary artery bypass grafting by one surgeon agreed to participate in a study of alternative techniques. All patients signed a consent form approved by the Human Experimentation Committee. Patients admitted to the study were 39 to 79 years old, had double- or triple-vessel coronary artery disease, and had preserved preoperative ventricular function (left ventricular ejection fraction greater than 0.30 by preoperative single-plane contrast ventriculography). Table 1 describes the patients in this study.

Cardioplegia Groups
Patients were randomly assigned, by means of computer-generated randomization table, to one of three cardioplegic strategies (see Table 1).

Blood cardioplegia was prepared by mixing four parts of oxygenated blood to each part of crystalloid solution [5] and was delivered via the Buckberg-Shiley Plus system (Sorin Biomedical Inc, Irvine, CA). The cardioplegic technique is depicted in Figure 1. In all patients, cardiac arrest was achieved with an antegrade infusion of 500 mL of high-potassium cardioplegia (containing 27 mEq/L of potassium) delivered into the aortic root at a pressure of 70 mm Hg measured through a separate port of the cardioplegia cannula (Research Medical Inc, Midvale, UT). After cardiac arrest was achieved with the initial antegrade infusion, the aortic root was vented and retrograde delivery of low-potassium cardioplegia (containing 13 mEq/L) was commenced via an autoinflating coronary sinus cannula (Research Medical Inc) at a flow rate of 200 mL/min. Coronary sinus pressure was monitored continuously by a separate pressure-monitoring line, and maintained less than 40 mm Hg throughout the procedure. The adequacy of cannula positioning was confirmed by observing distention of the posterior interventricular vein, maintenance of coronary sinus pressure and palpation of the position of the coronary sinus cannula. The autoinflating coronary sinus catheter frequently required repositing after the construction of circumflex grafts. Distal and proximal anastomoses were constructed in an alternating manner. Antegrade cardioplegic infusions (250 mL) were given intermittently through the aortic root at a flow rate sufficient to maintain the aortic root pressure at 50 mm Hg after completion of each proximal saphenous vein graft anastomosis. The pressure measured in the coronary sinus during retrograde cardioplegia or in the aortic root during antegrade cardioplegia was recorded carefully and was used to calculate the coronary vascular resistance. Cardioplegic infusions were never given simultaneously by both routes. Cardioplegic flow was interrupted whenever necessary to achieve adequate visualization during the construction of the distal anastomoses. A ``catch-up'' infusion was given to maintain the average retrograde cardioplegic flow rate near 200 mL/min [6]. Patients were randomized to either cold (n = 14), tepid (n = 14), or warm (n = 14) cardioplegia, delivered at temperatures of 9°C, 29°C, or 37°C, respectively.

View larger version (24K): [in this window] [in a new window]   Fig 1. . Cardioplegic technique is depicted. (CPB = cardiopulmonary bypass; LIMA = anastomoses of the left internal mammary artery; SVG = anastomoses of saphenous vein grafts; XCL = aortic cross-clamp.)

Oxygen, Lactate, and pH Assays
Arterial and coronary venous blood samples were obtained simultaneously on bypass before application of the cross-clamp, immediately after cross-clamp release, 10 minutes after cross-clamp removal, and 10 minutes after discontinuing cardiopulmonary bypass. During cross-clamping, cardioplegic and coronary venous blood samples were obtained immediately before the completion of proximal anastomoses during retrograde cardioplegia and 30 seconds after the initiation of intermittent antegrade cardioplegia. Coronary venous samples were taken from the coronary sinus during antegrade cardioplegic delivery and from the aortic root during retrograde cardioplegic delivery.

Blood samples were assayed for the partial pressure of oxygen (Po₂) and carbon dioxide, pH (Acid-Base Laboratory, Radiometer, Copenhagen, Denmark), and oxygen saturation (Co-Oximeter, Instrumentation Laboratory Inc., Lexington, MA). Oxygen content (O₂Con) was calculated from the formula: O₂Con = 1.39 hemoglobin x S + 0.0031 Po₂, where S is the oxygen saturation. Myocardial oxygen extraction was calculated as the arterial or cardioplegic oxygen content minus the coronary venous oxygen content. Measurements were made at 37°C and corrected to the myocardial temperature at the time of sampling, which was measured in the left anterior descending region with a temperature probe (Sorin Biomedical Inc) [3–5].

Blood samples for lactate concentration were mixed with a measured volume of 6% perchloric acid. Lactate concentration was measured in the protein-free supernatant by an enzymatic method (Rapid Lactate Stat Pack kit; Calbiochem-Behring, La Jolla, CA). Myocardial lactate extraction was calculated in the same manner as oxygen extraction. Negative lactate extraction was expressed as lactate production.

The concentration of hydrogen ion ([H⁺]) in the blood sample was determined by converting the measured pH value to [H⁺] by the formula [H⁺] = antilog (-pH). Measurements were made at 37°C and corrected to the myocardial temperature at the time of sampling. Myocardial acid production was calculated as the coronary venous effluent [H⁺] minus the arterial or cardioplegic [H⁺] [3, 4].

During the cardioplegic arrest myocardial consumption of oxygen, lactate release, and acid release were calculated as cardioplegic flow multiplied by the difference between the arterial and coronary venous content [3–5].

Hemodynamic Measurements
Heart rate (HR), mean arterial blood pressure (MAP), mean pulmonary artery pressure (MPA), mean right atrial pressure (RAP), and pulmonary capillary wedge pressure (PCWP) were measured. Cardiac output (CO) was measured in triplicate by the thermodilution technique. Derived hemodynamic indices were calculated as follows: cardiac index (CI) = CO/body surface area (L • min^-1 • m^-2); stroke index (SI) = CI/HR (mL • min^-1 • m^-2); left ventricular stroke work index = SI x (MAP - PCWP) x 0.0136 (g • m/m²); and right ventricular stroke work index = SI x (MPA - RAP) x 0.0136 (g • m/m²). These hemodynamic variables were measured before initiation of cardiopulmonary bypass and at 10 minutes, 1 hour, 4 hours, 12 hours, and 24 hours after cessation of cardiopulmonary bypass. An analysis of covariance was employed to compare left and right ventricular stroke work indices (the independent variable) between the three cardioplegic groups with preload (left and right atrial pressure) as the covariate. Postoperative volume repletion followed a standard protocol and was accomplished by individuals who were unaware of the intraoperative cardioplegic technique employed.

Creatine Kinase
An antibody inhibition technique was employed to measure the MB isozyme of creatine kinase (CK-MB). The sequential CK-MB measurements were performed 2, 4, 8, 16, 24, and 48 hours after cross-clamp release. Integration of the area under the concentration-time curve for CK-MB within the 48 hours postoperatively allowed calculation of the total CK-MB release, expressed as units x hours per liter [2–6]. The CK-MB measurements of 1 patient in whom a new postoperative Q wave developed was excluded.

Statistical Analysis
Statistical analysis was performed with SAS program (SAS Institute, Cary, NC). One-way or two-way repeated measures analysis of variance was used to test the effect of cardioplegic group and time on myocardial oxygen utilization, lactate and acid metabolism, coronary vascular resistance, hemodynamic variables, and postoperative creatine kinase isoenzyme release. When analysis of variance indicated a significant effect of cardioplegic group or time (p < 0.05), the differences were specified with Duncan's multiple range test. Categoric data are displayed as the absolute and percent frequency. Continuous variables are listed as the mean and standard error of the mean. Statistical significance was assumed at a probability level of less than 0.05.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Myocardial Temperature
Mean myocardial temperatures during cardioplegic arrest in the territory of left anterior descending coronary artery were lowest in cold (18.7° ± 0.6°C; p < 0.05 versus tepid and warm), intermediate in tepid (29.2° ± 0.2°C; p < 0.05 versus cold and warm), and highest in warm (34.7° ± 0.2°C; p < 0.05 versus cold and tepid) combination cardioplegia.

Cardioplegic Flow Rates and Continuity
The initial antegrade cardioplegic infusion had similar flow rates between groups (cold, 288 ± 18 mL/min; tepid, 299 ± 16 mL/min; warm, 311 ± 16 mL/min; p = 0.60). There was no statistical difference in the mean cardioplegic flow rate during continuous retrograde cardioplegia (cold, 136 ± 7 mL/min; tepid, 148 ± 8 mL/min; warm, 160 ± 8 mL/min; p = 0.08). There was no significant difference in the frequency of infusion of intermittent antegrade cardioplegia (cold, 2.3 ± 0.2; tepid, 2.1 ± 0.2; warm, 2.3 ± 0.2 times per patient; p = 0.70). Intermittent antegrade cardioplegia was delivered at a flow rate sufficient to provide an aortic root pressure of 50 mm Hg. Differences in flow rates therefore represent differences in coronary vascular resistance. The flow rates of intermittent antegrade cardioplegia was greater in tepid or warm than in cold cardioplegia (cold, 216 ± 10 mL/min; tepid, 254 ± 9 mL/min; warm, 249 ± 12 mL/min; p < 0.05). The percentage of cross-clamp time during which cardioplegia was interrupted was similar between the groups (cold, 20% ± 4%; tepid, 16% ± 3%; warm, 20% ± 3%; p = 0.64).

Coronary Vascular Resistance
The mean aortic root pressure was similar between the groups during intermittent antegrade cardioplegia (cold, 51.4 ± 1.4 mm Hg; tepid, 50.5 ± 1.8 mm Hg; warm, 49.6 ± 1.8 mm Hg; p = 0.75), and coronary sinus pressures were similar during continuous retrograde cardioplegia (cold, 19.7 ± 1.2 mm Hg; tepid, 19.3 ± 1.4 mm Hg; warm, 18.5 ± 1.2 mm Hg; p = 0.79). Mean coronary vascular resistances during intermittent antegrade and continuous retrograde cardioplegia are shown in Figure 2. The mean coronary vascular resistance was significantly greater with cold than with tepid or warm cardioplegia (p < 0.05) during intermittent antegrade cardioplegia and tended to be greater during continuous retrograde cardioplegia (p = 0.06).

View larger version (34K): [in this window] [in a new window]   Fig 2. . Mean coronary vascular resistance (CVR) during continuous retrograde and intermittent antegrade cardioplegia in three cardioplegic groups. Coronary vascular resistance was greater with cold than tepid or warm combination cardioplegia during intermittent antegrade cardioplegia (p < 0.05). During retrograde cardioplegia CVR was not different between the groups.

View larger version (33K): [in this window] [in a new window]   Fig 3. . Mean myocardial oxygen consumption (MVO2), lactate release (LR), and acid release (AR) were greatest with warm, intermediate with tepid and least with cold combination cardioplegia during intermittent antegrade cardioplegia (p < 0.05). The values of MVO2, lactate, and acid were greater with intermittent warm antegrade than continuous warm retrograde cardioplegia (p < 0.05).

Myocardial Metabolism During Reperfusion
Myocardial oxygen extraction, lactate production, and acid production before cross-clamping and during reperfusion are shown in Figure 4. Myocardial oxygen extraction increased (p = 0.001) similarly in the three groups after cross-clamp removal. Myocardial lactate production (p = 0.02) and acid production (p = 0.02) were significantly greater immediately after cross-clamp release in the warm than in the tepid or cold cardioplegic groups.

View larger version (39K): [in this window] [in a new window]   Fig 4. . Myocardial oxygen extraction (O2Ex), lactate production (LP), and acid production (AP) before cross-clamp (pre XCL), immediately after cross-clamp removal (XCL off), 10 minutes after cross-clamp removal (XCL 10') and 10 minutes after cessation of cardiopulmonary bypass (CPB 10'). Lactate production and acid production were greatest after warm and least after tepid cardioplegia (p < 0.05) at the time of cross-clamp release.

View larger version (22K): [in this window] [in a new window]   Fig 5. . Relation between left ventricular stroke work index (LVSWI) and pulmonary capillary wedge pressure (PCWP) before cardiopulmonary bypass (pre) and 1 hour (1 hr) and 4 hours (4 hrs) after cardiopulmonary bypass are depicted. Tepid group resulted in greater LVSWI than cold or warm 1 hour after cardiopulmonary bypass and greater than cold 4 hours after cardiopulmonary bypass despite similar filling pressure (PCWP).

Postoperative Release of the MB Isoenzyme of Creatine Kinase
There was no significant difference in total CK-MB release between groups (cold, 1,285 ± 96 U x h/L; tepid, 1,262 ± 129 U x h/L; warm, 1,152 ± 119 U x h/L; p = 0.69).

Clinical Outcomes
None of the patients died in this series of 42 patients. One patient suffered perioperative myocardial infarction (a new Q wave with a concomitant increase in CK-MB level) in the cold group. None of the patients had low output syndrome (defined as the requirement for inotropic support for more than 30 minutes despite optimization of preload and afterload) and none required an intraaortic balloon pump postoperatively. The incidence of these events was not statistically different between groups.

Although there were no statistically significant differences between the three cardioplegic groups for baseline variables (see Table 1) we evaluated whether any of these variables could predict myocardial lactate or acid production at the time of cross-clamp removal (see Fig 4). By univariate analyses none of the preoperative factors attained statistical significance. In addition, a multivariable analysis identified that only the cardioplegic group predicted lactate and acid production independent of the influences of other variables in Table 1.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
In a recent study we found that warm antegrade blood cardioplegia improved myocardial metabolic recovery better than cold cardioplegia provided aortic root flow rates exceeded 80 mL/min with a hemoglobin concentration greater than 80 g/L [5]. In addition, warm antegrade cardioplegia improved early postoperative end-systolic elastance, preload recruitable stroke work, and postoperative early diastolic relaxation compared with cold cardioplegia [2]. However, inadequate or interrupted distribution of warm cardioplegia may induce anaerobic myocardial metabolism and ischemic injury during cardioplegic arrest. Critically stenotic or obstructed coronary arteries may limit the distribution of antegrade cardioplegia to the myocardium beyond the diseased vessels [7–9]. Furthermore, the benefits of cardioplegic vein graft infusion cannot be employed when arterial grafts are employed. We found that warm antegrade cardioplegia resulted in greater accumulation of lactate in biopsy specimens obtained from the territory of the left anterior descending coronary artery probably because of inadequate cardioplegic perfusion of this region when the left internal mammary artery was employed for revascularization [3].

Retrograde coronary sinus cardioplegia has been proposed as a superior method to deliver cardioplegia to the myocardium distal to an occluded coronary artery [7–9]. However, venovenous shunting through arteriosinusoidal and thebesian communications may limit the nutritive retrograde cardioplegic flow to the right ventricular free wall and posterior ventricular septum [9, 10]. Warm retrograde cardioplegia decreased anaerobic lactate production when flow rates were increased from 50 to 200 mL/min [6]. However, further increases to 300 or 500 mL/min increased the shunt flow without reducing anaerobic lactate production. Warm retrograde cardioplegia resulted in greater anaerobic lactate production during and after cardioplegic arrest compared with other cardioplegic techniques [4, 11, 12]. To avoid ischemic myocardial damage during cardioplegic arrest and to restore immediate postoperative functional recovery, improved techniques of cardioplegic delivery are required.

Combination of Antegrade and Retrograde Cardioplegia
To overcome the limitations of either antegrade or retrograde cardioplegia alone, antegrade and then retrograde cold blood cardioplegia was given intermittently in animals [13] and patients [14, 15]. Intermittent infusions of antegrade and then retrograde cold blood cardioplegia every 20 minutes provided more homogeneous myocardial cooling, complete left and right ventricular functional recovery in animals, and excellent clinical outcomes in patients. However, this cardioplegic technique can not be employed for warm heart operations. We developed the technique of continuous warm retrograde cardioplegia with intermittent antegrade infusions for warm heart operations [3]. The technique reduced the accumulation of anaerobic metabolites and preserved myocardial adenosine triphosphate concentrations and ventricular function better than either antegrade or retrograde cardioplegia alone. In the present study, myocardial oxygen consumption increased with intermittent antegrade cardioplegia compared with continuous retrograde in all groups suggesting the repayment of an oxygen debt accumulated during retrograde cardioplegia. Lactate and acid release also increased during intermittent antegrade infusion compared with continuous retrograde infusions in the warm group suggesting the washout of anaerobic metabolites accumulated during warm retrograde cardioplegia. These findings are similar to the previous report in which we found that myocardial lactate release increased with time during warm retrograde but not warm combination cardioplegia [3].

Cardioplegic Temperature
The myocardial oxidation of glucose [16], lactate [16], and fatty acids [17] was depressed during and after cold cardioplegia. Cold cardioplegic arrest induced a defect in mitochondrial state 3 respiration and a decrease in citrate synthetase activity [18]. Furthermore, cold cardioplegia depressed metabolic activity and delayed ventricular functional recovery [2]. Therefore, cold cardioplegia will not permit resuscitation of the ischemic myocardium with the immediate restoration of ventricular function. Excessively cold cardioplegia also may cause coronary artery endothelial dysfunction [19]. Because coronary endothelial cells are more vulnerable than cardiomyocytes to ischemic injury, the measurements of coronary vascular resistance may be a sensitive index of metabolic and functional recovery. In the present study cold cardioplegia resulted in greater coronary vascular resistance than tepid or warm cardioplegic arrest. The delay of cardiac functional recovery after cold cardioplegia may be related to the endothelial dysfunction as well as cardiomyocyte mitochondrial dysfunction after hypothermic cardioplegic arrest.

Tepid cardioplegia produced a similar myocardial oxygen consumption to warm cardioplegia during cardioplegic arrest suggesting preservation of mitochondrial function. However, tepid cardioplegia reduced anaerobic lactate release compared with warm cardioplegia perhaps because myocardial metabolic demands were slightly reduced. Reducing the heart temperature to 29°C also provided a buffer to ischemic injury when cardioplegia was interrupted or inhomogeneous. Myocardial oxygen consumption was greater with tepid or warm than cold cardioplegia but anaerobic lactate and acid washout with intermittent antegrade cardioplegia were less with tepid or cold than warm cardioplegia. Lactate and acid washout were least after tepid and greatest after warm cardioplegia at the time of cross-clamp release. Furthermore, postoperative cardiac function was best preserved after tepid cardioplegia. These findings suggest that the combination of intermittent antegrade and continuous retrograde tepid cardioplegia provided superior myocardial protection when coronary obstructions or interruptions limited cardioplegic delivery.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Supported by the Medical Research Council of Canada (grant MT9829) and the Heart and Stroke Foundation of Ontario (grant B2267). J.S.I. is a Fellow of the Medical Research Council of Canada, and R.D.W. is a Career Investigator of the Heart and Stroke Foundation of Ontario.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Weisel, The Toronto Hospital, 200 Elizabeth St, EN 14-215, Toronto, Ont M5G 2C4, Canada.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

1. The warm heart investigators. Randomised trial of normothermic versus hypothermic coronary bypass surgery. Lancet 1994;343:559–63.[Medline]
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3. Hayashida N, Ikonomidis JS, Weisel RD, et al. Adequate distribution of warm cardioplegia. J Thorac Cardiovasc Surg (in press).
4. Hayashida N, Ikonomidis JS, Weisel RD, et al. The optimal cardioplegic temperature. Ann Thorac Surg 1994;58:961–71.[Abstract]
5. Yau TM, Weisel RD, Mickle DAG, et al. Optimal delivery of blood cardioplegia. Circulation 1991;84(Suppl 3):380–8.
6. Ikonomidis JS, Yau TM, Weisel RD, et al. Optimal flow rates for retrograde warm cardioplegia. J Thorac Cardiovasc Surg 1994;107:510–9.[Abstract/Free Full Text]
7. Partington MT, Acar C, Buckberg GD, Julia P, Kofsky ER, Bugyi HI. Studies of retrograde cardioplegia. I. Capillary blood flow distribution to myocardium supplied by open and occluded arteries. J Thorac Cardiovasc Surg 1989;97: 605–12.[Abstract]
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14. Buckberg GD, Drinkwater DC, Laks H. A new technique for delivering antegrade/retrograde blood cardioplegia without right heart isolation. Eur J Cardiothorac Surg 1990;4:163–8.[Abstract]
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