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Ann Thorac Surg 1995;60:1087-1093
© 1995 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Normothermic Versus Mild Hypothermic Retrograde Blood Cardioplegia: A Prospective, Randomized Study

Departments of Anesthesiology, Thoracic Surgery, and Internal Medicine, Oulu University Hospital, Oulu, Finland

Accepted for publication May 18, 1995.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Continuous retrograde blood cardioplegia has been introduced as a promising alternative for myocardial protection during cardiac operations, although the optimal conditions for its delivery have been poorly studied.

Methods. We randomized a prospective series of 101 patients to receive either retrograde warm (37°C) or mild hypothermic (28° to 29°C) blood cardioplegia during elective coronary artery bypass grafting. Warm blood cardioplegia was delivered to the aortic root until the heart was arrested, after which the regimen was switched to retrograde and continued either as warm or mild hypothermic cardioplegia. Oxygen consumption and transcardiac pH differences during aortic cross-clamping were determined, and postoperative creatine kinase-MB efflux, hemodynamic recovery, and clinical complications monitored.

Results. Clinical characteristics, cardioplegia delivery rates, aortic cross-clamp and cardiopulmonary bypass times, and the number of distal anastomoses were similar in both patient groups. Short intermissions in cardioplegia delivery during construction of distal anastomoses were allowed, the ischemia time in the mild hypothermic group being somewhat longer (8.3% ± 1.1% versus 5.1% ± 0.8% of cross-clamp time; p = 0.05). Myocardial oxygen consumption was lower in the mild hypothermic group (2.49 ± 0.23 versus 3.93 ± 0.33 mL/min at 30 minutes of cross-clamping; p < 0.01), and the transcardiac pH difference was smaller (0.05 ± 0.01 versus 0.07 ± 0.01 at 30 minutes of cross-clamping; p < 0.03). Postoperative creatine kinase-MB levels were higher in the normothermic group. Heart rate was higher and left ventricular stroke work index smaller in the warm group, but otherwise there were no major differences between the groups in hemodynamic recovery. The number of postoperative complications was also similar in both groups.

Conclusions. Although both normothermic (37°C) and mild hypothermic (28° to 29°C) retrograde blood cardioplegia, when delivered in near-continuous fashion, will offer safe myocardial protection during coronary artery bypass grafting, mild hypothermia seemed to provide somewhat better protection under the conditions prevailing here. The effects of different cardioplegia temperatures should perhaps be tested further in patients with recent myocardial infarction, unstable angina, or severely depressed left ventricular function.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
See also page 1093.

Hypothermia has long been considered a widely acknowledged component of myocardial protection in cardiac surgery, although warm cardioplegia offers some theoretical advantages, such as a more effective supply of oxygen to the arrested heart, and avoids many of the potential side effects of hypothermia. Accordingly, the concept of warm heart surgery and normothermic cardiopulmonary bypass was introduced some years ago, and clinical trials have shown that it offers a good alternative to conventional cold blood cardioplegia [1–6].

Optimal myocardial protection relies on adequate delivery of the cardioplegic solution to all parts of the heart. Because areas distal to complete coronary artery occlusions are poorly protected by antegrade cardioplegia, retrograde administration through the coronary sinus has emerged as an attractive alternative in these cases, as also in combined valve and coronary operations [7–99]. Retrograde blood cardioplegia entails some potential disadvantages, however, including the possibility of inhomogeneous distribution of cardioplegia [10, 11], inadequate protection of the right and posterior left ventricles [9, 12], and the possibility of coronary sinus injuries [13]. Moreover, the occasional need for discontinuation of retrograde blood cardioplegia may predispose the myocardium to ischemic damage, especially when warm cardioplegia is used [14, 15].

Although retrograde cardioplegia has gained popularity in clinical practice, prospective, randomized studies of its protective capacity and optimal modes of administration in cases of severe coronary artery disease are rare [16–18]. We therefore decided to conduct a trial comparing retrograde continuous warm and hypothermic cardioplegia regimens during coronary artery bypass grafting. Altogether 101 patients with severe coronary artery disease were included in the series. Oxygen consumption and transcardiac pH differences during aortic cross-clamping were determined, and immediate hemodynamic recovery, postoperative creatine kinase-MB efflux, and complications were recorded.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Patients
This study was approved by the Ethical Committee of Oulu University Hospital, and the patients gave their informed consent before operation. One hundred one patients admitted for elective aortocoronary bypass grafting were randomized into two groups: (1) normothermic bypass and continuous retrograde blood cardioplegia (37°C) and (2) mild hypothermic bypass (32° to 33°C) and cardioplegia (28° to 29°C). Coronary reoperation was an exclusion criterion (Table 1).

Surgical Technique
The operations were performed by two experienced cardiac surgeons (M.L. and J.N.). Cardiopulmonary bypass was established with a single two-stage right atrial cannula and ascending aortic cannula. A cardioplegic cannula with venting and pressure monitoring ports (DLP Inc, Grand Rapids, MI) was used for initial antegrade cardioplegia delivery, a retrograde, self-inflating coronary sinus catheter (Research Medical Inc., Midvale, UT) being positioned by the closed transatrial technique before the initiation of full cardiopulmonary bypass. The distal and proximal anastomoses of the grafts were performed during a single period of aortic cross-clamping.

Perfusion
A membrane oxygenator was used (Compactflo; Dideco, Mirandola, Italy). The hematocrit was maintained at more than 28% during cardiopulmonary bypass, pump flows varied from 2.2 to 2.4 L•min^-1•m^-2, and mean arterial pressures were kept at 60 to 80 mm Hg with the aid of nitroglycerin/nitroprusside or phenylephrine hydrochloride/norepinephrine. The systemic temperature of the patients receiving normothermic cardioplegia (group 1) was kept at 37°C, whereas for those who received mild hypothermic cardioplegia (group 2) it was allowed to drift down to 32° to 33°C. The group 2 patients were rewarmed to 37°C during completion of the proximal anastomoses. All the anesthesias and perfusions were taken care of by the same anesthesiologist (P.K.).

Cardioplegia
The same cardioplegic solution was used in both groups: 500 mL of aspartate + glutamate (26 mmol/L), 150 mL of TRIS/bicarbonate buffer, 40 mL of KCl (2 mmol/mL), 125 mL of citrate-phosphate-dextrose solution, and 250 mL of 5% glucose. One part of solution and 7 parts of blood (1:7) was delivered by a commercial cardioplegia set (D720; Dideco). Extra KCl (2 mmol/mL) was injected directly into the cardioplegia line when arresting the heart and whenever electrical activity reappeared.

In both groups warm cardioplegia (37°C) was delivered to the aortic root until the heart was arrested, after which the regimen was switched to retrograde and continued either as warm cardioplegia or cooled to 28° to 29°C. Occasionally cardioplegia had to be interrupted for short periods to improve visibility during construction of the distal anastomoses. Coronary sinus pressure was monitored continuously and maintained at less than 40 mm Hg throughout the procedure. The aortic root was vented continuously during retrograde cardioplegia. The mild hypothermic group received a terminal infusion of 37°C retrograde cardioplegia (``hot shot''; 400 to 600 mL) immediately before cross-clamp removal.

Hemodynamics
Heart rate, mean arterial pressure, central venous pressure, pulmonary artery wedge pressure, and cardiac output with the thermodilution technique were measured before the induction of anesthesia, when the patients arrived at the intensive care unit, and at 4 and 24 hours thereafter. Cardiac index, stroke index, right and left ventricular stroke work indices, and pulmonary and systemic vascular resistances were calculated using standard formulas.

Laboratory Data
Blood samples obtained from the cardioplegia line and aortic root every half hour during cardioplegic arrest were assayed for oxygen tension, carbon dioxide tension, pH, and oxygen saturation with a 288 blood gas system (Ciba-Corning, Medfield, MA). Oxygen content was calculated as 1.39 hemoglobin concentration x oxygen saturation + 0.003 oxygen tension. The difference in oxygen content between the cardioplegia line and aortic root was multiplied by the cardioplegic flow rate to calculate myocardial oxygen consumption. The transcardiac pH differences were also calculated.

The MB isoenzyme of creatine kinase (CK-MB) was measured by an electrophoretic method (REP; Helena Laboratories, Beaumont, TE), samples for the CK-MB assays being collected every 4 hours after aortic cross-clamp removal for the first 48 hours.

Postoperative Follow-up
The electrocardiograms were analyzed by the same cardiologist (K.P.), who was blinded to the temperature of the cardioplegia used. Perioperative myocardial infarction was defined as the appearance of new Q waves, left bundle-branch block, or poor R wave progression associated with an elevation in the CK-MB level greater than 60 IU/L. A patient was considered to be suffering from low output syndrome whenever systolic blood pressure was less than 90 mm Hg and the cardiac index was less than 2 L•min^-1•m^-2 despite adequate preload, inotropic support, and afterload reduction. Mortality was calculated within 30 days of the operation.

Statistical Analysis
Statistical analyses were performed using the CSS statistical package program (StatSoft, Tulsa, OK). The unpaired Student's t test and ² test were used when comparing clinical variables between the two groups, and two-way analysis of variance to test time-dependent changes in the measured variables. Scheffé's post-hoc test was applied when testing differences in CK-MB level and metabolic parameters at different points in time. The data are presented as means ± standard error of the mean. Significance was assumed when the p value was less than 0.05.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Preoperative Data
Fifty-one patients were randomized into the normothermic group and 50 into the mild hypothermic group. The two groups had similar preoperative characteristics, without any significant differences in New York Heart Association classification, risk factors, previous myocardial infarctions, medication, number of diseased vessels, incidence of left main coronary artery stenosis, or ejection fraction. Thirteen patients in the warm group (25.5%) and 15 in the mild hypothermic group (30%) were considered to have unstable angina (see Table 1).

Perioperative Course
Myocardial oxygen consumption was significantly lower in the mild hypothermic group at 30 minutes after aortic cross-clamping (2.49 ± 0.23 versus 3.93 ± 0.33 mL/min; p < 0.01), but the difference between the groups was no longer significant at 60 minutes (Fig 1). The transcardiac pH difference was significantly smaller in the mild hypothermic group at 30 minutes after aortic cross-clamping (0.05 ± 0.01 versus 0.07 ± 0.01; p < 0.03), but no longer at 60 minutes (Fig 2).

View larger version (17K): [in this window] [in a new window]   Fig 1. . Oxygen consumption (MVO2) after 30 and 60 minutes of aortic cross-clamping. The values represent means ± standard error of the mean. (Black bars = warm cardioplegia; white bars = mild hypothermic cardioplegia; *p < 0.05.)

View larger version (19K): [in this window] [in a new window]   Fig 2. . The transcardiac pH difference (inflow - outflow) after 30 and 60 minutes of aortic cross-clamping. The values represent means ± standard error of the mean. (Black bars = warm cardioplegia; white bars = mild hypothermic cardioplegia; *p < 0.05.)

View larger version (23K): [in this window] [in a new window]   Fig 3. . Postoperative creatine kinase-MB (CK-MB) efflux profiles. The values represent means ± standard error of the mean. (Circles = warm cardioplegia; triangles = mild hypothermic cardioplegia; *p < 0.05.)

Postoperative Complications
The two groups of patients had a similar number of reoperations for hemostasis (see Table 3), and 1 case of low output syndrome was encountered in each upon arrival at the intensive care unit, but both these patients recovered during the next 4 hours without an intraaortic balloon pump. The number of other postoperative complications was equal in both groups (see Table 3). The incidence of supraventricular arrhythmias was 27% and 24% in the normothermic and mild hypothermic groups, respectively, and 1 patient in the normothermic group died suddenly 14 days after revascularization while still in the hospital. The autopsy revealed a fresh myocardial infarction, and the death was regarded as being arrhythmogenic. Neurologic complications were rare, with only 1 patient in the normothermic group suffering from a transient ischemic attack and 1 in the mild hypothermic group a cerebral infarction diagnosed by computed tomography.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Warm heart surgery has recently been introduced as a safe alternative means of myocardial protection during cardiac operations [1–6]. It has been suggested that retrograde cardioplegia may provide some additional advantages for patients undergoing combined valve and bypass operations or patients with severe coronary artery obstructions [9]. It is therefore not surprising that the combining of these two techniques has proved a tempting possibility and has gained in popularity in spite of the limited number of good, prospective, randomized trials [16–18]. As pointed out by Menasché [15], there is a trend even with continuous normothermic cardioplegia for many surgeons and perfusionists to allow a drift in core temperature (usually down to 32° to 33°C) and interruptions in the delivery of cardioplegia. For these reasons, we decided to perform a prospective, randomized comparison of near-continuous normothermic (37°C) and mild hypothermic (28° to 29°C) retrograde blood cardioplegia (core temperatures of 37°C and 32° to 33°C, respectively). All the patients had severe coronary artery disease and typical angina pectoris, but less than one third in each group had unstable angina.

The groups were comparable in their preoperative clinical characteristics (see Table 1), and the perioperative course was also similar, except that the ischemia time (cardioplegia off) during aortic cross-clamping tended to be longer in the hypothermic group (see Table 2). Myocardial protection seemed to be better in the mild hypothermic group, in view of the lower postoperative CK-MB values (see Fig 3). There were minor differences in the hemodynamic recovery and the number of postoperative complications was similar in both groups (see Tables 3, 4).

It has been suggested that retrograde blood cardioplegia results in inhomogeneous delivery of the cardioplegic solution [10, 11] and inadequate protection of the right and posterior left ventricles [9, 12], and that it should therefore be used with caution, especially in patients with preexisting right ventricular hypertrophy [19]. The right ventricular stroke work index remained at a lower level than preoperatively in the present patients, but so did the left ventricular stroke work index, and this was observed in both patient groups. On the other hand, the immediate preoperative stroke work indices were abnormally high, probably due to anxiety aroused by the operation (see Table 3). Pulmonary vascular resistance almost doubled postoperatively, but in spite of this we did not observe any right ventricular failure. Although right ventricular function was not specifically addressed here, we believe that there is no evidence of the right ventricular myocardium being less well protected than the left. The postoperative left ventricular stroke work index was lower and the CK-MB leakage greater in the normothermic group, which may indicate less optimal protection of the left myocardium in normothermia. In general, our results are in accordance with those of Menasché and associates [20], which show that poor preservation of the right ventricle during retrograde blood cardioplegia is not a major clinical problem.

The blood samples taken from the aortic root represent a mixture of blood cardioplegia draining off the coronary arteries and that shunted from the left ventricle and collaterals. This may have some effects on the absolute values of myocardial oxygen consumption and the transcardiac pH difference. The cardioplegia delivery rates were similar in both patient groups, and the blood in the aortic root was continuously renewed because of the zero pressure venting. It is therefore reasonable to assume that transcardiac oxygen and pH differences can be compared at different points in time both within and between patient groups. The average oxygen consumption and pH difference were calculated to be somewhat higher in the normothermic group (see Figs 1, 2), most probably reflecting higher residual metabolic activity and tissue acidosis. The higher CK-MB leakage may indicate more prominent myocardial injury in this group. It is significant that the somewhat shorter ischemia time in the normothermic cardioplegia group could not correct this difference (see Table 2). One cannot conclude on the basis of these results, however, that hypothermic retrograde blood cardioplegia is superior to normothermic.

Hayashida and associates [18] recently compared different cardioplegic temperatures in antegrade and retrograde cardioplegias with a rather limited number of patients, and found that the production of acid metabolites was more prominent during warm (37°C) than tepid (29°C) retrograde blood cardioplegia, but in spite of this, the total release of CK-MB within 48 hours postoperatively was smaller after warm retrograde cardioplegia. The reasons for the discrepancies in CK-MB data between the report of Hayashida and associates and ours are not obvious, but they could be due to the smaller number of distal anastomoses and shorter cross-clamp and CPB times in their series. On the other hand, CK-MB differences can remain undetected when measured later than 5 to 6 hours after aortic cross-clamping, as demonstrated in our data (see Fig 3). The delivery rates of retrograde cardioplegia varied from 50 to 200 mL/min in the material of Hayashida and associates, but the average delivery rates in different cardioplegia groups were not reported.

Ikonomidis and colleagues [17], studying optimal flow rates for retrograde warm blood cardioplegia, found that it should be administered at 200 mL/min or more to minimize lactate and acid production. The average flow rate in our warm blood cardioplegia cases was only 128 mL/min, which may partly explain the suboptimal protection provided by it. A flow rate of 122 mL/min may be sufficient to protect the myocardium in mild hypothermia, however, although its metabolic effects may be suboptimal. Mild hypothermia could also minimize the unwanted consequences of high volumes of cardioplegia and systemic hyperkalemia, which would certainly be beneficial for patients with renal failure.

Measurements of the hemodynamic parameters during the first 24 hours postoperatively showed minor differences between the study groups (see Table 3). The heart rate increased more in the normothermic group, which might have been due to the more prominent decrease in systemic vascular resistance. Accordingly, it is evident that the patients needed more fluids, as was reflected in the higher central venous pressure. The left ventricular stroke work index recovered better in the mild hypothermic group, this being in concordance with the less pronounced CK-MB leakage and better protection of the myocardium in the mild hypothermic group. The better myocardial protection after mild hypothermia was not reflected as fewer postoperative complications. It is thus possible that normothermia offers advantages over hypothermia that were not specifically addressed in this trial but were reflected in good clinical recovery.

In conclusion, we have shown in this prospective, randomized study that both normothermic (37°C) and mild hypothermic (28° to 29°C) retrograde blood cardioplegias, when delivered in near-continuous fashion, offer safe myocardial protection during coronary artery bypass grafting performed on patients with severe coronary artery disease. On the other hand, hypothermia seems to offer somewhat better myocardial protection in terms of enzyme leakage than normothermia, at least when retrograde flow rates of 120 to 130 mL/min are used. The effects of different flow rates should perhaps be tested in further trials studying patients with recent myocardial infarction, unstable angina, or severely depressed left ventricular function.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This research was supported by grants from the Finnish Angiology Foundation. We are grateful to the staff of the operative and postoperative intensive care units of the Oulu University Hospital for their assistance in conducting this investigation.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Peuhkurinen, Division of Cardiology, Department of Internal Medicine, Oulu University Hospital, Kajaanintie 50, 90220 Oulu, Finland.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Martti Lepojärvi Juha Nissinen Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kaukoranta, P. Articles by Peuhkurinen, K. J. Search for Related Content PubMed PubMed Citation Articles by Kaukoranta, P. Articles by Peuhkurinen, K. J. Related Collections Related Article