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Ann Thorac Surg 1996;61:1310-1314
© 1996 The Society of Thoracic Surgeons
Departments of Surgery, Pathology, and Medical Biology, Montreal Heart Institute, Montreal, Quebec, Canada
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Abstract |
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Methods. Hearts in both groups were arrested with a standard crystalloid solution and maintained in a cold saline solution during transportation. In the retrograde group, cardioplegia was administered through a catheter in the coronary sinus during surgical implantation. An average of 471 ± 30 mL of hyperkalemic crystalloid solution diluted 1:4 in warm blood from the oxygenator was infused. In the standard group, the heart was kept cold by topical irrigation of cold saline solution and was reperfused only when the ascending aorta was unclamped.
Results. Preoperative characteristics of donors and recipients were similar in the two cohorts. Ischemic time averaged 139 ± 12 minutes in the retrograde group compared with 130 ± 11 minutes in the standard group (p = 0.57). Cardiopulmonary bypass time averaged 89 ± 4 minutes in the retrograde group and 110 ± 12 minutes in the standard group (p = 0.12). Defibrillation at reperfusion was performed in 4 patients (4/17, 24%) in the retrograde group and 12 patients (12/18, 67%) in the standard group (p = 0.01). There were no deaths in the retrograde group (0/17), whereas in the standard group, 3 patients (3/17) died of early graft failure (p = 0.11). Four early graft failures occurred in the standard group (p = 0.06). Two patients (2/17, 12%) were weaned from bypass with ventricular assist devices in the standard group. The number of subendocardial necrotic cells in the first two weekly endomyocardial biopsy specimens averaged 2.7 ± 0.8 cells/mm2 in the retrograde group and 5.9 ± 2.4 cells/mm2 in the standard group (p = 0.12).
Conclusions. Retrograde warm blood reperfusion appears to improve the initial recovery of transplanted hearts. The technique is easy to use and may be a useful approach to graft protection during surgical implantation.
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Introduction |
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Elevated pulmonary vascular resistance and poor donor heart function at the time of transplantation are most often responsible for early deaths [1]. Moreover, the donor organ shortage prompted a liberalization of the classic donor criteria with respect to age, ischemic time, inotropic support, and donor/recipient size matching. This emphasizes the key role of donor heart preservation technique in the overall outcome for patients having heart transplantation. In a survey of 237 heart transplant centers, Wheeldon and associates [2] provided evidence of the diversity of techniques used for preservation and found that only 15 centers (6%) used secondary blood cardioplegia at reperfusion. The objective of the present study was to compare myocardial preservation techniques and recovery of donor hearts maintained with retrograde continuous warm blood cardioplegia reperfusion versus standard cold topical irrigation during surgical implantation.
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Material and Methods |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Surgical Techniques
The operation was performed according to the usual technique of orthotopic transplantation of the heart. Cardiopulmonary bypass was conducted with moderate hemodilution, the hematocrit level being maintained between 20% and 25%, and with light systemic hypothermia permitting body temperature to drift down to between 33° and 34°C. A single flush of cold crystalloid cardioplegia with 1 L of Ringer's lactate containing 40 mmol of potassium, 20 g of mannitol, 80 mg of lidocaine hydrochloride, and 1.9 mL of 8.4% sodium bicarbonate solution to obtain a pH of 7.4 was used for induction of the donor heart in situ. Donor hearts were stored in cold saline solution during transportation.
In the standard group, the heart was maintained cold throughout the implantation period by topical irrigation with cold saline solution and ice slush with reperfusion when the ascending aorta was unclamped. In the retrograde group, a 14F self-inflating balloon catheter (Research Medical Inc, Midvale, UT) was placed under direct vision and secured by balloon inflation in the coronary sinus after completion of the left atrial anastomosis, and retrograde continuous infusion of crystalloid solution diluted 1:4 in warm blood from the oxygenator at a rate of 100 mL/min was maintained until the ascending aorta was unclamped. Patients in the latter group received an average of 471 ± 30 mL of the crystalloid cardioplegic solution (averaging 1,884 mL of warm blood cardioplegic solution during 19 minutes). Pressure in the coronary sinus was measured during cardioplegia injection and maintained lower than 40 mm Hg.
Preoperative and Postoperative Follow-up
All patients were in functional class 3 or 4 before transplantation, and all had a pulmonary vascular resistance lower than 6 Wood units. Three donors, 2 in the retrograde group (2/18, 11%) and 1 in the standard group (1/17, 6%) needed cardiopulmonary resuscitation before hemodynamic stabilization and evaluation for transplantation. Two donor hearts for the standard group (2/18, 11%) had an abnormal echocardiographic evaluation (akinetic segments) prior to harvesting, and several donors (30/35, 86%, 14 in the retrograde group and 16 in the standard group) were maintained on vasopressor agents. Cerebral death was caused by trauma in 10 donors for the retrograde group (10/17, 59%) and 8 donors (8/18, 44%) for the standard group and by cerebral hemorrhage in 6 donors (6/17, 35%) for the retrograde group and 9 donors for the standard group (9/18, 50%). Postoperatively, patients were maintained initially on a triple-drug immunosuppression regimen of cyclosporine, prednisone, and azathioprine, and rabbit antithymocyte globulin was used as induction treatment [3]. Endomyocardial biopsies were performed every week during the first month after transplantation. All patients who died underwent postmortem examination.
Outcome Measurements
In the study, the primary outcomes included all deaths from any cause and graft failure occurring during the hospitalization period after transplantation. The secondary outcomes were changes in the biochemical markers of ischemia, troponin T and the myocardial-specific isoenzyme of creatine kinase (CK-MB). Blood samples for the determination of serum levels of catalytic activity of CK-MB and troponin T were taken at the beginning of the operation and 1, 3, 6, 12, 24, and 48 hours after chest closure. The CK-MB catalytic activity (normal range, 0 to 30 IU/L) was measured by the standard method using reagents from Boehringer Mannheim (Mannheim, Germany) with a Hitachi 717 analyzer (Hitachi, Tokyo, Japan). The serum cardiac troponin T concentration (normal range, 0 to 0.02 µg/L) was analyzed by an enzyme immunoassay method using reagents and ES300 analyzer from Boehringer Mannheim.
An additional secondary outcome was the quantification of myocardial necrosis at the first two endomyocardial biopsies by an observer blinded to the treatment group allocation. Usually, four or five biopsy specimens were stained with hematoxylin and eosin at each procedure. The total endomyocardial area available at biopsy was calculated, and the total number of necrotic cells for the two biopsies was added for every patient. There was no evidence of acute cellular rejection in these endomyocardial biopsy specimens. Two patients who died before a biopsy could be performed had a similar sampling of the interventricular septum at postmortem examination to complete the histologic analysis.
Statistical Analysis
A small sample of 34 patients was chosen on the basis of the available information in the literature and the difficulty of enrolling a larger number of patients in a single-center study. Data were expressed as the mean ± the standard error of the mean. The confounding effect of the cause of death of donors was analyzed with the Mantel-Haenszel procedure [4]. The relative rate of recipient survival (relative risk of success) for patients treated with the experimental approach compared with that of patients receiving the standard treatment was determined [5]. Continuous data were analyzed with unpaired Student t test and categoric data, with 
2 test. Fisher's exact test was also used to analyze the 2 x 2 table when one cell was equal to zero, the hypothesis being that the experimental group would have increased patient and graft survival compared with the standard group at a significance of 95% (p < 0.05). Analysis of variance for repeated measures was performed to test the difference in CK-MB release and troponin T release between groups.
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Results |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Mortality and Graft Failure
Three patients (3/17) in the standard group died of early graft failure compared with no patients in the retrograde group (p = 0.11). There were four early graft failures in the standard group, as 1 patient received two donor hearts. No graft failure occurred in the retrograde group (p = 0.06). All other patients survived the period of initial hospitalization after transplantation and were discharged from the hospital.
Two patients in the standard group (2/17, 12%) were weaned from bypass with ventricular assist devices; 1 was supported for 11 hours and died of mediastinal bleeding, and the other underwent retransplantation 48 hours later and died of multisystem failure and low cardiac output 2 weeks after operation. Echocardiography of the second transplanted heart showed inferior akinesia, and the electrocardiogram was characterized by Q waves in the inferior derivations. We concluded donor heart failure was due to inferior myocardial infarction.
Three of the donor hearts that failed came from patients who died of cerebral hemorrhage and the fourth donor heart, from the victim of an accident. One of these donor hearts showed anterior hypokinesia at angiographic evaluation prior to transplantation. The relative rate of graft survival with the retrograde approach was 1.33 in analyzing grafts from donors who died of cerebral hemorrhage and 1.25 from donors who died of other causes. The Mantel-Haenszel relative rate combining the two strata averaged 1.27.
Overall, 2 ± 1 inotropic and vasopressor drugs were used to support hemodynamic status 24 hours after transplantation in both groups. Isoproterenol hydrochloride, norepinephrine, and amrinone lactate were most often used.
Patients who died after transplantation underwent postmortem examination. All four hearts showed marked areas of coagulative and contraction band necrosis, lesions that were more extensive in the right ventricle than in the left ventricle. Two hearts showed moderate and unimportant atherosclerotic lesions in the coronary arteries.
Biochemical Markers of Myocardial Damage and Cell Necrosis
After operation, there was a significant (p < 0.05) increase in serum CK-MB activity and in the level of cardiac troponin T in both groups (Figs 1, 2
). The peak increase in CK-MB activity occurred 1 hour postoperatively and averaged 118 ± 9 IU/L in the retrograde group and 112 ± 10 IU/L in the standard group (p = 0.67). With retrograde cardioplegia, troponin T release peaked after 1 hour with an average of 3.3 ± 0.5 µg/L compared with 3 ± 0.8 µg/L in the standard group, although a second peak averaging 3 ± 0.8 µg/L occurred after 48 hours in the latter group. These differences between groups were not significant (p > 0.05). In the standard group, serum values for CK-MB and troponin T were not available for 2 patients who died immediately after transplantation.
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Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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In an experimental study, Tixier and colleagues [8] found that warm substrate-enriched blood solutions for cardioplegic induction may increase tolerance to subsequent ischemia during organ storage. In a clinical study, Nataf and coauthors [9] suggested that warm blood cardioplegia at reperfusion improved preservation of the donor heart. In the present study, reperfusion with warm blood cardioplegia during surgical implantation of the graft resulted in a lower mortality rate, a decrease in the number of early graft failures, and a decrease in myocardial cell necrosis at endomyocardial biopsy. Reperfusion injury characterized by intracellular calcium accumulation, myocardial cell swelling, and inability of the heart to use delivered oxygen can be minimized by warm blood cardioplegia reperfusion prior to aortic unclamping even after prolonged periods of preservation [7–9]. We [10] have shown in an experimental study that myocyte necrosis can be detected at histologic evaluation up to 2 weeks after induction of the ischemic event when animals were treated with standard immunosuppression. In the present study, we used the samples from the first two routine endomyocardial biopsies to quantify subendocardial cell necrosis after transplantation. Less endomyocardial cell necrosis was found in the retrograde group than in the standard group, and there was no sign of acute cellular rejection in these biopsy specimens. Thus, we suggest that the lower number of necrotic cells early after transplantation reflects a decrease in ischemic preservation injury, although the difference was not significant.
The CK-MB and troponin T levels were analyzed to assess myocardial damage with indices more sensitive than clinical outcomes [11]. Although the analysis of troponin T was found to be very useful to evaluate a new myocardial protection technique after coronary artery bypass grafting in a recent trial [7], there was no significant difference in troponin T release between the two groups in the present study. This could be due to the small number of patients in the study, the absence of blood samples from patients with early graft failure, or the study design that analyzed the release of troponin throughout the first 48 hours after transplantation only. In the standard group of patients, a second peak of troponin T release was shown after 48 hours, which contrasts with the slow decrease in the slope of release of the cardiac protein in the retrograde group. The former pattern of troponin T release is similar to that in patients with perioperative myocardial infarction, and the latter is closer to that of patients without major ischemic events after a cardiac operation [7, 12]. Therefore, it is possible that an evaluation of troponin T over a longer period would have answered the question.
Several clinical studies have evaluated the effect of University of Wisconsin (UW) solution in preservation of the donor heart for transplantation. Jeevanandam and associates [13] showed that UW solution-preserved hearts regain myocardial function faster after implantation. On the other hand, Stein and colleagues [14] found that adenosine triphosphate and creatine phosphate levels were higher at the end of ischemia in UW solution-preserved hearts, and Kawai and coauthors [15] reported that UW solution did not improve cardiac function after transplantation compared with a standard cold crystalloid solution. Therefore, the clinical benefit of UW solution remains unproven, and none of these studies have shown that that solution can prevent reperfusion injury. Moreover, Drinkwater and associates [16] have suggested that UW solution is associated with an increased incidence of coronary vasculopathy after transplantation. Thus, we have chosen to use our standard crystalloid solution to arrest the donor heart [7] and a cold saline solution for preservation during transportation [2]. In a clinical study, Pearl and co-workers [17] showed that leukocyte-depleted blood reperfusion resulted in a significant decrease in the release of thromboxane B2 from the coronary sinus, biochemical evidence that reperfusion injury was partly prevented despite the absence of major clinical benefit.
Several authors have shown that retrograde administration of cardioplegic solution provides nonuniform distribution of the solution in the myocardium, although results with the retrograde route were satisfactory in clinical studies [18, 19]. We have chosen the retrograde route because of the direct visual access to the coronary sinus during surgical implantation, but a tourniquet was placed around the coronary sinus ostia in addition to balloon inflation to secure cardioplegia delivery in the most recent patients. Also, we now use a higher flow rate of blood reperfusion of between 150 and 200 mL/min to meet the metabolic demands of the warm arrested myocardium [19]. We have not seen any clinical right heart failure requiring specific medication in patients in the retrograde group. The optimal cardioplegic temperature remains controversial, and cold or tepid delivery was also suggested [20, 21]. Nevertheless, warm blood reperfusion was chosen on the basis of the work on warm reperfusion by Buckberg [22].
Our results support the approach of blood cardioplegia reperfusion of the donor heart during surgical implantation. Although the data should be interpreted cautiously because of the small number of patients in the study, the lower mortality and the lower number of early graft failures suggest that retrograde warm blood reperfusion during surgical implantation is effective in decreasing the deleterious effects of reperfusion injury. Moreover, histologic quantification of endomyocardial necrosis showed that blood reperfusion resulted in less cell necrosis, although the difference was not significant. In our experience, 5 patients undergoing transplantation between 1983 and 1992 (5/121, 4%) and 3 recipients in the present study having transplantation in 1993 or 1994 (3/34, 8.8%) died of primary graft failure. In the first 8 months of 1995, 15 donor hearts were implanted using retrograde warm blood reperfusion without any primary graft failure. The increase in early mortality experienced in 1993 and 1994 could be related to the donor organ shortage in our geographic area and to the use of less than ideal organs from donors with cardiopulmonary resuscitation, abnormal echocardiogram, or inotropic support. Clearly, the organ shortage had an effect on the decision to use those organ donors, although this aspect cannot be well quantified.
The results of this prospective clinical trial suggest that retrograde blood cardioplegia reperfusion of the donor heart is a safe and appropriate method of reperfusion that improves myocardial protection and recovery of the transplanted heart. Whereas clinical outcomes showed a borderline effect on mortality and graft failure, the release of biochemical markers of ischemia was not significantly different, although a lesser degree of myocardial cell necrosis was found in the retrograde group. Moreover, although donor ischemic time was similar in both groups, cardiopulmonary bypass time was longer in the standard group and electric defibrillation was more often used. However, in the study, there was a relatively short preservation time, which reflects the situation of a donor shortage where several hearts were harvested locally and most were used despite the presence of some classic contraindications to heart donation. Overall, retrograde warm blood cardioplegia appears advantageous, and it is currently our method of reperfusion during surgical implantation of the transplanted heart. Larger multicenter trials should study the effect of several newer approaches for protection of the transplanted heart.
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Acknowledgments |
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Address reprint requests to Dr Carrier, Department of Surgery, Montreal Heart Institute, 5000 Belanger St. Montreal, PQ HIT IC8, Canada.
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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