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Ann Thorac Surg 1996;61:1734-1739
© 1996 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Cardiac Transplantation After Mechanical Circulatory Support: A Canadian Perspective

Divisions of Surgery, Cardiology, and Pathology, University of Ottawa Heart Institute, Ottawa Civic Hospital, Ottawa, Ontario, Canada

Accepted for publication January 26, 1996.

	Abstract

Top Footnotes Abstract Introduction Patients and Methods Results Comment References

 
Background. To assess the relative efficacy of cardiac transplantation after mechanical circulatory support with a variety of support systems, we analyzed our consecutive series of patients who had and did not have mechanical support before transplantation.

Methods. A review of 209 patients undergoing cardiac transplantation from 1984 to May 1995 was performed. Group 1 consisted of 110 patients who were maintained on oral medications while awaiting transplantation, and group 2 consisted of 60 patients who required intravenous inotropic support. Group 3 included 39 patients who had transplantation after mechanical circulatory support for cardiogenic shock. The indication for device implantation was acute onset of cardiogenic shock in 38 patients and deterioration while awaiting transplantation in 1 patient. The support systems were an intraaortic balloon pump in 13 (subgroup 3A), a ventricular assist device in 7 (subgroup 3B), and a total artificial heart in 19 patients (subgroup 3C).

Results. After transplantation, infection was more common in group 3 (56%) than in group 1 (28%) or group 2 (32%) (p = 0.005). Survival to discharge was lower for group 3 (71.7%) than for group 1 (90.9%) or 2 (88.3%) (p = 0.009). For mechanically supported patients, survival to discharge was 84.6% in subgroup 3A, 71.4% in subgroup 3B, and 63.1% in subgroup 3C (p = not significant).

Conclusions. Transplantation after mechanical support offers acceptable results in this group of patients for whom the only alternative is certain death. Patient selection and perioperative management remain the challenge to improving these results.

	Introduction

Top Footnotes Abstract Introduction Patients and Methods Results Comment References

 
See also page 1739.

In the past decade, cardiac transplantation has become a well-established option for the treatment of end-stage heart disease. For patients in cardiogenic shock to benefit from this therapy, temporary circulatory support is required until a donor heart becomes available. Staged cardiac transplantation after mechanical support continues to evolve, and many problems remain to be solved. To assess the relative efficacy of circulatory support systems, we compared our results with transplantation after support with the intraaortic balloon pump (IABP), the total artificial heart (TAH), and the ventricular assist device (VAD).

	Patients and Methods

Top Footnotes Abstract Introduction Patients and Methods Results Comment References

 
Data from consecutive patients undergoing cardiac transplantation at the University of Ottawa Heart Institute to April 30, 1995, have been prospectively compiled in a database. For the purpose of this study, patients were grouped according to priority in receiving a donor heart: group 1, the lowest priority, consisted of patients maintained on oral medications either in the hospital or at home; group 2 comprised patients who required intravenous (IV) inotropic agents preoperatively; and group 3, the highest priority, consisted of patients in cardiogenic shock who required mechanical circulatory support. Group 3 patients were further divided into subgroups according to the type of mechanical support used: subgroup 3A, the IABP; subgroup 3B, the VAD; and subgroup 3C, the TAH.

We defined cardiogenic shock using the following criteria: cardiac index lower than 2.0 L•min^-1•m^-2, pulmonary artery wedge pressure higher than 20 mm Hg, and systolic arterial blood pressure lower than 90 mm Hg, despite maximal inotropic drug support with sympathomimetic amines, phosphodiesterase inhibitors, or a combination of both.

In general, our approach to the treatment of patients in cardiogenic shock is to correct, where possible, any lesion amenable to surgical intervention. For patients who are considered to have an inoperable lesion or who remain in shock despite operation, IV inotropic support is initiated. Mechanical support, usually with the IABP, is introduced after failure of inotropic drugs to support the circulation. More advanced circulatory support with either the VAD or the TAH is considered after failure of the IABP and one or two inotropic agents to support the circulation and when the patient has been assessed as an acceptable transplant recipient. The VAD used in this study was the Thoratec device (Thoratec Laboratories, Berkeley, CA). The TAH used is currently manufactured by CardioWest (CardioWest Laboratories, Richmond, BC, Canada) though previously it was produced by Symbion (Symbion Inc, Salt Lake City, UT). The choice of device for biventricular support was at the discretion of the operating surgeon.

After device implantation, patients were monitored in the cardiac surgical intensive care unit. Anticoagulation during mechanical support consisted of intermittent low-dose heparin sodium for IABP patients, a continuous IV infusion of heparin (partial thromboplastin time, 1.5 to 2.0 times normal) for VAD patients, and a continuous IV infusion of heparin (partial thromboplastin time, 1.5 to 2.0 times normal) in conjunction with IV administration of dipyridamole (10 mg/h) for TAH patients. Warfarin sodium was not used in this study because of the relatively short duration of mechanical support.

All donor hearts were preserved with St. Thomas' Hospital crystalloid cardioplegia and topical cold saline solution. Donor hearts retrieved prior to 1986 were transported in a cooler at 4°C; since then, the temperature has been maintained between 8° and 10°C [1]. All transplantations were performed using a standard technique as previously described [2].

For all patients, induction of immunosuppression was with IV steroids in conjunction with either IV cyclosporine prior to 1988 or IV immunoglobulin since that time. The immunoglobulin used for induction was either antilymphocyte globulin (15 mg•kg^-1•d^-1) or antithymocyte globulin (10 mg•kg^-1•d^-1). Maintenance of immunosuppression in all patients consisted of triple therapy based on steroids (1 mg•kg^-1•d^-1 in tapering doses), azathioprine (2 mg•kg^-1•d^-1), and cyclosporine (2.5 to 5.0 mg/kg twice daily to achieve a trough plasma level of 200 to 400 ng/mL).

We defined hospital survival as survival to discharge home from the hospital. Comparisons between groups were performed using Student's t test or analysis of variance for continuous variables and a ² test or Fisher's exact test for discrete variables. Actuarial survival was calculated using the life-table technique of Grunkemeier and Starr [3] and was reported with 95% confidence limits. Comparisons between groups were considered significant at a p value of less than 0.05.

	Results

Top Footnotes Abstract Introduction Patients and Methods Results Comment References

 
From May 1984 through April 1995, 213 transplantations were performed in 209 patients with complete follow-up. Four patients underwent retransplantation, 3 emergently within 30 days of the initial procedure and before discharge from the hospital and 1 late, 9 years after the first transplantation. Group 1 consisted of 110 patients (53%), 1 of whom required late retransplantation. In group 2, there were 60 patients (29%), 1 of whom required retransplantation on an emergency basis. There were 39 patients (19%) who required mechanical support prior to transplantation (group 3) as follows: subgroup 3A (IABP), 13 patients; subgroup 3B (VAD), 7 patients; and subgroup 3C (TAH), 19 patients. Two patients in subgroup 3C required retransplantation emergently.

In addition to these patients, 3 patients had VAD implantation as a bridge to transplantation but subsequently were not offered transplantation. The identification of a pulmonary malignancy, the development of right ventricular failure and intraoperative hemorrhage precluded transplantation in these 3 patients, and all died.

The clinical characteristics of groups 1, 2, and 3 are shown in Table 1. The recipient ages (p = 0.30) and sex ratios (p = 0.87), the donor ages (p = 0.06), and the total anoxia times (p = 0.16) were similar in the three groups. However, a greater proportion of recipients in group 3 had coronary artery disease as the primary diagnosis (p = 0.003).

In subgroup 3B, there were 6 patients with CAD who were seen in shock emergently and 1 patient with cardiomyopathy whose condition deteriorated while he was hospitalized and awaiting transplantation. Biventricular support was used in 6 patients and left ventricular support, in 1 patient. Previous coronary artery bypass grafting had been performed in 3 patients, in all on the same admission. Two patients with inoperable coronary disease sustained preoperative cardiac arrest with cardiac massage, and 4 patients had the IABP preoperatively.

In subgroup 3C, all patients were seen acutely in cardiogenic shock, and the condition of none deteriorated while he or she was on the transplant list. Previous coronary artery bypass grafting had been performed in 8 patients, remotely in 1 patient and on the same admission in 7 patients. Cardiac arrest with massage occurred preoperatively in 4 patients, and 11 patients had an IABP preoperatively. Two patients required implantation of a second TAH after transplantation because of rejection and failure of the donor heart. Therefore, 21 artificial hearts were used in subgroup 3C. Both patients received a second transplant but subsequently died.

Infection was the most common complication during mechanical support, and there was little difference between subgroups 3A, 3B, and 3C (p = 0.78) (Table 3). In subgroup 3A, this complication included IV line sepsis in 3 patients and infection at the IABP insertion site in 1 patient. There was one case each of cellulitis, pneumonia, and IV line sepsis in subgroup 3B. In subgroup 3C, 8 patients experienced 12 infections: pneumonitis (7), IV line sepsis (3), oral Candida (1), and disseminated Candida (1).

Reoperation for hemorrhage or tamponade was required in 3 patients each in subgroups 3B and 3C (p = 0.29). Renal failure requiring dialysis or hemofiltration occurred during circulatory support in 3 patients, 1 patient in subgroup 3B and 2 patients in subgroup 3C (p = 0.10). Two of the patients, 1 in each subgroup, were anuric at the time of device implantation after a cardiac arrest. Hemofiltration was required in both until after transplantation, at which time the renal failure resolved. In the third patient, renal failure developed after implantation of a second TAH because of donor heart failure and was treated with hemodialysis.

Other complications during circulatory support included transient hepatic insufficiency with an elevated prothrombin time in 2 patients, one each in subgroups 3B and 3C, with resolution in both after transplantation. The patient in subgroup 3B who had left ventricular support required IV inotropic support for right ventricular dysfunction.

After transplantation, rejection and infection were the most common complications encountered in the hospital in groups 1, 2, and 3. Rejection requiring treatment occurred in 17 patients (0.6 episode/100 hospital days) in group 1, 5 patients (0.4 episode/100 hospital days) in group 2, and 7 patients (0.5 episode/100 hospital days) in group 3 (p = 0.58). Infection, however, was more common in group 3. Infection occurred in 31 patients (28%) in group 1, 19 patients (32%) in group 2, and 22 patients (56%) in group 3 (p = 0.005).

In group 3, infection after transplantation occurred in 6 patients in subgroup 3A, 6 patients in subgroup 3B, and 10 patients in subgroup 3C (p = 0.21) (see Table 3). In subgroup 3A, there were eight infections in 6 patients: urinary tract infection (four), colitis (two), and pneumonitis (two). In subgroup 3B, there were 14 infections in 6 patients: sternal wound infection (three), infection at the driveline exit site (two), pneumonitis (three), urinary tract infection (two), oral herpes (three), and cytomegalovirus infection (one). In subgroup 3C, there were 16 infections in 10 patients: sternal wound infection (four), IV line sepsis (four), pneumonitis (six), oral herpes (one), and driveline infection (one). Sepsis in conjunction with multiorgan failure accounted for two deaths in subgroup 3C.

Rejection in the hospital occurred in 1 patient in subgroup 3B (0.4 episode/100 hospital days) and resolved with medical therapy. Rejection occurred in 6 patients in subgroup 3C (0.8 episode/100 hospital days) (p = 0.29). There was resolution with medical treatment in 3 of these patients, but in 1 patient, rejection caused sudden death before therapy could be initiated. In 2 patients, rejection caused profound donor heart dysfunction, and implantation of another TAH was performed after failure of medical treatment. Both patients subsequently died after retransplantation; 1 sustained rejection again and died in the operating room, and the other died of sepsis and multiorgan failure in the hospital.

Other complications after transplantation in subgroup 3A included leg ischemia after IABP removal in 2 patients, which resolved with surgical exploration, a seizure possibly related to cyclosporine in 1 patient, and heart block requiring a permanent pacemaker in 1. Intraoperative hemorrhage and intraoperative graft failure each occurred in 1 patient, and both patients died. Other complications in subgroup 3B included hemorrhage, deep venous thrombosis, right ventricular dysfunction, and transient ischemic attack in 1 patient each. The patient with a transient ischemic attack awoke immediately after transplantation with a left arm deficit that completely resolved within hours. This was considered likely to represent an air embolism during VAD removal. One patient in subgroup 3B died intraoperatively of graft failure of undetermined etiology, and 1 patient had development of a tracheoarterial fistula after prolonged oral intubation and died of massive hemoptysis. In subgroup 3C, 2 patients died, 1 of graft failure of undetermined etiology and 1 with normal coronary arteries, of myocardial infarction.

Overall, the hospital survival rate was less for patients who required mechanical support before transplantation. The survival rates for groups 1 and 2, were 90.9% and 88.3%, respectively, whereas for group 3, the rate was 71.7% (p = 0.009). Survival to discharge after transplantation was 84.6% for subgroup 3A, 71.4% for subgroup 3B, and 63.1% for subgroup 3C (p = 0.42). The actuarial 5-year survival rate was 78% ± 5% for group 1, 74% ± 7% for group 2, and 57% ± 9% for group 3 (Fig 1). The difference in 5-year survival estimates was not significant between groups 1 and 2 (p = 0.62) and between groups 2 and 3 (p = 0.12). However, the actuarial 5-year survival was significantly lower for patients in group 3 compared with group 1 (p = 0.04).

View larger version (14K): [in this window] [in a new window]   Fig 1. . Actuarial 5-year survival.

	Comment

Top Footnotes Abstract Introduction Patients and Methods Results Comment References

In the present study, we found that patients who required mechanical circulatory support presented a higher operative risk with a lower 5-year survival compared with those who did not. For this group of patients in profound acute cardiovascular collapse, the only alternative was certain death. That more than 70% of patients in this group survived and were discharged home, however, deserves emphasis. A number of patients in this study who required mechanical support were sustained with an IABP with an obvious survival advantage, a finding demonstrating the enduring effectiveness of this therapy. However, two thirds of our patients required more invasive support systems because of the severity of the impairment of cardiac function. Of this group of critically ill patients who required either a VAD or an artificial heart, all but 1 were seen on an emergency basis, 40% had postcardiotomy shock, and approximately 25% had sustained preoperative cardiac arrest.

The 1993 report of the voluntary combined registry experience with VADs and TAHs [6] contains data on 544 patients from 66 centers with an overall survival to discharge after transplantation of 66.2%. Survival was 87.4% for patients supported with a left VAD, 69.5% for patients supported with a biventricular assist device, and 49.6% for TAH patients. Although the 1-year and 2-year survival estimate was 65% for the group overall, it was 86% and 83%, respectively, for univentricular support. In that report, however, the indication for device implantation was deterioration while awaiting transplantation in 92% of patients.

Comparing methods of circulatory support, Reedy and associates [7] reported an early survival advantage with the VAD (100%) compared with the IABP (70%). Of the 14 patients supported with a VAD, 10 had left ventricular assist. Similarly, both Frazier and co-workers [8] and Kormos and colleagues [9] reported excellent results with left VAD support with 80% and 100% hospital survival, respectively, among patients undergoing transplantation. However, it is important to note that these results were obtained in patients for whom the indication for device implantation was deterioration while awaiting transplantation. In contrast to the present study, mechanical support was not used in a resuscitative setting or in patients with acute-onset shock.

The survival data in the present study for patients having transplantation after biventricular support or the TAH are similar to those of the combined registry [6]. In our study, only 1 patient showed deterioration while awaiting transplantation. Most patients were seen acutely with cardiogenic shock, and the circulatory support systems were implanted emergently and in a resuscitative setting. We believe that these patients present an even greater risk for successful device use. Further, we submit that these patients, many of whom were undergoing cardiac massage, are less amenable to univentricular support.

Farrar and Hill [10] in 1993 reported a multicenter evaluation of 151 patients who received the Thoratec VAD prior to transplantation. After transplantation, 83% and 87% were discharged after biventricular and left ventricular assistance, respectively. Of note, these excellent results were achieved in a group of patients of whom 42% had sustained cardiac arrest prior to implantation and in whom device implantation was often used for resuscitation. Farrar and colleagues [11] subsequently reported that blood urea nitrogen was the only independent predictor of hospital survival in these patients.

In 1992, Johnson and coauthors [12] summarized a multicenter experience with clinical use of the TAH in conjunction with transplantation in 171 patients. For the 118 patients receiving transplantation, survival was 72% at 30 days and 57% at 1 year. More recent results with the TAH have been reported by Copeland and associates [13] in a multicenter study. Since 1993, the CardioWest TAH has been used in 40 patients in the United States, Canada, and France with 93% survival to discharge after transplantation. In our experience since 1991, the TAH has been used in 5 patients with 100% survival to discharge after transplantation.

In the present study, although both early survival and late survival were lower in patients with mechanical circulatory support, beyond the hospital period, the actuarial survival curves are parallel. The challenge, therefore, remains patient selection and perioperative management. The most common complication in our experience with mechanical circulatory support was infection, with the respiratory tract being the most frequent site. Although resolution can be expected in most patients with appropriate antibiotic use, prevention must be the goal.

The high incidence of infection in these patients is likely multifactorial, related to immunosuppression, implantation of the device, reoperation for bleeding, prolonged extracorporeal circulation, and the emergency circumstances under which all of these devices were implanted. The high incidence of infection also serves to emphasize the importance of aggressive perioperative management of these patients with early extubation, ambulation, and physical therapy. During this study, patients were maintained on prophylactic antibiotics throughout the support period. Currently, patients receive five doses of cefazolin sodium perioperatively, two intraoperatively and three postoperatively.

In summary, transplantation after mechanical circulatory support can salvage many patients who are seen emergently in profound cardiogenic shock. Patient selection, choice of device, and timing of implantation remain a challenge in the management of these patients, who are at increased risk for device implantation and transplantation. With the current trend toward somewhat more elective use of circulatory assist devices, we must not lose sight of patients who are seen on an emergency basis and require mechanical support for resuscitation before transplantation.

	Footnotes

Top Footnotes Abstract Introduction Patients and Methods Results Comment References

 
Address reprint requests to Dr Masters, Ottawa Heart Institute, 1053 Carling Ave, Ottawa ON KIY 4E9, Canada.

	References

Top Footnotes Abstract Introduction Patients and Methods Results Comment References

 

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4. Kaye MP. Registry of the International Society for Heart and Lung Transplantation: tenth official report-1993. J Heart Lung Transplant 1993;4:541–8.
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6. Pae WE Jr. Ventricular assist devices and total artificial hearts: a combined registry experience. Ann Thorac Surg 1993;55:295–8.[Abstract]
7. Reedy JE, Pennington DG, Miller LW, et al. Status I heart transplant patients: conventional versus ventricular assist support. J Heart Lung Transplant 1992;11:246–52.[Medline]
8. Frazier OH, Rose EA, Macmanus Q, et al. Multicenter clinical evaluation of the HeartMate 1000 IP left ventricular assist device. Ann Thorac Surg 1992;53:1080–90.[Abstract]
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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): Roy G. Masters Paul J. Hendry Wilbert J. Keon Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Masters, R. G. Articles by Keon, W. J. Search for Related Content PubMed PubMed Citation Articles by Masters, R. G. Articles by Keon, W. J.