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Clinical Heart Transplantation With Extended Preservation Time (>5 Hours): Experience With University of Wisconsin Solution
Clinical Heart Transplantation With Extended Preservation Time (>5 Hours): Experience With University of Wisconsin Solution F. Kur, A. Beiras-Fernandez, B. Meiser, P. U¨berfuhr, and B. Reichart ABSTRACT Background. Use of University of Wisconsin solution has been suggested for extended organ preservation ⬎4 hours in experimental cardiac transplantation, but few data have been reported from clinical use. This study investigated the impact of preservation with UW solution after prolonged ischemic times on myocardial damage and outcomes after heart transplantation. Materials and Methods. Between 1994 and 2006, 34 orthotopic heart transplantations were performed at our institution with cold ischemic times of ⱖ300 minutes (mean, 325.1 ⫾ 21.3). Donor organs were perfused with and stored in 1000 mL of University of Wisconsin solution. No significant differences were observed with regard to age, gender, diagnosis, donor inotropic support, and donor–recipient weight ratio when compared with recipients undergoing an ischemic time ⬍300 minutes. Results. After a mean follow-up of 47.6 months (range, 1 day to 147.1 months), Kaplan– Meier survival analysis revealed survivals of 91.0% at 3 months, and 82.9% for the entire observation period. The time required to wean from bypass (mean, 78.1 minutes) was equal when compared with that of recipients experiencing grafts undergoing an ischemic time of ⬍300 minutes, but there was a significantly greater average need for inotropic support over the first 48 posttransplant hours. Neither hospital stay in the ICU (mean, 13.0 days; range, 1–55 days) nor the incidence of acute graft failure or survival was different. Conculsion. We conclude that heart preservation with UW limited ischemic damage from prolonged storage and improved myocardial function in the early posttransplant period, thus allowing transplantation of organs with ischemic times ⬎300 minutes. NFORCEMENT of the German Transplantation Law (8/2000) resulted in longer ischemia times at our institution.1 An ischemic time ⬎4 hours has been reported to be a significant factor leading to primary graft failure.2 Thus, optimal heart preservation is mandatory for transplant procedures with prolonged ischemic times. Use of University of Wisconsin (UW) solution, an intracellular preservation solution, has been suggested for extended organ preservations of ⱖ4 hours in experimental cardiac transplantation3; however, few clinical data have been reported. This study investigated the impact of prolonged ischemic times (⬎300 minutes) on myocardial damage and outcome after heart transplantation using preservation with UW solution.
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PATIENTS AND METHODS Between June 1994 and September 2006, 137 patients underwent orthotopic heart transplantation at our institution after preserva-
tion with UW solution. Donor organs perfused with UW were stored in 1000 mL of UW solution. All patients underwent orthotopic biatrial heart transplantation under general anesthesia (isofluorane/sufentanil). These patients were retrospectively evaluated as 2 groups according to the length of cold ischemia time: 103 patients underwent heart transplantation with an ischemia time ⬍300 minutes (group I), and 34 patients after heart transplantation with a cold ischemia time of ⱖ300 minutes (mean, 325.1 ⫾ 21.3; group II). No significant differences were observed with regard to age, gender, diagnosis, donor inotropic support, and donor–recipient
From the Department of Cardiac Surgery, Ludwig Maximilians University, Munich, Germany. Address reprint requests to Dr Andres Beiras-Fernandez; Department of Cardiac Surgery, University Hospital Grosshadern, LM-University, Marchioninistrasse 1581377 Munich, Germany. E-mail: [email protected]
© 2009 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2009.06.010
Transplantation Proceedings, 41, 2247–2249 (2009)
2247
2248
KUR, BEIRAS-FERNANDEZ, MEISER ET AL Table 1. Demographics and Clinical Data Parameter
Recipient age Recipient gender (w/m) Donor age Pulmonary pressure (wood units) Reoperation Cause of death spontaneous ICB/trauma Donor gender (w/m) Donor Na⫹ HU vs elective Tx Indication DCM/ICM/ congenital
RESULTS
Group I (⬍5 h; n ⫽ 103)
Group II (⬎5 h; n ⫽ 34)
Test
51.9 21/82 36.8 ⫾ 12.6 2.7 ⫾ 1.4
46.2 8/26 39.3 ⫾ 12.2 2.7 ⫾ 1.9
NS NS NS NS
54/49 41/62
22/12 23/11
NS .028
26/77 146.7 48/55 53/46/4
13/21 150.6 13/21 11/17/6
NS NS NS NS
ICB, intracraneal bleeding; HU, high urgency; Tx, transplantation; w/m, women/men; DCM, dilative cardiomyopathy; ICM, ischemic cardiomyopathy; NS, not significant.
weight ratio among patients in group II when compared with recipients undergoing an ischemia time of ⬍300 minutes (Table 1). Postoperative laboratory values including troponin, creatinekinase (CK), and CK-MB fraction were assessed to evaluate the myocardial damage. We also evaluated the onset of primary graft dysfunction as well as the postoperative catecholamine therapy. First-choice inotropic support was the combination of epinephrine and milrinone; the first choice vasopressor was norepinephrine. All therapies were tapered according to hemodynamic measurements. We assessed the lengths of stay (LOS) in the intensive care unit (ICU) and in the general ward, as well as the survivals. Descriptive analyses of the results are presented as mean values ⫾ standard deviations. The analytical studies were performed with the Fisher exact test. Kaplan-Meier and log-rank tests were performed to investigate survivals. All analyses were performed using SPSS software (version 15.1 for Windows, SPSS, Inc., Chicago, Ill). P ⬍ .05 was considered to be significant.
Myocardial damage was significantly higher among group II subjects than those with an ischemia time ⬍300 minutes. Values of troponin, CK, and CK-MB fraction were increased in group II (Fig 1). Time required to wean from cardiopulmonary bypass (mean, 78.1 minutes) in group II was similar to that of recipients undergoing an ischemic time of ⬍300 minutes. The average need for inotropic support over the first 48 posttransplant hours was slightly increased among the longer ischemia time patients (82%) compared with group I (69%). Postoperative need for mechanical ventilation and LOS in the ICU (mean, 13.0 days; range, 1–55) were similar for both groups. However, LOS including both the ICU and the general ward was significantly longer for group II (36 days) compared with group I (25 days). The incidence of primary graft dysfunction was similar in both groups (7% vs 6%) and the 30day hospital mortality was also comparable (7% in both groups). After a mean follow-up of 47.6 months (range, 1 day to 147.1 months), Kaplan–Meier survival analysis revealed a survival of 91.0% at 3 months, and 82.9% for the observation period, respectively, for group II. In comparison, group I showed 92% 3-month survival, and 82.5% for the observation period. The differences regarding the long-term survival were not significant (Fig 2). DISCUSSION
Several factors influence the outcome of engrafted organs in clinical practice; among them, length of the ischemic time plays a central role. In animal experiments, there is direct evidence of free radical production in ischemic reperfused hearts proportional to the length of ischemia.4 Although the ischemia periods have been reduced due to better
Fig 1. Markers for myocardial damage on postoperative day 1. Difference within the studied groups was in all cases significant (P ⬍ .05).
PRESERVATION TIME ⬎5 HOURS IN HEART TX
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Fig 2. Group I: 30-days survival, 97.1%; 1-year survival, 87.7%; 5-year survival, 82.9%. Group II: 30-day survival, 91.8%; 1-year survival, 85.5%; 5-year survival, 82.5%. Statistical analysis: Kaplan– Meier and log-rank (P ⫽ NS; .44).
logistics (e.g., the warm ischemia period has been almost eliminated with “in situ” perfusion), ideal conditions have not yet been achieved; thus, organs still suffer short periods of ischemia before definitive engraftment. Furthermore, there are differences between the lengths of cold ischemia time according to the engrafted organ. Cold ischemia times ranging from 12 to 30 hours can be accepted in a kidney transplantation, whereas they would not be acceptable for heart transplantation. There are also logistical situations in which the ischemic time must be extended due to procurement of organs at distant locations.1 Therefore, satisfactory organ preservation is mandatory for successful heart transplantation after a prolonged ischemia time (⬎5 hours). Since the mid 1980s, UW preservation solution has been one of the most widely used solutions in abdominal organ transplantation.5 UW has proven effective to prolong ischemic time beyond 4 hours in experimental heart transplantation.3 UW also has been proven to be effective for myocardial protection in clinical heart transplantation.6,7 In our study, myocardial damage was significantly increased among patients with extended ischemic times (⬎300 minutes). The need for catecholamine support was also increased, although not significantly. Further parameters, such as LOS in the ICU, ventilation time, and incidence of primary graft dysfunction were not significantly different between the groups. Although the myocardial damage and the need for catecholamines were increased in the extended ischemic time patients, preservation with UW seems effective and safe; these patients showed similar
initial outcomes, incidences of complications, and 30-day outcomes. Furthermore, 1-year survival was similar in both groups, allowing us to conclude that preservation with UW for extended ischemic times (⬎300 minutes) is safe and effective. Extended ischemic times may allow us to increase the pool of transplantable organs, thus reducing waiting list mortality.
REFERENCES 1. Groetzner J, Kaczmarek I, Meiser B, et al: The new German allocation system for donated thoracic organs causes longer ischemia and increased costs. Thorac Cardiovasc Surg 50:376, 2002 2. Marasco SF, Esmore DS, Negri J, et al: Early institution of mechanical support improves outcomes in primary cardiac allograft failure. J Heart Lung Transplant 24:2037, 2005 3. Caus T, Bernard M, Sciaky M, et al: Heterotopic rat heart transplant as an in vivo model for reperfusion in long term heart preservation with a modified UW solution. Transplant Proc 28:367, 1996 4. Bolli R: Mechanism of myocardial “stunning”. Circulation 82:723, 1990 5. Olthoff KM, Millis JM, Imagawa DK, et al: Comparison of UW solution and Euro-Collins solutions for cold preservation of human liver grafts. Transplantation 49:284, 1990 6. Stein DG, Drinkwater DC Jr, Laks H, et al: Cardiac preservation in patients undergoing transplantation. A clinical trial comparing University of Wisconsin solution and Stanford solution. J Thorac Cardiovasc Surg 102:657, 1991 7. Reichenspurner H, Russ C, Wagner F, et al: Comparison of UW versus HTK solution for myocardial protection in heart transplantation. Transpl Int 7 (suppl 1):S481, 1994
E
PATIENTS AND METHODS Between June 1994 and September 2006, 137 patients underwent orthotopic heart transplantation at our institution after preserva-
tion with UW solution. Donor organs perfused with UW were stored in 1000 mL of UW solution. All patients underwent orthotopic biatrial heart transplantation under general anesthesia (isofluorane/sufentanil). These patients were retrospectively evaluated as 2 groups according to the length of cold ischemia time: 103 patients underwent heart transplantation with an ischemia time ⬍300 minutes (group I), and 34 patients after heart transplantation with a cold ischemia time of ⱖ300 minutes (mean, 325.1 ⫾ 21.3; group II). No significant differences were observed with regard to age, gender, diagnosis, donor inotropic support, and donor–recipient
From the Department of Cardiac Surgery, Ludwig Maximilians University, Munich, Germany. Address reprint requests to Dr Andres Beiras-Fernandez; Department of Cardiac Surgery, University Hospital Grosshadern, LM-University, Marchioninistrasse 1581377 Munich, Germany. E-mail: [email protected]
© 2009 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2009.06.010
Transplantation Proceedings, 41, 2247–2249 (2009)
2247
2248
KUR, BEIRAS-FERNANDEZ, MEISER ET AL Table 1. Demographics and Clinical Data Parameter
Recipient age Recipient gender (w/m) Donor age Pulmonary pressure (wood units) Reoperation Cause of death spontaneous ICB/trauma Donor gender (w/m) Donor Na⫹ HU vs elective Tx Indication DCM/ICM/ congenital
RESULTS
Group I (⬍5 h; n ⫽ 103)
Group II (⬎5 h; n ⫽ 34)
Test
51.9 21/82 36.8 ⫾ 12.6 2.7 ⫾ 1.4
46.2 8/26 39.3 ⫾ 12.2 2.7 ⫾ 1.9
NS NS NS NS
54/49 41/62
22/12 23/11
NS .028
26/77 146.7 48/55 53/46/4
13/21 150.6 13/21 11/17/6
NS NS NS NS
ICB, intracraneal bleeding; HU, high urgency; Tx, transplantation; w/m, women/men; DCM, dilative cardiomyopathy; ICM, ischemic cardiomyopathy; NS, not significant.
weight ratio among patients in group II when compared with recipients undergoing an ischemia time of ⬍300 minutes (Table 1). Postoperative laboratory values including troponin, creatinekinase (CK), and CK-MB fraction were assessed to evaluate the myocardial damage. We also evaluated the onset of primary graft dysfunction as well as the postoperative catecholamine therapy. First-choice inotropic support was the combination of epinephrine and milrinone; the first choice vasopressor was norepinephrine. All therapies were tapered according to hemodynamic measurements. We assessed the lengths of stay (LOS) in the intensive care unit (ICU) and in the general ward, as well as the survivals. Descriptive analyses of the results are presented as mean values ⫾ standard deviations. The analytical studies were performed with the Fisher exact test. Kaplan-Meier and log-rank tests were performed to investigate survivals. All analyses were performed using SPSS software (version 15.1 for Windows, SPSS, Inc., Chicago, Ill). P ⬍ .05 was considered to be significant.
Myocardial damage was significantly higher among group II subjects than those with an ischemia time ⬍300 minutes. Values of troponin, CK, and CK-MB fraction were increased in group II (Fig 1). Time required to wean from cardiopulmonary bypass (mean, 78.1 minutes) in group II was similar to that of recipients undergoing an ischemic time of ⬍300 minutes. The average need for inotropic support over the first 48 posttransplant hours was slightly increased among the longer ischemia time patients (82%) compared with group I (69%). Postoperative need for mechanical ventilation and LOS in the ICU (mean, 13.0 days; range, 1–55) were similar for both groups. However, LOS including both the ICU and the general ward was significantly longer for group II (36 days) compared with group I (25 days). The incidence of primary graft dysfunction was similar in both groups (7% vs 6%) and the 30day hospital mortality was also comparable (7% in both groups). After a mean follow-up of 47.6 months (range, 1 day to 147.1 months), Kaplan–Meier survival analysis revealed a survival of 91.0% at 3 months, and 82.9% for the observation period, respectively, for group II. In comparison, group I showed 92% 3-month survival, and 82.5% for the observation period. The differences regarding the long-term survival were not significant (Fig 2). DISCUSSION
Several factors influence the outcome of engrafted organs in clinical practice; among them, length of the ischemic time plays a central role. In animal experiments, there is direct evidence of free radical production in ischemic reperfused hearts proportional to the length of ischemia.4 Although the ischemia periods have been reduced due to better
Fig 1. Markers for myocardial damage on postoperative day 1. Difference within the studied groups was in all cases significant (P ⬍ .05).
PRESERVATION TIME ⬎5 HOURS IN HEART TX
2249
Fig 2. Group I: 30-days survival, 97.1%; 1-year survival, 87.7%; 5-year survival, 82.9%. Group II: 30-day survival, 91.8%; 1-year survival, 85.5%; 5-year survival, 82.5%. Statistical analysis: Kaplan– Meier and log-rank (P ⫽ NS; .44).
logistics (e.g., the warm ischemia period has been almost eliminated with “in situ” perfusion), ideal conditions have not yet been achieved; thus, organs still suffer short periods of ischemia before definitive engraftment. Furthermore, there are differences between the lengths of cold ischemia time according to the engrafted organ. Cold ischemia times ranging from 12 to 30 hours can be accepted in a kidney transplantation, whereas they would not be acceptable for heart transplantation. There are also logistical situations in which the ischemic time must be extended due to procurement of organs at distant locations.1 Therefore, satisfactory organ preservation is mandatory for successful heart transplantation after a prolonged ischemia time (⬎5 hours). Since the mid 1980s, UW preservation solution has been one of the most widely used solutions in abdominal organ transplantation.5 UW has proven effective to prolong ischemic time beyond 4 hours in experimental heart transplantation.3 UW also has been proven to be effective for myocardial protection in clinical heart transplantation.6,7 In our study, myocardial damage was significantly increased among patients with extended ischemic times (⬎300 minutes). The need for catecholamine support was also increased, although not significantly. Further parameters, such as LOS in the ICU, ventilation time, and incidence of primary graft dysfunction were not significantly different between the groups. Although the myocardial damage and the need for catecholamines were increased in the extended ischemic time patients, preservation with UW seems effective and safe; these patients showed similar
initial outcomes, incidences of complications, and 30-day outcomes. Furthermore, 1-year survival was similar in both groups, allowing us to conclude that preservation with UW for extended ischemic times (⬎300 minutes) is safe and effective. Extended ischemic times may allow us to increase the pool of transplantable organs, thus reducing waiting list mortality.
REFERENCES 1. Groetzner J, Kaczmarek I, Meiser B, et al: The new German allocation system for donated thoracic organs causes longer ischemia and increased costs. Thorac Cardiovasc Surg 50:376, 2002 2. Marasco SF, Esmore DS, Negri J, et al: Early institution of mechanical support improves outcomes in primary cardiac allograft failure. J Heart Lung Transplant 24:2037, 2005 3. Caus T, Bernard M, Sciaky M, et al: Heterotopic rat heart transplant as an in vivo model for reperfusion in long term heart preservation with a modified UW solution. Transplant Proc 28:367, 1996 4. Bolli R: Mechanism of myocardial “stunning”. Circulation 82:723, 1990 5. Olthoff KM, Millis JM, Imagawa DK, et al: Comparison of UW solution and Euro-Collins solutions for cold preservation of human liver grafts. Transplantation 49:284, 1990 6. Stein DG, Drinkwater DC Jr, Laks H, et al: Cardiac preservation in patients undergoing transplantation. A clinical trial comparing University of Wisconsin solution and Stanford solution. J Thorac Cardiovasc Surg 102:657, 1991 7. Reichenspurner H, Russ C, Wagner F, et al: Comparison of UW versus HTK solution for myocardial protection in heart transplantation. Transpl Int 7 (suppl 1):S481, 1994