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Myocardial protection during heart transplantation using blood cardioplegia
ELSEVIER
Myocardial Protection During Heart Transplantation Using Blood Cardioplegia G.B. Luciani, G. Faggian, A. Forni, G. Montalbano, B. Chiominto, and A. Mazzucco
A
of interest around optimal techniques for myocardial preservation during heart transplantation (Htx) has recently occurred, due to the need for continued extension of donor selection criteria and the frequent necessity to use “marginal” donor organs. A recent review has documented the extreme diversity of preservation techniques currently used during Htx.’ Nevertheless, a trend toward the use of some form of maintenance of cardiac standstill and, more commonly, toward the use of reperfusion of the graft prior to clamp removal is being established.’ While intermittent or continuous reperfusion using blood cardioplegia have been reported in a variety of clinical series,2-6 adoption of blood cardioplegia for induction of cardiac arrest in the donor has never been documented. Reported here are the preliminary results with a novel technique of myocardial protection during Htx, which includes induction, preservation, and reperfusion with blood cardioplegia. REVIVAL
PATIENTS
AND
METHODS
Beginning in June 1995, a new method of cardiac preservation during Htx was devised and adopted. The technique was initially employed in a nonrandomized fashion to prove its safety and subsequently a prospective, randomized trial comparing the standard (crystalloid) and modified (blood) cardioplegic solutions was commenced and is currently under way. The present report describes the methods and preliminary results in patients having myocardial protection with blood cardioplegia.
Operative Technique All patients underwent orthotopic Htx using atria1 cuff and direct bicaval anastomosis, as described elsewhere. After dissection of the donor heart, a double-outlet needle (Research Medical Inc, Midvale, Utah) is inserted in the donor ascending aorta and secured with a 4-O polypropylene pursestring. One port of the needle is connected with a disposable cardioplegia bag where the blood is collected and mixed with the Buckberg (A2) solution.’ The bag is connected with a heat exchanger (Biomedicus, Minneapolis, Minn.) and a roller pump used to cool the solution to 0 to 4°C and infuse it at a constant pressure (60 to SO mm Hg) via a line connected with the second port of the cardioplegia needle. After heparin administration, 800 to 1000 mL of donor blood is slowly allowed to drain via the outflow port of the needle. Occasional systemic hypotension episodes are treated with colloid fluid administration. The hematocrit of the induction solution is kept around 20% to 22%. The aorta is then cross-clamped and 1500 to 2000 mL
of blood cardioplegia is administered via the antegrade route, while the heart is decompressed via the right superior pulmonary vein and inferior vena cava. After excision of the heart, the graft is stored in cold (0 to 4°C) sterile saline. In cases where the preservation time exceeds 3 hours (final ischemic time expected longer than 4 hours), a maintenance dose (150 mL/min for 3 minutes) of recipient blood cardioplegia (Buckberg B2) is administered via the cross-clamped aorta of the graft on the bench. Prior to exposing the graft to the recipient’s own blood, 1000 mg of methylprednisolone are given intravenously. Upon completion of the left atrial, inferior caval, pulmonary, and aortic anastomosis, the ascending aorta is again cannulated and warm (30 to 32°C) antegrade reperfusion using blood cardioplegia (Buckberg C3) is begun. The superior caval anastomosis is completed after aortic clamp removal. Patients
Between June 1995 and January 1997, 21 of 69 (30%) patients undergoing Htx with bicaval anastomosis had preservation of the graft using the above method. There were 12 males and 9 females, aged 53 2 10 years, and having dilated (57%), ischemic (33%), or other cardiomyopathy (10%) as indication for Htx. Five (24%) patients had pre-Htx increased pulmonary vascular resistance (~4 Woods units). Donors were 16 males and 5 females, aged 33 ? 11 years, with trauma (76%) and cerebrovascular accident (24%) as cause of brain death. High-dose inotropic requirements and episodes of profound hypotension or cardiac arrest were present in the history of 36% and 10% of donors, respectively. Mean ischemic time averaged 176 2 21 minutes. Post-transplant
immunosuppressive
Therapy
The same treatment protocol was applied to all recipients regardless of the technique used for preservation of the heart. This included oral cyclosporine (CyA) (5 to 8 m&g/d) to maintain a whole blood trough level of 300 to 500 ng/dL, azathioprine (2 to 4 mglkgid) to maintain a total white blood cell count of 40OO/mL,and oral prednisone (starting at a maintenance dose of 1 mg/kdd and tapered to 0.5 m&g/d by the third month). Discontinuation of chronic steroid therapy was attempted after the 6th post-Htx month. Surveillance of rejection was done using a schedule of programmed endomyocardial biopsies and treatment of it by
From the Division of Cardiac Surgery, University of Verona, Verona, Italy. Address reprint requests to Dr G.B. Luciani, Division of Cardiac Surgery, University of Verona, O.C.M. Piazzale Stefani 1, 37126 Verona, Italy.
0041-t 345/97/$17.00 PII so041 -1345(97)00950-0
0 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
3386
Transp/antation
Proceedings,
29, 3386-3388
(1997)
BLOOD CARDIOPLEGIA
means of pulse doses of methylprednisolone and/or augmentation of immunosuppression on an individual basis.
RESULTS
There were no perioperative and only one early death (5%), in a 41-year-old male with chemotherapy- and radiationtherapy-induced cardiomyopathy who was on pre-Htx inotropic support and in chronic renal failure. The patient never resolved the renal insufficiency and died of hemorrhagic complications thereof 2 months after Htx. Cardiac function and rhythm had proved and remained satisfactory throughout the postoperative period. The remaining 20 patients were discharged from the hospital in good clinical condition. One (5%) patient died of acute allograft rejection 18 months after Htx. The actuarial survival for this patient cohort was 95 + 5% and 90 2 10% at 1 and 2 years, respectively. During the same time interval, early and late mortality in patients having standard crystalloid cardioplegia preservation of the donor heart and matched for demographic variables, were 8% (right heart failure 2, multiple organ failure 1, sepsis 1) and 5% (rejection 1, infection l), respectively. The actuarial survival in the control group was thus 91 ? 2% and 86 + 6% at 1 and 2 years. High-dose (association of three inotrops or two inotrops, including epinephrine) inotropic support was necessary in 3 (14%) patients, including 2 (9%) with preoperative pulmonary hypertension experiencing acute right heart failure. Both cases resolved without the need for mechanical life support. No cases of overt left ventricular failure were observed. The prevalence of high dose inotropit requirement and right heart failure in the control group were 31% (P = .04) and 15% (P = .06). Spontaneous resumption of sinus rhythm was not uncommon upon aortic clamp removal (28%) and atrioventricular conduction disturbances were rare (9%) and always transient, with no need for permanent pacing, in patients undergoing the blood cardioplegia protocol. This did not prove true for the control patients who rarely showed spontaneous recovery of sinus activity in the operating room (8%) and more commonly presented atrioventricular block requiring temporary (29%) or permanent (9%) pacing. Peak post-Htx CPK-MB levels were 97 5 45 units/L (181 + 122 units/l control, P = .006) and ischemic changes at first endomyocardial biopsy were found in 19% of recipients (42% control, P = .005).
DISCUSSION The necessity to expand the donor pool to face the everincreasing demand for Htx has forced acceptance of donors once classified as marginal based on the coexistence of one or more relative contraindications to selection, including older (>40 years) age, long (>4 hours) ischemic time, profound circulatory instability, moderate left ventricular hypertrophy, significant (~20%) size mismatch, evidence of
3387
organ infection or contusion, among others. It is noteworthy that acute failure of the graft, particularly in the presence of elevated pulmonary vascular resistance, remains the leading cause of early death after Htx.’ The revival of interest in techniques to protect and preserve the heart seems thus fully justified.2-6 While it is hardly debatable that crystalloid solutions can be used for myocardial preservation during Htx allowing for satisfactory results,’ occurrence of post-Htx graft failure remains a definite problem. Encouraging observations have been reported with techniques using hybrid techniques of cardiac muscle protection, including crystalloid induction and maintenance followed by warm blood reperfusion,* or crystalloid induction and blood maintenance and reperfusion,3,4 or crystalloid induction and continuous warm blood retrograde reperfusion.5 Unfortunately all the reported studies are flawed by the lack of randomization and thus represent retrospective analyses, the results of which are at best indicative. On the contrary, a prospective, randomized clinical trial comparing the effects of crystalloid cardioplegia versus crystalloid induction and continuous warm blood retrograde reperfusion was recently pub1ished.6 The authors observed a significant decrease in mortality and early graft failure in the group of patients receiving warm blood cardioplegia, with no difference in terms of biochemical markers of cell necrosis. Even though this study represents the only attempt focusing on the method for analysis, closer scrutiny of the data reveals high mortality and morbidity in the control group of patients at variance with currently accepted risks of Htx. The implications of the comparison with blood cardioplegia are thereby greatly diminished. In addition, the ischemic times are inexplicably short in both treatment groups. In spite of the randomization, inferences seem difficult to draw from that study and the problem of validation of new techniques for myocardial preservation remains unsolved. We report the preliminary and, thus, merely descriptive results observed with the first few transplants where a novel concept of cardiac protection was employed. Translating Buckberg’s principle into the practice of Htx, we started to use a method where standstill of the donor heart is achieved using induction cold blood cardioplegia. From a strictly theoretic standpoint, if indeed the routine preservation of the heart is optima1 when a blood-based solution is used this must hold even more true for an operation where ischemic times will be the longest. The practice of drawing blood from the donor immediately before clamping the aorta proved safe and well tolerated. Thus far, no compromise of the other parenchymatous organs being harvested has been observed. While the need for a perfusion technician, carrying a heat exchanger and a roller pump, may appear awkward and costly, a modification of the technique using pressurized cardioplegia bags is under investigation, which will eliminate the need for this more complex set-up. The preliminary outcome using antegrade cold blood induction and antegrade warm blood reperfusion cardioplegia for Htx is reported here in a descriptive fashion. The results have
LUCIANI,
thus far been rewarding and the merely indicative retrospective comparison with a control cohort of patients having crystalloid cardioplegia have encouraged us to begin a prospective, randomized clinical trial that may allow more rigorous inferences. Thus far we can state that the use of this novel method of myocardial preservation in selected patients is associated with a low prevalence of acute failure of the graft and of disturbance of the cardiac rhythm. The initial metabolic and histologic indices of cell damage would also suggest satisfactory protection of the myocytes. In conclusion, induction and reperfusion using blood cardioplegia seems to offer an adequate myocardial protection during Htx in selected recipients. The technique is simple, safe, and easily reproducible. A prospective, randomized study is needed to establish its superiority over currently available methods of preservation.
FAGGIAN, FORNI ET AL
REFERENCES
1. Wheeldon D, Sharples L, Wallwork J, et al: J Heart Lung Transplant 11:986, 1992 2. Kirklin JK, Neves J, Naftel DC, et al: Ann Thorac Surg 49:625, 1990 3. Soots G, Crepin F, Prat A, et al: Em J Cardiothorac 5:400, 1991
Surg
4. Nataf P, Pavie A, Bracamontes L, et al: Ann Thorac Surg 53:525, 1992 5. Pradas G, Cuenca J, Juffe A: J Thorac Cardiovasc Surg 111:784, 1996 6. Carrier M, Leung TK, Solymoss C, et al: Ann Thorac Surg 61:1310, 1996 7. Form A, Faggian G, Luciani GB, et al: Transplant 28:289, 1996
Proc
8. Buckberg GD: J Thorac Cardiovasc Surg 93:127, 1987 9. Hosenpud JD, Novick RJ, Breen TJ, et al: J Heart Lung Transplant 13:571, 1994
Myocardial Protection During Heart Transplantation Using Blood Cardioplegia G.B. Luciani, G. Faggian, A. Forni, G. Montalbano, B. Chiominto, and A. Mazzucco
A
of interest around optimal techniques for myocardial preservation during heart transplantation (Htx) has recently occurred, due to the need for continued extension of donor selection criteria and the frequent necessity to use “marginal” donor organs. A recent review has documented the extreme diversity of preservation techniques currently used during Htx.’ Nevertheless, a trend toward the use of some form of maintenance of cardiac standstill and, more commonly, toward the use of reperfusion of the graft prior to clamp removal is being established.’ While intermittent or continuous reperfusion using blood cardioplegia have been reported in a variety of clinical series,2-6 adoption of blood cardioplegia for induction of cardiac arrest in the donor has never been documented. Reported here are the preliminary results with a novel technique of myocardial protection during Htx, which includes induction, preservation, and reperfusion with blood cardioplegia. REVIVAL
PATIENTS
AND
METHODS
Beginning in June 1995, a new method of cardiac preservation during Htx was devised and adopted. The technique was initially employed in a nonrandomized fashion to prove its safety and subsequently a prospective, randomized trial comparing the standard (crystalloid) and modified (blood) cardioplegic solutions was commenced and is currently under way. The present report describes the methods and preliminary results in patients having myocardial protection with blood cardioplegia.
Operative Technique All patients underwent orthotopic Htx using atria1 cuff and direct bicaval anastomosis, as described elsewhere. After dissection of the donor heart, a double-outlet needle (Research Medical Inc, Midvale, Utah) is inserted in the donor ascending aorta and secured with a 4-O polypropylene pursestring. One port of the needle is connected with a disposable cardioplegia bag where the blood is collected and mixed with the Buckberg (A2) solution.’ The bag is connected with a heat exchanger (Biomedicus, Minneapolis, Minn.) and a roller pump used to cool the solution to 0 to 4°C and infuse it at a constant pressure (60 to SO mm Hg) via a line connected with the second port of the cardioplegia needle. After heparin administration, 800 to 1000 mL of donor blood is slowly allowed to drain via the outflow port of the needle. Occasional systemic hypotension episodes are treated with colloid fluid administration. The hematocrit of the induction solution is kept around 20% to 22%. The aorta is then cross-clamped and 1500 to 2000 mL
of blood cardioplegia is administered via the antegrade route, while the heart is decompressed via the right superior pulmonary vein and inferior vena cava. After excision of the heart, the graft is stored in cold (0 to 4°C) sterile saline. In cases where the preservation time exceeds 3 hours (final ischemic time expected longer than 4 hours), a maintenance dose (150 mL/min for 3 minutes) of recipient blood cardioplegia (Buckberg B2) is administered via the cross-clamped aorta of the graft on the bench. Prior to exposing the graft to the recipient’s own blood, 1000 mg of methylprednisolone are given intravenously. Upon completion of the left atrial, inferior caval, pulmonary, and aortic anastomosis, the ascending aorta is again cannulated and warm (30 to 32°C) antegrade reperfusion using blood cardioplegia (Buckberg C3) is begun. The superior caval anastomosis is completed after aortic clamp removal. Patients
Between June 1995 and January 1997, 21 of 69 (30%) patients undergoing Htx with bicaval anastomosis had preservation of the graft using the above method. There were 12 males and 9 females, aged 53 2 10 years, and having dilated (57%), ischemic (33%), or other cardiomyopathy (10%) as indication for Htx. Five (24%) patients had pre-Htx increased pulmonary vascular resistance (~4 Woods units). Donors were 16 males and 5 females, aged 33 ? 11 years, with trauma (76%) and cerebrovascular accident (24%) as cause of brain death. High-dose inotropic requirements and episodes of profound hypotension or cardiac arrest were present in the history of 36% and 10% of donors, respectively. Mean ischemic time averaged 176 2 21 minutes. Post-transplant
immunosuppressive
Therapy
The same treatment protocol was applied to all recipients regardless of the technique used for preservation of the heart. This included oral cyclosporine (CyA) (5 to 8 m&g/d) to maintain a whole blood trough level of 300 to 500 ng/dL, azathioprine (2 to 4 mglkgid) to maintain a total white blood cell count of 40OO/mL,and oral prednisone (starting at a maintenance dose of 1 mg/kdd and tapered to 0.5 m&g/d by the third month). Discontinuation of chronic steroid therapy was attempted after the 6th post-Htx month. Surveillance of rejection was done using a schedule of programmed endomyocardial biopsies and treatment of it by
From the Division of Cardiac Surgery, University of Verona, Verona, Italy. Address reprint requests to Dr G.B. Luciani, Division of Cardiac Surgery, University of Verona, O.C.M. Piazzale Stefani 1, 37126 Verona, Italy.
0041-t 345/97/$17.00 PII so041 -1345(97)00950-0
0 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
3386
Transp/antation
Proceedings,
29, 3386-3388
(1997)
BLOOD CARDIOPLEGIA
means of pulse doses of methylprednisolone and/or augmentation of immunosuppression on an individual basis.
RESULTS
There were no perioperative and only one early death (5%), in a 41-year-old male with chemotherapy- and radiationtherapy-induced cardiomyopathy who was on pre-Htx inotropic support and in chronic renal failure. The patient never resolved the renal insufficiency and died of hemorrhagic complications thereof 2 months after Htx. Cardiac function and rhythm had proved and remained satisfactory throughout the postoperative period. The remaining 20 patients were discharged from the hospital in good clinical condition. One (5%) patient died of acute allograft rejection 18 months after Htx. The actuarial survival for this patient cohort was 95 + 5% and 90 2 10% at 1 and 2 years, respectively. During the same time interval, early and late mortality in patients having standard crystalloid cardioplegia preservation of the donor heart and matched for demographic variables, were 8% (right heart failure 2, multiple organ failure 1, sepsis 1) and 5% (rejection 1, infection l), respectively. The actuarial survival in the control group was thus 91 ? 2% and 86 + 6% at 1 and 2 years. High-dose (association of three inotrops or two inotrops, including epinephrine) inotropic support was necessary in 3 (14%) patients, including 2 (9%) with preoperative pulmonary hypertension experiencing acute right heart failure. Both cases resolved without the need for mechanical life support. No cases of overt left ventricular failure were observed. The prevalence of high dose inotropit requirement and right heart failure in the control group were 31% (P = .04) and 15% (P = .06). Spontaneous resumption of sinus rhythm was not uncommon upon aortic clamp removal (28%) and atrioventricular conduction disturbances were rare (9%) and always transient, with no need for permanent pacing, in patients undergoing the blood cardioplegia protocol. This did not prove true for the control patients who rarely showed spontaneous recovery of sinus activity in the operating room (8%) and more commonly presented atrioventricular block requiring temporary (29%) or permanent (9%) pacing. Peak post-Htx CPK-MB levels were 97 5 45 units/L (181 + 122 units/l control, P = .006) and ischemic changes at first endomyocardial biopsy were found in 19% of recipients (42% control, P = .005).
DISCUSSION The necessity to expand the donor pool to face the everincreasing demand for Htx has forced acceptance of donors once classified as marginal based on the coexistence of one or more relative contraindications to selection, including older (>40 years) age, long (>4 hours) ischemic time, profound circulatory instability, moderate left ventricular hypertrophy, significant (~20%) size mismatch, evidence of
3387
organ infection or contusion, among others. It is noteworthy that acute failure of the graft, particularly in the presence of elevated pulmonary vascular resistance, remains the leading cause of early death after Htx.’ The revival of interest in techniques to protect and preserve the heart seems thus fully justified.2-6 While it is hardly debatable that crystalloid solutions can be used for myocardial preservation during Htx allowing for satisfactory results,’ occurrence of post-Htx graft failure remains a definite problem. Encouraging observations have been reported with techniques using hybrid techniques of cardiac muscle protection, including crystalloid induction and maintenance followed by warm blood reperfusion,* or crystalloid induction and blood maintenance and reperfusion,3,4 or crystalloid induction and continuous warm blood retrograde reperfusion.5 Unfortunately all the reported studies are flawed by the lack of randomization and thus represent retrospective analyses, the results of which are at best indicative. On the contrary, a prospective, randomized clinical trial comparing the effects of crystalloid cardioplegia versus crystalloid induction and continuous warm blood retrograde reperfusion was recently pub1ished.6 The authors observed a significant decrease in mortality and early graft failure in the group of patients receiving warm blood cardioplegia, with no difference in terms of biochemical markers of cell necrosis. Even though this study represents the only attempt focusing on the method for analysis, closer scrutiny of the data reveals high mortality and morbidity in the control group of patients at variance with currently accepted risks of Htx. The implications of the comparison with blood cardioplegia are thereby greatly diminished. In addition, the ischemic times are inexplicably short in both treatment groups. In spite of the randomization, inferences seem difficult to draw from that study and the problem of validation of new techniques for myocardial preservation remains unsolved. We report the preliminary and, thus, merely descriptive results observed with the first few transplants where a novel concept of cardiac protection was employed. Translating Buckberg’s principle into the practice of Htx, we started to use a method where standstill of the donor heart is achieved using induction cold blood cardioplegia. From a strictly theoretic standpoint, if indeed the routine preservation of the heart is optima1 when a blood-based solution is used this must hold even more true for an operation where ischemic times will be the longest. The practice of drawing blood from the donor immediately before clamping the aorta proved safe and well tolerated. Thus far, no compromise of the other parenchymatous organs being harvested has been observed. While the need for a perfusion technician, carrying a heat exchanger and a roller pump, may appear awkward and costly, a modification of the technique using pressurized cardioplegia bags is under investigation, which will eliminate the need for this more complex set-up. The preliminary outcome using antegrade cold blood induction and antegrade warm blood reperfusion cardioplegia for Htx is reported here in a descriptive fashion. The results have
LUCIANI,
thus far been rewarding and the merely indicative retrospective comparison with a control cohort of patients having crystalloid cardioplegia have encouraged us to begin a prospective, randomized clinical trial that may allow more rigorous inferences. Thus far we can state that the use of this novel method of myocardial preservation in selected patients is associated with a low prevalence of acute failure of the graft and of disturbance of the cardiac rhythm. The initial metabolic and histologic indices of cell damage would also suggest satisfactory protection of the myocytes. In conclusion, induction and reperfusion using blood cardioplegia seems to offer an adequate myocardial protection during Htx in selected recipients. The technique is simple, safe, and easily reproducible. A prospective, randomized study is needed to establish its superiority over currently available methods of preservation.
FAGGIAN, FORNI ET AL
REFERENCES
1. Wheeldon D, Sharples L, Wallwork J, et al: J Heart Lung Transplant 11:986, 1992 2. Kirklin JK, Neves J, Naftel DC, et al: Ann Thorac Surg 49:625, 1990 3. Soots G, Crepin F, Prat A, et al: Em J Cardiothorac 5:400, 1991
Surg
4. Nataf P, Pavie A, Bracamontes L, et al: Ann Thorac Surg 53:525, 1992 5. Pradas G, Cuenca J, Juffe A: J Thorac Cardiovasc Surg 111:784, 1996 6. Carrier M, Leung TK, Solymoss C, et al: Ann Thorac Surg 61:1310, 1996 7. Form A, Faggian G, Luciani GB, et al: Transplant 28:289, 1996
Proc
8. Buckberg GD: J Thorac Cardiovasc Surg 93:127, 1987 9. Hosenpud JD, Novick RJ, Breen TJ, et al: J Heart Lung Transplant 13:571, 1994