The first experimental heart transplantation was performed

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1 Myocardial Preservation Using Celsior Solution in Cardiac Transplantation: Early Results and 5-Year Follow-Up of a Multicenter Prospective Study of 70 Cardiac Transplantations Jean-Paul Remadi, MD, Olivier Baron, MD, Jean C. Roussel, MD, Oussana Al Habash, MD, Michele Treilhaud, MD, Philippe Despins, MD, Daniel Duveau, MD, and Jean-Luc Michaud, MD Cardiovascular Surgery Unit and Department of Anesthesiology, The G and R Laënnec University Hospital, Nantes, France Background. Several storage methods using a wide variety of extracellular or intracellular solutions applied either as continuous perfusion, intermittent perfusion, or simple immersion of the heart have been commonly used. We have performed a prospective randomized multicenter study of 70 cardiac transplantation recipients to evaluate the Celsior solution for cardiac preservation. Methods. Seventy consecutive patients were included in this trial and received a cardiac graft arrested and preserved with Celsior. The first follow-up period was 1 month. The mean age of the recipients was 49 years (range, 28 to 66 years), and 81.7% were male. The main disease was nonobstructive cardiomyopathy (64.3%). The age range of donors was between 14 and 56 years with a mean of 33 years. The majority of grafts (73%) were stored in 1 L of Celsior. A midterm follow-up at 5 years was performed and was 100% complete. Results. The operative mortality (<30-day) rate was 6 of 70 (8.6%). Sixty-three patients (90%) had at least satisfactory hemodynamic measurements on day 2. The first postoperative echocardiograms showed good myocardial performance for 90% of the grafts. Actuarial survival rate at 5 years was 75% 5.1%. Conclusions. The use of Celsior in cardiac transplantation was safe and very effective. This solution proved very valuable in at-risk patients. (Ann Thorac Surg 2002;73:1495 9) 2002 by The Society of Thoracic Surgeons The first experimental heart transplantation was performed by Carrel and Guthrie in 1905 [1] and afterwards by Mann and associates in 1933 [2], who transplanted dog hearts heterotopically. In 1959, Lower and colleagues [3] at Stanford University succeeded in transplanting a dog heart in the orthotopic position. In 1993 there were 4,789 heart and 191 heart-lung transplantations performed in Europe and the United States [4]. Myocardial protection in a cardiac transplantation procedure consists of four steps: inducing cardiac arrest, preservation of the transplant, global ischemia associated with the implantation of the graft, and reperfusion. One of the principal reasons for failure of the procedure as a whole is malfunctioning of the graft owing to improper preservation during the explantation, storage, and transport period, which becomes apparent after restoration of blood flow. Thus far, storage intervals of 4 to 5 hours represent the safe maximum in clinical heart preservation [5, 6]. Several storage methods using a wide variety of extracellular or intracellular solutions applied either as continuous perfusion, intermittent perfusion, or simple Accepted for publication Jan 11, Address reprint requests to Dr Remadi, Cardiovascular Surgery Unit, South Hospital, Amiens Cedex 1, Nantes, France; remadijean-paul@chu-amiens.fr. immersion of the heart have been commonly used. Celsior is an organ preservation solution designed for myocardium, especially for transplantation procedures [7]. Several preclinical trials and two clinical studies were performed with Celsior [8 12]. In these trials, Celsior has proven to be as safe as and slightly more effective than the currently approved myocardial preservation solutions for cardiac transplantation. Celsior is an organ preservation solution designed for myocardial protection. Its chemical composition accounts for the basic principles of organ preservation in general and that of the myocardium specifically. Celsior also takes into account the specific requirements of graft during the four different stages of transplantation: initial cardioplegia of the donor s heart, conservation, ischemia, and reperfusion. Celsior is an extracellular solution. The reduction of the oxidative lesions is caused by mannitol, histidine, and reduced glutathione, which are the essential components of the solution. Celsior also has been designed to counteract the two major mechanisms causing calcium overload: ischemia-induced loss of high-energy phosphates and entry of calcium from the extracellular space. This is achieved by using an appropriate balanced solution of low calcium that is slightly hyperkalemic and contains high concentrations of sodium and magnesium; this 2002 by The Society of Thoracic Surgeons /02/$22.00 Published by Elsevier Science Inc PII S (02)

2 1496 REMADI ET AL Ann Thorac Surg MYOCARDIAL PRESERVATION USING CELSIOR SOLUTION 2002;73: Table 1. Baseline Recipient Data Characteristic Range Mean Age (years) Retransplantation 0 0 Body surface PAP (mm Hg) PAR (Wood units) n % Sex Female Male Pathology Nonobstructive cardiomyopathy Ischemic cardiomyopathy Valvular cardiomyopathy PAP pulmonary artery pressure; resistance. permits energy production in anaerobic situations, thus limiting the ATP-dependent process of calcium contracture of the myocardium. The primary objective of this prospective and multicenter study was to confirm the positive results obtained from previous clinicals trials and to increase the amount of available safety data for Celsior. Patients and Methods PAR pulmonary arterial This study was multicenter (six French cardiac centers) and prospective. Seventy consecutive patients were included in this trial and received a cardiac graft arrested and preserved with Celsior. The follow-up periods were 1 month and 5 years. All patients reporting to each center were asked to participate if they fit within inclusion and exclusion criteria (Table 1). Patients who signed informed consent were subsequently included into the trial. The first patient was included in July 1995, and the last patient in November The mean age of the recipients was 49 years (range, 28 to 66 years), and 81.7% were male. The main disease was nonobstructive cardiomyopathy (64.3%). The majority of recipients had an elevated pulmonary artery resistance (PAR; Table 2). Patients with PAR more than 4 wood units have to be considered at risk for posttransplant complications such as right ventricular failure, especially when other risk factors, such as long ischemia time, are added. The efficacy of Celsior was therefore analyzed separately in cases of extremely increased PAR ( 5 Wood units). Five patients were using mechanical assist devices before transplantation. These included three total artificial hearts (Jarvick) and two left ventricular assist devices (one Novacor, one Thoratec). The age range of the donors was between 14 and 56 years, with a mean of 33 years. Four donors were older than 50 years, and their hearts were thus regarded as at-risk organs. All hearts derived from female donors (22.8%) were also classed as at-risk grafts. The average duration of anesthesia was 17 hours, ranging from 6 to 48 hours. Fifty-one donors required less than 5 mg kg 1 min 1 of dopamine or dobutamine support, and these patients were classed as stable. Consequently, 27.2% of the donors presented with an unstable circulation requiring epinephrine support or dopamine or dobutamine at doses more than 5 mg kg 1 min 1 at the time of harvesting. Forty percent of the donor hearts were arrested using 2LofCelsior solution; the remainder hearts were arrested using only 1 L. The majority of grafts (73%) were stored in 1 L of Celsior solution. The others were stored in either more (17%) or less (10%). The mean use of Celsior was approximately 3 L per procedure. Celsior solution was not used during the transplantation procedure, and the implantation was performed according to the usual protocol at the center. Thus, 64.3% of the procedures were performed with local and moderate systemic hypothermia, 13 patients received coldblood cardioplegic solution combined with blood reperfusion, and one patient received warm-blood reperfusion only. Measures of the quality of myocardial preservation for this trial were hemodynamic and clinical measurements, enzyme release, histologic assessment of biopsy samples, and assessment of adverse events. According to the data obtained the graft was classified as one of the following: hemodynamically satisfactory graft function; right ventricular insufficiency with or without pulmonary hypertension; and global cardiac insufficiency. All drugs prescribed for supporting the hemodynamic status of the graft were documented throughout the first week of the trial. To facilitate comparison with other authors and trials, an inotropic scoring system (Vlessis score), taking into account the medication within the first 24 hours, was produced. Univariate and multivariate analyses (logistic regressions) were performed to determine which preoperative factors were related to early and late mortality (Statistical logical Statview). A midterm follow-up was performed at 5 years with a cumulative total of 3,929 months and a mean of 51 months. Results Mean graft ischemia time was 186 minutes (Table 3). Reperfusion was defined as the time between removal of the aortic clamp and weaning from cardiopulmonary bypass; it was close to 30 minutes (Table 3). Fifty percent of the grafts defibrillated spontaneously; Table 2. Distribution of Patients According to Pulmonary Artery Resistance PAR (Wood units) n % PAR pulmonary arterial resistance.

3 Ann Thorac Surg REMADI ET AL 2002;73: MYOCARDIAL PRESERVATION USING CELSIOR SOLUTION 1497 Table 3. Implantation Data Variable Range Mean CPB time (min) Duration of storage (min) Reperfusion time (min) Total ischemia time (min) CPB cardiopulmonary bypass. the remainder required between one and two electrical shocks before converting to sinus rhythm. Only 1 patient required the insertion of an atrioventricular pacemaker. The mean hemodynamic data at 0, 24, and 48 hours are listed in Table 4. Mean blood pressure was approximately 80 mm Hg, mean pulmonary wedge pressure was approximately 11 mm Hg, and mean cardiac output was approximately 6 L/minute. The subjective opinion of the investigators appears to match the hemodynamic data closely. Sixty-three patients (90%) had at least satisfactory hemodynamic conditions on day 2. Seven patients experienced initial hemodynamic problems related to graft failure: 5 experienced right heart failure and 2 experienced global cardiac insufficiency. Four patients required postoperative insertion of a circulatory support device. Operative mortality ( 30-day) rate was 6 of 70 (8.6%). Main postoperative noncardiac complications are listed in Table 5. Seventeen patients (24.3%) experienced an infection, 5 patients (5.1%) experienced neurologic events, and 7 patients (10%) experienced renal failure. All cardioactive medications were recorded throughout the first week of the trial: the inotropic score amounted to 171 (Table 6). Cardiac enzymes were at normal levels at 0, 24, and 48 hours after transplantation (Table 7). Enzyme levels of cardiac creatine kinase were lower than 10%. This fact shows that Celsior solution achieves effective protection of the graft. The first postoperative echocardiograms showed good myocardial performance for 90% of the grafts (mean shortening fraction, 35%). The remaining 10% of patients experienced cardiac failure as outlined. Univariate analysis showed that age more than 60 years (p 0;02), PAR (p 0.001), and an ischemic time less than 4 hours (p 0.01) were related to a higher mortality rate. The multivariate regression analysis showed only the PAR (p 0.001) to be an independent factor related to early mortality. Table 5. Postoperative Complications Complication n % Renal failure 7 10 Infections Bacteriemia CMV Pneumonia Sternal Neurologic 5 7 Convulsions CVA Cubital compression CMV cytomegalovirus; CVA cerebrovascular accident. Early Results According to Risk Groups Clearly, when there is already some damage (long ischemia, older donor), less myocardial tissue (female donor), or a requirement for excellent immediate function (pulmonary artery hypertension, older recipient), it is of paramount importance to avoid preservation damage, and it may be then Celsior is at its most beneficial. Preoperative Pulmonary Hypertension Eight patients had preoperative PAR more than 5 Wood units. All of these patients required some form of cardiac drug support postoperatively coming off bypass or during the first 48 hours. A well-preserved graft in conjunction with vasodilators such as nitric oxide was beneficial for these recipients to overcome the difficult first days after the procedure. The mortality rate was 25%. Infection was the cause of the two deaths (pulmonary infection and septicemia after colic perforation) after prolonged intensive care stay caused by a primary graft failure (PAR, 5.6 and 8.8 Wood units preoperatively for the recipients). Ischemia Time More Than 4 Hours Ten patients received grafts with an ischemia time of more than 4 hours (14.3%). One patient died of right ventricular failure, 1 patient required temporarily a right ventricular assist device but recovered without problems, and 2 patients required inotropic agent support on coming off cardiopulmonary bypass or in the postoperative period but recovered without further problems. The outcome was thus favorable in 9 of 10 patients with prolonged ischemia time. Table 4. Early Hemodynamic Data Variable 0 hours 24 hours 48 hours Mean systemic arterial pressure (mm Hg) Mean right atrial pressure (mm Hg) Mean pulmonary artery pressure (mm Hg) Mean pulmonary wedge pressure (mm Hg) Cardiac frequency (beats/min) Cardiac output (L/mn)

4 1498 REMADI ET AL Ann Thorac Surg MYOCARDIAL PRESERVATION USING CELSIOR SOLUTION 2002;73: Table 6. Inotropic Score (Vlessis) Inotropic Agent Score Epinaphrine 56 Dobutamine 13 Dopamine 37 Isoprenaline 65 Total 171 Donor Age More Than 50 Years Five patients received hearts from donors older than 50 years. There was one death in this group with a long ischemia time added (270 minutes). One patient required a right ventricular support device (Biomedicus centrifugal pump) and recovered fully without further complications. Recipient Age More Than 50 Years Thirty recipients were older than 50 years (42.8%), and 11 patients were older than 60 years (15.7%). Four (13.3%) of the 30 patients more than 50 years of age died; thus the mortality rate was comparable to the overall mortality. Two (18.1%) of the 11 patients in the age group more than 60 years died. This mortality is higher than the global mortality (not significant). Female Donor Sixteen recipients received heart grafts from female donors. Among these recipients, 6 were women and 10 men. One patient died (6.3%), and 1 patient required circulatory assistance. Midterm Results The follow-up was 100% complete at 5 years. Sixteen deaths (including operative mortality) occurred. The actuarial survival rate at 5 years was 75% 5.1% (Fig 1). The main cause of the 10 late deaths was neoplasm (40%). There was only one terminal cardiac failure responsible for one late death (6.25%). We obtained echocardiogram data for 32 patients who were alive (59.25%): the mean shortening fraction was 31% 3.1%. A multivariate analysis showed none of the factors were significantly related to the late mortality. Comment The deleterious effects of myocardial ischemia have been extensively demonstrated [13], and there is convincing evidence that oxygen-derived free radicals are important Table 7. Postoperative Myocardial Enzyme Levels Enzyme 0 hours 24 hours 48 hours CK CKMB LDH CK creatine kinase; CKMB cardiac creatine kinase; LDH lactate dehyrogenase. Fig 1. Actuarial survival curve. mediators of myocardial damage resulting from ischemia [14, 15]. Additionally, calcium overload has been shown to be a key determinant in myocardial stiffness. Celsior achieves superior results when compared with standard preservation fluids by reducing myocardial edema [7], reducing free oxygen radical production [8 14], and limiting calcium overload [7]. The use of Celsior in this trial setting was associated with a low 30-day mortality rate of 8.6%. These results compare favorably with the international standards set for heart transplantation (Clinical transplant 1994, ISHLT registry 1996). Atrial fibrillation and heart block rates were very low (only one posttransplantation pacemaker was necessary). We also used Celsior solution for cardioplegia in a standard cardiac procedure (coronary artery bypass grafting with valve replacement). In this trial, 300 patients were operated on during a period of 3 months: 150 were perfused with Bretschneider solution and 150 with Celsior. This trial showed that atrial fibrillation and heart block rates were significantly lower with Celsior, as we observed with cardiac transplantation. These results confirm that Celsior is very effective for preserving cardiac sinus rhythm. The low cardiac output syndrome rate was also low, and inotropic support was not frequent ( 10%). Taking into consideration that Celsior achieved the same results when the patient population was stratified according to different risk groups, one can state that this study had an excellent clinical outcome. Indeed, the morbidity and mortality for at-risk patients did not significantly differ from standard cardiac recipients. For the severe pulmonary hypertension group (PAR 5 Wood units), operative mortality was significantly higher. The center at Stanford University published similar results with an operative mortality of 7.9% and an increased mortality risk for the pulmonary hypertension subgroup and for women. Other clinical trials with Celsior solution to preserve donor hearts have shown similar good early results [16, 17]. The late results show a high survival rate (75% 5.1%), comparable to published data (ISHLT registry 1996), and confirm the good early results. The use of Celsior in cardiac transplantation was safe and very effective. This solution to be very valuable in at-risk patients. Further clinical work can and should be performed using it. The midterm evaluation of this group of patients shows an excellent survival rate at 5 years and leads us to use Celsior for cardiac preservation.

5 Ann Thorac Surg REMADI ET AL 2002;73: MYOCARDIAL PRESERVATION USING CELSIOR SOLUTION 1499 The authors acknowledge five cardiac centers: Lyon (Prof Champsaur and Prof Ninet), Lille (Prof Warembourg and Prof Prat), Strasbourg (Prof Eisenmann), Foch (Prof Guilmet and Prof Dreyfus), and Nancy (Prof Villemot). References 1. Carrel A, Guthrie CC. The transplantation of veins and organs. Am J Med 1905;10: Mann RD, Priestly IR, Markowits I. Transplantation of the intact mammalian heart. Arch Surg 1933;26: Lower RR, Stofer RC, Shumway NE. Homovital transplantation of the heart. J Thorac Cardiovasc Surg 1961;41: Hardy ID, Chavez CM, Kurru FD, et al. Heart transplantation in man. Developmental studies and report of a case. JAMA 1964;188: Transplant Council of Europe, Report. Volume 6, July 1994, Fondation Marcel Merieux, Fabiani IN, Ponzio V, Iebhera V. La protection myocardique. Techniques chirurgicales. In: Encycl Méd Chir (Paris, France) 1989, Thorax, Menasché P, Pradier F, Grousset C, et al. Improved recovery of heart transplants with a specific kit of preservation solutions. J Thorac Cardiovasc Surg 1993;105: Menasché P, Pradier F, Peynet J, et al. Limitation of free radical injury by reduced glutathione: an effective means of improving the recovery of heart transplants. Transplant Proc 1991;23: Menasché P, Termignon JL, Pietri S. Experimental evaluation of a new heart preservation solution (CELSIOR). European Society for Organ Transplantation, 6th Congress, Rhodes, October Menasché P, Termignon J-L, Pradier F, et al. Experimental evaluation of Celsior, a new heart preservation solution. Eur J Thorac Cardiovasc Surg 1994;8: Zaiac M. Comparison of the antiradical and cardioprotective effects of Celsior vs. Ringer lactate as preservation fluids for human cardiac transplantation. LPO-01 report. PMsv data on file. 12. Zaiac M, Marie V, Menasche P. Myocardial preservation using Celsior: evaluation of efficacy and safety compared to standard preservation fluids. LPO-02 study report, PMsv data on file. 13. Singh A, Lee KJ, Lee CY, Golfarb RD, Tsan MF. Relation between myocardial glutathione content and extent of ischemia-reperfusion injury. Circulation 1989;80: Menasché P, Grousset C, Gauduel Y, Piwnica A. A comparative study of free radical scavengers in cardioplegic solutions. J Thorac Cardiovasc Surg 1986;92: Astier A, Paul M. Instability of reduced glutathione in commercial Belzer cold storage solution. Lancet 1989;2: Bourdillion PDV, Poole Wilson PA. Effects of ischemia and reperfusion on calcium exchange and mechanical function in isolated rabbit myocardium. Cardiovasc Res 1981;15: Sarris EG, Moore K, Shroder J. Cardiac transplantation: the Stanford experience in the cyclosporine era. J Thorac Cardiovasc Surg 1994;108: