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ТРАНСПЛАНТОЛОГИЯ И ИСКУССТВЕННЫЕ ОРГАНЫ ■
ПРОГРАММА ТРАНСПЛАНТАЦИИ СЕРДЦА В ЭПОХУ МЕХАНИЧЕСКОЙ ПОДДЕРЖКИ КРОВООБРАЩЕНИЯ: ОПЫТ РЕСПУБЛИКИ КАЗАХСТАН
Пя Ю.В., Бекбосынов С.Т., Бекбосынова М.С., Куатбаев Е.М., Лесбеков Т.Д., Калиев Р.Б., Джетыбаева С.К., Медресова А.Т., Нурмыхаметова Ж.А., Мурзагалиев М.У., Новикова С.П., Капышев Т.С., Смагулов Н.К., Фаизов Л.Р., Вахрушев И.А.,. Андосова С.А., Мырзахметова Г.Ш., Надирбекова Г.Е., Шайсултанова С.Т., Дюсенбина Ж.С.
Национальный научный кардиохирургический центр, Астана, Республика Казахстан
ДЛЯ КОРРЕСПОНДЕНЦИИ
Медресова Асель Тураровна -кандидат медицинских наук, кардиохирург кардиохирургического отделения № 2 Национального научного кардиохирургический центра (Астана, Республика Казахстан) E-mail: [email protected]
C 2012 по 2016 г. выполнено 42 пересадки сердца. Выживаемость к 12 мес составила 80%. С учетом особенностей Казахстана разработана программа дистанционной доставки и консервации сердца с помощью системы сохранения органов (OCS-Transmedics - Organ Care System). В статье дано сравнение этой методики с холодовой консервацией донорского сердца. 5-летний опыт авторы расценивают как довольно успешный. Клин. и эксперимент. хир. Журн. им. акад. Б.В. Петровского. 2017. № 3. С. 49-53. Статья поступила в редакцию: 25.05.2017. Принята в печать: 15.06.2017.
Ключевые слова:
дистанционная пересадка, механическая поддержка кровообращения сердца, консервация сердца
Heart transplantation program in the era of mechanical circulatory support: Republic of Kazakhstan experience
Pya Yu.V., Bekbossynov S.T., Bekbossynova M.S., Kuatbayev Ye.M., Lesbekov T.D., Kaliyev R.B., Dzhetybayeva S.K., Medressova A.T., Nurmykhametova Zh.A., Murzagaliyev M.U., Novikova S.P., Kapyshev T.S., Smagulov N.K., Faizov L.R., Vakhrushev I.A., Andossova S.A., Myrzakhmetova G.Sh., Nadirbekova G.Ye., Shayssultanova S.T., Duyssenbina Zh.S.
National Research Center for Cardiac Surgery, Astana, Republic of Kazakhstan
CORRESPONDENCE
Medressova Assel Turarovna -MD, Cardiac Surgeon of the Cardiac Surgery Department # 2, National Research Cardiac Surgery Center (Astana, Republic of Kazakhstan) E-mail: [email protected]
Aim. Kazakhstan is a country where mechanical circulatory support program was established prior to heart transplantation (HT). Given the countries large land area and small population density transportation of scarce amount of donor hearts was the primary challenge for healthcare providers. Advances in the area of cardiac surgery, such as development of left ventricular assist device (VAD) and organ care system (OCS) Transmedics, allowed us to overcome the obstacles. In this study we aim to analyze and describe the results of the first 5 years of heart transplantation program in Kazakhstan. Methods. A prospective descriptive study analyzing the data of 42 patients was conducted. All the enrolled study subjects have undergone heart transplantation within a period between 2012 and 2016 in the National Research Cardiac Surgery Center, Astana, Kazakhstan. Primary and secondary outcomes of interest were cumulative survival, graft failure free period and incidence of adverse events.
Results. Kaplan-Meier survival estimates for all patients after HT were 90% after 3 months, 82% after six months and 80% after twelve months. In the early postoperative period after HT 11 (26.1%) patients have experienced the following adverse events: 13 (30%) - resternotomy due to bleeding, 3 (7%) - sepsis, 1 (2.3%) - stroke, 2 (4.7%) - lymphorrhea from groin area, 2 (4.7%) -heart rhythm disturbances, and 6 patients (14.3%) had pneumonia. No cases of graft rejection were recorded.
Keywords:
Organ Care System, Transmedics, ex-vivo preservation of heart, left ventricular assist device, mechanical circulatory support, heart failure, Kazakhstan, heart transplantation
Conclusion. With all the confidence we can state that Kazakhstan has fully benefited from new advances. OCS Transmedics allowed preserving the heart for much longer period of time and making long distance transportation of donor heart possible. This study can further be followed up by studying the HT outcomes after OSC compared to standard cold storage. Moreover, another research studying the impact of heart preservation time in the OCS on the outcome of patient survival after HT can also be conducted.
Clin. Experiment. Surg. Petrovsky J. 2017; 5 (3): 49-53.
Received: 25.05.2017. Accepted: 15.06.2017.
Technical advances in the field of left ventricular assist devices (VAD) offer solutions that are not only about survival but also about improving the quality of patients' life in time of donor scarcity [1]. Possibly, VADs can replace heart transplantation (HTx) in the future, especially with the advancement of new technologies in the field of medicine [2]. But today, HTx is the treatment of choice for patients with end-stage heart failure [3-5].
The first open-heart surgery in Kazakhstan was performed in 1958. Prior to 2011, there were no mechanical circulatory support and HTx programs. Patients with severe heart failure could only receive medical treatment. In 2011 new National Research Cardiac Surgery Center (NRCSC) in Astana, Kazakhstan, was first in the country to establish mechanical circulatory support program. The Center provides VAD support to all regions of our country. From November 2011 to April 2017, 226 patients underwent implantation of 232 VADs at NRCCS. In 2012 we initiated heart transplantation program in Kazakhstan. Between 2012 and 2017, 51 patients with heart failure underwent heart transplantation, and we used the TransMedics (Transmedics, Inc., An-dover, MA, USA) Organ Care System (OCS) for donor heart preservation in 43 cases. So, before performing the first HTx we implanted approximately 50 VADs
(Fig. 1).
Kazakhstan is the 9th largest country in the world, for donor hearts to be transplanted from distant regions to our Center they often need to be transported up to 2000 km [6]. There are currently two methods for ex vivo preservation of donor hearts: standard cold storage and a system for ex vivo heart perfusion. The
Fig. 1. Number of VAD and HTx by year from November 2011 till April 2017 at NRCSC
50
£ 50 n= 45
"I 40 ra 35
£ 30 g 25 u- 20
2 15 ber10 m5
u0
-49
November 2012 2011
2013 2014 2015 2016 .VAD nHTx
April 2017
TransMedics OCS is a portable ex vivo organ perfusion and monitoring system that was designed to preserve donor hearts in near-physiologic functioning state [7]. This method decreases the risk of time-dependent ischemic injury that usually takes place during standard cold storage. At some institutions usage of the OCS is now standard of care [8]. This report describes the initial experience and clinical results of the first five years of the HTx program in Kazakhstan.
Methods
In this study we performed a prospective descriptive analysis of 42 patients underwent heart transplantation from 2012 to 2016. We used OCS in 34 (81%) cases.
All the data were collected at NRCSC. Perfusion and cardiac function parameters were continuously monitored and the donor heart was perfused in the OCS device.
The primary outcome was cumulative survival. Secondary outcomes evaluated included freedom from graft failure and incidence of adverse events. We also collected data on perioperative parameters including OCS perfusion measures. Post-operative parameters of interest were time in intensive care unit (ICU), extracorporeal membrane oxygenation (ECMO) duration (if used) and Tissue Doppler Imaging (TDI) on days 3, 7. Eligible recipients were on the waiting list for HTx at our center. All patients provided written informed consent to be involved in the study and to allow their data to be used for this analysis. We defined total preservation time as the heart perfusion time while in the OCS. Total ischemic time was defined as time from donor heart explantation to recipient implantation.
OCS Transmedics
In the OCS "Transmedics" (Fig. 2), oxygenated blood is pumped into the aorta, perfusing the coronary arteries [7]. The coronary sinus flow then passes through the tricuspid valve (as both the superior and inferior vena cava are sutured closed) and is ejected by the right ventricle into a pulmonary artery cathe ter, and returned to the blood reservoir. After the
Pya Yu.V., Bekbossynov S.T., Bekbossynova M.S., Kuatbayev Ye.M., Lesbekov T.D., Kaliyev R.B., Dzhetybayeva S.K., Medressova A.T., Nurmykhametova Zh.A., Murzagaliyev M.U., Novikova S.P., Kapyshev T.S., Smagulov N.K., Faizov L.R., Vakhrushev I.A., Andossova S.A., Myrzakhmetova G.Sh., Nadirbekova G.Ye., Shayssultanova S.T., Duyssenbina Zh.S. ■ HEART TRANSPLANTATION PROGRAM IN THE ERA OF MECHANICAL CIRCULATORY SUPPORT: REPUBLIC OF KAZAKHSTAN EXPERIENCE
donor has been heparinized, a portion of the normo-thermic blood (500-750 ml) is retrogradely collected for blood cardioplegia. The donor blood (12001500 ml) is collected prior to antegrade cardioplegia and aortic cross-clamping and is used to prime the perfusion module. A portion of the normothermic blood (500-750 ml) is used for short-acting cardioplegia. The aorta and pulmonary artery of the donor heart are cannulated and the heart is connected to the OCS device. Then, the heart is reanimated to normal sinus rhythm. Pulsatile flow is generated by a diaphragmatic pump, and an integrated plate heater maintains normothermia [9]. The pump flow and solution flow rates of the OCS are adjusted to maintain the mean aortic pressure between 60 and 90 mm Hg, and coronary blood flow between 650 and 850 ml/min. Throughout the perfusion process with the OCS, arterial and venous lactate samples are taken every 30 min from the system perfusate to assess the adequacy of perfusion. The samples are analysed with a handheld lactate analyser (i-Stat, Abbott Diagnostics, East Windsor, NJ, USA). Upon arrival at our Center, the donor heart is arrested with approximately one liter of blood cardioplegia and is disconnected from the OCS for implantation into the recipient. Transplantation and preoperative care proceeded according to the standard procedures of our Center.
Table 1. Baseline characteristics of the recipients
Characteristics of recipients (n=42) n (%) or mean±SD (range)
Age, year 40+14(17-63)
Gender, male/female 30 (71.4)/12 (28.6)
Body mass index, kg/m2 23.25+3.2
Diagnosis, cardiomyopathy Dilated Ischemic Hypertensive Valvular Other 21 (50) 7 (16.7) 4 (9.5) 3 (7.1) 7 (16.7)
VAD support prior to HTx, n BiVAD, n 18 (42.85) 2 (4.76)
VAD support duration prior to HTx, days 807+685(15-1941)
LV ejection fraction, % 22.12+9.8
450 400 350 300 250 200 150 100 50 0
MJ
Total preservation time, min
250
200
150
100-
50-
04
Ischemia time, min
Fig. 2. Organ Care System "Transmedics". Explanation is within the text
Statistical analysis
Descriptive analysis was performed by presenting the mean±SD for continuous data. Outcome measures used were all-cause mortality using Kaplan-Meier survival curves. Statistical analyses were performed using SPSS Statistics version 22.
Results
The recipient and donor characteristics are shown in Tables 1, 2. There were 8 instances where recipients had a different blood type than their donors. The median (range) age of patients with a
Fig. 3. Mean total preservation (out-of-body) time and total ischemia time in the Organ Care System group versus the standard cold storage group (p<0.001)
Note. VAD - ventricular assist device; HTx - heart transplantation; BiVAD - biventricular assist device; LV - left ventricle.
I Standart cold storage □ Organ Care System
Table 2. Baseline characteristics of the donors
Characteristics of donors (n=42) n (%) or mean±SD (range)
Age, year 41.5+13.8 (18-68)
Gender, male/female 26 (62)/16 (38)
Body mass index, kg/m2 23.3+2.1
Cause of death Stroke Head trauma Other 21 (50) 19 (45) 2 (5)
LV ejection fraction, % 59.3+5
784
63
Note. LV - left ventricle.
I Coronary flow
■ Heart rate
г 1000
-900
-800
-700
-600
-500
-400
-300
-200
-100
1 -0
□ Aortic pressure
Fig. 4. Mean changes in perfusion measures for transplanted hearts in the Organ Care System
Fig. 5. Kaplan-Meier analysis: survival for all patients after HTx
0 6 12 18 24 30 36 42 48 54 60 Month
-П Survival function + Censored
Fig. 6.
Kaplan-Meier analysis: survival for patients transplanted with donor hearts with using of standard cold storage and OCS Transmedics
0 6 12 18 24 30 36 42 48 54 60 Month
Type of intervention -П Cold storage + Cold storage-censored -П Transmedics + Transmedics-censored
transplanted heart is 40+14 (17-63) years. 71.4% (n=30) of recipients were males. 42.82% of transplanted patients had left VAD implantation prior to the HTx, and 2 (4.76%) of them had right VAD implantation. The average waiting time of transplantation was 275+443 days (2-1610). All patients received immunosuppressive therapy consisting of induction therapy - anti-thymocyte immunoglobulin and the basic therapy: calcineurin inhibitors, my-cophenolic acid preparations and glucocorticoids.
Table 3. Tissue Doppler Imaging data at days 3, 7 after HTx
Mean ex vivo perfusion time in the OCS was 266.5+86.7 min. The longest preservation time in the OCS was 7.5 hours. Mean total preservation time was significantly longer in the OCS group than in the standard cold storage group (Fig. 3). However, mean total ischemia time was significantly shorter in the OCS group than in the standard cold storage group. Mean venous lactate at the start of perfusion was 2.8+0.7 mmol/l. At the end of perfusion, the mean venous lactate was 7.1+1.1 mmol/l. All the donor hearts had stable perfusion and metabolic characteristics in the OCS (Fig. 4). Three, seven days TDI results were normal in all recipients (Table 3). Mean ICU stay was 15+22 days (range: 2-122). Mean time on ECMO for the 23 (54.76%) patients were 3.6+2.4 days. Mean length of stay at Center after operation was 29.7+12.5 days.
Kaplan-Meier survival estimates for all patients after HTx were 90% after 3 months, 82% after six months and 80% after twelve months (Fig. 5). Survival rate of patients in OCS group was slightly different from standard cold storage group recipients' survival (Fig. 6). In total, 8 patients (7 cases from OCS group, 1 - standard group) died (19%): before 30 days - 1 patient, 60 days - 2 patients, and more than 60 days - 5 patients.
Adverse events
In the early postoperative period after HTx 11 (26.1%) patients had the following complications: 13 (30%) - resternotomy due to bleeding, 3 (7%) - sepsis, 1 (2.3%) - stroke, 2 (4.7%) - lym-phorrhea from groin area, 2 (4.7%) - heart rhythm disturbances, and 6 patients (14.3%) had pneumonia. There was no graft rejection.
Discussion
Kazakhstan is a large country with low population density (6.4 persons/km2). Prior to 2011 year there were no VAD and HTx programs in our country. The reasons of undeveloped HTx program were donor deficit, huge territory, and mentality of people. In 2011 the NRCSC launched the surgical heart failure treatment program in Kazakhstan with starting of the VAD implantation. VAD program was the trigger to development of HTx program in our country.
Currently, we are the sole HTx center in a large country and therefore, donor hearts often need
TDI parameters, mean±SD 3 day 7 day p value (CI 95%)
S>V lateral, cm/s 8.0 (2.1) 9.1 (1.7) 0.01
S'V medial, cm/s 7.9 (1.4) 8.8 (1.3) 0.03
S>RV, cm/s 8.1 (1.7) 9.1 (1.9) 0.01
LVEF, % 53 (7.6) 60.3 (9.3) 0.002
Note. TDI - tissue Doppler imaging; S1LV - myocardial velocity associated with isovolumic contraction of left ventricle; S1RV ■ myocardial velocity associated with isovolumic contraction of right ventricle; LVEF - left ventricular ejection fraction.
Pya Yu.V., Bekbossynov S.T., Bekbossynova M.S., Kuatbayev Ye.M., Lesbekov T.D., KaLiyev R.B., Dzhetybayeva S.K., Medressova A.T., Nurmykhametova Zh.A., MurzagaLiyev M.M., Novikova S.P., Kapyshev T.S., SmaguLov N.K., Faizov L.R., Vakhrushev I.A., Andossova S.A., Myrzakhmetova G.Sh., Nadirbekova G.Ye., ShayssuLtanova S.T.,
Duyssenbina Zh.S. ■ HEART TRANSPLANTATION PROGRAM IN THE ERA OF MECHANICAL CIRCULATORY SUPPORT: REPUBLIC OF KAZAKHSTAN EXPERIENCE
to be transported over long distances (more than 2000 km). Despite the prolonged mean preservation time, the patients from OCS group had a shorter mean ischemia time than the standard cold storage group. The OCS prolongs out of body time to at least 8 hours, expanding possibilities for organ procurement from distant sites. In Australia, a donor heart was successfully transplanted after 10.5 h on the OCS [9]. We initiated this study to investigate a new method of heart preservation in this context. Also, the using of ex vivo perfusion system is good option for redo recipients, when additional time is needed to perform cardiolysis. The ability of the OCS to reanimate hearts from donors after cardiac death might present a new pool of donor hearts for transplantation [7].
In our small cohort, survival and incidence of adverse events were acceptable compared with the experience of other centers [10-11], and demonstrate the feasibility of the OCS. Other outcomes such as OCS perfusion measures, lactate trends and length of ICU stay were all within the expected range for our Center. Hamed et al. [12] defined a cut-off value of ending
lactate 4.9 mmol/l as the most powerful predictor of graft failure after HTx. In our study we use donor hearts with the venous lactate at the end of perfusion more than 5 mmol/l, due to the severe shortage of donor organs. We commonly use ECMO after HTx, during the postoperative recovery period to reduce the adverse effects of roller cardiopulmonary bypass.
In conclusion, our analysis has several limitations including lack of randomization and a small cohort of patients. Children are not eligible to be heart donors in Kazakhstan under current laws, therefore, we rarely perform HTx in children because of the low possibility of appropriate adult donor hearts becoming available. Our observations, while preliminary, show that OCS could be a safe method for myocardial protection in distant procurement and preservation of donor hearts. Further research in this direction will be helpful to understand outcomes in different clinical subgroups.
Source of Funding: This work was supported by the Government of Kazakhstan.
Declaration of interest: none declared.
References
1. Reineke D.C., Mohacsi P.J. New role of ventricular assist devices as bridge to transplantation: European perspective. Curr Opin Organ Transplant. 2017; 22 (3): 225-30.
2. Pya Y.V., Bekbossynov S.T., Bekbossynova M.S., Medressova A.T., et al. New mechanical circulatory devices as an alternative to the heart transplantation in end-stage heart failure patients. Clin. Experiment. Surg. Petrovsky J. 2016. 2017; 1 (15): 7-14. (in Russian)
3. Hunt S.A. Taking heart: Cardiac transplantation past, present, and future. N Engl J Med. 2006; 355: 231-35.
4. Hunt S.A., Haddad F. The changing face of heart transplantation. J Am Coll Cardiol. 2008; 52: 587-98.
5. Lund L.H., Edwards L.B., Kucheryavaya A.Y., et al. The Registry of the International Society for Heart and Lung Transplantation: thirty-first official adult heart transplant report-2014; focus theme: retransplantation. J Heart Lung Transplant. 2014; 33: 996-1008.
6. Pya Yu., Bekbossynova M., Jetybayeva S., Bekbossynov S., et al. Initial three year outcomes with left ventribular assist devices in a country with a nascent heart transplantation program. ESC Heart Fail. 2016; 3. P. 26-34. Published online 30 October 2015 in Wiley Online Library (wileyonlinelibrary.com). doi: 10.1002/ ehf2.12066.
7. Ardehali A., Esmailian F., Deng M., Soltesz E., et al.; for the PROCEED II trial investigators. Ex-vivo perfusion of donor hearts for human heart transplantation (PROCEED II): a prospective, open-label, multicenter, randomised non-inferiority trial. Lancet. 2015; 385: 2577-84.
8. Aron-Frederik Popov, Diana Garcia Saez, Anton Sabashnikov, Nikhil P. Patil, Mohamed Zeriouh, Prashant N. Mohite, Bartlomiej Zych, Bastian Schmack, Arjang Ruhparwar, Klaus Kallenbach, Pascal M. Dohmen, Matthias Karck, Andre R. Simon, Alexander Weymann. Utilization of the Organ Care System - a game changer in combating donor organ shortage. Med Sci Monit Basic Res. 2015; 21: 29-32.
9. Simon Messer, Abbas Ardehali? Steven Tsui. Normothermic donor heart perfusion: current clinical experience and the future. Transplant International. 2015; 28 (6): 634-642. doi: 10.1111/ tri.12361.
10. Michael M Koerner, Ali Ghodsizad, Uwe Schulz, Aly El Banayosy, Reiner Koerfer, Gero Tenderich. Normothermic ex vivo allograft blood perfusion in clinical heart transplantation. The Heart Surgery Forum. 2014; 17 (3): E141-5. doi: 10.1532/HSF98. 2014332.
11. oshua L. Chan, Jon A. Kobashigawa, Heidi J. Reich, Danny Ramzy, Maria M. Thottam, Zhe Yu, Tamar L. Aintablian, Frank Liou, Jignesh K. Patel, Michelle M. Kittleson, Lawrence S. Czer, Alfredo Trento, and Fardad Esmailian. Intermediate outcomes with ex-vivo allograft perfusion for heart transplantation. J Heart Lung Transplant; http://dx.doi.org/10.1016/j.healun.2016.08.015.
12. Hamed A., Tsui S., Huber J., Lin R., Poggio E.C., Ardehali A. Serum lactate is a highly sensitive and specific predictor of post cardiac transplant outcomes using the Organ Care System. J Heart Lung Transplant. 2009; 28: S71.
