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■ ТРАНСПЛАНТОЛОГИЯ И ИСКУССТВЕННЫЕ ОРГАНЫ
НОВЫЙ МЕТОД СОХРАНЕНИЯ ДОНОРСКОГО СЕРДЦА С ИСПОЛЬЗОВАНИЕМ КРОВЯНОЙ КАРДИОПЛЕГИИ И КОНДИЦИОНИРОВАНИЯ
ДЛЯ КОРРЕСПОНДЕНЦИИ
Нурмыхаметова Жулдыз Аскаровна - врач-перфузиолог операционного отделения с лабораторией вспомогательного кровообращения Национального научного кардиохирургического центра (Астана, Республика Казахстан) E-mail: [email protected]
Ключевые слова:
кондиционирование донорского сердца, кровяная кардиоплегия, Organ Care System, трансплантация сердца
Пя Ю.В., Калиев Р.Б., Бекбосынов С.Т., Лесбеков Т.Д., Нурмыхаметова Ж.А., Смагулов Н.К., Новикова С.П., Аширов Ж.З., Фаизов Л.Р., Медресова А.Т., Мурзагалиев М.О.
Национальный научный кардиохирургический центр, Астана, Республика Казахстан
Актуальность. В 2012 г. в нашем центре начала работу программа трансплантации сердца в Казахстане. Для трансплантации донорские сердца транспортируются из отдаленных регионов страны (>1000 км) в устройстве Organ Care System.
Цель работы - оценка безопасности и эффективности нового метода сохранения донорского сердца с использованием кровяной кардиоплегии и кондиционирования в устройстве Organ Care System.
Материал и методы. Были проанализированы данные 20 пациентов после трансплантации сердца, прооперированных с мая 2014 г. по февраль 2016 г. Пациенты были рандомизированы в 2 группы: в исследуемой группе (п=10) защиту миокарда донорского сердца осуществляли с использованием кровяного раствора и кондиционирования, в контрольной группе (п=10) -с использованием стандартного кристаллоидного раствора (Кустодиол). Клинические данные пациентов до операции в обеих группах не различались.
Результаты. 30-дневная выживаемость в обеих группах была 100%. Результаты сравнения в исследуемой группе и группе контроля (средние значения): общее время ишемии миокарда составило 84,2+28 и 86,9+8,4 мин (р=0,001), время ex vivo перфузии - 266,5+86,7 и 260,4+ 88,4 мин (р=0,87), уровень лактата в венозной крови в начале перфузий - 2,2+0,7 и 3,4+ 0,8 ммоль/л (р=0,001) и перед остановкой ex vivo перфузии - 5,0+1,9 и 9,2+2,1 ммоль/л (р=0,001). Показатели тканевой миокардиальной допплерографии на 7-й день после операции были в пределах нормы в обеих группах, за исключением одного пациента с дисфункцией правого желудочка в группе контроля.
Заключение. Кондиционирование донорского сердца с применением кровяной кардиоплегии - безопасный и эффективный метод сохранения сердца при длительной транспортировке с использованием Organ Care System. Дизайн исследования: уровень доказательности II.
Клин. и эксперимент. хир. Журн. им. акад. Б.В. Петровского. 2017. № 3. С. 54-59.
Статья поступила в редакцию: 15.05.2017. Принята в печать: 15.06.2017.
Novel method for ex vivo preservation of donor heart using blood cardioplegia and conditioning
CORRESPONDENCE
Nurmykhametova Zhuldyz A. -Perfusionist, Operating Room with a Laboratory of Ancillary Circulation, National Research Cardiac Surgery Center (Astana, Republic of Kazakhstan) E-mail: [email protected]
Pya Yu.V., Kaliyev R.B., Bekbossynov S.T., Lesbekov T.D., Nurmykhametova Zh.A., Smagulov N.K., Novikova S.P., Ashyrov Zh.Z., Faizov L.R., Medressova A.T., Murzagaliyev M.O.
National Research Center for Cardiac Surgery, Astana, Kazakhstan
Background. In 2012, we initiated the first heart transplant programme in Kazakhstan. Donor hearts are transported from distant regions (>1000 km) to be transplanted at our Center. The ob-
jective of this study was to assess the feasibility of blood cardioplegia as an alternative method to Custodiol for heart preservation.
Methods. We performed a retrospective analysis of prospectively collected data. Between May 2014 and February 2016, 20 patients with heart failure underwent heart transplantation using the Organ Care System. Of these, we arrested the donor hearts before explant and before implant using blood cardioplegia and conditioning (ultrafiltration, levosimendan) in ten patients and with standard Custodiol - in ten other patients.
Results. Preoperative risk factors were comparable in both groups. All patients were alive on the 30th day post implant in both groups. Results were similar for the blood cardioplegia compared to the Custodiol groups for: mean total warm ischemic time was 84.2+28 vs 86.9+8.4 min (p=0.001). Mean ex vivo perfusion time was 266.5+86.7 vs 260.4+88.4 min (p=0.87). Mean venous lactate at the start of perfusion 2.2+0.7 vs 3.4+0.8 mmol/l and at the end of perfusion 5.0+1.9 vs 9.2+ 2.1 mmol/l (p=0.001). Seven-day tissue myocardial Doppler results were normal in both groups, except for one patient in the Custodiol group who had right ventricular dysfunction. There were no statistically significant differences in ICU stay between the two groups. Mean ECMO duration was 29.5+28.4 vs 78.4+89 hours (p=0.002).
Conclusion. Our observations show that blood cardioplegia and conditioning could be an alternative method for myocardial protection in distant procurement and preservation of donor hearts in the Organ Care System.
Keywords:
ex vivo preservation, blood cardioplegia, Organ Care System, heart transplantation
Clin. Experiment. Surg. Petrovsky J. 2017; 5 (3): 54-9.
Received: 15.05.2017. Accepted: 15.06.2017.
Heart transplantation is the treatment of choice for patients with end-stage heart disease [1-3]. However, heart transplantation has a high early mortality, mostly attributable to donor organ failure [4]. Under conventional conditions of donor organ preservation, prolonged cold ischemic time is the most significant risk factor for primary allograft dysfunction, morbidity and mortality in the heart recipients [5]. In 2012, we initiated the first heart transplant programme in Kazakhstan. Donor hearts are often transported from distant regions (>1000 km) to be transplanted at our Center in the city of Astana [6]. There are currently two methods for ex vivo preservation of donor hearts: cold storage and a system for ex vivo heart perfusion. The latter method eliminates the risk of time-dependent ischemic injury to the donor heartduring cold storage.
The TransMedics Organ Care System (OCS) is a portable organ perfusion and monitoring system that designed to preserve donor hearts in near-physiologic functioning state ex vivo for transplantation. In this context, the standard approach for heart preservation is to use a Cardioplegicsolution such as Custodiol. The duration of the cold ischemic time when using Custodiol is between 1.5-2 hours and the solution is perfused under hypothermic conditions. Several reports have compared OCS to standard cold storage [7-8] and others have investigated OCS in the context of donation after circulatory determined death [9-10], and in cases with adverse donor/recipient profile [11].
Blood cardioplegia is an alternative method for heart preservation, which would provide perfusion at normothermic and physiologic conditions. We hypothesized that blood cardioplegiacould provide perfusion at normothermic (34 oC) and physiologic conditions and may result in better postoperative clinical outcomes. To our knowledge, blood cardioplegia and conditioning has not been previously studied in the OCS.
Methods
In this study, we performed a retrospective analysis of prospective collected data at our center. Between May 2014 and February 2016, 20 patients with heart failure underwent heart transplantation at our Center and we used the OCS for donor heart preservation in all cases. Of these, we arrested the donor hearts before explant and before implant using blood cardioplegia and conditioning in ten patients and in another ten patients we used standard Custodiol solution (SC group). Recipients were assigned to blood cardioplegia or Custodiol in alternating fashion (e.g. blood cardioplegia, Custodiol, blood cardioplegia etc) based on their order in the recipient waiting list. Perfusion and cardiac function parameters were continuously monitored and the donor heart was perfused in the OCS device.
The main outcomes of interest were 30 day graft survival and cardiac-related adverse events. We also collected data on peri-operative parameters including OCS perfusion measures and lactate trends. Post-
operative parameters of interest were time in ICU, ECMO duration (if used) and tissue myocardial Dop-pler onday 7. Eligible recipients were at least 18 years of age and had to be on the heart-transplant waiting list 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 explant to recipient implantation.
In the OCS, oxygenated blood is pumped into the aorta, perfusing the coronary arteries. The coronary sinus flow then passes throughthe tricuspid valve (as both the superior and inferiorvena cava are sutured closed) and is ejected by the rightventricle into a pulmonary artery catheter, and returnedto the blood reservoir. After the donor has been heparinized, a portion of the normothermic blood (500-750 ml) is retrogradely collected for blood cardioplegia. The donor blood (1200-1500 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 (in blood cardioplegia group) or standard Cus-todiol solution (for the control group) 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. 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 regularly 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) [12]. Upon arrival at our Center, the donor heart is arrested with approximately one liter of blood cardio-plegia in the blood cardioplegia group or Custodiol solution in the Custodiol group and is disconnected from the OCS for implantation into the recipient. Transplantation and preoperative care proceeded according to the standard procedures of our Center in both groups.The solution we used for in the blood cardioplegia group consisted of blood and crystalloid solution at a ratio of 1:5 and a cardioplegia flow rate of 200-300 ml/min. The crystalloid solution contained KCl, MgSO4, NaHCO3, Mannitol, Lidocaine.
To protect and improve donor heart function we conditioned with Levosimendan 45|jg/kg and he-mofiltration 200-500 ml during transportation in the OCS. This positive inotrope is used to treat severe heart failure. We used this drug because there is some evidence to suggest that it has cardioprotective effects [13-16]. We used ultrafiltration during perfu-
sion in the OCS (MedosMedizintechnik AG, Germany) to reduce the levels of circulating inflammatory factors and endotoxins and to increase hematocrit [17-20].
Results
The recipient and donor characteristics and risk factors are shown in table 1. In the recipient group, the median age was slightly higher in the Custodiol group compared to the blood cardioplegia group. Other prognostic risk factors at baseline were similar between the two groups, including gender, body mass index and proportion of patients who were on a ventricular assist device at time of transplant. Most recipients and their donors had the same blood type with the following exceptions. In the blood cardioplegia group, there were three instances where recipients had a different blood type than their donors (recipients: type AB (+), AB (+) and B (+) and donors had B (-), B (+) and O (+), respectively). In the Custodiol group one recipient had a different blood type [O (+)] than their donor was [A (+)].
Median (range) follow up time for the blood cardioplegia group was 255 (30-360) days and for the Custodiol group was 360 (30-600) days. All patients were alive on the 30th day post implant in two groups. One patient developed right ventricular dysfunction one month after implant in the Custodiol group. Ischemic times and perfusion times of donor hearts in the OCS are shown in Fig. 1. Mean (+standard deviation) total warm ischemic time was 84.2+28 min in the blood cardioplegia group compared to 86.9+ 8.4 min in the Custodiol group (p=0.001). Mean ex vivo perfusion time was 266.5+86.7 min in the blood cardioplegia group compared to 260.4+88.4 min in the Custodiol group (p=0.87). Mean venous lactate at the start of perfusion was 2.2+0.7 mmol/l in the blood cardioplegia group and 3.4+0.8 mmol/l in the Custodiol group (p=0.001). At the end of perfusion, the mean venous lactate was lower in the blood cardioplegia group 5.0+1.9 mmol/l compared to the Custodiol group 9.2+2.1 mmol/l. All the donor hearts had stable perfusion and metabolic characteristics in the OCS and the measures were similar between the two groups (Fig. 2, 3). Seven-day myocardial velocity (tissue myocardial Doppler TMD) results were normal in all recipients and similar between the 2 groups, except for one patient in the Custodiol group who developed right ventricular dysfunction (ejection fraction 39%). Median ICU stay was 11 days (range: 4-40 days) in the blood cardioplegia group and 19 days (range: 5-42) in the Custodiol group. Median time on ECMO for the six patients who received mechanical support was 29.5 hours (range: 24-73 hours) in the blood cardioplegia group compared to 78.4 hours (range: 26312 hours, n=8) in the Custodiol group (table 2).
Table 1. Donor and recipient characteristics
Characteristics Blood cardioplegia group Custodiol solution group
(n=10) (n=10)
Recipient characteristics
Median Age (range), years 30(18-63) 38 (24-59)
Mean Age (SD), years 33 (±15,5) 38 (±12,1)
Sex
Male 8 (80%) 7 (70%)
Female 2 (20%) 3 (30%)
Weight, kg 67 (44-85) 64(54-76)
Height, cm 168 (155-193) 167 (154-180)
Body mass index, kg/m2 23 (17-28) 23 (18-26)
Diagnosis of cardiomyopathy, n (%)
Ischemic 1 (10%) 1 (10%)
Dilated 8 (80%) 7 (70%)
Other 1 (10%) 2 (20%)
On ventricular assist device, n (%) 5 (50%) 5 (50%)
United Network Organ Sharing status 1A+LVEF (%) 8 (80%) 7 (70%)
Donor characteristics 20 (15-26) 21 (15-26)
Median Age (range), years 39 (18-56) 49 (23-65)
Mean Age (SD), years 40 (±14.7) 46 (±14.7)
Sex
Male 6 (60%) 5 (50%)
Female 4 (40%) 5 (50%)
Weight, kg 63 (50-75) 64 (52-75)
Height, cm 168 (160-180) 167 (160-185)
Body mass index, kg/m2 22 (19.5-24.5) 22 (20.3-25.4)
Cause of death
Head trauma 6 (60%) 2 (20%)
Stroke or cerebrovascular accident 3 (30%) 8 (80%)
Other 1 (10%)
LVEF (%) 61(58-65) 63 (59-67)
Note. Data are median (range) unless otherwise noted. +Most urgent status for heart transplant candidates.
Custodiol
Blood cardioplegia
26
21
50
100
150
200
250
300
350
400
Fig. 1. Cold/warm ischemic times and perfusion times for donor hearts preserved with blood cardioplegia or Custodiol in the Organ Care System
I Cold/Warm ischemia before the Organ Care System Perfusion
Cold/Warm ischemia after the Organ Care System
0
Discussion
We are the sole heart transplant center in a large country and therefore, donor hearts often need to be transported over long distances (more than 1000 km). The OCS prolongs out of body time to at least 8 hours, expanding possibilities for organ procurement from distant sites. We initiated this study to investigate a new method of heart preservation
in this context. To our knowledge, this is the first clinical report of blood cardioplegia using the OCS for heart transplantation.
We hypothesized that blood cardioplegia could provide near physiologic conditions (oxygenated environment, normothermia) and could result in favorable patient outcomes. Ischemic time between explant from donor and implant to the OCS is gener-
Table 2. Tissue Myocardial Doppler, ICU length of stay and ECMO duration at day 7 (Data are mean - S.D.)
Parametres Blood cardioplegia group (n=10) Custodiol group (n=10) p value
S>LV lateral (cm/s)TMD 10+1.6 9.2+1.8 0.73
S>LV medial (cm/s)TMD 8.93+1.35 8.58+1.6 0.60
S>RV (cm/s)TMD 10+2.66 8.95+1.96 0.36
LVEF (%)TMD 61.4+2.31 57.5+7.9 0.001
ICU length of stay (day) 11.7+10.3 19.6+13 0.44
Inotrope Dose (mcg/kg/minute IV)
24 hours
Dobutamine 6.5+1.9 6.5+1.7 0.74
Milrinone 1.75+1.25 1.8+1.3 0.90
48 hours
Dobutamine 6.0+2.6 6.8+1.3 0.39
Milrinone 0.2 (n=1) 0.3 (n=1)
72 hours
Dobutamine 3.6+0.8 5.4+2.7 0.05
Milrinone 0.2 (n=1) 0.2 (n=1)
ECMO duration (h) 29.5+28.4 n=6 78.4+89 n=8 0.002
Note. TMD - tissue myocardial Doppler; 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; ICU - intensive care unit; ECMO -extracorporeal membrane oxygenation.
Fig. 2. Mean changes in perfusion measures for transplanted hearts in the Organ Care System (p=0.001)
Error bars indicate standard deviation.
785
783
70 65 ~TT-1"
CD
I Coronary flow
г 1000
-900
-800
-700
-600
-500
-400
-300
7 с -200
-100
-0
□ Aortic pressure
Fig. 3. Mean changes 12 in lactate for transplanted hearts in the Organ
Care System 10
0
9.2
3.4
2.2
Starting concentration Ending concentration ■ Blood cardioplegia group □ Custodiol group
three hours and therefore could be still active after the heart has been reanimated in the OCS, with unknown effects. In addition, Custodiol must be perfused under hypothermic conditions (4 °C), lowering the heart temperature to 15 °C. This may cause adverse effects related to the temperature gradient because in the OCS, the donor heart is transported at 34 °C.
In our small cohort, survival and incidence of serious cardiac related adverse events at 30 days post-implant were acceptable and demonstrate the feasibility of blood cardioplegia with 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. We did not observe any statistically significant differences in TMD parameters between the two groups, but this study was not powered to detect differences in these outcomes and understanding impact on these outcomes will be important for future studies. There were no statistically significant differences in ECMO duration between the two groups. We commonly use ECMO after heart transplant, during the postoperative recovery period to reduce the reperfusion time.
Our analysis has several limitations including lack of randomization to blood cardioplegia or Custodiol and a small cohort. Our observations, while preliminary, show that blood cardioplegia and conditioning could be a safe method for myocardial protection in distant procurement and preservation of donor hearts in the OCS. Further research in this direction will be helpful to understand the efficacy and safety of this method.
8
6
4
2
ally between 20-30 min and a single dose of blood Funding
cardioplegia has a similar duration of action. On the This work was supported by the Kazakhstan Mi-
other hand, Custodiol preserves the heartfor up to nistry of Health.
Acknowledgements
Philip la Fleur (EBM Research and Consulting) assisted with the writing of the manuscript.
Dr. Robertas Samalavicius (Vilnius University Hospital Santariskiu Klinikos in Vilnius, Lithuania)
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None declared.
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