Новый метод сохранения донорского сердца с использованием кровяной кардиоплегии и кондиционирования

Резюме

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 (n=10) защиту миокарда донорского сердца осуществляли с использованием кровяного раствора и кондиционирования, в контрольной группе (n=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. 

Ключевые слова:кондиционирование донорского сердца, кровяная кардиоплегия, Organ Care System, трансплантация сердца

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. 

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 Cardioplegiсsolution 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 includ- ing OCS perfusion measures and lactate trends. Postoperative parameters of interest were time in ICU, ECMO duration (if used) and tissue myocardial Doppler 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 Custodiol 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 cardioplegia 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 45μg/kg and hemofiltration 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 perfusion 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). 

Fig. 1. Cold/warm ischemic times and perfusion times for donor hearts preserved with blood cardioplegia or Custodiol in the Organ Care System 

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). Sevenday 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: 26- 312 hours, n=8) in the Custodiol group (table 2).

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 generally between 20-30 min and a single dose of blood cardioplegia has a similar duration of action. On the other hand, Custodiol preserves the heartfor up to three hours and therefore could be still active after the heart has been reanimated in the OCS, with un- known 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.

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Funding

This work was supported by the Kazakhstan Ministry 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) provided comments on an earlier version of this article.

Conflict of Interest

None declared. 

Литература

1. Hunt S.A. Taking heart: Cardiac transplantation past, present, and future. N Engl J Med. 2006; 355: 231-35.

2. Hunt S.A., Haddad F. The changing face of heart transplantation. J Am Coll Cardiol. 2008; 52: 587-98.

3. 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.

4. Banner N.R., Thomas H.L., Curnow E., et al. The importance of cold and warm cardiac ischemic for survival after heart transplantation. Steering Group of the United Kingdom Cardiothoracic Transplant Audit. Transplantation. 2008; 86: 542-7.

5. Russo M.J., Iribarne A., Hong K.N., et al. Factors associated with primary allograft failure after heart transplantation. Transplantation. 2010; 90: 444-50.

6. Pya Y., Bekbossynova M., Jetybayeva S., Bekbossynov S., et al. Initial 3-year outcomes with left ventricular assist devices in a country with a nascent heart transplantation program. ESC Heart Fail 2016; 3: 26-34. doi: 10.1002/ehf2.12066.

7. Ardehali A., Esmailian F., Deng M., Soltesz E., et al. 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. Koerner M.M., Ghodsizad A., Schulz U., El Banayosy A., et al. Normothermic ex vivo allograft blood perfusion in clinical heart transplantation. Heart Surg Forum. 2014; 17 (3): E141-5.

9. Dhital K.K., Lyer A., Connelan M., et al. Adult heart transplantation with distant procurement and ex-vivo preservation of donor hearts after circulatory death: a case series. Lancet 2015; 385: 2585-91.

10. Garcia-Saez D., Elbetanony A., Lezberg P., Hassanein A., et al. Ex vivo heart perfusion after cardiocirculatory death; a porcine model. J Surg Res. 2014; 195: 311-314.

11. Garcia-Saez D., Zych B., Sabashnikov A., Bowles C.T., et al. Evaluation of the organ care system in heart transplantation with an adverse donor/recipient profile. Ann Thorac Surg. 2014; 98 (6): 2099-105.

12. Hamed A., Tsui S., Huber J., et al. Serum lactate is a highly sensitive and specific predictor of post cardiac transplant out-comes using the organ care system. J Heart Lung Transplant. 2009; 28 (suppl): S71.

13. Lillerberg J., Nieminen M.S., Akkila J., et al. Effects of a new calcium sensitizer, Levosimendan, on hemodynamics, coronary blood flow and myocardial substrate utilization early after coronary bypass grafting. Eur Heart J. 1998; 19 (4): 660-8.

14. Sonntag S., Sundberg S., Lehtonen L.A., Kleber F.X. The calcium sensitizer Levosimendan improves the function of stunned myocardium after percutaneous transluminal coronary angioplasty in acute myocardial ischemia. J Am Coll Cardiol. 2004; 43 (12): 2177-82.

15. Eriksson H.I., Jalonen J.R., Heikkinen L.O., et al. Levosimendan facilitates weaning from cardiopulmonary bypass in patients undergoing coronary bypass grafting with impaired left ventricular function. Ann Thorac Surg. 2009; 87 (2): 448-54.

16. Nijhawan N., Nicolosi A.C., Montgomery M.W., et al. Levosimendan enhances cardiac performance after cardiopulmonary bypass: a prospective, randomized placebo-controlled trial. J Cardio- vasc Pharmacol. 1999; 34 (2): 219-28.

17. Mohsen Z., Azin A., Gholamreza M., et al. Modified ultra- filtration during cardiopulmonary bypass and postoperative course of pediatric cardiac surgery. Res Cardiovasc Med. 2014; 3 (2): e17830. doi: 10.5812/cardiovascmed.17830

18. Naik S.K., Knight A., Elliott M.J. A successful modification of ultrafiltration for cardiopulmonary bypass in children. Perfusion. 1991; 6 (1): 41-50.

19. Spiess B.D. The contribution of fibrinolysis to postbypass bleeding. J Cardiothorac Vasc Anesth. 1991; 5 (6): 13-7.

20. Elliott M.J. Ultrafiltration and modified ultrafiltration in pediatric open heart operations. Ann Thorac Surg. 1993; 56 (6): 1518-22.