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).
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.
_________________________________________________
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.
None declared.
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