Cardiocirculatory Death Research Articles

How France launched its donation after cardiac death program

On the basis of the literature and results presented at the 6th International Conference, donation after cardio-circulatory death provides a significant, practical, additional high quality source of transplantable organs. The vast majority of DCD are ‘controlled’ Maastricht category III donors. In 2010, the parliamentary information mission on the revision of the bioethics laws invited the Intensive Care Societies to debate and to make recommendations to implement controlled donation after circulatory death. They came to the conclusion that such retrieval is possible in France and insisted on the medical criteria that frame it: the writing of the medical procedures, the ethical aspects and the delay. The major recommendations of the ethics committees were firstly, The WLST decision is independent of the possibility of organ donation; secondly, the strict respect of “The dead donor and organ transplantation rule” and the updated national guidance for the WLST; thirdly, the drafting of a nationally agreed protocol defining the mandatory conditions to determine death and to perform procurement and transplantation. Organ donation after WLST will be authorised only in pilot centres with a locally agreed WLST policy including external second opinion and written transcript of the WLST decision, experienced intensive care staff, a local organ procurement coordination team familiar with DBD and DCD protocols and only in hospitals authorised for organ procurement. It is important to have an optimal and standardized national guidance to limit the known risk factors of graft failure (donor and recipient choice, warm and cold ischemia time), to increase acceptance by medical community and civil society and to improve results and allow more powerful analysis.

Ethically Informed Pragmatic Conditions for Organ Donation after Cardiocirculatory Death: Could They Assist in Policy Development?

The modern practice of organ donation after cardiocirculatory death (DCD) emerged in the 1990s as a response to the alarmingly wide gap between the number of transplantable organs available through organ donation after neurological death and the urgent organ transplantation needs of persons in end-organ failure. Various important ethical dimensions of DCD have been considered and debated by prominent organ donation/transplantation theorists and clinicians. In this article, consideration of some of these ethical elements provides a foundation for a proposed set of ethically informed, pragmatic conditions that could assist in the development of health policies to guide the practice of organ donation after cardiocirculatory death.

Further Evaluation of Somah: Long-Term Preservation, Temperature Effect, and Prevention of Ischemia-Reperfusion Injury in Rat Hearts Harvested After Cardiocirculatory Death

ObjectiveTo identify and evaluate the ideal temperature for long-term storage of hearts from donation after cardiocirculatory death, in the novel organ preservation solution Somah. MethodsDCD hearts from Sprague-Dawley rats were harvested after 30 minutes of euthanasia, preserved in Somah at 4°C, 10°C, 21°C, or 37°C for 24 hours and then reperfused with blood:Somah (3:1) perfusate at 37°C for 30 minutes. Myocardial biopsies were taken during storage and before and after reperfusion to assess the structural and functional viability of tissue using multiphoton imaging, biochemistry, and immunofluorescence. ResultsMyocyte viability, determined by Live-Dead and esterase assays, was similar at 4°C, 10°C, and 21°C (193, 198 and 217 normalized fluorescence counts [NFC]) with a significant decrease at 37°C (131 NFC). Upon reperfusion, esterase activity was enhanced in DCD hearts stored in Somah at 21°C but noticeably decreased at all other temperatures. High-energy adenosine triphosphate/creatine phosphate (ATP/CP) syntheses and the expression of structural/contractile proteins was well preserved at 21°C, both after 24-hour storage and upon reperfusion. In contrast, hearts stored at all other temperatures demonstrated variable degenerative changes, loss of protein expression, and/or deranged ATP/CP synthesis after 24 hours of storage and/or upon reperfusion. ConclusionThe robust maintenance of structural/functional integrity of cardiac tissue and the preservation of protein expression and cellular energy metabolism in DCD hearts after long-term preservation at subnormothermic temperature suggests that 21°C is ideal for long-term storage of DCD hearts in Somah solution.

A cardioprotective preservation strategy employing ex vivo heart perfusion facilitates successful transplant of donor hearts after cardiocirculatory death

Ex vivo heart perfusion (EVHP) has been proposed as a means to facilitate the resuscitation of donor hearts after cardiocirculatory death (DCD) and increase the donor pool. However, the current approach to clinical EVHP may exacerbate myocardial injury and impair function after transplant. Therefore, we sought to determine if a cardioprotective EVHP strategy that eliminates myocardial exposure to hypothermic hyperkalemia cardioplegia and minimizes cold ischemia could facilitate successful DCD heart transplantation. Anesthetized pigs sustained a hypoxic cardiac arrest and a 15-minute warm ischemic standoff period. Strategy 1 hearts (S1, n = 9) underwent initial reperfusion with a cold hyperkalemic cardioplegia, normothermic EVHP, and transplantation after a cold hyperkalemic cardioplegic arrest (current EVHP strategy). Strategy 2 hearts (S2, n = 8) underwent initial reperfusion with a tepid adenosine-lidocaine cardioplegia, normothermic EVHP, and transplantation with continuous myocardial perfusion (cardioprotective EVHP strategy). At completion of EVHP, S2 hearts exhibited less weight gain (9.7 ± 6.7 [S2] vs 21.2 ± 6.7 [S1] g/hour, p = 0.008) and less troponin-I release into the coronary sinus effluent (4.2 ± 1.3 [S2] vs 6.3 ± 1.5 [S1] ng/ml; p = 0.014). Mass spectrometry analysis of oxidized pleural in post-transplant myocardium revealed less oxidative stress in S2 hearts. At 30 minutes after wean from cardiopulmonary bypass, post-transplant systolic (pre-load recruitable stroke work: 33.5 ± 1.3 [S2] vs 19.7 ± 10.9 [S1], p = 0.043) and diastolic (isovolumic relaxation constant: 42.9 ± 6.7 [S2] vs 65.2 ± 21.1 [S1], p = 0.020) function were superior in S2 hearts. In this experimental model of DCD, an EVHP strategy using initial reperfusion with a tepid adenosine-lidocaine cardioplegia and continuous myocardial perfusion minimizes myocardial injury and improves short-term post-transplant function compared with the current EVHP strategy using cold hyperkalemic cardioplegia before organ procurement and transplantation.

Continuous Crystalloid Microperfusion Provides Excellent Preservation for Transplantation of Donation After Cardiocirculatory Death Hearts

Purpose: Epidemiological studies demonstrated that particulate air pollution (PM) can trigger adverse health effects. We demonstrated that chronic exposure to air pollution is associated with increased risk of chronic rejection and mortality after lung transplantation (LTx). In the present study, we investigated whether short-term elevations in PM10 increased the risk of acute rejection after LTx.

An International Comparison of the Effect of Policy Shifts to Organ Donation following Cardiocirculatory Death (DCD) on Donation Rates after Brain Death (DBD) and Transplantation Rates

During the past decade an increasing number of countries have adopted policies that emphasize donation after cardiocirculatory death (DCD) in an attempt to address the widening gap between the demand for transplantable organs and the availability of organs from donation after brain death (DBD) donors. In order to examine how these policy shifts have affected overall deceased organ donor (DD) and DBD rates, we analyzed deceased donation rates from 82 countries from 2000–2010. On average, overall DD, DBD and DCD rates have increased over time, with the proportion of DCD increasing 0.3% per year (p = 0.01). Countries with higher DCD rates have, on average, lower DBD rates. For every one-per million population (pmp) increase in the DCD rate, the average DBD rate decreased by 1.02 pmp (95% CI: 0.73, 1.32; p<0.0001). We also found that the number of organs transplanted per donor was significantly lower in DCD when compared to DBD donors with 1.51 less transplants per DCD compared to DBD (95% CI: 1.23, 1.79; p<0.001). Whilst the results do not infer a causal relationship between increased DCD and decreased DBD rates, the significant correlation between higher DCD and lower DBD rates coupled with the reduced number of organs transplanted per DCD donor suggests that a national policy focus on DCD may lead to an overall reduction in the number of transplants performed.

Urine Neutrophil Gelatinase-Associated Lipocalin Determination as a Donor Auxiliary Examination Method — First Results

A growing lack of donor organs has caused extension of criteria for deceased donation. Therefore, elderly donors and donors with increased serum creatinine levels, as well as donors after cardiocirculatory death, have become used more frequently. The examination of such donors is strongly limited due to the lack of time, and the determination of the quality of donor organs is still based on clinical and laboratory screening data of donors. Implementation of new examination methods is required to determine the functional condition of donor organs more accurately, which would allow correct selection of donors. This retrospective study included all consecutive deceased donor (DD) kidney transplantations (KTx) performed in a single centre during the period from 1 January 2010 till 30 November 2011. The donor examination was supplemented by the urine neutrophil gelatinase-associated lipocalin (U-NGAL) test. Recipients were available for follow- up for at least 12 months (totally 97 KTx from 63 DD). All cases were divided into four groups according to U-NGAL and serum creatinine (S-Crea) levels in donors: group I - normal U-NGAL and S-Crea (n = 70); group II - elevated U-NGAL and S-Crea (n = 10); group III - elevated U-NGAL and normal S-Crea (n = 9); group IV - normal U-NGAL and elevated S-Crea (n = 8). Information about rates of delayed graft function (DGF) and immediate graft function (IGF), acute rejection (AR), recipient S-Crea levels during the first post-transplant year for functioning grafts, graft losses and recipient deaths were summarised. Donor urine NGAL level showed moderate correlation with donor S-creatinie level (r = 0.543, P &lt; 0.001). DGF was observed in 20 recipients (21%) and demonstrated association with increased donor S-creatinine (0.135 ± 0.061 vs. 0.108 ± 0.04 mmol/l in IGF, p &lt; 0.05). Combination of increased donor S-Crea and U-NGAL (group II) was associated with worse graft function during the first year after transplantation. Recipients in group III had increased S-Crea at the time of discharge from hospital and at one year after transplantation. One-year death censored graft survival and recipient survival was similar in all groups (P = NS). Determination of U-NGAL can be used as a donor auxiliary examination method for determination of the kidney graft functional condition and for prediction of post-transplant results. The study needs to be continued with a higher number of observations and longer post-transplant follow-up.

The use of extracorporeal membranous oxygenation in donors after cardiac death

The purpose of the present review is to describe the methods using an extracorporeal membranous oxygenation (ECMO) circuit in donors after cardiac death and to evaluate their impact on the outcome of renal transplantation. ECMO can be used either in hypothermic conditions for total body cooling or in normothermic conditions and limited to the abdomen in a first phase, before subsequent in-situ cooling. In both cases, oxygen is added to the perfusion, as compared with the usual and simple cold in-situ perfusion. There is a strong experimental rationale to use ECMO in normothermic conditions. The clinical studies in renal transplantation are still few, retrospective with small cohorts (level 3 or 4, according to the Oxford Centre for Evidence-Based Medicine). However, they all reach consistent conclusions with better kidney transplant outcome, both in uncontrolled (type I and II) and controlled (type III) donors, according to the Maastricht classification. The use of ECMO in donors after cardio-circulatory death should be encouraged and further developed. Experimental work is in progress to better define the optimal conditions of the technique, which will help to limit or even repair the injuries, induced by warm ischaemia.

Right Ventricular Distension in Donor Hearts Following Cardiocirculatory Death: Implications for Post-Transplant Function

<h3>Purpose</h3> Donation after cardiocirculatory death (DCD) may expand the donor pool for heart transplantation; however, right ventricular (RV) dysfunction has been observed in resuscitated DCD hearts and the cause of this is not well understood. We sought to characterize changes in RV pressure and volume following withdrawal of life-sustaining therapy (WLST) in a large animal model of DCD. <h3>Methods and Materials</h3> Thirteen pigs were anesthetized and mechanically ventilated with room air. Mechanical ventilation was discontinued, hypoxic cardiac arrest ensued, and a 10-minute standoff period was observed. Changes in RV pressure and volume were monitored using a conductance catheter and magnetic resonance imaging (MRI). <h3>Results</h3> The arterial partial pressure of oxygen decreased rapidly and reached its nadir after 2 minutes (Figure 1). This corresponded with an increase in RV systolic pressure (baseline RVSP 24.1±0.9 vs. 35±2 mmHg, p<0.01), diastolic function (baseline dPdt_min −172±24 vs. −267±24 mmHg/s, p<0.01), and systolic function (baseline dPdt_max 254±32 vs. 378±32 mmHg/s, p=0.01) compared to baseline. Subsequent RV function progressively declined leading to an 18±6% (p<0.01) increase in RV end-diastolic volume and an increase in RV end diastolic pressure (baseline 4.2±0.5 vs. 7.3±0.4 mmHg, p<0.01). MRI confirmed an 18±12% increase in RV end diastolic volume compared to baseline. <h3>Conclusions</h3> Following WLST the RV experiences significant distension that may exacerbate myocardial injury. Assessment of RV function prior to transplantation of the DCD heart is essential, highlighting the need for an <i>ex vivo</i> perfusion device capable of biventricular functional assessment.

An International Analysis of Policy Shifts to Donation After Cardio-circulatory Death (DCD) and Their Effect on Deceased Organ Donation and Transplantation Rates

Introduction: During the past decade an increasing number of countries have adopted policies that emphasize donation after cardio-circulatory death (DCD) in an effort to address the widening gap between demand and supply of transplantable organs. An analysis of international donation activity between 1989-2010 identified 25 countries that reported regular DCD activity. This research reports the impact of policy shifts towards increasing DCD upon overall deceased organ donation rates (DD), donation after brain death rates (DBD) and organ transplantation rates. Methods: Donor and transplant data was collected from multiple international donation and transplantation agencies and supplemented and cross-checked against responses to questionnaires sent to relevant national organ donor and transplant related bodies. Data was analyzed to determine correlations and associations between; DCD (both uncontrolled - Maastricht Class 1 & 2 (uDCD) and controlled Maastricht Class 3 & 4 (cDCD)); DBD; overall DD; and organ transplantation rates, with p = 0.05 considered significant. Results: Our results show that high national DD rates (> 20 DD pmp per year) were strongly associated with high DBD rates. In contrast, high DCD rates negatively impacted on a country's overall DD rate. In addition, there was a significant negative correlation (p = 0.0002) between DCD and DBD rates in countries with policies that resulted in high DCD rates. Finally, international data demonstrates that the total number of organs transplanted per donor is reduced by a factor of 1.5 in DCD when compared to DBD (p < 0.0001).Figure: [DCD Effect on DBD Rates]Figure: [Transplanted Organs per DCD & DBD Donor]Conclusion: While policies focused on uDCD may increase overall DD rates, increases in DD from policies that focus on cDCD come at the expense of DBD. We conclude that cDCD negatively impacts the number of donations from brain dead donors and may lead to an overall reduction in the number of transplants performed due to reduced organ retrieval rates.

Predictive Parameters of Primary Non Viable Kidney Grafts from Uncontrolled Donors after Cardio-Circulatory Death (DCD)

Predictive Parameters of Primary Non Viable Kidney Grafts from Uncontrolled Donors after Cardio-Circulatory Death (DCD)

684 Donor Heart Allocation in QuÉbec During the Year 2011: The Impact of Cardiocirculatory Deaths

684 Donor Heart Allocation in QuÉbec During the Year 2011: The Impact of Cardiocirculatory Deaths

Abstract 255: A Normokalemic Nondepolarizing Cardioplegia Minimizes Myocardial Injury and Improves Cardiac Function in a Large Animal Model of Donation After Cardiocirculatory Death

Background: Procurement of donor hearts is typically preceded by delivery of a cold hyperkalemic cardioplegia (CP) that achieves arrest by depolarization of the membrane potential. This method has no intrinsic cardioprotective properties and may exacerbate ischemia-reperfusion (IR) injury. A tepid adenosine-lidocaine (AL) non-depolarizing CP has been shown to limit IR injury and improve myocardial functional recovery in a small animal model of orthotopic heart transplantation. We sought to determine the impact of AL CP on myocardial injury and function, in a porcine model of donation after cardio-circulatory death (DCD). Methods: Female Yorkshire pigs (60 kg) were subjected to a hypoxic cardiac arrest. Following a 15-minute standoff period donor hearts were procured, resuscitated ex-vivo, and transplanted into a recipient animal. Hearts in group 1 (N=7) were protected with a cold blood-Plegisol CP, perfused with a blood-crystalloid solution during ex-vivo assessment, and arrested with a cold blood-Plegisol CP prior to transplantation. Hearts in group 2 (N=5) were protected with a tepid AL-STEEN CP and perfused with a blood-STEEN solution in a continuous fashion during ex-vivo assessment and transplantation. Results: Animals in group 2 had a significantly longer ex-vivo perfusion time compared to those in group 1 (174±29 vs. 135±45 min, p&lt;0.05), yet they demonstrated significantly less weight gain (14±4 vs. 25±8 grams/hour, p&lt;0.05). Further, animals in group 2 exhibited less troponin I release during ex-vivo perfusion and had significantly better diastolic function following wean from cardiopulmonary bypass (left ventricular end-diastolic pressure volume relationship 0.115±0.052 vs. 0.508±0.223, p&lt;0.05). However, there was no significant difference in level of calpain activity between groups (171.3±68.6 vs. 140.12±50.6, p=0.36). Conclusion: A tepid non-depolarizing AL CP results in less myocardial edema during ex-vivo perfusion, minimizes myocardial injury, and improves diastolic function following transplantation of DCD hearts, but fails to eliminate the activation of calcium-dependent proteases. Further studies should investigate if a calpain inhibitor delivered at reperfusion could further minimize IR injury in DCD hearts.

Contribution of the ethics committee of the French Intensive Care Society to describing a scenario for implementing organ donation after Maastricht type III cardiocirculatory death in France

French law allows organ donation after death due to cardiocirculatory arrest. In the Maastricht classification, type III non-heart-beating donors are those who experience cardiocirculatory arrest after the withdrawal of life-sustaining treatments. French authorities in charge of regulating organ donation (Agence de la Biomédecine, ABM) are considering organ collection from Maastricht type III donors. We describe a scenario for Maastricht type III organ donation that fully complies with the ethical norms governing care to dying patients. That organ donation may occur after death should have no impact on the care given to the patient and family. The dead-donor rule must be followed scrupulously: the organ retrieval procedure must neither cause nor hasten death. The decision to withdraw life-sustaining treatments, withdrawal modalities, and care provided to the patient and family must adhere strictly to the requirements set forth in patient-rights legislation (the 2005 Léonetti law in France) and should not be influenced in any way by the possibility of organ donation. A major ethical issue regarding the family is how best to transition from discussing treatment-withdrawal decisions to discussing possible organ retrieval for donation should the patient die rapidly after treatment withdrawal. Close cooperation between the healthcare team and the organ retrieval team is crucial to minimize the distress of family members during this transition. Modalities for implementing Maastricht type III organ donation are discussed here, including the best location for withdrawing life-sustaining treatments (operating room or intensive care unit).

Categories of Donation After Cardiocirculatory Death

The interest in donation after cardiocirculatory death (DCD) was renewed in the early 1990s, as a means to partially overcome the shortage of donations after brain death. In some European countries and in the United States, DCD has become an increasingly frequent procedure over the last decade. To improve the results of DCD transplantation, it is important to compare practices, experiences, and results of various teams involved in this field. It is therefore crucial to accurately define the different types of DCD. However, in the literature, various DCD terminologies and classifications have been used, rendering it difficult to compare reported experiences. The authors have presented herein an overview of the various DCD descriptions in the literature, and have proposed an adapted DCD classification to better define the DCD processes, seeking to provide a better tool to compare the results of published reports and to improve current practices. This modified classification may be modified in the future according to ongoing experiences in this field.

Survey of determination of death after cardiac arrest by intensive care physicians*

The controversy regarding death determination in the context of organ donation after cardiocirculatory death requires investigation. We sought to describe the manner in which Canadian adult and pediatric intensive care physicians report death determination after cardiac arrest. Pilot-tested paper survey. Mail out between June and November 2009. Canadian adult and pediatric intensive care physicians. Paper-based survey. Forty-nine percent of 501 Canadian intensive care physicians responded. Eighty-five percent practiced in tertiary care, university-affiliated centers, and 26% were from pediatric centers. Physicians had a median of 10 yrs (range 0-35) experience. Physicians reported that they performed determination of death after cardiac arrest a median of seven (range 0-60) times per year. Of 11 tests or procedures used, the absence of heart sounds by auscultation, palpable pulse, and breath sounds were the most common, although there was high variability in practice. No diagnostic test/procedure was uniformly performed or omitted. Sixty-five percent of respondents believed autoresuscitation exists and 37% of physicians reported to have seen a possible case during their career. Forty-eight percent had formal training for determining death after cardiac arrest and 22% used guidelines. The majority of respondents agreed that standardized methods for determination of death after cardiac arrest are required in general (69%) and specifically for donation after cardiocirculatory death (91%). Intensive care physicians in Canada report: 1) variability in the practice of determining death after cardiac arrest; 2) the existence of autoresuscitation; and 3) a need for standardization of practice. The results of this survey support the need to develop more robust education, guidelines, and standards for the determination of death after cardiac arrest, in general, as well as within the context of donation after cardiocirculatory death.

89 Continuous Crystalloid Microperfusion Provides Excellent Preservation for Transplantation of Donation after Cardiocirculatory Death Hearts

89 Continuous Crystalloid Microperfusion Provides Excellent Preservation for Transplantation of Donation after Cardiocirculatory Death Hearts

When GLP-1 hits the liver: a novel approach for insulin resistance and NASH

nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to steatohepatitis (NASH), increasing fibrosis and eventually, cirrhosis ([22][1]). Importantly, NASH accompanied by fibrosis and severe inflammation is the most relevant predictor for disease progression

Donation after cardio-circulatory death liver transplantation

The renewed interest in donation after cardio-circulatory death (DCD) started in the 1990s following the limited success of the transplant community to expand the donation after brain-death (DBD) organ supply and following the request of potential DCD families. Since then, DCD organ procurement and transplantation activities have rapidly expanded, particularly for non-vital organs, like kidneys. In liver transplantation (LT), DCD donors are a valuable organ source that helps to decrease the mortality rate on the waiting lists and to increase the availability of organs for transplantation despite a higher risk of early graft dysfunction, more frequent vascular and ischemia-type biliary lesions, higher rates of re-listing and re-transplantation and lower graft survival, which are obviously due to the inevitable warm ischemia occurring during the declaration of death and organ retrieval process. Experimental strategies intervening in both donors and recipients at different phases of the transplantation process have focused on the attenuation of ischemia-reperfusion injury and already gained encouraging results, and some of them have found their way from pre-clinical success into clinical reality. The future of DCD-LT is promising. Concerted efforts should concentrate on the identification of suitable donors (probably Maastricht category III DCD donors), better donor and recipient matching (high risk donors to low risk recipients), use of advanced organ preservation techniques (oxygenated hypothermic machine perfusion, normothermic machine perfusion, venous systemic oxygen persufflation), and pharmacological modulation (probably a multi-factorial biologic modulation strategy) so that DCD liver allografts could be safely utilized and attain equivalent results as DBD-LT.

Results of kidney transplantation from controlled donors after cardio-circulatory death: a single center experience

The aim of this study was to determine results of kidney transplantation (KT) from controlled donation after cardio-circulatory death (DCD). Primary end-points were graft and patient survival, and post-transplant complications. The influence of delayed graft function (DGF) on graft survival and DGF risk factors were analyzed as secondary end-points. This is a retrospective mono-center review of a consecutive series of 59 DCD-KT performed between 2005 and 2010. Overall graft survival was 96.6%, 94.6%, and 90.7% at 3 months, 1 and 3 years, respectively. Main cause of graft loss was patient's death with a functioning graft. No primary nonfunction grafts. Renal graft function was suboptimal at hospital discharge, but nearly normalized at 3 months. DGF was observed in 45.6% of all DCD-KT. DGF significantly increased postoperative length of hospitalization, but had no deleterious impact on graft function or survival. Donor body mass index ≥30 was the only donor factor that was found to significantly increase the risk of DGF (P < 0.05). Despite a higher rate of DGF, controlled DCD-KT offers a valuable contribution to the pool of deceased donor kidney grafts, with comparable mid-term results to those procured after brain death.