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Organ donation with the use of normothermic regional perfusion in patients who die after cardiac and respiratory arrest after withdrawal of life-sustaining treatment
Abstract and Figures
Donation of organs from patients with severe brain injury who die after cardiac and respiratory arrest after withdrawal of life sustaining treatment, referred to as controlled Donation after circulatory death (cDCD), has been proposed for use in Norway. The proposed method - cDCD using normothermic regional perfusion (NRP) - is one of several methods under the common designation cDCD. Today's method is referred to as "Donation after Brain Death" (DBD), and means that patients with irreversible cessation of brain function are declared dead while still on mechanical ventilation. cDCD will come in addition to DBD. We conducted a health technology assessment of cDCD’s efficacy and safety, and we considered medical, legal and ethical issues raised by the method. Based on this review, our findings are as follows:
Efficacy and safety
We found no convincing difference in organ quality or graft survival after kidney and liver transplantation when comparing cDCD with DBD, because the confidence intervals were wide. We assessed the certainty of the evidence as very low using the GRADE approach mainly because there were few and small studies.
Law
No legal barriers performing organ donation after cDCD have been identified. The professional medical community will ultimately be responsible for specifying and formulating a detailed description of death criteria. The description will be crucial for how the law and accompanying regulations are to be understood. The description may be included in a brief or by including more precise provisions in existing regulations.
Ethics
A review of the ethical discussion in international academic literature revealed how cDCD has been a subject of debate for many years, particularly in the early phase of establishing the method internationally. Three criteria must be met for cDCD to be ethically sound:
1) The decision to withdraw life-sustaining treatment and the decision to perform organ donation must be separated from each other in a satisfactory way.
2) The premortem interventions must be regarded as very limited.
3) The "Dead Donor Rule" must be adhered to.
A fourth criterion requires an ethically sound process for providing information and obtaining consent.
The ethical review discusses arguments for and against these criteria are discussed. The conclusion is that with some minor modifications to the cDCD procedure, it will be possible to implement cDCD in an ethically sound manner. Our expert panel agreed about many of the underlying premises needed for the method to be considered ethically sound, but there was disagreement about others.
Medical issues
There have been different assessments in the expert panel regarding the death criteria and the interpretation of the wording of law.
If cDCD with normothermic regional perfusion is to be introduced, the expert panel believes that the professional medical community must design a more robust quality assurance concerning the death criteria and update the current cDCD procedure. This will include specific neurological tests to evaluate brain function and documentation of ceased breathing when confirming death. Some in the expert panel also believe that further measurement methods in addition to invasive measurement of blood pressure and heart rate should be used to ensure that cardiac arrest is achieved. The criteria proposed by the professional medical community can be stated in a brief or specified in existing regulations.
The report is written in Norwegian. There is a summary in English.
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... Multiple NRP protocols are available online, which vary depending on their country of origin (72,95,(100)(101)(102). The development of an institutional and national protocol for NRP is a difficult process. ...
... "that the antemortem insertion of thin cannulas into the femoral arteries and veins does not deviate from good patient care or differ in ethical terms from practices adopted to support DBD." (102). ...
Background and Objective: The goal for healthcare professionals in organ donation is to honour the
wishes of the donor patient. Securing the best outcome from their altruistic gift to others is central to this
goal. This must be achieved in the context of optimal and ethical end-of-life care. Our objectives are first, to
examine attitudes towards organ donation after circulatory death (DCD) with particular emphasis on barriers
to its widespread acceptance. Second, we present the options for limiting organ injury and organ preservation
in DCD. In-situ perfusion may be isolated to the abdomen alone, or to the thorax and abdomen combined:
abdominal-normothermic regional perfusion (A-NRP), or thoraco-abdominal-normothermic regional
perfusion (TA-NRP). Our literature search focuses on the efficacy of normothermic regional perfusion (NRP)
in DCD. Third, we briefly outline developments in ex-situ perfusion and finally, we outline areas of discourse
which emerge as a consequence of the incorporation of these technological advances into DCD.
Methods: We performed a literature search of PubMed, EMBASE, the Cochrane Library, and individual
websites of learned bodies and societies under the headings of organ donation, transplantation, ethics, and
regional perfusion. We included papers published in English between January 2000 and June 2023.
Key Content and Findings: Position and consensus statements from learned bodies together with expert
opinion and recommendations are presented on DCD in general and in-situ perfusion specifically. The
impact of NRP on transplantation outcomes are tabulated and discussed.
Conclusions: There are contentious areas where attitudes and bias may influence the adoption of
DCD. The use of NRP in DCD is expanding, though it requires careful planning, an agreed protocol,
audit, training and governance. With NRP, most international guidelines allow increased flexibility in
recommended wait times. Importantly, this will result in less stand-downs and improve the chances of organ
donation proceeding. While the evidence for NRP is evolving, studies report increased organ utilisation rates
(OURs) and improved function. On this basis and acknowledging the depth of motivation and reflection
that typically underpins familial choices around DCD, we advocate the more widespread adoption of NRP.
Although ex-situ technologies are less complex from an ethical perspective, costs may be prohibitive.
Keywords: Donation after circulatory death (DCD); abdominal-normothermic regional perfusion (A-NRP);
organ utilisation; in-situ preservation
... Thereafter, the family must leave the room quite rapidly, and the organ donation procedure is performed. This OD method is now available in Scandiatransplant's member countries, Norway, Sweden, Denmark, and Finland [13,30]. There is a significant need for further knowledge about relatives' experiences related to both methods of OD. ...
Background
In organ donation from deceased donors, the interaction between the donor’s relatives and intensive care personnel is an important factor. The organ donation (OD) process is complex, and patients’ relatives play a vital role. Intensive care professionals need knowledge about how relatives perceive and experience the process to create a caring environment and support them throughout. Therefore, this collaborative project aims to explore both relatives’ and intensive care personnel’s perspectives of care in deceased organ donation in Scandinavia.
Objective
This study aims to (1) investigate donor relatives’ satisfaction and ICU personnel’s perception of their own professional competence and (2) explore donor relatives’ and ICU personnel’s experiences in the OD process to design for care and support in OD.
Methods
This protocol outlines a Scandinavian (Norway, Sweden, and Denmark) project, including 4 work packages. Work package 1 started in 2023 with the translation and validation of the Family Satisfaction in the Intensive Care Unit questionnaire into a Danish version and the translation of the Professional Competence in Organ Donation Questionnaire into a Swedish and Danish version. A cross-sectional survey measuring Scandinavian relatives’ perception of support in and satisfaction with the organ donation process and a cross-sectional survey measuring Scandinavian intensive care personnel’s competence in organ donation are the foundation for work package 2 (2024). The data from both surveys will be analyzed using descriptive and comparative analysis. The results will inform the interview guides in qualitative studies (work packages 3 and 4). Participants in the quantitative study will be invited to participate in in-depth interviews. In work package 3, in-depth interviews will be conducted to illuminate relatives’ experiences in the organ donation process. The interviews will be analyzed using thematic analysis, according to Braun and Clarke. In work package 4 (2025-2026), 1 qualitative design study will be conducted to illuminate ICU personnel’s experiences. Furthermore, the results from work packages 2 and 3 will inform the development of specific programs for care, support, and communication in the organ donation process.
Results
The project was funded by the Norwegian Organ Donor Foundation in 2022 and Scandiatransplant in 2023. The Norwegian Nurses Organisation supports the project by funding a PhD student. The PhD student was employed by the University in Agder in May 2024.
Conclusions
This project will provide new knowledge that will assist us in designing and establishing programs for care, support, and donor relatives’ involvement in OD processes.
International Registered Report Identifier (IRRID)
PRR1-10.2196/55643
Donation after circulatory death (DCD) has become an accepted practice in many countries and remains a focus of intense interest in the transplant community. The present study is aimed at providing a description of the current situation of DCD in European countries. Specific questionnaires were developed to compile information on DCD practices, activities and post‐transplant outcomes. Thirty‐five countries completed the survey. DCD is practiced in 18 countries: 8 have both controlled DCD (cDCD) and uncontrolled DCD (uDCD) programs, 4 only cDCD and 6 only uDCD. All these countries have legally binding and/or non‐binding texts to regulate the practice of DCD. The no‐touch period ranges from 5 to 30 minutes. There are variations in ante and post mortem interventions used for the practice of cDCD. During 2008‐2016, the highest DCD activity was described in the United Kingdom, Spain, Russia, the Netherlands, Belgium and France. Data on post‐transplant outcomes of patients who receive DCD donor kidneys show better results with grafts obtained from cDCD versus uDCD donors. In conclusion, DCD is becoming increasingly accepted and performed in Europe, importantly contributing to the number of organs available and providing acceptable post‐transplantation outcomes. This article is protected by copyright. All rights reserved.
Background
Normothermic regional perfusion (NRP) is a novel technique that aids organ recovery from donors after circulatory death (DCDs). However, ethical concerns exist regarding the potential return of spontaneous cerebral and cardiac activity (ROSCCA). This study aimed to determine the likelihood of ROSCCA in NRP‐DCDs of abdominal organs.
Methods
Extracorporeal cardiopulmonary resuscitation (ECPR) for refractory out‐of‐hospital cardiac arrest (OOHCA) was identified as a comparator for NRP‐DCDs and as a validation cohort. A systematic search identified all articles relating to NRP‐DCDs and ECPR‐OOHCA. Rates of ROSCCA and survival outcomes (ECPR‐OOHCA only) were recorded and analysed according to the duration of no perfusion.
Results
In NRP‐DCDs, 12 of 410 articles identified by database searching were eligible for inclusion. There were no instances of ROSCCA recorded among 493 donors. In ECPR‐OOHCA, eight of 947 screened articles were eligible for inclusion (254 patients). Where the absence of perfusion exceeded 5 min in ECPR‐OOHCA, there were no survivors with a favourable neurological outcome.
Conclusion
ROSCCA is unlikely following commencement of NRP and has not occurred to date. Strict observance of the 5‐min interval following asystole provides satisfactory assurance that ROSCCA will not occur following NRP.
Livers from controlled donation after circulatory death (DCD) donors suffer a higher incidence of non‐function, poor function, and ischemic cholangiopathy. In situ normothermic regional perfusion (NRP) restores a blood supply to the abdominal organs after death using an extracorporeal circulation for a limited period before organ recovery. We undertook a retrospective analysis to evaluate whether NRP was associated with improved outcomes of livers from DCD donors. NRP was performed on 70 DCD donors from which 43 livers were transplanted. These were compared with 187 non‐NRP DCD donor livers transplanted at the same two UK centers in the same period. The use of NRP was associated with a reduction in early allograft dysfunction (12% for NRP vs 32% for non‐NRP livers, p=0.0076), 30‐day graft loss (2% NRP livers vs. 12% non‐NRP livers, p=0.0559), freedom from ischemic cholangiopathy (0% vs. 27% for non‐NRP livers, p<0.0001), and fewer anastomotic strictures (7% vs. 27% non‐NRP, p=0.0041). After adjusting for other factors in a multivariable analysis, NRP remained significantly associated with freedom from ischemic cholangiopathy (p<0.0001). These data suggest that NRP during organ recovery from DCD donors leads to superior liver outcomes compared to conventional organ recovery.
This article is protected by copyright. All rights reserved.
Background & aims:
Although there is increasing interest in its use, definitive evidence demonstrating a benefit for postmortem normothermic regional perfusion (NRP) in controlled donation after circulatory death (cDCD) liver transplantation is lacking. The aim of this study was to compare results of cDCD liver transplants performed with postmortem NRP vs. super-rapid recovery (SRR), the current standard for cDCD.
Methods:
This was an observational cohort study including all cDCD liver transplants performed in Spain between June 2012 and December 2016, with follow-up ending in December 2017. Each donor hospital determined whether organ recovery was performed using NRP or SRR. The propensity scores technique based on the inverse probability of treatment weighting (IPTW) was used to balance covariates across study groups; logistic and Cox regression models were used for binary and time-to-event outcomes.
Results:
During the study period, there were 95 cDCD liver transplants performed with postmortem NRP and 117 with SRR. The median donor age was 56 years (interquartile range 45-65 years). After IPTW analysis, baseline covariates were balanced, with all absolute standardised differences <0.15. IPTW-adjusted risks were significantly improved among NRP livers for overall biliary complications (odds ratio 0.14; 95% CI 0.06-0.35, p <0.001), ischaemic type biliary lesions (odds ratio 0.11; 95% CI 0.02-0.57; p = 0.008), and graft loss (hazard ratio 0.39; 95% CI 0.20-0.78; p = 0.008).
Conclusions:
The use of postmortem NRP in cDCD liver transplantation appears to reduce postoperative biliary complications, ischaemic type biliary lesions and graft loss, and allows for the transplantation of livers even from cDCD donors of advanced age.
Lay summary:
This is a propensity-matched nationwide observational cohort study performed using livers recovered from donors undergoing cardiac arrest provoked by the intentional withdrawal of life support (controlled donation after circulatory death, cDCD). Approximately half of the livers were recovered after a period of postmortem in situ normothermic regional perfusion, which restored warm oxygenated blood to the abdominal organs, whereas the remainder were recovered after rapid preservation with a cold solution. The study results suggest that the use of postmortem normothermic regional perfusion helps reduce rates of post-transplant biliary complications and graft loss and allows for the successful transplantation of livers from older cDCD donors.
Background Controlled donation after circulatory death (cDCD) has been associated with a high incidence of ischemic cholangiopathy (IC) and other perioperative complications. In an attempt to avoid these complications, we implemented an active protocol of cDCD liver transplant (LT) with normothermic regional perfusion (NRP) preservation.
Methods This is a descriptive analysis of data collected from a prospective date base of cDCD LT preserved with NRP, from January 2015 to June 2017 with a minimum follow up of 9 months.
Results Fifty-seven potential cDCD donors were connected to the NRP system. Of these, 46 livers were transplanted over a 30-months period (80% liver recovery rate). The median posttransplant peak in alanine transaminase was 1136 U/L (220–6683 U/L). Seven patients (15%) presented postreperfusion syndrome and eleven (23%) showed early allograft dysfunction. No cases of ischemic cholangiopathy were diagnosed and no graft loss was observed over a medium follow-up period of 19 months. Of note, 13 donors were older than 65 years, achieving comparable perioperative and midterm results to younger donors.
Conclusions As far as we know, this represents the largest published series of cDCD LT with NRP preservation. Our results demonstrate that cDCD liver grafts preserved with NRP appear far superior to those obtained by the conventional rapid recovery technique
Background: In order to meet the increasing demand for donor organs, the concept of donation after circulatory death (DCD) was reintroduced in Norway, first as a pilot study, followed by the use of DCD as institutional practice. We report the current Norwegian experience with liver transplant after DCD. Methods: After acceptance from next of kin, life support was withdrawn from patients with devastating brain injury and cardiac arrest observed. After a 5-minute “no-touch” period, extracorporeal membrane oxygenation for post mortem normothermic regional perfusion (NRP) by extracorporeal membrane oxygenator circuit was established. Data from all liver transplant recipients receiving controlled DCD (cDCD) livers in Oslo were analyzed. Results: From 2015 to 2017, a total of 8 patients underwent liver transplant with cDCD and NRP liver grafts in Norway. Median Model for End-Stage Liver Disease score was 26 (range, 6–40). There were no cases of delayed graft function or graft loss. Seven patients have reached 1 year of follow-up, and 1 patient has reached 6 months. Two patients have recurrence of primary disease (primary sclerosing cholangitis and steatohepatitis). All patients had normalized liver function at last follow-up. Two patients underwent procedures for biliary complications. In 1 patient, leakage from the cystic duct was successfully handled endoscopically by stenting. In the other patient, a suspected stricture on magnetic resonance imaging led to an endoscopic retrograde cholangiopancreatography, which did not confirm signs of biliary stenosis. There was 1 instance of hepatic artery stenosis, which was managed with endovascular technique. Conclusion: The results after liver transplant using cDCD with NRP are good. The rate of complications seems to be within the same range as when using conventional donation after brain death grafts.
Organ donation after the circulatory determination of death (DCDD) accounts for a growing percentage of deceased organ donations. Although hospital DCDD protocols stipulate donor death determination, some do not adhere to national guidelines that require mechanical, not electrical, asystole. Surrogate decisions to withdraw life-sustaining therapy should be separated from decisions to donate organs. Donor families should be given sufficient information about the DCDD protocol and its impact on the dying process to provide informed consent, and donors should be given proper palliative care during dying. An unresolved ethical question is whether and how donor consent should be seen as authorizing manipulation of a living donor during the dying process solely for to benefit of the organ recipient.
In recent years, donation after circulatory death (DCD) has increased as an option to overcome the organ donor shortage crisis and decrease the large number of patients on liver transplant waiting lists. The “super-rapid” technique is now the “gold standard” procurement method because of its availability, reproducibility, low cost, and extensive experience. Recently, extracorporeal support has been implemented, with encouraging results. Strict donor acceptance criteria have proven to be essential to optimize the DCD liver graft outcomes and minimize biliary complication rates. In this study we assessed the state of the art of DCD liver transplantation with regard to its development and the actual strategies to prevent graft complications, with aim of expanding the pool of marginal liver donors.
Background
Liver transplantation from donors after either controlled or uncontrolled cardiac death (DCD) is associated with considerable rates of primary nonfunction (PNF) and ischemic cholangiopathy (IC). Normothermic regional perfusion (NRP) could significantly reduce such rates.
Methods
Retrospective study to analyze short-term (mortality, PNF, vascular complications) and long-term (IC, survival) complications in 11 liver transplants from controlled DCDs using NRP with extracorporeal membrane oxygenation (ECMO) (group 1). They were compared with 51 patients transplanted with grafts from donors after brain death (DBD) (group 2). Mean recipient age, sex, and Model for End-stage Liver Disease (MELD) score were not significantly different.
Results
In group 1, mean functional warm ischemia time was 15.8 (range, 7–40) minutes and 94.1 (range, 20–150) minutes on NRP. The ischemic damage was minimal, as shown by the slight alanine aminotransferase (ALT) and aspartate aminotransferase (AST) rises in the donor serum after 1 hour on NRP and similar rises 24 hours after transplantation in both groups. No patient had IC or acute renal failure. No significant difference was found between the groups for vascular or biliary complications. One group 1 patient had PNF (9.1%), resulting in death. Overall retransplantation and in-hospital death rates were 8.1% and 4.8%, respectively, with no significant difference between groups. Estimated mean survival was 24.6 (95% confidence interval [CI], 20.2–29.1) months in group 1 and 32.3 (95% CI, 30.4–34.2) months in group 2 (not a statistically significant difference).
Conclusion
In our experience, liver transplants from controlled DCDs using NRP with ECMO is associated with a low risk of PNF and IC, with short- and long-term results comparable to those in DBD transplants.