In situ normothermic perfusion of livers in controlled circulatory death donation may prevent ischemic cholangiopathy and improve graft survival

Livers from controlled donation after circulatory death (DCD) donors suffer a higher incidence of nonfunction, 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 whom 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 = .0076), 30‐day graft loss (2% NRP livers vs. 12% non‐NRP livers, P = .0559), freedom from ischemic cholangiopathy (0% vs. 27% for non‐NRP livers, P < .0001), and fewer anastomotic strictures (7% vs. 27% non‐NRP, P = .0041). After adjusting for other factors in a multivariable analysis, NRP remained significantly associated with freedom from ischemic cholangiopathy (P < .0001). These data suggest that NRP during organ recovery from DCD donors leads to superior liver outcomes compared to conventional organ recovery.     

Use of ex vivo normothermic machine perfusion after normothermic regional perfusion to salvage a poorly perfused DCD kidney

Normothermic regional perfusion (NRP) and normothermic machine perfusion (NMP) have both been used in the procurement and conditioning of abdominal organs from donation after circulatory death donors with reported improved outcomes for the recipients. Here, we describe an unusual case of a kidney that underwent NMP after NRP. After 2 hours of abdominal NRP, the intra‐abdominal organs were cold flushed in situ. The liver and right kidney were well flushed, but the left kidney was poorly flushed. Further attempts to clear the left kidney by flushing on the backtable were unsuccessful, and the kidney was thought to be unsuitable for transplant. The left kidney then underwent a 1‐hour period of NMP using a red cell–based perfusate. During NMP, the kidney met previously described quality assurance criteria for transplant with good global perfusion and adequate renal blood flow and urine production. The kidney was transplanted into a suitable recipient who had slow early graft function but did not require dialysis posttransplant. The recipient was discharged 6 days posttransplant, and the serum creatinine level was 160 μmol/L (1.8 mg/dL) at 2 months posttransplant.     

Improved short-term outcomes of kidney transplants in controlled donation after the circulatory determination of death with the use of normothermic regional perfusion

Normothermic regional perfusion (NRP) allows the in situ perfusion of organs with oxygenated blood in donation after the circulatory determination of death (DCDD). We aimed at evaluating the impact of NRP on the short-term outcomes of kidney transplants in controlled DCDD (cDCDD). This is a multicenter, nationwide, retrospective study comparing cDCDD kidneys obtained with NRP versus the standard rapid recovery (RR) technique. During 2012–2018, 2302 cDCDD adult kidney transplants were performed in Spain using NRP (n = 865) or RR (n = 1437). The study groups differed in donor and recipient age, warm, and cold ischemic time and use of ex situ machine perfusion. Transplants in the NRP group were more frequently performed in high-volume centers (≥90 transplants/year). Through matching by propensity score, two cohorts with a total of 770 patients were obtained. After the matching, no statistically significant differences were observed between the groups in terms of primary nonfunction (p = .261) and mortality at 1 year (p =  .111). However, the RR of kidneys was associated with a significantly increased odds of delayed graft function (OR 1.97 [95% CI 1.43–2.72]; p < .001) and 1-year graft loss (OR 1.77 [95% CI 1.01–3.17]; p = .034). In conclusion, compared with RR, NRP appears to improve the short-term outcomes of cDCDD kidney transplants.     

Ethical Issues in the Use of Extracorporeal Membrane Oxygenation in Controlled Donation After Circulatory Determination of Death

The use of donor extracorporeal membrane oxygenation (ECMO) to improve graft outcomes by some controlled donation after circulatory determination of death (cDCDD) programs raises ethical issues. We reviewed cDCDD protocols using ECMO and the relevant ethics literature to analyze these issues. It is not obvious that ECMO in cDCDD improves graft outcomes. In our opinion, ECMO implemented before death can interfere with end‐of‐life care and damage bodily integrity. By restoring systemic circulation, ECMO risks invalidating the preceding declaration of death if brain and cardiac perfusion is not adequately excluded because of malfunction or misplacement of the supradiaphragmatic aortic occlusion balloon. The use of ECMO is not compatible with the acronym DCDD because circulation is restored after the determination of death. Because of these deficiencies, we concluded that other techniques are preferable, such as rapid recovery or in situ cold infusion. If ECMO is performed, it requires a specific informed consent and transparency.     

Impact of a National Controlled Donation After Circulatory Death (DCD) Program on Organ Donation in the United Kingdom: A 10‐Year Study

Organ transplantation is the most successful treatment for some forms of organ failure, yet a lack of organs means many die on the waiting list. In the United Kingdom, the Organ Donation Taskforce was set up to identify barriers to organ donation and in 2008 released its first report (Organ Donation Taskforce Report; ODTR). This study assesses the success since the ODTR and examines the impact of the United Kingdom's controlled donation after circulatory death (DCD) program and the controversies surrounding it. There were 12 864 intended donation after brain death (DBD) or DCD donors from April 2004 to March 2014. When the 5 years preceding the ODTR was compared to the 5 years following, intended DCD donors increased 292% (1187 to 4652), and intended DBD donors increased 11% (3327 to 3698). Organs retrieved per intended DBD donor remained static (3.30 to 3.26), whereas there was a decrease in DCD (1.54 to 0.99) due to a large rise in donors who did not proceed to donation (325 to 2464). The majority of DCD donors who proceeded did so within 30 min from time of withdrawal. Our study suggests further work on converting eligible referrals to organ donation and exploring methods of converting DCD to DBD donors.     

Controlled donation after circulatory death up to 80 years for liver transplantation: Pushing the limit again

Our main objective was to compare liver transplant (LT) results between donation after circulatory death (DCD) and donation after brainstem death (DBD) in our hospital and to analyze, within the DCD group, the influence of age on the results obtained with DCD donors aged >70 years and up to 80 years. All DCD‐LTs performed were analyzed prospectively. The results of the DCD group were compared with those of a control group who received a DBD‐LT immediately after each DCD‐LT. Later, the results obtained within the DCD group were analyzed according to the age of the donors, considering 2 subgroups with a cut‐off point at 70 years. Survival results for LT with DCD and super rapid recovery were not inferior to those obtained in a similar group of patients transplanted with DBD livers. However, the cost of DCD was a higher rate of biliary complications, including ischemic cholangiopathy. Donor age was not a negative factor.     

Combined lung and liver procurement in controlled donation after circulatory death using normothermic abdominal perfusion. Initial experience in two Spanish centers

Combining simultaneously lung and liver procurement in controlled donation after circulatory death (cDCD) using normothermic abdominal perfusion (NRP) for abdominal grafts and cooling and rapid recovery technique (RR) for the lungs increases the complexity of the procurement procedure and might injure the grafts. A total of 19 cDCDs from two centers using this combined procedure were evaluated, and 16 liver and 21 lung transplantations were performed. As controls, 34 donors after brain death (DBDs) were included (29 liver and 41 lung transplantations were performed). Two cDCD liver recipients developed primary nonfunction (12.5%). No cases of ischemic cholangiopathy were observed among cDCD recipients. The 1‐year and 2‐year liver recipients survival was 87.5% and 87.5% for the cDCD group, and 96% and 84.5% for the DBD group, respectively (P = .496). The 1‐year and 2‐year lung recipients survival was 84% and 84% for the cDCD group and 90% and 90% for the DBD group, respectively (P = .577). This is the largest experience ever reported in cDCD with the use of NRP combined with RR of the lungs. This combined method offers an outstanding recovery rate and liver and lung recipients survival comparable with those transplanted with DBDs. Further studies are needed to confirm our findings.     

Factors influencing the family consent rate for organ donation in the UK

The refusal rate for organ donation in the UK is 42%, among the highest in Europe. We extracted data on every family approach for donation in UK ICUs or Emergency Departments between 1st April 2012 and 30th September 2013, and performed multiple logistic regression to identify modifiable factors associated with consent. Complete data were available for 4703 of 4899 approaches during the study period. Consent for donation after brain death was 68.9%, and for donation after circulatory death 56.5% (p < 0.0001). Patient ethnicity, knowledge of a patient's wishes and involvement of a specialist nurse in organ donation in the approach were strongly associated with consent (p < 0.0001). The impact of the specialist nurse was stronger for donation after circulatory death than for donation after brain death, even after accounting for the impact of prior knowledge of patients' wishes. Involvement of the specialist nurse in the approach, encouraging family discussions about donation wishes and promotion of the organ donor register are key strategies to increase UK consent rates, and are supported by this study.     

Ethical and logistical concerns for establishing NRP‐cDCD heart transplantation in the United States

Controlled heart donation after circulatory determination of death (cDCD) is well established internationally with good outcomes and could be adopted in the United States to increase heart supply if ethical and logistical challenges are comprehensively addressed. The most effective and resource‐efficient method for mitigating warm ischemia after circulatory arrest is normothermic regional perfusion (NRP) in situ. This strategy requires restarting circulation after declaration of death according to circulatory criteria, which appears to challenge the legal circulatory death definition requiring irreversible cessation. Permanent cessation for life‐saving efforts must be achieved to assuage this concern and ligating principal vessels maintains no blood flow to the brain, which ensures natural progression to cessation of brain function. This practice—standard in some countries—raises unique concerns about prioritizing life‐saving efforts, informed authorization from decision‐makers, and the clinician's role in the patient's death. To preserve public trust, medical integrity, and respect for the donor, the donation conversation must not take place until after an un‐coerced decision to withdraw life‐sustaining treatment made in accordance with the patient's treatment goals. The decision‐maker(s) must understand cDCD procedure well enough to provide genuine authorization and the preservation/procurement teams must be kept separate from the clinical care team.     

Family and transplant professionals’ views of organ recovery before circulatory death for imminently dying patients: A qualitative study using semistructured interviews and focus groups

Donation before circulatory death for imminently dying patients has been proposed to address organ scarcity and harms of nondonation. To characterize stakeholder attitudes about organ recovery before circulatory death we conducted semistructured interviews with family members (N = 15) who had experienced a loved one's unsuccessful donation after circulatory death and focus groups with professional stakeholders (surgeons, anesthesiologists, critical care specialists, palliative care specialists, organ procurement personnel, and policymakers, N = 46). We then used qualitative content analysis to characterize these perspectives. Professional stakeholders believed that donation of all organs before circulatory death was unacceptable, morally repulsive, and equivalent to murder; consent for such a procedure would be impermissible. Respondents feared the social costs related to recovery before death were too high. Although beliefs about recovery of all organs were widely shared, some professional stakeholders could accommodate removal of a single kidney before circulatory death. In contrast, family members were typically accepting of donation before circulatory death for a single kidney, and many believed recovery of all organs was permissible because they believed the cause of death was the donor's injury, not organ procurement. These findings suggest that definitions of death and precise rules around organ donation are critical for professional stakeholders, whereas donor families find less relevance in these constructs for determining the acceptability of organ donation. Donation of a single kidney before circulatory death warrants future exploration.     

Defining the optimal duration for normothermic regional perfusion in the kidney donor: A porcine preclinical study

Kidneys from donation after circulatory death (DCD) are highly sensitive to ischemia‐reperfusion injury and thus require careful reconditioning, such as normothermic regional perfusion (NRP). However, the optimal NRP protocol remains to be characterized. NRP was modeled in a DCD porcine model (30 minutes of cardiac arrest) for 2, 4, or 6 hours compared to a control group (No‐NRP); kidneys were machine‐preserved and allotransplanted. NRP appeared to permit recovery from warm ischemia, possibly due to an increased expression of HIF1α‐dependent survival pathway. At 2 hours, blood levels of ischemic injury biomarkers increased: creatinine, lactate/pyruvate ratio, LDH, AST, NGAL, KIM‐1, CD40 ligand, and soluble‐tissue‐factor. All these markers then decreased with time; however, AST, NGAL, and KIM‐1 increased again at 6 hours. Hemoglobin and platelets decreased at 6 hours, after which the procedure became difficult to maintain. Regarding inflammation, active tissue‐factor, cleaved PAR‐2 and MCP‐1 increased by 4‐6 hours, but not TNF‐α and iNOS. Compared to No‐NRP, NRP kidneys showed lower resistance during hypothermic machine perfusion (HMP), likely associated with pe‐NRP eNOS activation. Kidneys transplanted after 4 and 6 hours of NRP showed better function and outcome, compared to No‐NRP. In conclusion, our results confirm the mechanistic benefits of NRP and highlight 4 hours as its optimal duration, after which injury markers appear.     

Donor prone positioning protects lungs from injury during warm ischemia

A large proportion of controlled donation after circulatory death (cDCD) donor lungs are declined because cardiac arrest does not occur within a suitable time after the withdrawal of life‐sustaining therapy. Improved strategies to preserve lungs after asystole may allow the recovery team to arrive after death actually occurs and enable the recovery of lungs from more cDCD donors. The aim of this study was to determine the effect of donor positioning on the quality of lung preservation after cardiac arrest in a cDCD model. Cardiac arrest was induced by withdrawal of ventilation under anesthesia in pigs. After asystole, animals were divided into 2 groups based on body positioning (supine or prone). All animals were subjected to 3 hours of warm ischemia. After the observation period, donor lungs were explanted and preserved at 4°C for 6 hours, followed by 6 hours of physiologic and biological lung assessment under normothermic ex vivo lung perfusion. Donor lungs from the prone group displayed significantly greater quality as reflected by better function during ex vivo lung perfusion, less edema formation, less cell death, and decreased inflammation compared with the supine group. A simple maneuver of donor prone positioning after cardiac arrest significantly improves lung graft preservation and function.     

Organ procurement center allows for daytime liver transplantation with less resource utilization: May address burnout,pipeline, and safety for field of transplantation

Abdominal organ transplantation faces several challenges: burnout, limited pipeline of future surgeons, changes in liver allocation potentially impacting organ procurement travel, and travel safety. The organ procurement center (OPC) model may be one way to mitigate these issues. Liver transplants from 2009 to 2016 were reviewed. There were 755 liver transplants performed with 525 OPC and 230 in‐hospital procurements. The majority of transplants (87.4%) were started during daytime hours (5 am ‐7 pm ). Transplants with any portion occurring after‐hours were more likely to have procurements in‐hospital (P < .001). Daytime cases (n = 400) had more OPC procured livers and hepatitis C recipients and were less likely to have a donation after circulatory death donor (all P < .05). In adjusted analyses, daytime cases were independently associated with extubation in the operating room and less postoperative transfusion. There were no significant differences in short‐ or long‐term postoperative outcomes. For exported livers, 54.3% were procured by a local team, saving 137 flights (151 559 miles). The OPC resulted in optimally timed liver transplants and decreased resource utilization with no negative impact on patient outcomes. It allows for ease in exporting organs procured by local surgeons, and potentially addresses provider burnout, the transplant surgery pipeline, and surgeon travel.     

Uncontrolled donation after circulatory death: A cohort study of data from a long‐standing deceased‐donor kidney transplantation program

Despite good long‐term outcomes of kidney transplants from controlled donation after circulatory death (DCD) donors, there are few uncontrolled DCD (uDCD) programs. This longitudinal study compares outcomes for all uDCD (N = 774) and all donation after brain death (DBD) (N = 613) kidney transplants performed from 1996 to 2015 at our center. DBD transplants were divided into those from standard‐criteria (SCD) (N = 366) and expanded‐criteria (N = 247) brain‐dead donors (ECD). One‐, 5‐, and 10‐year graft survival rates were 91.7%, 85.7%, and 80.6% for SCD; 86.0%, 75.8%, and 61.4% for ECD; and 85.1%, 78.1%, and 72.2% for uDCD, respectively. Graft survival was worse in recipients of uDCD kidneys than of SCD (P = .004) but better than in transplants from ECD (P = .021). The main cause of graft loss in the uDCD transplants was primary nonfunction. Through logistic regression, donor death due to pulmonary embolism (OR 4.31, 95% CI 1.65‐11.23), extrahospital CPR time ≥75 minutes (OR1.94, 95%CI 1.18‐3.22), and in‐hospital CPR time ≥50 minutes (OR 1.79, 95% CI 1.09‐2.93) emerged as predictive factors of primary nonunction. According to the outcomes of our long‐standing kidney transplantation program, uDCD could help expand the kidney donor pool.     

Maintaining the permanence principle for death during in situ normothermic regional perfusion for donation after circulatory death organ recovery: A United Kingdom and Canadian proposal

There is international variability in the determination of death. Death in donation after circulatory death (DCD) can be defined by the permanent cessation of brain circulation. Post‐mortem interventions that restore brain perfusion should be prohibited as they invalidate the diagnosis of death. Retrieval teams should develop protocols that ensure the continued absence of brain perfusion during DCD organ recovery. In situ normothermic regional perfusion (NRP) or restarting the heart in the donor's body may interrupt the permanent cessation of brain perfusion because, theoretically, collateral circulations may restore it. We propose refinements to current protocols to monitor and exclude brain reperfusion during in situ NRP. In abdominal NRP, complete occlusion of the descending aorta prevents brain perfusion in most cases. Inserting a cannula in the ascending aorta identifies inadequate occlusion of the descending aorta or any collateral flow and diverts flow away from the brain. In thoracoabdominal NRP opening the aortic arch vessels to atmosphere allows collateral flow to be diverted away from the brain, maintaining the permanence standard for death and respecting the dead donor rule. We propose that these hypotheses are correct when using techniques that simultaneously occlude the descending aorta and open the aortic arch vessels to atmosphere.     

External validation of prediction models for time to death in potential donors after circulatory death

Predicting time to death in controlled donation after circulatory death (cDCD) donors following withdrawal of life‐sustaining treatment (WLST) is important but poses a major challenge. The aim of this study is to determine factors predicting time to circulatory death within 60 minutes after WSLT and validate previously developed prediction models. In a single‐center retrospective study, we used the data of 92 potential cDCD donors. Multivariable regression analysis demonstrated that absent cough‐, corneal reflex, lower morphine dosage, and midazolam use were significantly associated with death within 60 minutes (area under the curve [AUC] 0.89; 95% confidenence interval [CI] 0.87‐0.91). External validation of the logistic regression models of de Groot et al (AUC 0.86; 95% CI 0.77‐0.95), Wind et al (AUC 0.62; 95% CI 0.49‐0.76), Davila et al (AUC 0.80; 95% CI 0.708‐0.901) and the Cox regression model by Suntharalingam et al (Harrell's c‐index 0.63), exhibited good discrimination and could fairly identify which patients died within 60 minutes. Previous prediction models did not incorporate the process of WLST. We believe that future studies should also include the process of WLST as an important predictor.     

The organ preservation and enhancement of donation success ratio effect of extracorporeal membrane oxygenation in circulatory unstable brain death donor

Between 2010 and 2013, we recorded 66 cases of failed organ donation after brain death (DBD) due to the excessive use of the vasoactive drugs resulting in impaired hepatic and/or renal function. To investigate the effect of extracorporeal membrane oxygenation (ECMO) in donor management, ECMO was used to provide support for DBD donors with circulatory and/or respiratory failure from 2013 to 2015. A retrospective cohort study between circulatory non‐stable DBD with vasoactive drugs (DBD‐drug) and circulatory non‐stable DBD with ECMO (DBD‐ECMO) was designed to compare the transplant outcomes. A total of 19 brain death donors were supported by ECMO. The incidence rate of post‐transplant liver primary non‐function (PNF) was 10% (two of 20) in DBD‐drug group and zero in DBD‐ECMO group. Kidney function indicators, including creatinine clearance and urine production, were significantly better in DBD‐ECMO group, as well as the kidney delayed graft function (DGF) rate was found to be decreased by the use of ECMO in our study. Donation success rate increased steadily from 47.8% in 2011 to 84.6% in 2014 after the ECMO intervention. The use of ECMO in assisting circulatory and respiratory function of DBD can reduce liver and kidney injury from vasoactive drugs, thereby improving organ quality and reducing the organ discard rates.     

Spanish experience with heart transplants from controlled donation after the circulatory determination of death using thoraco-abdominal normothermic regional perfusion and cold storage

Heart transplantation from controlled donation after the circulatory determination of death (cDCDD) may help to increase the availability of hearts for transplantation. During 2020, four heart transplants were performed at three different Spanish hospitals based on the use of thoraco-abdominal normothermic regional perfusion (TA-NRP) followed by cold storage (CS). All donors were young adults <45 years. The functional warms ischemic time ranged from 8 to 16 minutes. In all cases, the heart recovered sinus rhythm within 1 minute of TA-NRP. TA-NRP was weaned off or decreased <1L within 25 minutes. No recipient required mechanical support after transplantation and all were immediately extubated and discharged home (median hospital stay: 21 days) with an excellent outcome. Four livers, eight kidneys, and two pancreata were also recovered and transplanted. All abdominal grafts recipients experienced an excellent outcome. The use of TA-NRP makes heart transplantation feasible and allows assessing heart function before organ procurement without any negative impact on the preservation of abdominal organs. The use of TA-NRP in cDCDD heart donors in conjunction with cold storage following retrieval can eliminate the need to use ex situ machine perfusion devices, making cDCDD heart transplantation economically possible in other countries.     

Pretransplant sequential hypo‐ and normothermic machine perfusion of suboptimal livers donated after circulatory death using a hemoglobin‐based oxygen carrier perfusion solution

Ex situ dual hypothermic oxygenated machine perfusion (DHOPE) and normothermic machine perfusion (NMP) of donor livers may have a complementary effect when applied sequentially. While DHOPE resuscitates the mitochondria and increases hepatic adenosine triphosphate (ATP) content, NMP enables hepatobiliary viability assessment prior to transplantation. In contrast to DHOPE, NMP requires a perfusion solution with an oxygen carrier, for which red blood cells (RBC) have been used in most series. RBC, however, have limitations and cannot be used cold. We, therefore, established a protocol of sequential DHOPE, controlled oxygenated rewarming (COR), and NMP using a new hemoglobin‐based oxygen carrier (HBOC)‐based perfusion fluid (DHOPE‐COR‐NMP trial, NTR5972). Seven livers from donation after circulatory death (DCD) donors, which were initially declined for transplantation nationwide, underwent DHOPE‐COR‐NMP. Livers were considered transplantable if perfusate pH and lactate normalized, bile production was ≥10 mL and biliary pH > 7.45 within 150 minutes of NMP. Based on these criteria five livers were transplanted. The primary endpoint, 3‐month graft survival, was a 100%. In conclusion, sequential DHOPE‐COR‐NMP using an HBOC‐based perfusion fluid offers a novel method of liver machine perfusion for combined resuscitation and viability testing of suboptimal livers prior to transplantation.     

Harms of unsuccessful donation after circulatory death: An exploratory study

While donation after circulatory death (DCD) has expanded options for organ donation, many who wish to donate are still unable to do so. We conducted face‐to‐face interviews with family members (N = 15) who had direct experience with unsuccessful DCD and 5 focus groups with professionals involved in the donation process. We used qualitative content analysis to characterize the harms of nondonation as perceived by participants. Participants reported a broad spectrum of harms affecting organ recipients, donors, and donor families. Harms included waste of precious life‐giving organs and hospital resources, inability to honor the donor's memory and character, and impaired ability for families to make sense of tragedy and cope with loss. Donor families empathized with the initial hope and ultimate despair of potential recipients who must continue their wait on the transplant list. Focus group members reinforced these findings and highlighted the struggle of families to navigate the uncertainty regarding the timing of death during the donation process. While families reported significant harm, many appreciated the donation attempt. These findings highlight the importance of organ donation to donor families and the difficult experiences associated with current processes that could inform development of alternative donation strategies.