Normothermic regional perfusion (NRP) use in controlled donation after circulatory determination of death (cDCDD): results of the European Society for Organ Transplantation Bucharest consensus conference

Abstract

Normothermic Regional Perfusion (NRP) is emerging as a game-changer in enhancing outcomes for Donation after Circulatory Determination of Death (DCDD). NRP maintains physiological conditions through perfusion with oxygenated blood, outperforming conventional super-rapid recovery techniques significantly improving outcomes and organ utilization. Despite its clinical benefits, widespread adoption of NRP is impeded by heterogeneous organizational, legal, and ethical frameworks. At the ESOT Bucharest Consensus Conference, leading experts in transplantation achieved consensus on 130 relevant NRP-related open issues to facilitate its implementation and guide global practice. Key recommendations include criteria for adoption of NRP, minimal requirements, procedures to be adopted before and during NRP, donor organ evaluation criteria and sequence of organ harvesting. Consensus extends to procedural components (including the configuration of perfusion parameters and strategic team coordination), ethical integrity of NRP in the context of the dead donor rule and key unmet needs for future developments. While significant strides were made in unifying practice, unresolved issues regarding maximum warm ischemic time and variability in legal standards indicate avenues for future research. This consensus underscores the imperative for global standardization in NRP application, promising to elevate the success rates of organ transplants and establish NRP as a foundational element in the evolution of DCDD.

Introduction

Normothermic regional perfusion (NRP) has revolutionized organ utilization and graft outcomes following donation after circulatory determination of death (DCDD). NRP involves the in situ regional perfusion of the abdomen or chest and abdomen with oxygenated blood at normothermic temperature range (35 °C–37 °C), initiated after the formal declaration of death and prior to organ recovery [1].

The growing adoption of NRP in DCDD is primarily due to significant improvements in post-transplant outcomes and organ utilization compared to the conventional super rapid recovery (SRR) technique [2–8]. Unlike organ-specific ex situ perfusion technologies, NRP allows for the simultaneous perfusion of multiple organs, thereby potentially reducing costs, complexity and improving patient access to high-quality DCDD organs [5, 9, 10].

Broader implementation of NRP remains limited by organizational, legal, and ethical challenges. Most notably, the absence of standardized criteria and definitions for many technical and clinical aspects are key barriers to its global expansion. This heterogeneity hinders the comparison of outcomes and the harmonization of protocols across centers and countries.

A panel of international experts with extensive experience in the field of organ transplantation and particularly in the use of NRP participated in this Delphi study (cfr. Table 1 and Martin et al.; [11]) specifically focused upon controlled DCDD.

The objective was to identify and analyze areas of ongoing controversy regarding the application of NRP where there was a lack of standardized consensus across centers and countries (see Results for participant details). Therefore, the aim of this consensus was to address this lack of uniformity by proposing consensus-based recommendations to facilitate the safe and effective global implementation of NRP in controlled DCDD.

Methods

The Delphi process applied in the overarching DCDD Consensus project has been outlined in detail [11]. In essence, a steering committee of 10 members with expertise in NRP led by two coordinators, developed a questionnaire addressing a range of topics identified as priorities through literature review and group discussions. The committee also identified expert panelists according to the previously described criteria [11], who were invited to participate in the Delphi process. The two coordinators did not participate in the expert panel.

Two survey waves were conducted using an online questionnaire administered by the independent company Adelphi Targis. All panelists who completed the first questionnaire were invited to complete the second wave survey. The questionnaire was refined for the second wave as described [11].

In each survey round panelists indicated their level of agreement with a series of statements using a Likert scale (1–9, strongly disagree–strongly agree); responses were analysed using descriptive statistics with ‘disagreement’ assigned to ratings 1–3, “neither agree nor disagree” 4-6, and “agreement” to ratings 7–9. Participants could indicate if a question was not relevant to their expertise and their responses were removed from the denominator when evaluating consensus on specific questions. Statements that reached 75% agreement were deemed to achieve consensus.

Consistent with the design of the Bucharest consensus, paediatric DCDD was addressed separately by a dedicated panel.

Results

Thirty-one experts from nine countries completed the first round of the Delphi process, all of whom completed the second round. Panel demographics are shown in Table 1.

Consensus was achieved on 105 statements after the first round, and on an additional 25 statements after the second round. Following the first and the second round, 52 and 74 statements respectively were eliminated due to lack of consensus. In the second round 48 statements of the first round were reproposed or remodulated whereas 25 new statements were added. The recommendations summarised in Tables 2–14 below reflect the statements for which consensus was achieved, noting some were combined for efficiency.

Definitions in NRP adoption

The most appropriate term to describe donation following the withdrawal of life sustaining measures (WLSM) and subsequent circulatory arrest is donation after circulatory determination of death (DCDD) [12]. In this consensus, a high level of agreement was achieved on most of the definitions (Table 2). Terminology is discussed in a greater detail in the overview article on consensus methodology [11].

Although the group agreed on the definition of “functional warm ischemic time”, no consensus was reached regarding the specific hypoperfusion thresholds that delineate the onset of this period, and this is a remarkable point to discuss in the future to allow comparisons of results between countries and centers.

Adoption of machine perfusion

Provided that the panelists strongly agreed on the need of a routine use of Machine Perfusion (MP) to improve results in cDCDD, it should be remarked that sophisticated preservation techniques are not absolutely mandatory for a DCDD program to exist and provide appropriate outcomes even though NRP has shown, with intermediate level of evidence, to provide better recipient outcomes [8].

Team composition and training

There is strong consensus that a NRP team should include at least 5 different fully competent professionals (Table 4). This integrates what recommended in a recent ESOT consensus document on the topic [13]. The expansion of NRP programs requires well-prepared and adequately trained teams. There is clear agreement that new teams must achieve competence through a supervised training phase under expert oversight [14].

However, no consensus was reached regarding the minimum number of procedures required to achieve competent status within scientific societies or health authority organized training programs. These considerations should be taken into account when designing educational activities on the application of NRP in cDCDD.

There was also broad consensus on the minimum equipment required to perform NRP safely in routine clinical settings (Table 5).

NRP procedures

The legal framework governing premortem interventions varies considerably across countries [15, 16]. Nevertheless, there is broad consensus that the administration of heparin to the donor and the antemortem insertion of guidewires or cannulation, prior to initiating NRP, enhances the likelihood of optimal graft function. Indeed, antemortem insertion of guidewires or cannulation may help reducing the duration of warm ischemic time. However, such practices should only be performed if permitted under local laws and institutional guidelines. Interestingly, in the case of TA-NRP, but not in the A-NRP, peripheral cannulation before WLSM was generally considered appropriate (Table 6).

A team briefing and handover is recommended to ensure that all members understand their responsibilities. Volume replacement should be administered in cases of blood or fluid loss, to prevent NRP failure, always ensuring adequate hemoglobin levels (>8 mg/dL) to avoid inadequate oxygen delivery [17]. There is strong consensus on the recommended target parameters (Table 6, point 4). Adequate anticoagulation during NRP is essential for optimal procedural performance. However, no consensus was reached on the minimum monitoring frequency.

During multiorgan retrieval with NRP, chest bleeding after lung retrieval is a major concern in combined thoracic and abdominal recovery [18, 19]. Meticulous haemostasis, particularly in the chest, is highly recommended to prevent blood loss and circuit failure.

The NRP priming solution or perfusate after initiation should include a heparin-balanced crystalloid solution. No other components have been recommended (Table 6, point 3). If additional volume is required during NRP, plasma substitutes or packed red blood cells should be used.

Technical success of NRP

The optimal duration of NRP remains unclear in the literature. NRP is typically maintained for 1–2 h. Some retrospective studies have suggested no significant differences in outcomes between 1 and 4 h of perfusion [20–22], but, differently from previous consensuses [17], no consensus on the optimal duration was reached by the expert group. It was unequivocally agreed that abdominal NRP should never be initiated without first clamping the thoracic descending aorta, either surgically or via the placement of an intra-aortic balloon [5, 9, 23]. However, there was clear consensus against dividing the thoracic descending aorta with active drainage before starting A-NRP.

The use of TA-NRP for heart recovery in DCDD donors has expanded worldwide. To maximize the success of all retrieved organs, if prolonged time is anticipated for sternotomy and aortic arch vessel clamping, it is recommended to initiate A-NRP in the interim, using peripheral cannulation and a thoracic descending aortic balloon (particularly when antemortem interventions are permitted), as previously described [24, 25].

A major barrier to the global adoption of TA-NRP is the risk of restoring cerebral circulation following the declaration of death. It has been agreed that the aortic arch vessels must be clamped or ligated before starting TA-NRP (Table 8, point 2). However, no consensus was achieved on whether the vessels should also be transected and left to drain to atmospheric or negative pressure. This remains a point of contention, underscoring the need for further studies to clarify whether transection or drainage to negative pressure of the supra-aortic trunks is essential to definitively remove any risk of postmortem cerebral reperfusion. After the consensus emerged that in the United States for both A-NRP and TA-NRP venting above the clamp is now mandatory [26] but this is not the case for many other realities. Consensus was reached on several refinements regarding the TA-NRP technique (Table 8, point 1).

Preservation of lung/heart function

The combined retrieval of lungs and heart using TA-NRP presents significant technical challenges. To preserve optimal post-transplant lung and cardiac function, it is recommended to avoid excessive fluid transfusion and prevent cardiac distension during the procedure. If A-NRP is initiated before sternotomy and arch vessel clamping and an endovascular balloon is used, the balloon should be positioned below the left subclavian artery. Once optimal cardiac function is achieved, TA-NRP should be discontinued as soon as possible to facilitate the recovery of the stunned heart (Table 9).

Evaluation of donor organs in NRP

It is widely acknowledged that macroscopic assessment of the graft by the retrieval surgeon is indispensable for organ validation and may be supplemented, when appropriate, by complementary laboratory investigations. However, the routine histopathological (microscopic) evaluation of grafts and routine biopsies for the evaluation of kidneys and liver were not considered necessary.

There serial transaminases and serial lactate were agreed to be useful ancillary test to assess liver function during NRP. Traditionally, a marked elevation of serum aminotransferase (AST, ALT)—typically a threefold or greater increase from baseline levels (less decisive for many nowadays) — and a progressive rise in lactate have been interpreted as suggestive of an ischemic injury and suboptimal perfusion with high risk of primary non-function (PNF) [21, 27–29].

For pulmonary assessment, bronchoscopy was agreed as a valuable adjunctive tool for determining graft suitability. EVLP is an option for donor lungs that cannot be properly evaluated in the donor and/or for logistical reasons [30]. The consensus considered that EVLP should be recommended for lung evaluation or reconditioning only in the special cases, and not for routine cases (Table 10, point 2).

For heart retrieval using TA-NRP, the assessment of the heart has usually been performed with pulmonary arterial catheterization with serial cardiac output measurements and/or also with esophageal echocardiography [25, 31]. All consensus is detailed in Table 10, points 1, 2.

Sequence of organ recovery

The simultaneous retrieval of thoracic grafts (lungs and/or heart) and abdominal grafts using NRP remains challenging and increases the overall complexity of the procurement procedure, with a heightened risk of graft injury during retrieval [10, 18, 19, 25].

A major challenge in TA-NRP is managing situations where the procedure involves multiorgan recovery which could risk the other grafts because of problems with the heart. Current literature does not clearly define the point at which the heart should be deemed unsuitable for transplantation, and the focus shift toward the retrieval of lungs and abdominal organs. The panelists considered that if TA-NRP cannot be discontinued after an agreed perfusion time, and there is metabolic and/or macroscopic evidence that cardiac function cannot sustain systemic perfusion, the heart should be considered non-viable for transplantation (Table 11, point 2). At that point, the thoracic aorta should be clamped, and the NRP flow reduced to 2.0–2.4 L/min to ensure adequate perfusion of abdominal grafts [9, 25].

The panelists agreed that a designated person in the team should ideally be responsible for determining that TA-NRP has been unsuccessful and shifting the team’s focus to salvaging lungs and abdominal organs.

The agreed liver-pancreas sequence is clearly not the case when retrieval surgeons prefer to adopt the en bloc recovery.

Given the limited panel experience on this specific issue, the discussion did not face the appropriate retrieval sequence in cases of intestinal procurement, particularly regarding en-bloc harvesting of a multivisceral graft or the anticipation of intestinal retrieval prior to the liver.

One of the most debated aspects in the assessment of DCDD organs is determining the maximum acceptable limit of warm ischemic time (WIT). These limits have been progressively extended as clinical experience has accumulated since the earliest cases [32, 33]. However, a universally accepted cutoff is yet to be establish among experts.

Ethical issues

The authors slightly rephrased the statement 12b from the original voted form:

“…effectively and completely block all blood flow to the brain during NRP …” Rephrasing was considered opportune for semantic reasons since the verb “block” implies different intent.

Ethical concerns regarding the use of NRP in DCDD [34] include premortem interventions, and the theoretical possibility of restoring brain perfusion after death is declared [11]. This last concern is one of the most important obstacles that have prevented the expansion of NRP [35–38]. There was notably strong consensus among the panelists who disagreed with a series of normative and empirical claims that are often presented as justification for prohibiting NRP (Table 12).

The confidence demonstrated in the ethical integrity of NRP practices with regards to respect for the “dead donor rule”, when relevant clinical safeguards are effectively implemented likely reflects the inherent bias of the panel, who were selected for their experience with NRP.

Brain perfusion

There was a consensus that effective techniques must be used to maintain permanent cessation of cerebral perfusion and the delivery of oxygenated perfusate to the brain during NRP. Indeed, clamping or ligation of the aortic arch vessels and sectioning of the cephalic ends of the vessels, plus drainage and aspiration of blood to atmospheric pressure during TA-NRP were considered sufficient to ensure this. However, the exclusive ligation of the arch vessels was not considered an effective technique to maintain permanent cessation of brain circulation during TA-NRP (Table 13).

Thought the implementation of a system of brain monitoring during TA-NRP has been suggested to detect any potential failure in maintaining permanent absence of blood flow to the brain, which should immediately prompt the halting of NRP, mainly in those cases where cessation of brain circulation is maintained by only clamping the arch vessels [9, 39], it has not been considered mandatory to use transcranial Doppler, transcranial evoked potentials or invasive arterial blood pressure monitoring of the circle of Willis from WLSM until the end of TA-NRP. In fact, the use of transcranial Doppler during TA-NRP is highly controversial, and it has not been considered the most reliable monitoring technique to ensure no blood flow during TA-NRP.

Unmet needs and future research

There is a lack of standardization regarding A-NRP and TA-NRP practices between countries, which is concerning. This lack of standardization is considered to be the result of different legal frameworks between countries or the absence of national protocols. In future studies regarding NRP management techniques, organ utilization metrics should be incorporated.

Discussion

There is broad expert agreement that perfusion techniques—either in situ (NRP) or ex situ (NMP or HMP)—should be routinely implemented in all cDCDD donors to optimize post-transplant graft function if they are available. In countries unable to incorporate these techniques, SRR and static cold storage can be adopted provided a strict control for other factors that affect post-transplant outcomes.

Recent studies have consistently demonstrated the positive impact of these perfusion strategies on recipient outcomes when compared with the standard rapid recovery technique [3–5, 7, 8, 25]. This Consensus did not aim at any point to assess the combined use of NRP with ex situ preservation techniques such as NMP or HMP. This topic has been recently described in the European Liver and Intestine Transplant Association (ELITA) consensus [17].

NRP is strongly recommended in many different situations (Table 3). However, no consensus was reached regarding scenarios of deceased donation involving conscious patients who can make their own decisions about end-of-life care (e.g., persons with end-stage respiratory failure or neurodegenerative diseases, or those in whom medical assistance in dying has been authorized). In countries where DCDD is possible under these circumstances, patients may require intensive care to facilitate organ donation (ICOD), including elective ventilation [40–42]. The limited clinical experience with these specific subgroups of donors and ICOD is likely the main reason for the lack of agreement.

These discrepancies regarding the patient groups in which NRP should be applied highlight the heterogeneity of current practices and underscore the urgent need for consensus statements and evidence-based clinical guidelines. This Delphi Consensus highlights the substantial differences observed in the implementation of NRP worldwide, all the more striking given that the participating experts have extensive experience in this field.

This study demonstrates a high degree of uniformity in the technical and human resource requirements to implement NRP in any center. It also shows broad consensus regarding the training needs of newly established NRP teams.

We believe there is an urgent need to agree on certain terms, such as functional warm ischemic time (FWIT), in order to promote uniformity across studies. Unfortunately, no consensus was achieved in defining the maximum acceptable limit of warm ischemic time (WIT) among experts.

One of the most important aspects of this Consensus is the agreement that the use of certain premortem measures, such as the administration of heparin or the placement of guidewires or cannulas before WLSM, improve post-transplant outcomes. This consensus may help to change the regulatory framework in many countries where these practices are still not permitted [15]. One of the most surprising findings in this area was that peripheral cannulation before WLSM was generally considered appropriate in the setting of TA-NRP, but not in A-NRP (Table 6).

Undoubtedly, the area that generates the greatest disagreement among experts is the use of TA-NRP, where there is considerable divergence regarding how to ensure the absence of cerebral perfusion during the procedure.

Due to the uncertainty that complete cessation of blood flow to the brain results by only clamping the arch vessels, current protocols in the United Kingdom and Spain have added the step of severing the arch vessels distal to the clamps and draining blood from the cephalad ends to atmospheric pressure [39, 43, 44]. However, no consensus was achieved regarding whether the vessels should be transected and left to drain to atmospheric pressure. Some authors, particularly in Europe, argue that clamping alone may be insufficient to ensure the absence of postmortem cerebral perfusion [43–46], whereas U.S. guidelines consider both clamping alone and clamping with transection as acceptable options [45, 47]. The American Society of Transplant Surgeons produced an updated statement supporting clamping and venting the supra-aortic trunks when using TA-NRP [26].

The differences observed between authors, and particularly between European and American guidelines regarding clamping alone or clamping and sectioning the supra-aortic trunks when using TA-NRP represent a point of controversy that will need to be solved [43–47]. A Spanish study evaluating the intracerebral blood pressure at the Circle of Willis and the basilar artery—which encompasses the anterior, middle and posterior cerebral circulations—provides strong evidence to alleviate concerns regarding reperfusion of the brain during the TA-NRP procedure, as long as the arch vessels are clamped and the cephalad ends are vented to the atmosphere [48].

We believe that one reason for the significant divergences regarding TA-NRP is the limited global experience with this technique. In fact, in some of the countries represented by the experts in this consensus, TA-NRP has not yet been implemented. Furthermore, there is significant inconsistency in the recommendation to clamp or to ligate the aortic arch vessels (see Table 8, point 2) in order to improve the technical success of the TA-NRP, with no agreement on whether they should be also sectioned. On the contrary, when the focus is on prevention of brain perfusion during TA-NRP (Table 13), there was consensus that it is precluded by clamping or ligation of the aortic arch vessels and sectioning of the cephalic ends of the vessels, plus drainage and aspiration of blood from their caudal ends to achieve atmospheric pressure in the arteries is sufficient to maintain cessation of cerebral perfusion.

This study found broad consensus on how to assess grafts during A-NRP or TA-NRP (Table 10) and how to perform the sequence of a multiorgan donation with NRP, as well as on how to successfully retrieve the heart and lungs using TA-NRP.

There was a great consensus in the recommendations regarding the evaluation of organs in donors undergoing NRP, with routine biopsies for the evaluation of kidneys and liver considered not necessary. There was a wide consensus in the use of serial transaminases and serial lactate as useful ancillary test to assess liver function during NRP as was also detailed in the recent ELITA consensus report [17]. However, the systematic use of EVLP for the evaluation of lungs in DCDD donors remains a matter of considerable debate. Certain programs report a high proportion of lungs being assessed with EVLP [49], whereas others employ this modality only infrequently [18, 19, 50, 51]. The authors of this report considered that EVLP should be recommended for lung evaluation or reconditioning only in special cases, and not for routine cases (Table 10, point 2).

Since the use of TA-NRP is still in its early stages, different protocols exist regarding how to assess the heart and how to coordinate its maintenance with that of the other organs [25, 50, 52]. There was a clear agreement that when optimal cardiac function is achieved, TA-NRP should be discontinued as soon as possible to facilitate the recovery of the stunned heart (Table 9).

One of the major challenges in TA-NRP for the panelists were those situations where the procedure involves multiorgan recovery, which could risk the other grafts because of problems with the heart. The panelists agreed that a designated person in the team should ideally be responsible for determining that TA-NRP has been unsuccessful and shifting the team’s focus to the recovery of lungs and abdominal organs. This named person has demonstrated a great benefit in Spain, where the donor transplant coordinator, mostly an intensive care physician, has a pivotal role in organizing the different surgical teams participating in NRP procedures, particularly when TA-NRP is used [9].

The ethical concerns regarding NRP have substantially impeded the adoption of this technique worldwide [53, 54]. It was notable that more than 90% of panellists disagreed with a series of normative and empirical claims that are often presented as justifications for prohibiting NRP (Table 12). It is evident that the most critical ethical concern relates to the respect for the “dead donor rule”, with consensus among panellists that interventions are essential to ensure that the permanency standard for the determination of death is maintained during TA-NRP by preventing cerebral reperfusion.

There was a consensus that effective techniques must be used to maintain permanent cessation of cerebral perfusion and the delivery of oxygenated perfusate to the brain during NRP. Indeed, clamping or ligation of the aortic arch vessels and sectioning of the cephalic ends of the vessels, plus drainage and aspiration of blood to atmospheric pressure during TA-NRP was considered sufficient to ensure this. However, ligation of the arch vessels alone was not considered an effective technique to maintain permanent cessation of brain circulation during TA-NRP (Table 13). There is thus a critical need for research that will establish interventions that conclusively demonstrate the absence of brain perfusion after TA-NRP [55]. Two recent studies monitoring intracerebral blood pressure circle of Willis and using perfusion scintigraphy with technetium-99m hexamethylpropyleneamine oxime as a radiotracer during TA-NRP provided the first strong evidence that permanent cessation of brain perfusion could be maintained by clamping and sectioning the supra-aortic vessels [39, 46]. It remains unclear whether clamping of the supra-aortic vessels in isolation, which has been considered acceptable in some parts of the U.S, excludes any risk of postmortem cerebral perfusion [45, 46]. The US guidelines accepted both options [47].

Emerging evidence regarding the absence of cerebral perfusion during TA-NRP [39, 46], together with recent studies providing direct evidence of the temporal relationship between the loss of brain blood flow, brain activity, and systemic circulation in humans [56], helps strengthening the confidence within the scientific community—and may facilitate a more widespread adoption of NRP in the setting of DCDD.

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