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Abdominal Normothermic Regional Perfusion in Donation After Circulatory Death: A Systematic Review and Critical Appraisal

van de Leemkolk, Fenna E.M. MD1,2; Schurink, Ivo J. BSc3; Dekkers, Olaf M. MD, PhD4; Oniscu, Gabriel C. MD, PhD5; Alwayn, Ian P.J. MD, PhD1,2; Ploeg, Rutger J. MD, PhD2,6; de Jonge, Jeroen MD, PhD3; Huurman, Volkert A.L. MD, PhD1,2

Author Information
doi: 10.1097/TP.0000000000003345

Abstract

INTRODUCTION

Donation after circulatory death (DCD) remains associated with significantly lower organ recovery rates per donor compared with donation after brain death (DBD). Furthermore, the results after transplantation using DCD donors are acceptable but remain associated with poorer initial graft function when compared with organs from DBD donors.1-5 Due to the uncertainty about their quality and ability to provide immediate life-sustaining function, DCD organs are often declined and discarded. This raises the question whether the underutilization of these organs is justified and unnecessarily reduces the size of the potential donor organ pool.

To date, in some countries (eg, United Kingdom, Netherlands, United States), DCD donors are an important resource to balance the persistent shortage of donor organs. The different categories of DCD donors are described in Table 1.6 In 2018 in The Netherlands, > 57% of deceased donors were controlled DCD (cDCD),7 while in the United Kingdom, cDCD is now a main pathway to donation.8

TABLE 1.
TABLE 1.:
Modified Maastricht classification for DCD donors6

To reduce uncertainty and increase utilization, better assessment of organ viability and optimization of preservation strategies are required, reducing ischemia-reperfusion injury and enhancing quality and function of the potential grafts.

Abdominal normothermic regional perfusion (aNRP), also called normothermic recirculation or normothermic extracorporeal membrane oxygenation, is an emerging in situ organ preservation technique in the donor. First pioneered in 1989 in Spain, it demonstrated to improve liver graft viability in a porcine DCD model.9,10 Experimental studies, mostly performed in pig models of liver or kidney transplantation, have evaluated the possible beneficial effects of aNRP.11-16 During a period of warm ischemia, ATP declines progressively. During aNRP, the cellular energy status was found to increase due to partial restoration of ATP content, which suggests that the ischemic injury obtained during the warm ischemia time (WIT) can be partially reversed before transplantation.11,13,17 Therefore, an “ischemic preconditioning” effect can be observed when using aNRP. Not only do intracellular adenosine levels rise, but also a significant decrease in xanthine levels, as an important nucleotide degradation product, has been observed.14,15

The initial clinical experience with aNRP was obtained with uncontrolled DCD (uDCD) type II donors. In these donors, who suffered from an unexpected circulatory arrest and where resuscitation was unsuccessful, aNRP is often started before the donor is subjected to the mandatory screening process and before consent is obtained. Currently, aNRP is used in both uDCD and cDCD donors in several countries, such as Spain, United Kingdom, Norway, France, and Italy.18 aNRP was implemented for marginal cDCD donors in part of the Netherlands in 2018, aiming at an increase of liver organ utilization as these cDCD donors exceeded the existing “regular” criteria (eg, cDCD donors >60 y).

The concept of aNRP in DCD donors is based on 3 principles: (1) after circulatory arrest and a mandatory no-touch period normothermic oxygenated circulation is reestablished. As such, it not only reduces the extent of ischemic injury but is also allows all abdominal organs to recover by recharging their energy content; (2) during aNRP, organs can be inspected, and blood samples are obtained for biochemical analyses. This allows for better assessment of the quality of the perfused organ, assisting the clinician in deciding whether to accept or decline the organ; and 3) damage to donor organs may be minimized by converting a “hasty” DCD procedure into a less rushed DBD-type operation, resulting in less organ damage and increased organ utilization.19

Despite the rapid development of aNRP in clinical practice, the number of large cohort studies is limited, and reports are hampered by heterogeneity. To date, the evidence that aNRP increases the organ utilization rate (OUR) and improves outcomes after transplantation remains limited. Such evidence is needed to allow for wider clinical implementation and necessary approval by regulatory and healthcare authorities in countries considering implementation of aNRP.

In this systematic review, we aim to evaluate the present clinical evidence for the use of aNRP to improve donor organ assessment and better function and outcomes following transplantation of abdominal donor organs.

MATERIALS AND METHODS

Search Strategy

A systematic literature review was reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses guideline20 and was registered with PROSPERO (CRD42019125387).

A search strategy was developed, and the following databases were explored: PubMed (incl. MEDLINE), Embase (OVID-version), Web of Science, COCHRANE Library, Emcare, Academic Search Premier, ScienceDirect, and Google Scholar. The final search was performed on January 29, 2020. For the complete search strategy, see Appendix S1, SDC, http://links.lww.com/TP/B954.

Inclusion and Exclusion Criteria

We aimed to include randomized trials and cohort studies comparing clinical aNRP to local standard perfusion techniques or single-arm cohorts with data on outcomes. Furthermore, only articles written in English were considered. In case of duplicate data, the most recent article was included. Articles with duplicate data on 1 organ were included. However, articles with duplicate data on one organ were included if one of the articles also included additional data of another organ. Case reports, editorials, letters to the editors, meeting abstracts, and reviews without original data were excluded.

Outcomes

Primary outcomes included OUR21 and 1-year patient and graft survival. For the purpose of this review, OUR was calculated as the number of organs actually transplanted, divided by the total number of available organs when procurement was initiated. In studies that based their selection on recipients, the OUR could not be calculated.

Secondary outcomes included delayed graft function (DGF), primary nonfunction (PNF), serum creatinine, estimated glomerular filtration rate (eGFR) or measured glomerular filtration rate for kidneys, PNF, and biliary complications, including ischemic cholangiopathy (IC), early allograft dysfunction (EAD) as defined by Olthoff et al22 for livers and yield after islet isolation for pancreas.

Data Extraction

Title and abstracts were screened by 2 independent reviewers (F.E.M.v.d.L. and V.A.L.H.) to meet predefined inclusion criteria, followed by full-text review of eligible articles. Consensus regarding inclusion was obtained between reviewers. Data extraction was performed using a predetermined Microsoft Excel template. The extracted variables are provided in Table S1, SDC, http://links.lww.com/TP/B954. When additional information was needed, the corresponding authors of the studies were contacted.

Risk of Bias

Two reviewers determined independently the risk of bias according to the Risk of Bias In Nonrandomized Studies of Interventions tool (Table S2, SDC, http://links.lww.com/TP/B954) for cohort and case-control studies.23

Statistical Analysis

We did not consider statistical pooling appropriate because of sparsity and heterogeneity of data.

RESULTS

The literature search identified 1558 records. One additional reference was identified through the snowball method. After initial screening of titles and abstracts, 94 full-text articles were assessed for eligibility. In total, 24 studies21,24-46 were included in the systematic review (Figure 1).

FIGURE 1.
FIGURE 1.:
Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow diagram. aNRP, abdominal normothermic regional perfusion; DBD, donation after brain death; ECMO, extracorporeal membrane oxygenation.

Study Characteristics

All studies were observational in their design; no randomized controlled trials were found. The transplanted abdominal organs included in the studies concerned: kidney (n = 9),24,26-28,34,36,37,41,45 liver (n = 11),21,25,29,31,32,39,40,42-44,46 kidney and liver (n = 1),30 and kidney, liver, and pancreas/islets (n = 3).33,35,38 The overlap in partly duplicate reporting on the same organ is outlined in Table 2. The inclusion period of the studies ranged from 1986 to 2019.

TABLE 2.
TABLE 2.:
Study characteristics

Fifteen studies were single-center studies,25,27,29-31,33,34,36-39,41-43,46 and 7 multicenter studies21,28,32,35,40,44,45 were included in this review. Two articles24,26 used the national registry system to analyze data.

The articles described results in uDCD type I or II (n = 10),24,26-29,34,37,40,41,43 cDCD type III (n = 12),21,30-33,35,36,38,39,42,44,45 cDCD type IV (n = 1),42 or both uDCD and cDCD (n = 2).25,46 Regarding control groups, aNRP was compared with DBD,25,29,30,33,34,37,40,43,44 uDCD,24,27,28,41 or cDCD21,32,42 without aNRP. Del Río et al26 used both cold in situ perfusion (ISP) and hypothermic regional perfusion as controls (Table 2). The remaining 7 studies31,35,36,38,39,45,46 did not use controls.

The sample sizes in the actual donor cohort ranged from 5 to 186 donors. However, the potential donor cohort (including mostly donors not yet exposed to the different inclusion or exclusion criteria) accumulated to approximately 568 donors.

aNRP Protocols

For clarification purposes, the technique used for aNRP in clinical practice is briefly described below for uDCD and cDCD donors.

In uDCD type II, in which repeated attempts of resuscitation failed, the donor is declared dead in the hospital. In some countries, cardiopulmonary resuscitation using cannulas in the femoral vessels and mechanical ventilation is then restarted to preserve organ viability. To prevent blood flow to the thoracic organs, a balloon catheter is introduced via the contralateral femoral artery and inflated, thus occluding the supraceliac aorta. To ensure proper positioning of the balloon, a chest radiograph can be used. The aNRP system, already primed with perfusate solution (eg, Ringers lactate added with heparin and/or antibiotics), is then connected to the cannulas, and the pump is started. A regular DBD-like surgical procurement will take place after the donation consent is obtained.

In cDCD type III, the opportunity to cannulate under local anesthesia before withdrawal of life-sustaining therapy differs per country. If allowed, rapidly after the declaration of death (including the obligated no-touch period), the balloon is inflated, and the cannulas are connected to the aNRP system, after which perfusion is commenced. However, if interventions, such as cannulation or the administration of heparin, before the declaration of death are prohibited, time becomes an important factor. After death has been declared and a no-touch period has been observed, the rapid laparotomy is undertaken by the surgical team. The abdominal aorta and infrarenal inferior vena cava are cannulated. aNRP is initiated when the thoracic aorta, just above the diaphragm, is cross clamped.

In DCD type IV, cardiac arrest occurs unexpectedly due to hemodynamic instability in a brain-dead donor (uDCD IV). In some countries (ie, Japan and China), there is no legislation on brain death criteria resulting in withdrawal of treatment followed by cardiac arrest in a controlled setting (cDCD IV). In the latter case, the femoral vessels are cannulated before treatment is withdrawn, and aNRP is started when systolic blood pressure drops below 60 mm Hg while cardiac arrest is awaited.

The definition of donor WIT varies widely among the articles (Tables 3 and 4). In the study of Ding et al42 using cDCD (IV), there is no WIT as aNRP immediately started when the systolic blood pressure fell below 60 mm Hg while cardiac arrest was awaited. Overall, the flow for aNRP was targeted at >1.7 L/minute. The majority of studies used normothermic perfusion (36–37°C) during aNRP, while Savier et al40 did not use a heat-exchanger, resulting in temperatures of 32–33°C (Table 4). Reznik et al37 perfused with subnormothermic perfusion varying between 27°C and 32°C (Table 3).

TABLE 3.
TABLE 3.:
aNRP protocols for kidneys
TABLE 4.
TABLE 4.:
aNRP protocols for livers

After aNRP and procurement, preservation of grafts during cold ischemia time has been managed differently per country. In France, ex situ hypothermic machine perfusion (HMP) is systematically used for kidney grafts.24,27,28 Del Río et al26 described that 33% of kidneys analyzed in their Spanish National registry cohort were subjected to HMP. HMP for kidneys was also used in 3 other studies.36,38,45 Regarding the liver graft, HMP was used in 2 studies.25,46 The remaining studies used static cold storage for organ preservation.

Clinical Outcomes

For the purpose of this review, clinical outcomes are reported per abdominal organ transplanted.

Kidney

Thirteen articles24,26-28,30,33-38,41,45 described the effect of aNRP on clinical outcomes in kidney transplantation (Table 5). Seven articles included uDCD-aNRP, of which 5 24,26-28,41 and 234,37 used uDCD and DBD as controls, respectively. cDCD-aNRP was described in 6 studies, of which 230,33 used DBD as controls. The remaining 4 studies35,36,38,45 did not compare their results to controls.

TABLE 5.
TABLE 5.:
Clinical outcomes for the kidneys

Organ Utilization Rate

OUR varied from 64.8% to 100% and 64.9% to 92.7% in uDCD-aNRP34,37,41 and cDCD-aNRP,30,33,35,38 respectively. Valero et al41 demonstrated an OUR in uDCD-aNRP of 66.7% comparing with cold ISP (55%) and total body cooling (50%). In the remaining studies,24,26-28,36,45 the OUR was not described or was not calculated as selection was based on recipients.

1-year Patient and Graft Survival

As regards uDCD-aNRP, only 2 studies28,37 reported 1-year patient survival. This was 100% compared with 94.6% in DBD and 96.6% in uDCD. The 1-year patient survival was not reported in the 6 cDCD-aNRP studies.30,33,35,36,38,45

Regarding 1-year graft survival, 2 studies26,28 demonstrated a graft survival of 91%–94.4% in uDCD-aNRP compared with 62%–93.5% in uDCD. When uDCD-aNRP was compared with DBD, Reznik et al37 has shown similar 1-year graft survival in both groups. In cDCD-aNRP, however, 2 studies30,33 reported a lower 1-year graft survival when compared with DBD. The remaining 7 studies24,27,34-36,41,45 did not mention 1-year graft survival outcomes.

Secondary Outcomes

PNF rate was described in 11 studies.24,26-28,33,34,36-38,41,45 Five studies showed a range of 0%–8% in uDCD-aNRP compared with 3%–31% in uDCDs.24,26-28,41 When using DBD as controls, no differences were observed.34 In cDCD-aNRP, the PNF rate varied from 0% to 5%; however, no control group was used to compare these outcomes.33,36,38,45

DGF, generally defined as the need for at least 1 dialysis treatment in the first week after transplantation, varied from 12.5%–75.7% to 7.1%–40% in uDCD-aNRP and cDCD-aNRP, respectively. As regards the controls, DGF varied from 4.9%–46.4% in DBDs to 55%–87% in uDCDs.

Posttransplant kidney function was described differently. Whereas some studies used serum creatinine at 1-year, others preferred to assess the kidney function after transplantation via the eGFR or measured glomerular filtration rate.

Liver

Fourteen studies21,25,29-33,35,38-40,42-44,46 reported on the outcome of liver transplantation (Table 6). Three29,40,43 of those included uDCD-aNRP compared with DBDs. Ten studies included cDCD-aNRP with 2 studies33,44 using DBD as control and 2 others21,32 using cDCD as control, respectively. One study42 performed in China, in which organ DBD is followed by circulatory death, included cDCD type IV and compared aNRP in this type of donor with ISP. The remaining 5 studies30,31,35,38,39 did not have a control group. For 2 studies,25,46 we will not discuss the outcomes as these studies analyzed both uDCD and cDCD donors and did not distinguish between those 2 donor types in their analysis.

TABLE 6.
TABLE 6.:
Clinical Outcomes for the livers

Organ Utilization Rate

The OUR in uDCD-aNRP29,40,43 varied from 7.1% to 29.3%. This was lower when compared with DBD (76%).29 In cDCD-aNRP, Watson et al21 described an OUR of 61.4% compared with 27%–36% when using cold ISP. However, Hessheimer et al32 demonstrated a comparable OUR for both perfusion methods (62.5% cDCD-aNRP versus 61.6% controls). Furthermore, Ding et al42 demonstrated a 100% OUR for both perfusion methods in cDCD type IV.

1-year Patient and Graft Survival

In all 3 studies29,40,43 using uDCD-aNRP, the rates of 1-year patient and graft survival were lower than in DBD. In cDCD-aNRP,21,32 1-year patient survival varied between 93% and 97.7% when compared with 88%–94.2% in controls of the same donor type. Miñambres et al44 found a lower 1-year patient survival but compared the outcomes with DBDs (87.5% versus 96%). The graft survival was higher in cDCD-aNRP compared with cDCD21,32 (88%–97.7% versus 83%–86.5%).

Secondary Outcomes

Only 2 studies21,32 compared the incidence of PNF in cDCD-aNRP to cDCD, demonstrating a lower incidence of PNF (0%–2% cDCD-aNRP versus 3%–7% cDCD); however, the differences were not statistically significant for each study. When cDCD-aNRP was compared with DBD, the incidence of PNF was higher (12.5% cDCD-aNRP versus 0% DBD) but did not reach significance as well.

With regard to biliary complications after liver transplantation, the overall incidence varied widely, influenced by the donor type. In uDCD-aNRP,40,43 the incidence of IC was higher (11%–16%) when compared with DBD(2%–3%). However, the incidence was statistically significantly lower (0%–2%) in cDCD-aNRP when compared with cDCD21,32 (13%–27%).

The EAD rate was reported in 6 studies.21,32,35,39,40,44 When compared with controls, it ranged from 12% to 22% in cDCD-aNRP versus 17.2%–32% in cDCD21,32,44 and was found to be statistically different in 1 study.21 When compared with DBD, Miñambres et al44 found similar EAD rates (18.8% cDCD-aNRP versus 17.2% DBD).

Pancreas

Only 3 studies33,35,38 reported data on pancreas or islet transplantation when using aNRP. One pancreas as whole organ transplant with no information on short- or long-term outcomes,38 3 simultaneous pancreas-kidney (SPK) transplants and 1 islet transplantation were performed. Miñambres et al33 reported appropriate graft function in 1 SPK transplantation after 6 months, and Oniscu et al35 described primary kidney and pancreas function in 2 SPKs. The islet isolation was performed from 2 pancreases, of which 1 transplant was performed after obtaining a sufficient yield.

Risk of Bias Within Studies

The domains confounding, selection of participants into the study, and selection of reported results were frequently judged as moderate or serious risk of bias. Seven studies31,35-38,45,46 did not have a control group, resulting in a “non-applicable” judgment on different bias domains, whereas 7 studies25,30,33,37,40,43,44 used DBD as controls, resulting in a serious risk of bias in the confounding domain. In total, 11 studies24,25,30,32-34,40-44 were considered to have serious overall risk of bias and 521,26-28,37 to have moderate overall risk of bias (Tables 7 and 8). The most important selection bias was caused by surgical assessment of abdominal organs on its macroscopic appearance, resulting in declining or accepting the organ. However, this is present in all studies and probably inevitable as it is the only way that DCD organs are currently assessed in standard clinical practice.

TABLE 7.
TABLE 7.:
Risk of bias in studies focusing on the kidney
TABLE 8.
TABLE 8.:
Risk of bias in studies focusing on the liver

DISCUSSION

Despite the fact that aNRP was introduced in the 1990s, only in recent years has its use become more widespread. Especially in countries with an extensive DCD donation population, it was found to increase the OUR from DCD donors and improve transplant outcomes. For this reason, in France, Italy, and Norway, aNRP has become the standard procurement procedure for DCD donors mandated by the health authorities or preferred routine in several regions in the United Kingdom and Spain.18 This systematic review aims to assess the level of clinical evidence justifying expansion of aNRP in both donor types, uDCD and cDCD.

The results of this review show that aNRP is feasible and safe in both uDCD and cDCD. All available studies demonstrated successful implementation of the technique into clinical practice. Function and outcomes after kidney and liver transplantation using aNRP appear superior to non-aNRP DCD donors when comparing data to large cohorts described elsewhere.1-3 Some studies found increased survival and lower complication rates.21,32 Due to the low number of pancreas or islet transplantation after aNRP, it is difficult for the pancreas to draw conclusions whether this approach results in improved outcomes.

Local and national practice how DCD donors and organs are managed and procured differ across countries. The possibility of premortem interventions (eg, cannulation and heparinization) in both uDCD and cDCD may affect the OUR in countries where these are allowed. As such, reports of successful aNRP in uDCD donors may have convinced national competent authorities to implement such a program, while legal and ethical, but also practical concerns may prohibit its widespread applicability in similar settings in other countries. Therefore, these results should be considered in each individual country’s context.

In addition, the current definitions and protocols concerning aNRP will differ (eg, the definition of WIT, approach for lung donation, and the use of continuous versus end-ischemic ex situ machine perfusion). Protocols include different approaches for the addition of medication during aNRP, duration of perfusion, temperature, organ acceptance criteria, and uniform outcome measures. Uniform reporting of definitions and outcome measures would be preferable for aNRP and other novel perfusion technologies.47 Consensus on the definition of OUR should be reached and patient and graft survival mentioned, as well as short- and long-term graft function. Concerning liver transplantation, biliary complications appear to be an essential outcome parameter in DCD cohorts.48 As such, this outcome should be considered when reporting aNRP results. However, in this regard, a uniform definition needs to be agreed on by liver transplant groups on the precise classification of ischemic biliary complications to facilitate reporting. In January 2020, at the International Liver Transplantation Society Consensus Conference in Venice, an approach was made to achieve such consensus regarding DCD liver preservation and machine perfusion. In kidney transplantation, the use of DGF as outcome parameter is currently under heavy debate, as definitions differ and the correlation of DGF in DCD donors with graft survival is absent or at best limited. One-year graft function (expressed in eGFR) may therefore provide a better surrogate marker for long-term graft survival.49

This systematic review has its limitations. Current reports are heterogeneous and contain considerable bias. For example, although DBD and DCD donors are essentially different, both are used as control groups in different studies. Such heterogeneity may not be surprising due to the rapid development and innovation in the field. Unfortunately, due to the heterogeneity of the available data, pooled meta-analysis was precluded.

Recommendations and Future Developments

Summarizing, aNRP has been shown to be a feasible and safe strategy and technique, and organs can be successfully transplanted after this procedure. In addition to its successful clinical introduction, however, consensus is needed how to quantify its success by establishing guidelines of aNRP protocols, including viability assessment, acceptance criteria, and outcomes both after uDCD and cDCD donation. With regards to outcomes, studies should report a minimum dataset including 1-year graft and patient survival, image-proven and clearly defined IC in liver transplantation, and 1-year eGFR in kidney transplantation.47-49 Also, we suggest defining the OUR as the number of organs actually transplanted divided by the total number of available organs where procurement was initiated.

In order to be able to definitively answer the question whether aNRP leads to more and hopefully better quality grafts in cDCD donation, future studies should include a prospectively randomized comparison between current standard (cold ISP) and aNRP. Current clinical reports suggest superior outcomes for aNRP; however, many of them are somewhat hindered by selection or reporting bias. Therefore, to date, in many countries, randomized controlled trials are considered. Procurement in abdominal cDCD donors can be randomized to either aNRP or regular cold ISP in the donor. In this regard, the possible effect of end-ischemic perfusion techniques should not be underestimated. Therefore, such trials should be designed taking into account the current “standard of care” strategies in the different countries. This allows for comparison of multiple perfusion technologies and might help elucidating which technique is most effective. In such studies, not only organ utilization and graft survival, but also cost-effectiveness of the labor-intensive procedure will have to be analyzed.

In uDCD donation, a randomized trial may be of less significance and more difficult to achieve, due to the nature of the procurement and the clearer added value of aNRP compared with cold ISP in uDCD donors.

Another future development involves standardization of dual temperature perfusion, integrating aNRP, and thoracic cold ISP for lung procurement. Although this has been undertaken successfully, the experience is limited.44,50 Even combined thoracoabdominal NRP is possible, allowing resuscitation of both heart and lungs according to the promising results reported.51,52

Awaiting future developments on this subject, aNRP is likely to be wider implemented and studied in multiple countries. Standardization of protocols and outcome measures will help to further elucidate its potential positive effect on donor organ utilization and outcomes after transplantation.

ACKNOWLEDGMENTS

We thank J.W. Schoones, clinical librarian, for assistance with the literature search and R.A. Bulder and R.E.A. van de Leemkolk for their support in making the visual abstract.

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