**4.1 Kidney transplantation**

*Advances in Extracorporeal Membrane Oxygenation - Volume 3*

During thoracoabdominal NRP, pump flow is maintained ≥2.5 L/min/m<sup>2</sup>

lary wedge pressure ≤12 mmHg, cardiac index ≥2.5 L/min/m<sup>2</sup>

ejection fraction ≥50% [15–17].

*supraceliac abdominal or thoracic aorta.*

**after circulatory death**

perature 35°C, and hemoglobin >10 g/dL. Prompt laparotomy is performed to assess hepatic and intestinal perfusion and to exclude the lower extremities from the perfusion circuit. Once cardiac contractility has been restored, weaning from NRP is attempted. If the heart is able to take over circulation, functional assessment is performed using transesophageal echocardiography and pulmonary artery flotation catheter (Swan-Ganz) monitoring. In general, acceptance criteria for a cDCD heart recovered with NRP include central venous pressure ≤12 mmHg, pulmonary capil-

*Abdominal normothermic regional perfusion. Cannulae are placed in the femoral artery and vein in the groin region. A Fogarty balloon catheter is introduced through the contralateral femoral artery and positioned in the* 

**4. Clinical outcomes using normothermic regional perfusion in donation** 

To date, the great majority of human transplants performed using organs recovered with NRP have been donor using DCD kidneys and livers. In more recent years, the use of DCD pancreata and even hearts recovered with NRP has also been

, tem-

, and left ventricular

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reported.

**Figure 2.**

When compared with other solid organs for transplantation, the kidney is relatively resilient and withstands the ischemic insult inherent to the DCD process relatively well. Nonetheless, kidneys from DCD donors recovered with NRP as opposed to rapid *in situ* cold preservation or hypothermic perfusion/"total body cooling" (TBC) have demonstrated significantly better immediate as well as ongoing graft function [18–20]. Reports from different groups in Europe, the United States, and Asia have described the use of NRP in both uDCD and cDCD kidney transplantation, with rates of delayed graft function (DGF) around 50–70% and 30–40%, respectively; negligible (if any) primary non-function (PNF); and excellent 1-, 5-, and even 10-year graft survival rates [19–27]. While reported rates of DGF may still seem to be high even among DCD kidneys recovered with NRP (especially those arising through uDCD), the pathogenesis and, consequentially, implications of DGF seem to be less severe than those associated with DGF arising in the context of DBD kidney transplantation. Ischemic injury appears to be implicated to a greater extent in the development of DGF among DCD kidneys, whereas, in DBD, alloimmune phenomena prevail [28]. A recent large single-center study reported 73% DGF among 237 uDCD kidneys recovered with NRP versus 46% among a contemporary cohort of matched DBD kidneys, but 10-year graft survival rates did not vary at all between the two groups and were excellent in both (82 and 80%, respectively). The authors also noted that while donor age >50 years was significantly associated with graft loss among uDCD kidneys, the development of DGF in the immediate post-transplant period was not [27].

### **4.2 Liver transplantation**

The cells of the liver, in particular those lining the biliary tree, are particularly sensitive to warm ischemia, and initial experiences with DCD liver transplantation described high rates of graft dysfunction and non-function and non-anastomotic biliary strictures/ischemic type biliary lesions (ITBL) in up to 50% of cases [29]. While complication rates have improved with experience, the rate of post-transplant ITBL remains higher among recipients of DCD versus DBD grafts: 16 versus 3%, according to two meta-analyses [30, 31]. The clinical relevance of ITBL lies in the fact that up to 70% of patients with ITBL require re-transplantation or die [32].

After an initial period where different donor maintenance techniques were used, including rapid *in situ* cold preservation, simultaneous chest and abdominal compressions, and TBC, NRP has come to be the "gold standard" and primary means by which uDCD livers are recovered for transplantation. Using NRP, even livers with extensive pre-recovery warm ischemic periods of up to 2.5 hours have been successfully transplanted, with biliary complication and graft survival rates comparable to those seen using cDCD livers that have suffer considerably less warm ischemia [10, 11, 33–35].

In spite of its relative success in the setting of uDCD, the application of NRP in cDCD liver transplantation remains more limited. The great majority of cDCD livers that are transplanted in the world today are still recovered with rapid *in situ* cold preservation, and reports on the use of NRP in cDCD liver transplantation have been, until recently, anecdotal [12, 24–26, 36, 37]. In the past year, however, two larger multicenter studies have come out describing the benefits that may be achieved with post-mortem NRP in cDCD liver transplantation. First, a Spanish national study compared the results of 95 cDCD liver transplants performed with post-mortem NRP with those of 117 cDCD liver transplants performed with super rapid recovery (SRR). Median donor age in the study was relatively high (57 years [25-75% interquartile range, IQR 45–65] NRP, 56 years [25-75% IQR, 47–64] SRR). With a median

follow-up of 20 months, the use of post-mortem NRP appeared to significantly reduce rates of postoperative biliary complications (overall 8% NRP vs. 31% SRR, *p* < 0.001; ischemic type biliary lesions 2% NRP vs. 13% SRR, *p* = 0.008) and graft loss (12% NRP vs. 24% SRR, *p* = 0.008) [38]. Similarly, a combined experience from centers in Cambridge and Edinburgh in the United Kingdom compared the results of 43 cDCD liver transplants performed with post-mortem NRP with those of a contemporary cohort of 187 cDCD liver transplants performed with SRR. Median donor age was less for cDCD livers with NRP versus those with SRR: 41 years (25-75% IQR 33–57) vs. 54 years (25-75% IQR 38–63), respectively. Reported rates of anastomotic biliary strictures were 7% NRP vs. 27% SRR (*p* = 0.004), ITBL 0 NRP vs. 27% SRR (*p* < 0.001), and 90-day graft loss 2% NRP vs. 10% SRR (*p* = 0.102) [39].

#### **4.3 Pancreas transplantation**

The Michigan Group described one cDCD pancreas transplant in which the donor was maintained with NRP, though the outcome of the graft was not mentioned [24]. In another multicenter report from the United Kingdom, two SPK were described (again, outcomes not mentioned), and two more pancreata were sent for isolation of islets, one with good yield [25]. In Spain, where NRP is now routinely used to recover abdominal organs when cDCD liver and/or pancreas transplantation is contemplated, a total of five cDCD pancreas transplants were performed between 2015 and 2017, and all these grafts remain functional at the time of this writing [40].

#### **4.4 Heart transplantation**

The application of thoracoabdominal NRP has been described in clinical series on cDCD heart transplantation; however, no report has been published to date describing the transplantation of the lungs from these same cDCD donors. (Transplantation of DCD lungs recovered with "dual temperature" *in situ* cold flushing in the chest with abdominal NRP running simultaneously, on the other hand, has been described and is performed routinely in some settings.) The fact remains that DCD donor lungs tolerate warm ischemia and the process of DCD donation and recovery relatively well, and post-DCD lung transplantation outcomes without NRP appear to be comparable to those of DBD lung transplantation [41].

The cDCD heart, on the other hand, is more susceptible to warm ischemic injury, and cDCD hearts recovered and transplanted after *in situ* cold preservation followed by static *ex situ* cold storage can offer suboptimal outcomes. A recent report on pediatric cDCD heart transplantation describes 61% 1-year graft survival as opposed to 91% for DBD hearts of similar baseline characteristics [42]. Performing thoracic NRP, on the other hand, allows for restoration of contractile function and performance of a standard functional assessment in ischemically injured cDCD cardiac allografts prior to recovery. Clinical application of thoracoabdominal NRP in cDCD heart transplantation has been described by the Papworth Hospital Group from the United Kingdom. In combination with subsequent *ex situ* normothermic machine perfusion (NMP), the use of thoracoabdominal NRP has allowed 100% utilization of organs subsequently undergoing NMP and lower early allograft dysfunction versus cDCD hearts undergoing NMP only (8% vs. 17%, respectively) [16, 17]. Thoracoabdominal NRP followed by static cold storage has even been used to successfully transplant a cDCD heart procured at the same center [17]. If broader application of this last strategy is shown to be just as efficacious, it has the potential to significantly reduce the costs associated with cDCD heart transplantation by obviating the need for *ex situ* NMP, which is a very expensive modality costing approximately \$45,000 for each heart perfusion unit.

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*Normothermic Regional Perfusion in Solid Organ Transplantation*

not NRP may be applied in DCD and, if so, how and when.

**5.1 Uncontrolled donation after circulatory death**

**5.2 Controlled donation after circulatory death**

**5. Ethical and legal concerns surrounding the use of normothermic** 

There are some ethical concerns surrounding the use of NRP in donation after circulatory death, and laws vary from one country to another regarding whether or

In uDCD, cardiac arrest is sudden and unexpected, and death is declared based on the irreversible loss of cardio-respiratory function (demonstrated after prolonged efforts to reverse it have failed). Death is usually declared in the emergency room by a team entirely independent of that responsible for organ recovery and preservation. More often than not, potential uDCD donors are declared dead prior to the arrival of next-of-kin. Based on a consequentialist ethical standpoint and the principles of utility and donor autonomy, certain countries, including Spain and France, allow cannulation maneuvers to commence in this setting, even in cases where first-person consent may not have yet been obtained [43, 44]. The will of the patient regarding donation is always subsequently investigated in the context a family interview, where information regarding the circumstances of the arrest, the outcome of resuscitation maneuvers, and the measures taken related to the donation process is relayed. Next-of-kin then decide, taking into consideration the potential donor's wishes, whether to proceed with donation or abort the process. It should be clear that NRP is organ maintenance and not therapy. While the technology employed is similar, terms such as "extracorporeal membrane oxygenation/ECMO" and "extracorporeal life support/ECLS" should not be used in relation to organ donation. Such terminology is confusing, especially considering the fact that it is used to describe therapeutic maneuvers that may be used to recover patients suffering sudden cardiac arrest more commonly occurring inside the hospital itself.

In cDCD, the usual stand-down period of 2–5 min of asystole that is used to declare death does not necessarily reflect an irreversible loss of cardiac function, evidenced by the fact that cDCD hearts have been recovered and successfully transplanted [17, 45]. The "irreversibility" of death in cDCD is therefore predicated on the concept of permanence—the fact that loss of cardiac function will eventually become irreversible because it will not be reversed (and eventually lead to the loss of all brain and brain stem functions, as well). As it re-establishes circulation to some parts of the body, however, the use of NRP in this context remains controversial. At the least, clear and effective measures need to be put in place to ensure that cerebral reperfusion does not occur when NRP is established. Through the use of NRP, circulation is only restored to a limited region of the body, and a critical aspect of NRP in cDCD is ensuring lack of flow to the aortic arch vessels, thereby maintaining the permanence of circulatory arrest in the brain and brainstem. With pre-mortem cannulation, positioning of the aortic occlusion balloon in the supradiaphragmatic aorta distal to the left subclavian artery is confirmed radiographically prior to withdrawal of care. As additional measure, the aortic occlusion balloon may be briefly inflated for a few seconds prior to ventilatory withdrawal, in order to ensure disappearance of femoral arterial pressure and simultaneous maintenance of a normal pressure waveform in the left radial arterial line. In doing so, the minimum filling volume needed to entirely blocks the supradiaphragmatic aorta may be recorded [46]. Once NRP is initiated, adequate occlusion is confirmed through the use of a left radial artery catheter demonstrating absence of flow.

**regional perfusion in donation after circulatory death**

*DOI: http://dx.doi.org/10.5772/intechopen.84771*

*Advances in Extracorporeal Membrane Oxygenation - Volume 3*

**4.3 Pancreas transplantation**

**4.4 Heart transplantation**

follow-up of 20 months, the use of post-mortem NRP appeared to significantly reduce rates of postoperative biliary complications (overall 8% NRP vs. 31% SRR, *p* < 0.001; ischemic type biliary lesions 2% NRP vs. 13% SRR, *p* = 0.008) and graft loss (12% NRP vs. 24% SRR, *p* = 0.008) [38]. Similarly, a combined experience from centers in Cambridge and Edinburgh in the United Kingdom compared the results of 43 cDCD liver transplants performed with post-mortem NRP with those of a contemporary cohort of 187 cDCD liver transplants performed with SRR. Median donor age was less for cDCD livers with NRP versus those with SRR: 41 years (25-75% IQR 33–57) vs. 54 years (25-75% IQR 38–63), respectively. Reported rates of anastomotic biliary strictures were 7% NRP vs. 27% SRR (*p* = 0.004), ITBL 0 NRP vs. 27% SRR

(*p* < 0.001), and 90-day graft loss 2% NRP vs. 10% SRR (*p* = 0.102) [39].

The Michigan Group described one cDCD pancreas transplant in which the donor was maintained with NRP, though the outcome of the graft was not mentioned [24]. In another multicenter report from the United Kingdom, two SPK were described (again, outcomes not mentioned), and two more pancreata were sent for isolation of islets, one with good yield [25]. In Spain, where NRP is now routinely used to recover abdominal organs when cDCD liver and/or pancreas transplantation is contemplated, a total of five cDCD pancreas transplants were performed between 2015 and 2017, and all these grafts remain functional at the time of this writing [40].

The application of thoracoabdominal NRP has been described in clinical series on cDCD heart transplantation; however, no report has been published to date describing the transplantation of the lungs from these same cDCD donors. (Transplantation of DCD lungs recovered with "dual temperature" *in situ* cold flushing in the chest with abdominal NRP running simultaneously, on the other hand, has been described and is performed routinely in some settings.) The fact remains that DCD donor lungs tolerate warm ischemia and the process of DCD donation and recovery relatively well, and post-DCD lung transplantation outcomes without NRP appear to be comparable to those of DBD lung transplantation [41]. The cDCD heart, on the other hand, is more susceptible to warm ischemic injury, and cDCD hearts recovered and transplanted after *in situ* cold preservation followed by static *ex situ* cold storage can offer suboptimal outcomes. A recent report on pediatric cDCD heart transplantation describes 61% 1-year graft survival as opposed to 91% for DBD hearts of similar baseline characteristics [42]. Performing thoracic NRP, on the other hand, allows for restoration of contractile function and performance of a standard functional assessment in ischemically injured cDCD cardiac allografts prior to recovery. Clinical application of thoracoabdominal NRP in cDCD heart transplantation has been described by the Papworth Hospital Group from the United Kingdom. In combination with subsequent *ex situ* normothermic machine perfusion (NMP), the use of thoracoabdominal NRP has allowed 100% utilization of organs subsequently undergoing NMP and lower early allograft dysfunction versus cDCD hearts undergoing NMP only (8% vs. 17%, respectively) [16, 17]. Thoracoabdominal NRP followed by static cold storage has even been used to successfully transplant a cDCD heart procured at the same center [17]. If broader application of this last strategy is shown to be just as efficacious, it has the potential to significantly reduce the costs associated with cDCD heart transplantation by obviating the need for *ex situ* NMP, which is a very expensive

modality costing approximately \$45,000 for each heart perfusion unit.

**192**
