Maintaining the Permanence Principle of Death During Normothermic Regional Perfusion in Controlled Dcd: Results of a Prospective Clinical Study

doi:10.21203/rs.3.rs-2977641/v1

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Maintaining the Permanence Principle of Death During Normothermic Regional Perfusion in Controlled Dcd: Results of a Prospective Clinical Study

https://doi.org/10.21203/rs.3.rs-2977641/v1

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Purpose

The use of normothermic regional perfusion (NRP) in donation after the circulatory determination of death (DCD) is limited by concerns associated with the reestablishment of circulation after death declaration. The aim of this study is to confirm that certain technical maneuvers applied during NRP preclude circulation to the brain.

Methods

A non-randomized trial was performed at two Spanish centers. Consecutive adult controlled DCD donors were included. In abdominal NRP (A-NRP), the thoracic aorta was blocked with an intra-aortic occlusion balloon. In thoraco-abdominal NRP (TA-NRP), the arch vessels were clamped and the cephalad ends vented to the atmosphere. Blood from the vented arch vessels drained to the thorax. The mean intracerebral arterial blood pressure (ICBP) was invasively measured at the circle of Willis.

Results

Ten cDCD donors subject to A-NRP (n = 8) and TA-NRP (n = 2) were included. Mean ICBP and mean blood pressure at the thoracic and the abdominal aorta during the circulatory arrest were 16.9 (SD:3.0), 17.2 (SD:3.0) and 17.6 (SD:4.4), respectively. When A-NRP was started, pressure at the abdominal aorta increased to 49.9 (SD:12.5) mmHg, while the ICBP remained unchanged. When TA-NRP was initiated, pressure at the thoracic aorta reached values of 70.5 (SD:17.7) mmHg, but the ICBP remained unmodified. Registered values of ICBP during NRP were 10 mmHg.

Conclusion

Appropriate technical measures applied during NRP preclude circulation to the brain in DCD procedures. This study can help to expand NRP, respecting the dead donor rule and increasing the number and quality of organs available for transplantation.

Normothermic regional perfusion

donation after the circulatory determination of death

brain perfusion

death donor rule

Appropriate technical measures applied during normothermic regional perfusion (NRP) preclude circulation to the brain in donation after the circulatory determination of death (DCD) procedures

This is the first clinical study that collects coherent and solid measurements that abdominal NRP and thoracoabdominal NRP respect the dead donor rule, increasing the number and quality of organs available for transplantation

Donation after the circulatory determination of death (DCD) has become an important component of deceased organ donation programs [1]. In 2021, 8 545 DCD donors were reported to the Global Observatory on Donation and Transplantation by 22 countries [2]. Of those, 7 771 (91%) were controlled DCD (cDCD) donors -- who had been declared dead after the withdrawal of life-sustaining therapies (WLST) [3].

Because of the inferior transplant outcomes of organs obtained from cDCD donors compared with donors declared dead by neurological criteria, different preservation strategies are used targeted to organ reconditioning and validation prior to their clinical use. Normothermic regional perfusion (NRP) is an in situ preservation method, based on the use of ECMO devices, that allows to perfuse organs with oxygenated blood in normothermia after the determination of death and prior to organ recovery [4]. Perfusion may be limited to the abdominal cavity (A-NRP) or to the thorax and the abdomen (TA-NRP). Compared to the standard rapid recovery (SRR) technique, NRP reduces the incidence of delayed graft function and graft loss of cDCD kidneys [5, 6]. Two multicenter studies have shown the capacity of NRP to reduce the frequency of biliary complications and ischemic-type biliary lesions and to improve graft and patient survival [7, 8]. TA-NRP allows cDCD heart transplant procedures after the in situ validation of the donor heart, with appropriate post-transplant outcomes [9–11]. More recently, the first successful transplant of the small bowel from a cDCD donor has been reported– with the use of NRP [12]. NRP avoids the need to resort to organ-specific ex situ machine perfusion devices with a potential reduction of costs and increased accessibility of patients to good quality cDCD donor organs [13]. Finally, A-NRP has shown to be consistent with the rapid retrieval of lungs [14, 15].

There are legal-ethical concerns that prevent the full expansion of NRP. The reestablishment of circulation in the donor after the declaration of death has raised the debate of whether NRP retroactively invalidates the death of the individual [16]. There is general consensus that death can be declared based on the permanent loss of brain functions, defined by the permanent loss of consciousness, the capacity to breath, and all brain stem functions [17–20]. The permanent loss of brain functions is assured by the permanent absence of circulation to the brain. Thus, the permanence principle of death entails that circulation to the brain should not be restored by an extracorporeal pump as done with NRP. Hence, when NRP is used, some technical maneuvers must be implemented to ensure that flow is limited to organs subject to transplantation and that the brain is excluded [21–24].

The aim of the present clinical study is to confirm, for the very first time, that specific technical maneuvers applied during NRP effectively preclude circulation to the brain, in order to solve the ethical concerns posed by this type of organ preservation procedure.

This is a non-randomized interventional trial, undertaken at two Spanish centers, to assess intracerebral arterial blood pressure (ICBP) during NRP in cDCD procedures. All adult cDCD donors in whom organ recovery was performed with either A-NRP or TA-NRP were included in the study. Consecutive cases were recruited, except when the assessment of ICBP was not feasible due to technical or logistical issues.

Normothermic Regional Perfusion

Specific authorization from the donor or their surrogate decision maker is required for any ante mortem interventions. Peripheral femoral cannulation is performed percutaneously or surgically, followed by heparin administration (300–600 units/kg). Through the contralateral femoral artery or through a double lumen cannula, an intraluminal occlusive balloon is placed in the descending aorta that is inflated once death is declared and before the initiation of A-NRP. With the aim of ensuring that the thoracic aorta is properly blocked, two arterial lines (one from the femoral artery and one from the left radial artery) are monitored during the procedure [25]. WLST usually takes place in the operating room. The circulatory arrest is considered when no pulsatile wave form is observed in the invasive arterial line, respecting a no-touch period of at least 5 minutes to declare death. After the declaration of death, the intra-aortic balloon is inflated and A-NRP is initiated and maintained until organ recovery.

When TA-NRP is performed to recover the heart, once death is declared and A-NRP initiated as described above, a sternotomy is rapidly performed and the pericardium opened. The three aortic arch vessels are ligated and cephalad ends are vented to the atmosphere. Then, the thoracic balloon is de-inflated and TA-NRP started. Simultaneously, the donor is intubated and mechanical ventilation initiated using a FiO₂ of 1, a positive end-expiratory pressure of 5 cm H₂O, and a tidal volume of 6–8 mL/kg. Based on continuous transesophageal echocardiography and mean arterial pressure, noradrenaline, dobutamine, or isoprenaline is administered, when required, to support heart automaticity and contractility. Once the heart spontaneously reverts to sinus rhythm and the heart function is assessed, the TA-NRP is gradually weaned off. The heart function is evaluated by transesophageal echocardiography and visual inspection. Blood from the vented arch vessels drains to the thorax and is reinfused to the circuit to prevent hemodynamic instability. As it is necessary to have an open circuit to reinfuse the drained blood, TA-NRP is performed with conventional extracorporeal circulation. Neuromonitoring from the WLST up to the end of the procedure is continuously performed by bispectral index (BIS).

Assessment of intra-cerebral arterial blood pressure

The potential cDCD donor is transferred to the neuro-intervention theater. Under aseptic conditions and sedo-analgesia, an ultrasound-guided puncture of the common carotid artery is performed. Using the Seldinger technique, a guidewire is inserted up to the internal carotid artery in its cervical segment, serving as support for the placement of a 6 French arterial introducer. A control series is performed through the introducer to verify the absence of post-puncture complications. A 0.014" microwire (Traxcess®-MicroVention) and a hydrophilic microcatheter (Penumbra System® 3MAX™ Reperfusion Catheter) are navigated to the circle of Willis, specifically to the supraclinoid segment of the internal carotid artery (Fig. 1). The microwire is removed. A series is performed through the catheter to confirm its correct positioning and absence of complications. The correct measurement of the ICBP is confirmed by verifying the shape of the pulse wave and consistency of values with those of the radial pressure. The catheter and the introducer are fixed. The potential donor is transferred to the theater, where the usual procedure of WLST and organ donation occurs.

The mean ICBP is monitored every 5 minutes for at least 60 minutes following the start of NRP or until the procedure is ceased, whichever occurs first. The mean ICBP is also monitored at different time points: 1) prior to the WLST; 2) during the WLST; 3) during the circulatory arrest; 4) after A-NRP is started; 5) after TA-NRP is started; 6) when TA-NRP is weaned-off.

Simultaneously, the mean arterial pressure is measured at the thoracic aorta through the left radial line (thoracic pressure) and at the abdominal aorta though the side line of the intra-aortic occlusion balloon or the arterial cannula of the extracorporeal circuit (abdominal pressure).

Variables and statistical analysis

Total warm ischemic time is defined as the time between the WLST and the start of NRP. Functional warm ischemic time is defined as the period extending from the moment the systolic blood pressure in the donor is < 60 mmHg until the start of NRP.

Values of blood pressure are represented in mmHg by the mean and the standard deviation (SD).

Ethics

The study was approved by the Institutional Review Boards of the University Hospital Virgen de la Arrixaca (Murcia, Spain) and the University Hospital Marqués de Valdecilla (Santander, Spain). Authorization was obtained from the donor when first-person consent was possible, or from their surrogate decision maker, following a specific informative process for their participation in the trial.

In total, 10 cDCD donors subject to NRP were included in the study, 8 subject to A-NRP and 2 to TA-NRP. Baseline clinical and demographic data of cDCD donors and details of the DCD procedure are displayed in Table 1. Notably, the conditions that lead to the decision to WLST were variable, including cases of devastating brain injury, progression of neoplasia of the central nervous system and of advanced amyotrophic lateral sclerosis.

Table 1

Baseline clinical and demographic data of cDCD donors, warm ischemia times and data on NRP
	Age (years)	Sex	Cause of death	Comorbidities	Time in the ICU (days)	Total WIT (min)	Functional WIT (min)	Type of NRP	Duration of NRP (min)	Organs recovered	Organs transplanted
1	59	M	CNS neoplasia	Smoking, COPD	2	19	13	A-NRP	101	Liver	Liver
2	38	M	Cerebrovascular accident	Crohn´s disease	2	26 (abdominal) 29 (thoracic)	10 (abdominal) 13 (thoracic)	TA-NRP	31 (abdominal) 28 (thoracic)	Heart, Liver, Kidneys	Heart, Liver, Kidneys
3	54	F	CNS neoplasia	Thromboembolism, epilepsia	3	23	12	A-NRP	123	Liver	Liver
4	51	F	Amiotrophic lateral sclerosis	Smoking	4	16	14	A-NRP	97	Liver, Kidneys	Liver, Kidneys
5	57	M	Anoxic encephalopathy	Ischemic heart disease	11	17	8	A-NRP	87	Liver, Kidneys	Liver, Kidneys
6	34	M	Brain stem infarction (dissection of vertebral artery)	-	11	17 (abdominal) 26 (thoracic)	8 (abdominal) 17 (thoracic)	TA-NRP	21 (abdominal) 12 (thoracic)	Heart, Liver, Pancreas, Lungs, Kidneys	Heart, Liver, Lungs, Kidneys
7	75	M	Intracerebral hemorrhage	Arterial hypertension, diabetes mellitus	11	28	18	A-NRP	83	Lungs, Kidneys	Kidneys
8	68	M	Intracerebral hemorrhage	-	2	20	13	A-NRP	42	Liver, Lungs, Kidneys	Liver, Kidneys
9	57	M	Anoxic encephalopathy	Hypertrophic cardiomiopathy	2	14	7	A-NRP	117	Liver, Kidneys	Liver, Kidneys
10	72	F	Intracerebral hemorrhage		12	29	19	A-NRP	105	Kidneys	-
A-NRP: Abdominal Normothermic Regional Perfusion; CNS: Central nervous system; F: Female; M: Male; TA-NRP: Thoraco-Abdominal Normothermic Regional Perfusion

Figure 2 represents the mean ICBP and the mean blood pressure at the thoracic and the abdominal aorta during the procedure in each individual case. Prior to the WLST, mean values arterial pressure values were 64.4 (SD:10.0), 70.7 (SD:9.3) and 67.7 (SD:10.3) mmHg, respectively. Corresponding values during the circulatory arrest were 16.9 (SD:3.0), 17.2 (SD:3.0) and 17.6 (SD:4.4), respectively.

When A-NRP was started, the blood pressure at the abdominal aorta increased to 49.9 (SD:12.5) mmHg. To the contrary, the ICBP remained stable, with a mean value of 11.9 (SD:3.0 mmHg). Similarly, the blood pressure at the thoracic aorta remained at 17.4 (SD:15.5) mmHg.

In the two cases of TA-NRP, the blood pressure at the thoracic aorta reached values of 70.5 (SD:17.7) mmHg once TA-NRP was started. At this time point, the ICBP was 8 (SD:2.8) mmHg and the blood pressure at the abdominal aorta was 73.5 (SD:19.1) mmHg.

Table 2 displays arterial pressure values during NRP. In the two TA-NRP cases, when TA-NRP was weaned-off and heart automaticity restored, pulsatile pressure was detected at the thoracic and the abdominal aorta. However, the ICBP neither increased, nor became pulsatile.

Table 2

Mean intracerebral arterial blood pressure and mean arterial pressure at the thoracic and the abdominal aorta during normothermic regional perfusion (mmHg).
	A-NRP				TA-NRP
	N	Mean	Min	Max	N	Mean	Min	Max
Intracerebral	10	10	1	17	2	10	8	12
Thoracic Aorta	9*	11	4	18	2	68	60	84
Abdominal Aorta	10	51	33	81	2	60	51	77
The pressure at the thoracic aorta was not registered in case 1. A-NRP: Abdominal Normothermic Regional Perfusion; TA-NRP: Thoraco-Abdominal Normothermic Regional Perfusion*

BIS remained at values of 0 during NRP.

To the best of our knowledge, this is the first clinical study assessing brain flow during NRP. The study shows that, by applying specific maneuvers in NRP, we can effectively preclude circulation to the brain and be respectful with the permanence principle of death.

NRP is an in situ preservation strategy that allows to perfuse organs with oxygenated blood after the determination of death and before the recovery of organs in cDCD procedures. The use of NRP in cDCD has become a standard procedure in several European countries and is now being initiated in the United States [1, 25]. The expansion of NRP is explained by its impact upon the utilization of abdominal organs and improved post-transplant outcomes compared with the SRR procedure [6, 26]. TA-NRP has emerged as an option to make cDCD heart transplantation feasible, without the need of expensive ex situ machine perfusion devices [10, 11, 27].

NRP raises legal and ethical concerns. In particular, restoring systemic circulation after the determination of death can be considered a practice in violation of the dead donor rule (DDR) in some jurisdictions. The permanence principle of death explains why NRP does not retroactively negate the death of the person. Since the cessation of circulation that is relevant to declare death is circulation to the brain, if techniques applied in NRP are effective in excluding the brain, then NRP is respectful with the DDR [23].

The rapid expansion of NRP has occurred without clear and robust evidence of the permanent absence of circulation to the brain. In pioneer programs of TA-NRP for the transplantation of the cDCD heart, the aortic arch vessels were only clamped before TA-NRP was started [28, 29]. A study undertaken in a small sample of pigs showed that the clamping of the arch vessels effectively prevented brain activity, as assessed by electroencephalography, evoked potentials, cerebral blood flow and oxygen uptake [30]. However, ethical concerns persisted since collateral circulation may perfuse the brain despite the clamping of the arch vessels [23, 24] and because of the absence of a human study showing that circulation to the brain could be effectively excluded.

A panel of experts from Canada and the UK recommended not only to ligate the aortic arch vessels, but to also open the cephalad ends to allow them to drain either to atmospheric or negative pressure in order to avoid the potential risk of collateral intercostal arteries establishing brain perfusion when using TA-NRP [24]. The authors described three cases where TA-NRP was used and these maneuvers applied. Approximately 50 mL/min of blood drained from the open distal ends of the arch vessels. It was not clear whether this minimum blood flow might indicate perfusion, and whether such perfusion was sufficient to re-establish brain functions. However, this observation confirmed the potential for collateral blood flow, and made evident that the simple clamp of the arch vessels was not ethically acceptable for the practice of TA-NRP. Additional measures to divert collateral circulation were required, as venting the cephalad ends of the arch vessels to the atmosphere, as performed in the present study.

By using the simultaneous measure of different arterial blood pressures, our experience shows the absence of brain circulation during NRP when such technical measures are implemented. Immediately after the determination of death and the start of A-NRP, the abdominal aortic blood pressure increases to normal values, while the ICBP and the thoracic aortic blood pressure (assessed by the left radial artery) remain static and at values similar to those observed after the circulatory arrest and during the no-touch period (Fig. 2). When TA-NRP is used (Fig. 2, cases 2 and 6), once TA-NRP is started, the blood pressure at the thoracic aorta reaches values similar to those measured at the abdominal aorta, whereas the ICBP remains static at the same values than the ones registered during the circulatory arrest. Moreover, when TA-NRP is weaned off and heart activity restored, a pulsatile pressure becomes evident at the thoracic and the abdominal aorta, with no impact upon the ICBP that remains non-pulsatile. The absence of any increased value of the ICBP once A-NRP or TA-NRP are started and during the entire procedure is the key finding of our study.

In Spain, the national cDCD heart transplant protocol makes mandatory to ligate the aortic arch vessels and to vent them to the atmosphere to exclude brain flow through collateral thoracic circulation, before TA-NRP is started [31]. Our study presents the first human data showing that brain circulation is excluded when using such technical maneuvers, confirming that TA-NRP is consistent with the DDR. Based on our findings, TA-NRP is an appropriate method to increase the utilization of hearts from cDCD donors, as long as the arch vessels are both ligated and vented.

Manara et al. suggested to insert a cannula in the ascending aorta in A-NRP protocols to also avoid brain flow through collateral circulation [24], a proposal that has not been incorporated into the Spanish protocols. The reason for this is that, when the descending aorta is occluded at the level of the diaphragm in A-NRP, all the intercostal vessels are excluded and there is no further collateral circulation to the anterior spinal artery. In addition, the perfusion pressure in A-NRP is low, around 2-2.5 L/min, which is less than half of the normal blood flow and is likely dispersed supplying the abdominal contents and draining into the venous cannula backing to the ECMO circuit. Our results confirm our hypothesis that there is no need to insert a cannula in the ascending aorta, since the ICBP did not increase during A-NRP in our series. This observation is consistent with that of Manara et al. where in 12 cDCD donors subject to A-NRP, the descending aorta was occluded with a surgical clamp or an intraluminal balloon and a cannula inserted in the ascending aorta [24]. No aortic flow was observed in any of the donors and a pressure of 0–3 mm Hg in the cannula was detected. Our results are also consistent with the thousands of cDCD procedures performed with A-NRP in Spain, with no case of resuscitation reported with an appropriate technique, as described in this paper [32].

The main limitation of our study is the reduced number of cases included, in particular of TA-NRP. While it is our intention to enlarge this experience, we consider relevant to report these preliminary data at a moment of a very active debate on whether NRP is consistent with the permanence principle of death. We believe that the assessment of the ICBP at the circle of Willis during the entire procedure is an excellent method to assure the absence of brain circulation. Our preliminary findings are reassuring that the technical maneuvers performed in our NRP protocol are effective in excluding circulation to the brain.

In conclusion, this is the first clinical study that collects coherent and solid measurements using A-NRP and TA-NRP that allows us to discard reperfusion of the brain during the procedure, as long as appropriate technical measures are applied. This includes the blocking of the thoracic aorta in A-NRP and the clamping of the arch vessels along with the venting of the cephalad ends to the atmosphere in TA-NRP. Our study can help to expand the use of NRP worldwide, respecting the DDR and increasing the number and quality of organs available for transplantation.

ACKNOWLEDGEMENT: The authors would like to thank Prof. Francis L Delmonico for a critical review of the manuscript and editorial advice.

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Maintaining the Permanence Principle of Death During Normothermic Regional Perfusion in Controlled Dcd: Results of a Prospective Clinical Study

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Normothermic Regional Perfusion

Assessment of intra-cerebral arterial blood pressure

Variables and statistical analysis

Ethics

RESULTS

DISCUSSION

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