Clamping of the Aortic Arch Vessels During Normothermic Regional Perfusion Does Not Negatively Affect Donor Cardiac Function in Donation After Circulatory Death : Transplantation

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Original Basic Science

Clamping of the Aortic Arch Vessels During Normothermic Regional Perfusion Does Not Negatively Affect Donor Cardiac Function in Donation After Circulatory Death

Moeslund, Niels MD1,2; Zhang, Zhang Long MD3; Dalsgaard, Frederik Flyvholm MS1,2; Glenting, Sif Bay MD2; Ilkjaer, Lars Bo MD4; Ryhammer, Pia MD5; Palmfeldt, Johan PhD6; Pedersen, Michael PhD2; Erasmus, Michiel MD, PhD3; Eiskjaer, Hans MD, DMSc1

Author Information
Transplantation 107(1):p e3-e10, January 2023. | DOI: 10.1097/TP.0000000000004298
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Abstract

INTRODUCTION

Organs donated after circulatory death (DCD) have in recent years been established as a valuable addition to the donor organ pool. Especially, transplantation of abdominal organs has gained ground in several European countries.1,2 Controlled DCD, where the decision is made to withdraw life-sustaining therapies, is now the predominant form of DCD donation.3 Circulatory death inevitably exposes the potential donor organs to warm ischemia. The heart and liver are especially susceptible to warm ischemic damage and prohibit direct transplantation without some form of reperfusion and preservation. To mitigate ischemic damage and enable in situ organ reanimation and evaluation, normothermic regional perfusion (NRP) using extracorporeal membrane oxygenation has been established.4 NRP restores the flow of oxygenated blood and energy supply and reanimates the organ function.2 However, by resumption of central arterial blood flow, restoration of cerebral perfusion and subsequent activity may occur.5

It is debated whether reperfusion of the brain after circulatory death is ethically acceptable‚ as the donor has been declared dead by circulatory criteria (cessation of pulse and breathing for typically 5 min6) and not by neurological testing for brain death. Controversially, reperfusion of the brain has shown to restore some brain activity in pigs.7 Following this finding, we have demonstrated that clamping of the aortic arch vessels (AAVs) sufficiently prevents restoration of cerebral blood flow and electrical activity.7 However, little is known about the hemodynamic and inflammatory effects following clamping of the AAV in relation to DCD donation.

This study aimed to perform a randomized intervention-control study on donor heart function after clamp-NRP with clamping of AAV versus no clamp after circulatory death. We hypothesized that clamping provides superior perfusion, reduces use of vasopressors, and improves donor cardiac performance compared with no clamping.

MATERIALS AND METHODS

The study was approved by the Danish National Committee on Animal Research Ethics (2018-15-0201-01603) and conducted in accordance with the Principles of Laboratory Animal Care.

Anesthesia, Monitoring, and Surgical Procedure

Seventeen female Danish Landrace pigs approximately 80 kg were instrumented. Premedication of Zoletil Vet 50 (ketamine [6.25 mg/mL], tiletamine [6.25 mg/mL], benzodiazepine [6.25 mg/mL], synthetic opioid [butorphanol] [1.25 mg/mL], and xylazine [6.5 mg/mL]) was administered at the stable facility before transport to the surgical facilities. Upon arrival, the animals were orally intubated and mechanically ventilated with a tidal volume of 8 mL/kg, FiO2 of 40%, positive end-expiratory pressure of 5 cm H2O‚ and respiratory frequency of 12 to 15 to maintain an end-tidal CO2 of 4.5 to 5.6 kPa. Anesthesia and analgesia were maintained with propofol (3.5 mg/kg/h) and fentanyl (15 μg/kg/h). Infusion of amiodarone (10 μg/kg/min) and a bolus of 100 mg lidocaine were administered to stabilize heart rhythm during the experiment. Via the right femoral artery, an aortic occlusion balloon was advanced to the abdominal aorta above the iliac bifurcation. A central venous line was placed in the left external jugular vein‚ and a Swan-Ganz (7.5F CCOmbo, Edwards Lifescience, Irvine‚ CA, USA) (PA) catheter was inserted through the right external jugular vein and positioned to measure CO and wedge pressure. A median sternotomy was performed‚ and umbilical tapes were placed around the AAVs and inferior vena cava. Heparin (40 000 IU) was administered to achieve systemic anticoagulation. Pressure–volume admittance catheters, 7Fr (Transonic Systems, Ithaca, NY)‚ were inserted in the right and left ventricles via the right external jugular vein and left carotid artery, respectively, before cannulation of the ascending aorta and right atrium for the NRP circuit. A cardioplegia cannula was inserted in the pulmonary artery for blood sampling. After instrumentation, approximately 90 min of stabilization period was observed before baseline parameters were recorded and blood and tissue were sampled.

DCD and NRP

After recording of baseline parameters, the mechanical ventilation was disconnected, resulting in asphyxiation and circulatory arrest. Functional warm ischemic time (fWIT) was defined as the time from systolic blood pressure <50 mm Hg to the onset of reperfusion. Asystole was determined as central venous pressure (CVP) = mean arterial pressure (MAP). An additional 8 min of warm ischemic period was observed after asystole to uphold a “5-min no touch” and mimic the preparation time for NRP in clinical settings. Three minutes before reperfusion, blood and tissue samples were acquired, the abdominal aortic balloon was inflated and pulled distally to the iliac bifurcation, and the animal was randomized to nonclamp-NRP or clamp-NRP. The animals were randomized 1:1 in pairs, with the carotid artery umbilical tapes snared tight in the clamp group.

After the 8-min asystole period, NRP was commenced, and the ventilation was restarted with a FiO2 60% and titrated to partial pressure O2 levels between 12 and 16 kPa. The extracorporeal circuit, comprising a standard cardiopulmonary bypass extracorporeal membrane oxygenator, centrifugal pump, and heat exchanger, was primed with 1000 mL Ringers lactate, 100 mL 8.4% sodium bicarbonate, and 200 mL mannitol. At 15 min after onset of NRP, infusion of dobutamine (2.5 μkg/kg/min) was started and the heart gradually loaded and weaned from NRP. At 5-min intervals, arterial and mixed venous blood samples were collected. Biochemical parameters including arterial pH, K+, Ca2+, and glucose were corrected during NRP as reported earlier by our group.8 After the 30-min NRP period, the animal was fully weaned and observed for 180 min post-NRP with regular measurements of hemodynamic parameters, contractility, blood, and tissue samples at 15, 30, 60, 120, and 180 min post-NRP.

Cardiac Functional Assessment

Cardiac output (CO) measurements were obtained by thermodilution technique from the PA catheter. The admittance catheters were calibrated according to the manufacturer's specifications. Load independent contractility of the left ventricle (LV) and right ventricle (RV) was assessed using the end-systolic elastance (Ees). Diastolic function was assessed using Tau and dP/dt min. Pressure–volume data were also used to measure load-dependent hemodynamic measures: stroke volume, end-diastolic and end-systolic volumes, arterial elastance, and dP/dt max.

Biochemistry

Arterial and mixed venous samples were analyzed for partial pressures of oxygen, carbon dioxide, and lactate (ABL90 Flex Plus; Radiometer Medical, Denmark).

Inflammatory Response

Cytokine plasma levels were measured at baseline, 5 min after asystole, 30 min after NRP commencement‚ and 60 and 180 min after weaning from NRP. The Millipore MILLIPLEX porcine chemokine array (GMCSF, IFN-γ, IL-1ra, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-18, and TNF-α) was analyzed with the Luminex platform, Magpix (Millipore Corp, Burlington‚ MA‚ USA).

Statistical Analysis

Data were checked for normality by qq-plots. Group difference is shown as mean ± 95% confidence interval. Continuous data were analyzed using a linear mixed regression effects model. The linear mixed regression effects model was used to allow for repeated measures, taking the study design into account‚ and to allow for analysis of parameters containing missing data. The model was used to compare outcomes between intervention groups with intervention group and time as fixed effects and subjects as random effects. Fisher exact test was used for comparison of categorical data. Mann-Whitney and Student’s t tests were used to compare data when appropriate. P < 0.05 were considered statistically significant. Stata‚ version 15.1 (StataCorp, TX)‚ and GraphPad Prism‚ version 9.0 (GraphPad Software LCC, CA)‚ were used for analyses.

RESULTS

Protocol Feasibility

Seventeen animals were instrumented, and hereof 2 animals developed ventricular fibrillation before baseline measurements; 1 animal was quickly resuscitated and showed total recovery of vital parameters‚ and the other animal could not be resuscitated and was withdrawn from the study. Thus, 16 animals were included in the study and completed circulatory death, NRP, and subsequent repeated functional assessment. There was no difference in time from withdrawal of life-sustaining therapies to asystole between groups (8.6 ± 1.7 min in the clamp group and 8.9 ± 2.1 min in the nonclamp group, P = 0.80)‚ nor was there any difference in the fWIT (clamp: 12.3 ± 2.6 min and nonclamp: 12.6 ± 1.9 min, P = 0.75).

Hemodynamics

No pigs in either groups showed signs of profound vasoplegia or hemodynamic instability post-NRP (Figure 1). The mean arterial blood pressure was kept >60 mm Hg by titration of norepinephrine (NE) dosage‚ which was significantly higher in the nonclamp group (0.13 μg/kg/min) than in the clamp group (0.06 μg/kg/min) with a group difference of 0.071 (95% confidence interval: 0.010; 0.13 μg/kg/min) from start of NRP to 180 min post-NRP (Figure 1A). NE requirements increased in the final stages of weaning reflected in the dip in MAP at 20 and 25 min after the start of NRP; however, NE infusion was quickly reduced in the first 60 min post-NRP. The systemic vascular resistance (SVR) reflected NE infusion until 90 min post-NRP, where systemic vascular resistance continued to decrease in the nonclamp group despite increased NE infusion, whereas clamp systemic vascular resistance remained at baseline levels until 180 min post-NRP. Mean pulmonary artery pressure increased nonsignificantly post-NRP to a stable plateau with a tendency to higher mean pulmonary arterial pressure in the nonclamp group. CO developed significantly different between groups, with stable CO by 90 min post-NRP in the clamp group and increasing CO during the whole post-NRP period in the nonclamp group. CVP and pulmonary capillary wedge pressure were stable in both groups post-NRP, suggesting that no left or right ventricular failure was developed. The heart rate was significantly elevated from baseline in both groups after commencement of NRP. Post-NRP, Heart rate (HR) in the clamp group increased significantly compared with the nonclamp group by 90 min post-NRP.

F1
FIGURE 1.:
Hemodynamic function measured by invasive arterial catheter and SG catheter. A, Norepinephrine infusion from onset of NRP until 180 min post-NRP. (B) Systemic vascular resistance, (C) cardiac output, (D) mean arterial pressure (E) mean pulmonary artery pressure, (F) heart rate, (G) central venous pressure, and (H) pulmonary capillary wedge pressure. *Only the baseline measurement and post-NRP measurements are included in the statistical analysis. CA, circulatory arrest; NRP, normothermic regional perfusion.

Heart Function

Overall, biventricular heart function was preserved post-NRP (Figure 2). Left ventricular EF and biventricular stroke work showed small nonsignificant variations post-NRP with no group difference. Biventricular arterial elastance as a measurement for ventricular afterload increased significantly post-NRP with significantly higher LV afterload at 15 min post-NRP in the nonclamp group, which is also reflected in the significantly higher NE infusion at that time point; as NE infusion was similar between groups from 30 min post-NRP and onward, LV arterial elastance showed no between groups difference. Preload-dependent dP/dtmax showed improved ventricular systolic pressure generation post-NRP most predominant for the LV, whereas RV dP/dtmax only was significantly improved in the clamp group. Ventricular relaxation measured as dP/dtmin showed no signs of impaired diastolic function in both ventricles and between groups, and the HR-dependent active ventricular relaxation constant Tau decreased significantly post-NRP in both ventricles and for both groups as expected by the increased HR post-NRP indicating no signs of impaired active relaxation and diastolic function. Preload-independent LV contractility measured by Ees increased significantly post-NRP in both groups, which may indicate LV contractile reserve in response to inotropic support.

F2
FIGURE 2.:
Cardiac function measured by admittance catheters. A, LV ejection faction. B, Biventricular stroke work. C, Arterial elastance‚ a measurement of ventricular afterload. D and E, Derivative of ventricular pressure change, a load-dependent measurement of contractility and relaxation. F, Tau‚ a measurement of active load independent ventricular relaxation. G, End-systole elastance, a measurement of load independent ventricular contractility. LV, left ventricle; NRP, normothermic regional perfusion; RV, right ventricle.

Arterial Blood Gas

Oxygenation was similar in the 2 groups. Partial pressure O2 increased significantly in both groups during NRP compared with baseline and returned to baseline levels post-NRP. Mixed venous saturation increased likewise during NRP and returned to baseline levels post-NRP, with a tendency to higher oxygenation post-NRP in the clamp group‚ as can be seen in Figure 3. Arterial CO2 showed diverging trends post-NRP with clamp CO2 showing a slight decreasing trend post-NRP, whereas nonclamp CO2 showed an increasing trend post-NRP. Arterial lactate was similar in the 2 groups except from 120 min post-NRP‚ where the nonclamp group showed a trend to better lactate clearance.

F3
FIGURE 3.:
Blood gasses. A, partial pressure of dissolved oxygen in arterial blood. B, Oxygen saturation of mixed venous blood. C, partial pressure of dissolved CO2 in arterial blood. D, Arterial lactate concentration. CA, circulatory arrest; NRP, normothermic regional perfusion.

Inflammatory Response

Inflammatory cytokines were measured at baseline right before withdrawal of life-sustaining therapies, at circulatory arrest, at the end of NRP‚ and at 60 and 180 min post-NRP. The majority of the inflammatory cytokines were stable throughout the observation period post-NRP. However, notable proinflammatory cytokines IL-1β and IL-6 increased significantly in both groups with no between group differences‚ as can be seen in Figure 4.

F4
FIGURE 4.:
Relative change in cytokines from baseline. (A–I) Proinflammatory cytokines and (J–M) anti-inflammatory cytokines. CA, circulatory arrest; GMCSF, granulocyte macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; NRP, normothermic regional perfusion; TNF‚ tumor necrosis factor.

DISCUSSION

We found that occlusion of both the lower body (infrarenal aorta) and upper body (AAVs) resulted in isolated thoracoabdominal perfusion during and post NRP‚ which resulted in significant reduction of NE use while maintaining an adequate organ perfusion pressure of MAP >60 mm Hg. Clamping of the AAV did not seem to have detrimental effects on the cardiac function, which was similar in the 2 groups, and this effect was preserved at or even improved from baseline levels (left ventricular contractility) post-NRP in both groups. Exclusion (clamping the AAV) of a larger body volume (arms and head) in the clamp group did not result in any higher pro- or anti-inflammatory response, which potentially could harm the donor organs. In addition, we found that hemodynamic parameters remained stable for 180 min post-NRP despite differences in circulating volumes.

There is generally no consensus about the most optimal NRP duration‚ and different optimal reperfusion periods may exist for different organs.9 The lungs have been shown to withstand ischemia and may in fact become negatively affected by TA-NRP because of the known negative effects of cardiopulmonary bypass,3,4 whereas prolonged perfusion of the abdominal organs post-NRP is desired to mitigate the warm ischemic damage.4,10 Van de Leemkolk et al reported varying abdominal NRP durations for the kidney (median 150 min) and liver (median 123 min), respectively. There is large variation in the duration of TA-NRP in the reported cases for DCD TA-NRP heart transplantation, ranging between 5 and 190 min with a median of 56 min.11–14 TA-NRP duration is generally shorter than abdominal NRP, but TA-NRP perfusion of the abdominal organs is continued as the donor heart supports the circulation post-NRP. Only 2 groups reported reperfusion time after wean from NRP, ranging between 98 and 12512 and 20 and 89 min,13 respectively. In the latter study, they reported total reperfusion times between 41 and 134 min with procurement and transplantation of the liver, kidneys, and heart.13 We demonstrated in this study that post-NRP perfusion can safely be performed for 180 min post-NRP to accommodate the need for longer abdominal reperfusion with no adverse effects on donor post-NRP cardiac function.

This study is the first to investigate the effects of different circulating volumes during NRP. Although abdominal NRP has been extensively investigated,4 only case reports of liver and kidney transplantation after TA-NRP have been published, showing promising results of abdominal organ transplantation after TA-NRP.12–14 However, it remains unknown if TA-NRP affects abdominal organs differently than isolated abdominal NRP. We found that a larger effective circulation volume required a larger NE infusion to maintain adequate perfusion pressure. The use of NE has previously been reported to negatively affect kidney graft survival.15,16 This finding supports that only organs expected to be donated should undergo reperfusion during NRP to minimize the use of vasoactive drugs. We argue that the marginally higher contractility in the clamp group was due to a reduction in perfused volume compared with the nonclamp group, thus yielding an effectively higher plasma concentration of dobutamine; this was also reflected in the lower infusion rate of NE to sustain the same MAP.

The overall improved LV function in both groups post-NRP is indicative of preserved LV inotropic reserve. These findings are in line with previous porcine studies by Ali et al and Ribeiro et al‚ who also found increased LV contractility after DCD and cardiac reanimation with NRP.17,18 Ali et al found a massive increase of endogenous catecholamines released following DCD and NRP, which can be a contributing factor to increased LV contractility compared with baseline measurements before DCD. Conversely, both studies reported signs of impaired RV function following NRP with reduced ejection fraction, CO, and stroke work. These findings are supported by similar studies with brain dead donors, demonstrating an inversely correlated relationship between donor NE administration and RV contractility.19,20 The RV is susceptible to damage from high catecholamine concentrations in the donor. In addition, porcine studies on physiological and pathophysiological trends during hypoxic circulatory death have shown that the RV is prone to distension as circulatory arrest occurs.21,22 Distension of the thin-walled RV impairs myocardial perfusion that can exacerbate ischemic damage to the RV compared with the LV that does not distend during circulatory death. We found no signs of impaired RV function in this study with preserved RV load independent of Ees, CO, stroke work, and low CVP.

These findings are likely a result of the short fWIT and circulatory arrest used in this study compared with similar studies that have reported fWIT times of >20 min in contrast to an fWIT of 12 min in the present study. In another study by our group,8 we found a massive increase of proinflammatory cytokines during and post NRP where the animals were exposed to 15 min circulatory arrest. Contrary to this finding, we found that most inflammatory cytokines remained on baseline levels in this study, underscoring the importance of minimizing the damaging warm ischemic time and circulatory arrest as much as possible, which can be accomplished by antemortem actions such as heparinization and placement of femoral guidewire for fast cannulation. These actions are governed by national legislations that regulate which measures can be performed ante- or postmortem.

One controversial action that could expedite TA-NRP after declaration of circulatory death would be disregarding the generally accepted ethical mandate to exclude cerebral reperfusion. It has been speculated that cerebral reperfusion during NRP can have detrimental effects on organ function because of the risk of a sympathetic storm releasing massive amounts of endogenous catecholamines, inflammatory cytokines‚ and complement activation.19,20,23 In our study, we found no indications of cerebral incarceration as seen by the Cushing’s reflex24 or affected cardiac function in either the clamp or nonclamp groups. Neither did we find indications that systemic inflammation could be increased from clamping the AAV. This leads to the conclusion that, from a physiological perspective, clamping the AAV in the DCD NRP setting does not negatively influence organ function and may improve organ perfusion be reducing the effective circulating volume. This is in line with the general consensus that brain reperfusion during NRP must not be allowed because of risk of restoration of brain activity.5 We confirmed restoration of brain activity in a study of cerebral perfusion and activity following DCD and NRP in the animals from the present study.7 We found that cerebral reperfusion restored some kind of cerebral activity in all animals in the nonclamp group. Ethics mandate to uphold the permanence of death by AAV clamping when performing TA-NRP‚ and we have now shown no negative cardiac or inflammatory effects of AAV clamping during NRP.

LIMITATIONS

A major limitation of this study is that the donor hearts were not transplanted; hence, it remains unknown if cerebral reperfusion negatively impacts the heart after transplantation. However, hemodynamic function and cardiac performance were on levels similar to porcine DCD NRP studies where transplantation was performed.17,18 During the resuscitation phase, there may have been systematic differences in treatment between the groups. This was expected‚ as we used a goal-directed clinically relevant treatment approach. The goal of a mean arterial blood pressure of >60 mm Hg was achieved in both groups without statistical differences in MAP between the groups. In this study, we used a relatively short fWIT (approximately 12 min) compared with other NRP studies. This choice was made because of our interest in cerebral reperfusion where short fWIT increases the risk of cerebral activity after reperfusion. We found excellent biventricular cardiac function post-NRP; this highlights the importance of minimizing the warm ischemic time as much as possible for preservation of donor graft function in donation after circulatory death.

We used 8 animals in each group, which may have led to some results not reaching significance. However, on our main endpoint of NE infusion‚ we found statistical significance‚ and with this being a hypothesis-generating study‚ only large differences were expected to be found. In our data‚ there was large within group variance between the animals, which may obscure between group differences. To address this, we used the animals as their own control before comparison between groups.

The porcine model differs from humans in anatomy and age‚ as the pigs are young compared with human patients. The model is well established within cardiovascular research‚ as the physiological parameters of the pig are within the human physiological range and the pig reacts similarly to the treatment as humans.

CONCLUSION

We found that clamping of the AAVs, excluding reperfusion of the head and upper extremities during and post NRP, resulted in a significant reduction in the need of NE use to maintain a MAP >60 mm Hg. Clamping the AAV did not exert negative effects on cardiac performance of a DCD heart.

ACKNOWLEDGMENTS

The authors thank Kira Sonnichsen Graahede and Trine Louise Bang Østergaard for invaluable assistance with the handling of animals and preparation of surgical facilities; Ceren Ünal, Karsten Lund Soeberg, Peter Johansen, Oddvar Nils Klungreseth, and Debbie Richards for resuscitating the pigs with excellent handling of the heart-lung machine; Margrethe Kjeldsen for assistance with biochemical analysis; and Sif Bay, Lasse Tiroke, and Agnete Madsen for all the hours and help with pig handling and hard work in the basement.

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