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Heart transplant remains the gold standard of end-stage heart failure treatment. The number of heart transplants performed each year has increased and the number of recipient candidates has been increasing even more. As a result, recipients are now matched with donors over longer distances with increasing organ ischemic time. Organ preservation strategies have been evolving to minimize ischemia reperfusion injury following longer ischemic times. This chapter will include updated organ donation and preservation techniques for heart transplant including organ donation after brain death (DBD) and donation after circulatory death (DCD). The expansion of cardiac donation after circulatory death (DCD) and new techniques for heart preservation may increase the use of hearts from extended criteria donors and thus expand the heart donor pool.
Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA
Daniel M. Bethencourt
Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA
Tiffany Koyano
Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA
Yasuhiro Shudo
Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA
*Address all correspondence to: noot@stanford.edu
1. Introduction
The shortage of donors is a major limiting factor in cardiac transplantation [1]. To enlarge the donor pool, extended criteria heart donors, including those with older age, left ventricular hypertrophy, hepatitis B/C infection, donor/recipient size mismatch and prolonged ischemic time are often considered with acceptable outcomes [2]. Organ ischemic time was defined as the time between the aortic cross-clamp applied during procurement and heart reperfusion during heart implantation [3]. Donor hearts are now procured from longer distances; extending the cold ischemic time. The registry of the International Society for Heart and Lung Transplantation report in 2017 demonstrated an ischemic time < 4 hours was associated with improved survival at 30 days and 5 years compared with longer ischemic time [3]. Given older heart donors have been increasingly utilized. Studies have shown that the hearts of older donors are more sensitive to prolonged ischemic time compared to younger donors [4, 5]. Many new strategies have been developed to improve allograft preservation, and minimize the effect of ischemia reperfusion injury. For DCD donors, a period of warm ischemia occurs at the beginning when life support is discontinued. Recently, ex-vivo perfusion technology has been developed to minimize warm and cold ischemic times, enable organ resuscitation, evaluation and facilitate long-distance organ transportation. This technology has facilitated the expansion of the donor pool.
Heart transplantation was first performed by Christiaan Barnard in 1967 with a DCD approach. The recipient and donor were in adjacent operating rooms. Donor life support was discontinued, and death was pronounced after there was no electrical activity for 5 minutes. The chest was opened, cardiopulmonary bypass was initiated, cardiectomy was performed and the donor heart was perfused through the aortic root until the recipient was ready to implant. The transplant was successful, and the recipient was able to wean off from cardiopulmonary bypass. Unfortunately, the recipient passed away 18 days postoperatively due to pneumonia and acute rejection [6, 7, 8].
In 1968, the Harvard Ad Hoc committee included “irreversible coma” to be the criteria for death. Since then, DBD has become the majority method of heart retrieval with the benefit of controlled rapid diastolic cardiac arrest and shorter ischemic time [9]. In 1979, the Stanford team reported the experience of heart procurement at an outside hospital and found it to have equivalent outcomes compared to donor hearts procured in a hospital which led to nationwide organ sharing to increase the donor pool and subsequently decreased waitlist times [10]. The technique of heart preservation after initial cardioplegia infusion was cold storage with topical hypothermia. A Stanford experimental study demonstrated significant ultrastructural changes after 3–4 hours of ischemia which appeared reversible with satisfactory graft function [11].
The goals of donor management before a heart transplant include maintaining adequate intravenous volume with optimum cardiac filling pressure and ensuring adequate arterial pressure for entire organ perfusion. Arterial and central venous pressure (CVP) lines are essential and should be placed for continuous hemodynamic monitoring and allow blood samples to be obtained as needed. CVP is maintained in the range of 6–10 mmHg to ensure adequate volume status and mean arterial pressure is targeted between 60 and 80 mmHg. All cardiac donors should have an echocardiogram to evaluate cardiac function, LV wall thickness, wall motion and exclude any major structural heart defects. A coronary angiogram is recommended for donors >40 years old or with risk factors for coronary artery disease (smoking, hypertension, hyperlipidemia and methamphetamine users) [12].
Factors contributing to volume depletion include unrecognized blood loss associated with trauma, diminished vascular tone, hyperosmotic therapy from mannitol, third spacing generated by inflammatory mediators, hyperglycemia and diabetes insipidus (DI) resulting in massive diuresis. A total of 0.9% NaCl or Lactated Ringer’s solution is generally used in case of fluid depletion. In donors with hypernatremia, 0.45% NaCl or dextrose-containing crystalloids can be used for fluid repletion.
Despite adequate fluid repletion, progressive systemic hypotension still occurs in brain-dead donors requiring vasopressors and inotropes support. Many studies have suggested vasopressin as a first-line drug given simultaneously decreasing DI and catecholamine agonist (V1 and V2) actions [12, 13, 14]. Low doses of dopamine may be used as an alternative drug. The study demonstrated the use of dopamine in both kidney and heart transplants was associated with less requirement of postoperative dialysis [15]. Beta agonist treatment should be avoided given the effect of β-receptors down-regulation and subsequently impaired cardiac function post-transplantation [16]. Moreover, hormonal resuscitation (cortisol, anti-diuretic hormone, insulin and thyroid hormone) has been recommended in brain-dead donors [12, 13].
The donor is positioned, prepped and draped from the chin to the pubis. A midline incision is routinely performed for heart and lung dissection procedures along with a midline incision simultaneously made by abdominal surgeon for abdominal organs retrieval. Visual inspection is achieved to evaluate atrial and ventricular sizes, anatomic variations and cardiac contractility. Surface palpation is performed to evaluate coronary artery calcification, ischemic scarring, contusion and to detect thrills or abnormal flows. Pericardial stay sutures are placed bilaterally and secured with snaps on each side to allow lung evaluation in case of concurrent heart and lung retrieval. Some surgeons prefer minimal dissection to avoid arrhythmia and hemodynamic instability that may occur during heart manipulation. Preliminary dissection of key structures is mostly performed on all organs before heparin is given and cannulation. The ascending aorta and the main pulmonary artery are carefully dissected and separated to allow sufficient aortic cross-clamp placement and manipulate the ascending aorta safely and easily. The superior vena cava (SVC) is dissected off the right pulmonary artery circumferentially. The azygous vein is identified and may be encircled, ligated and finally divided after cardioplegia given to avoid massive bleeding. The inferior vena cava (IVC) is dissected to ensure adequate length. All procurement teams should communicate the timing of their preliminary dissection and readiness to proceed to heparinization [17].
Intravenous heparin (400 U/kg) is given before cannulation. The aortic cannulation site is prepared by placing a 4–0 polypropylene purse-string suture. 14 Fr aortic cannular is placed and secured. The antegrade cardioplegia line is de-aired and connected. The SVC is clamped or tied above the azygous vein. The IVC is partially cut. A pool-tip suction tubing should be inserted into the IVC to facilitate abdominal perfusate drainage and prevent right heart distension. To ensure the left ventricle is decompressed, left atrium venting is performed and ensure adequate drainage. If the lungs are not procured, pulmonary veins can be cut at the pericardial reflection. If the heart and lungs are procured in the donor, left atrium venting can be easily performed by cutting the left atrial appendage. To avoid the left atrial appendage cutting, venting of the left atrium can be done by making an incision in the Waterston’s groove or left atrial wall, anterior and medial to the left pulmonary veins at the base of the left atrial appendage. When the heart is empty, an aortic cross-clamp is applied. 1–2 L of cardiac preservation solution is delivered at a pressure of 150 mmHg using a pressure bag. The drainage of the left atrium and IVC is checked to ensure adequate perfusion and the left ventricle is decompressed. Inadequate distribution of organ perfusion may cause irreversible allograft damage [17, 18].
If the lungs are procured in the same donor, cardioplegia is given first and the surgeon must ensure the heart is completely stopped before infusing pulmoplegia to prevent pulmoplegic solutions circulating into the coronary circulation. Topical hypothermia is applied in the chest cavity. After infusion is completed, IVC is completely transected then the left atrial incision is made at the Waterston’s groove connecting the right inferior and superior pulmonary veins. When the heart is lifted, the next incision is made at the left atrium midway between the lower left and right pulmonary veins confluence and the coronary sinus then extended to the left to the base of the left atrial appendage and connected to the right side. Both heart and lung procurement surgeons must agree before incisions are made to avoid anatomical damages and ensure adequate left atrial cuff for the donor lungs. The SVC is transected proximal to the azygous vein to provide adequate length. The ascending aorta is transected at the aortic arch level. The pulmonary artery is divided at the bifurcation level. The heart is then explanted and transferred to the back table to examine for any surgical damages or anatomical anomalies [12, 17, 18].
4.1 Heart preservation methods
Donor heart preservation is crucial for a successful heart transplantation as measured by graft function and survival [19, 20]. Unlike other solid organs such as liver, kidney or pancreas, cold ischemic time for the heart is limited to 4–6 hours and longer ischemic times adversely affect survival outcomes [21]. Hypothermia slows metabolic rate and cell death by decreasing enzyme degradation which is necessary for cell viability [22].
4.2 Static cold storage
Static cold storage is the most common method of heart preservation worldwide. After the donor heart is visualized and accepted for transplant into the known recipient, careful organ dissection is performed. The ascending aorta is partially dissected off the main pulmonary trunk to be able to apply an aortic cross clamp. The superior vena cava is freely dissected off the right pulmonary artery and the azygous vein is ligated. Intravenous heparin is given before the aortic cross clamp is applied. Cold preservation solution is rapidly delivered through the ascending aorta via a cardioplegic needle to achieve diastolic arrest. Ice slush or cold water is immediately placed for topical hypothermia [17, 20]. The heart is then stored in preservation fluid within sequential sterile bags placed and transported in an ice cooler.
For every 10-degree Celsius temperature reduction, most enzymes of hypothermic animals demonstrate 1.5–2.0 fold reduction in activity according to the Vant Hoff’s rule. Still, prolonged ischemic hypothermia decreases the activity of the Na+/K+ pump and results in cell swelling. Moreover, cold ischemia stimulates anaerobic glycolysis and glycogenolysis as well as lactic acid production causing tissue acidosis. When tissue perfusion is restored, oxygen free radicals accumulated during anaerobic metabolism contribute to reperfusion cell injury [22]. Several preservation solutions have been developed to minimize these effects with differing electrolytes, supplements and antioxidant concentrations. University of Wisconsin (UW) solution, Celsior solution and Histidine-Tryptophan-Ketoglutarate (HTK) solution are the most common heart preservation solutions utilized in current practice and the posttransplant outcomes among these three solutions have not shown one to be clearly preferable [19, 20].
4.3 Temperature-controlled donor heart transport system
Organ temperature between 0 and 4 degree Celsius maintains high energy phosphates efficiently but there is a significantly increased risk of frostbite or cold injury due to protein denaturation at a temperature below 2 degree Celsius [23, 24]. At higher temperatures (> 12 degree Celsius), the study showed higher metabolic oxygen demand [24]. To avoid uneven cooling temperature and direct contact with ice, the novel Paragonix SherpaPak cardiac transport system (Paragonix Technologies Inc., MA, USA) was developed and designed to maintain organ temperature from 4 to 8 degree Celsius with special ice packs and temperature sensor. Studies demonstrated that organ storage within this temperature range prevents not only freezing injury and protein denaturization but also decreases metabolic rate and prevents tissue reperfusion injury [2, 23, 25].
The SherpaPak heart transport system (Figure 1) is a disposable device and has interchangeable aortic connectors fit for different sizes of hearts. Once the heart is securely attached to the connector, then it is fully submerged in a leak-proof inner canister filled with cold preservation solution. It is then placed in an outer canister surrounded by a specially designed ice pack and protective polystyrene outer shell [26, 27]. The device provides continuous real-time temperature monitoring and transmits temperature and geographic data via Bluetooth connected to a cell phone.
Figure 1.
SherpaPak™ device components. The donor heart is fully submerged in cold preservation solution. Image courtesy of Paragonix technologies, Inc.
The Stanford team reported the first en-bloc heart-lung transplant using the Paragonix lung guard preservation system, a similar preservation device from Paragonix designed for donor lungs storage. The donor graft was stored in 4 liters of 4 degree Celsius of PhysioSol preservation solution. The average temperature was 7.42 degree Celsius during transport. The recipient was extubated the next day of surgery with good biventricular function and uneventful recovery [28].
After the first clinical study confirmed the safety of SherpaPak used for donor heart preservation with no harmful effect [26], many clinical studies have been conducted to evaluate postoperative outcomes of using SherpaPak for organ transportation [24, 29, 30].
A recent multicentre registry using propensity score matching compared the SherpaPak heart transport system versus traditional static cold storage demonstrated better 1-year survival in the SherpaPak cohort (96.4% with SherpaPak vs. 88.7% with static cold storage). Moreover, significantly fewer patients experienced severe primary graft dysfunction (PGD) requiring an extracorporeal membrane oxygenator (ECMO) in the SherpaPak group resulting in lower overall hospital costs [31].
One of the shortcomings of cold preservation is limited cold ischemic time, with 4 hours generally accepted as safe. The ISHLT database demonstrated that ischemic times beyond 6 hours are associated with graft dysfunction and increased postoperative mortality [32]. Ex-vivo heart perfusion was developed based on the Langendorff perfusion model which demonstrated perfusing of coronary arteries was able to resuscitate a dead heart. Based on this concept, a commercial normothermic Ex-vivo heart perfusion system (Transmedics Organ Care System, OCS) was developed and recently FDA approved following many clinical trials. Due to its normothermic physiology, the cold ischemic time is lessened while using this platform.
5.1 Normothermic ex-vivo heart perfusion
Organ Care System (Figure 2) is a portable device with a wireless display monitor. This device consists of a pulsatile pump connected to a gas exchanger and heater which perfuses blood, nutrient solutions and supplements to the organ inside the perfusion module. The PROCEED II was a multicentre randomized trial performed in the United States comparing outcomes of the OCS and traditional cold storage, extended criteria donors were excluded. The study showed no significant differences in 30-day mortality, severe graft rejection, ICU stay or cardiac-related complications [33]. At 2 years, the OCS group had a lower survival compared to traditional cold storage but was not statistically different (72.2 vs. 81.6%, p = 0.38). There were no significant differences in major serious cardiac events, graft rejection and chronic vasculopathy at 2 years [34].
Figure 2.
Normothermic ex-vivo heart preservation, organ care system (OCS) is composed of a portable heart console (A), heart perfusion module (B) and heart solution set (C). The ascending aorta and pulmonary artery are cannulated. The left ventricular vent is placed and secured at the left atrium. The superior vena cava, inferior vena cava, right atrial incision and left atrial appendage are securely closed. The heart is actively beating inside the box (D). This picture has been reproduced by permission of TransMedics (Andover, MA).
After a visual assessment for anatomy and function is completed and the heart is accepted for transplant, the aortopulmonary window, superior and inferior vena cava are dissected. Heparin is given and a cardioplegic cannulation is placed. When the donor is ready for aortic cross-clamp, 1200–1400 ml of donor blood is drained into a pre-heparinized blood collection bag for OCS machine priming, using the right atrial cannula with the tip pointed to the inferior vena cava.
After blood collection, the superior vena cava is occluded. The left-sided heart is vented by cutting left the atrial appendage (LAA) or superior/inferior pulmonary vein if the donor’s lung is not being recovered for transplant. The right heart is vented from the previous right atrial appendage incision and augmented by cutting the inferior vena cava above the diaphragm. Then, the aortic cross clamp is applied, and cardioplegia is administered through the aortic cannula using a pressure bag to achieve a quick diastolic arrest [17]. Topical hypothermia is applied using ice slush or cold water until cardioplegia is finished. The donor heart is then removed and transferred to the back table for OCS instrumentation [17].
6.2 DCD heart donor using OCS
All necessary surgical instruments and the donor blood collection bag are prepped and set up at the side table before the procedure begins. Heparin 30,000 IU is given 5 minutes before withdrawal of life support. The donor is observed until 5 minutes after electromechanical arrest to ensure a complete cessation of circulation. Median sternotomy is performed quickly, the right atrial cannula is placed in the distended right atrial appendage connected to pre-heparized blood collection bag to retrieve 1200–1400 ml of donor blood using the OCS machine priming.
After blood collection is finished, the aortic cross clamp is applied, cardioplegia is administered, and the right and left heart are vented as described for the DBD donor. Topical ice slush or cold saline is applied. The donor heart explant is performed in a similar fashion as DBD procurement [17]. The donor heart is then transferred to the back table for OCS instrumentation.
6.3 OCS instrumentation
The donor heart is carefully inspected. Patent foramen ovale or any septum defects are carefully checked and repaired if present to ensure the right heart is a closed system for precise coronary blood flow monitoring via pulmonary artery cannula. Any right and/or left atrial appendage incision made previously for blood donor collection and left-sided heart venting are repaired. The superior vena cava is ligated, and the inferior vena cava is then closed using a polypropylene suture secured with a plastic tourniquet. The ascending aorta and pulmonary artery are cannulated. The left ventricle (LV) is vented by placing an LV vent through the left atriotomy.
6.4 Donor heart reanimation and ex-vivo preservation
During donor heart instrumentation, the OCS circuit is primed by mixing 1200–1400 ml of donor blood and TransMedics priming solution containing Mannitol and electrolytes. Antibiotics, steroids, albumin and supplements are added to the circuit. Epinephrine, Levothyroxine and the TransMedics maintenance solution containing multivitamins, electrolytes, dextrose, insulin and adenosine are also infused into the system. The aortic cannula is deaired and attached to the circuit with the left atrium and ventricle facing anteriorly. Thirty-four degree-Celsius of oxygenated blood enters and perfuses coronary arteries, returns to coronary sinuses at the right atrium, enters the right ventricle through the tricuspid valve and drains across the pulmonic valve to the pulmonary artery which connected to the pulmonary cannula [35].
After the aortic cannula is attached to the circuit, gentle cardiac massage is usually performed to decompress the heart. At this point, the heart usually starts to beat. If ventricular fibrillation occurs, electrical defibrillation is performed with small defibrillator pads located behind the heart. Biventricular pacing wires are placed, and the ventricular pacing rate is set for VVI at 80 beats per minute. The LV vent is opened and drains into the OCS box connected to the reservoir. When sinus rhythm is achieved, the pulmonary artery cannula is attached to its port [35].
Serial arterial and venous blood gases and lactate are sampled to determine myocardial lactate extraction. A lower venous lactate concentration indicates lactate absorption and reflects adequate myocardial perfusion. Maintenance solution infusion, epinephrine and pump flow are adjusted to keep aortic pressure 65–90 mmHg to maintain coronary flow 650–900 ml/min during transportation. Lactate levels should be absorbing, declining and less than 5 mmol/L before implantation [36, 37].
Once the recipient is ready to implant, the OCS pump is turned off, and cold cardioplegia is delivered to the aortic cannula to achieve rapid electromechanical arrest. The pulmonary artery cannula is disconnected and IVC is opened for drainage to avoid heart distension during the second cardioplegia dosing. After completion of cardioplegia, the aortic cannula is disconnected from the OCS box, and the heart is placed on ice and transferred to the recipient operative field [37].
In March 2023, the Stanford team initiated a new strategy of OCS beating heart transplant without a second cardioplegic arrest to avoid additional ischemic time after heart procurement and to minimize potential ischemic reperfusion injury. This technique can also be applied with DBD heart procurement utilizing OCS. The procedure is performed by perfusing the donor heart with warm blood from the cardiopulmonary bypass circuit via antegrade cardioplegic cannula while the donor heart is still connected to the OCS circuit, then the aortic cross clamp is placed above the antegrade cardioplegia cannula. The donor heart is disconnected from the OCS circuit without interrupting coronary perfusion [36]. The recipient recovered uneventfully with a full return to normal activities at 90 days of follow-up [36].
6.5 XVIVO nonischemic heart preservation device
Rather than perfusing the donor heart beating, with warm solutions using OCS, a Nonischemic Heart Preservation Device (NIHP) is a portable device that perfuses the heart continuously with hypothermic, oxygenated cardioplegia containing blood mixed with a nutrient-hormone solution. XVIVO (Figure 3) serves as a mini-cardiopulmonary bypass circuit consists of an oxygenator, roller pump, heat exchanger, filter and reservoir. The XVIVO consists of the XVIVO Sterile Heart Disposable kit, the XVIVO heart box and the XVIVO supplemented solution. The heart box controls the solution’s temperature set at 8° C. The mixed O2/CO2 gas flow is supplied to the solution and perfused by the coronary arteries with the control of pressure and flow limits. The sterile disposable kit consists of the tubing, the gas connectors, the pump, pressure and temperature sensors. Machine priming for XVIVO heart preservation system (XVIVO Inc., Gothenburg, Sweden) consists of 2.5 L of supplemented XVIVO heart solution mixed with 500 ml of washed, irradiated leucocyte-depleted red blood cells to achieve a hematocrit of 15%. Heart solution additives consist of sodium bicarbonate, insulin, unfractionated heparin, potassium and imipenem or equivalent broad-spectrum antibiotics. The ascending aorta is cannulated, and connected to the disposable kit then the heart is submerged into a reservoir. The donor heart receives continuous hypothermic oxygenated blood to maintain aortic root pressure at 20 mmHg with 150–250 ml/min of coronary flow in a static, non-beating state [38, 39].
Figure 3.
The XVIVO heart preservation system, the heart is submerged in the cold oxygenated perfusion solution in a protective reservoir. Pressure-controlled pump is used to control the perfusion pressure during perfusion of the heart. The system has integrated sensors that monitor real-time flows, pressures, and temperatures. The picture has been adapted by permission of XVIVO perfusion, Inc.
Animal studies have demonstrated the safety of using XVIVO to preserve a porcine heart for 24 hours with at least 8 hours of preserved contractile function and endothelial integrity of the coronary arteries [40, 41, 42]. Myocardial contractility and endothelium have been shown to be preserved up to 24 hours with a nonischemic heart preservation device [40].
A nonrandomized phase 2 trial compared six donor hearts perfused with XVIVO and 25 donor hearts perfused with standard cold storage with a median organ preservation time of 223 min in XVIVO and 194 min in the standard cold storage group. The study demonstrated excellent outcomes in XVIVO group with 100% major event-free survival at 6 months (including primary graft dysfunction within 24 hours, need for ECMO within 7 days or acute rejection >2R) compared to 72% major event-free survival in the standard cold storage cohort [38].
XVIVO was used for organ preservation in the first successful pig-to-human transplant by a team at the University of Maryland School of Medicine on January 7, 2022 [43, 44]. Further studies of the XVIVO should be evaluated and compared among the OCS and static cold storage to demonstrate itself as a feasible alternative preservation method. Moreover, this device should be evaluated on extended criteria donors [39].
6.6 Donation after circulatory death (DCD)
Donation after brain death (DBD) has been the primary method of heart procurement. This procedure allows the surgeons to assess visual cardiac function and anatomy and minimizes ischemic injury by controlled cardioplegic arrest. The ISHLT registry data shows that the heart recipient and donor age and comorbidities have been increasing [1]. As demand for heart donors continues to increase, DCD heart donors have become an important alternative in the expansion of the heart donor pool. However, a period of warm ischemic injury occurs during the procurement process when life support is withdrawn to allow electromechanical arrest. DCD procurement techniques and organ preservation methods have been developed to minimize ischemic times [20].
DCD donor categories were classified by the modified Maastricht criteria (Table 1) in 1995 [45]. At the present time, DCD donors are classified as controlled DCD or Masstricht category III: Irreversible neurological injury but not meeting the brain death criteria [8, 45, 46, 47].
Category
Sub-category
Definition
Category 1 - Found dead (Uncontrolled)
IA
Unexpected cardiac arrest out of hospital without attempted resuscitation
IB
Unexpected cardiac arrest in hospital without attempted resuscitation
Category II - Witnessed cardiac arrest (Uncontrolled)
IIA
Unexpected cardiac arrest out of hospital with unsuccessful resuscitation
IIB
Unexpected cardiac arrest in hospital with unsuccessful resuscitation
Category III - Withdrawal of life support (Controlled)
Expected, planed cardiac arrest after withdrawal of care
Category IV - Cardiac arrest whilst brain dead (Uncontrolled, controlled)
Sudden cardiac arrest following brain death diagnosis but prior to organ recovery
Table 1.
Modified Maastricht criteria for organ donation after cardiac death.
6.7 DCD donation pathway
In most cases, with some variability by hospital policies, 30,000 IU of heparin is administered 5 minutes before withdrawal of life support to ensure it is well circulated (Figure 4). Withdrawal of life support can be performed in a post-anesthesia care unit (PACU) or intensive care unit (ICU) to allow participation of family members depending on hospital policies. In some circumstances, withdrawal of life support is allowed to be performed in the operating theater to minimize warm ischemic time. The donor is then observed for progression of cardiac arrest as indicated by no pulse pressure via an arterial pressure line (mechanical asystole) [8]. The donor is then observed with no interaction (stand-off period) after asystole for an additional 2–5 minutes to ensure the absence of autoresuscitation. Median sternotomy and laparotomy incisions are then performed simultaneously. The warm ischemic time of the DCD donor heart is considered as an end when cold cardioplegia is administered.
Figure 4.
Donation pathway for DCD.
Thus “The total warm ischemic time” starts at the time of withdrawal of support and ends when the organ is perfused with cold cardioplegia. “Functional warm ischemic time” refers to the time which the onset of organ hypoperfusion, and typically starts when systolic blood pressure drops below 50 mmHg and ends when cold cardioplegia is infused [45]. Functional warm ischemic time reflects allograft ischemia. Based on previous studies, a DCD heart with functional warm ischemic time exceeding 30 minutes should be excluded from transplant [48, 49].
6.8 DCD reperfusion strategies
A major concern of DCD heart procurement is the potential for myocardial ischemic injury due to prolonged warm ischemic time [45]. Currently, two reperfusion strategies have been utilized to allow functional assessment of donor hearts following circulatory death: Normothermic regional perfusion (NRP) and Direct procurement and perfusion (DPP) using normothermic ex-vivo heart perfusion or Organ Care System (OCS) [8, 45, 46].
6.9 Normothermic regional perfusion
This perfusion method likely resembles the first heart transplant technique done by Christiaan Barnard. Once the donor is declared dead, a sternotomy is performed. There are two types of Normothermic regional perfusion (NRP) depending on which organs are planned for recovery. Four units of washed-packed red blood cells are prepared by the hospital blood bank for NRP circuit priming.
Thoracoabdominal normothermic regional perfusion (TA-NRP) (Figure 5) is used when the heart and/or lungs along with abdominal organs are procured. First, the cerebral circulation is excluded before restoring perfusion by clamping the three cephalic vessels, (the innominate, left common carotid artery and left subclavian arteries). The organs are then re-perfused by initiating veno-arterial extracorporeal membrane oxygenation (VA-ECMO) or cardiopulmonary bypass using central cannulation of ascending aorta and right atrium [48].
Abdominal normothermic regional perfusion (A-NRP) (Figure 6) is performed if only the abdominal organs are being recovered. The femoral artery and vein or abdominal aorta or inferior vena cava are cannulated. To exclude cerebral perfusion, the abdominal aorta is clamped below the diaphragm. Alternatively, an intraaortic balloon occluder can be used, inserted via the abdominal aorta incision, advanced, and inflated in the thoracic aorta. The inferior vena cava is also clamped to prevent cerebral and thoracic recirculation [50].
Figure 5.
Thoracoabdominal NRP (TA-NRP). The ascending aorta and right atrium are cannulated. The innominate artery, the left common carotid artery and the left subclavian artery are clamped.
Figure 6.
Abdominal NRP (A-NRP). The femoral artery and femoral vein are cannulated. Veno-arterial ECMO circuit is similar for both Thoracoabdominal NRP and abdominal NRP.
TA-NRP is initiated with the targeted flow at 5 L/min. The heart usually starts beating within 2–3 minutes. If the heart fibrillates, an internal defibrillation (10 J) is delivered. The heart visualization is first inspected. Inotropes or vasopressors are titrated to maintain a mean arterial blood pressure > 50 mmHg. Functional assessment is performed with transesophageal echocardiography (TEE) and pulmonary artery catheter monitoring. The donor is reintubated and ventilated with low tidal volume to avoid atelectasis which would increase pulmonary vascular resistance. As the heart function continues to improve, all inotropes and vasopressors are weaned. Arterial blood gas (ABG) and lactate are obtained to evaluate and confirm adequate perfusion. NRP will continue for 45–90 minutes depending on cardiac contractility [12]. The donor is then weaned off from NRP circuit to visualize unsupported cardiac function. Criteria for acceptance include LVEF ≥50% by TEE, cardiac index (CI) ≥ 2.5 L/min/m2, central venous pressure ≤ 12 mmHg and pulmonary capillary wedge pressure ≤ 12 mmHg [48]. If the heart is accepted, cold cardioplegia is administered to arrest the heart [51]. Heart explantation and venting are the same as those of DBD heart procurement. For transportation, the heart can be preserved using traditional static cold storage, a temperature-controlled heart transport system or re-perfused with an OCS system [12, 46].
Utilizing OCS after NRP could minimize cold ischemic time compared to using static cold storage. Moreover, in case of complicated redo-sternotomy recipients requiring additional time for mediastinal dissection, OCS provides extra time to achieve a meticulous dissection after the donor heart arrives at the recipient’s operating room [50].
NRP provides early continuous physiologic warm blood perfusion, restores cardiac function and establishes perfusion of other organs concomitantly. NRP could reduce the additional cost of ex-vivo perfusion machines for each individual organ. Although the NRP is considered less expensive when combined with static cold storage compared with the OCS system [20]. NRP has not been accepted in some regions of the US due to ethical issues related to the NRP protocol (cerebral reperfusion may still occur despite clamping of cephalic vessels [8, 20, 51].
6.10 Normothermic ex-vivo heart perfusion
The procurement process and OCS instrumentation are described in the DCD and DBD heart donor technique.
The study of 5-year DCD outcomes showed no differences in 30-day survival (97% for DCD vs. 99% DBD, p = 1.00) or 1-year (91% for DCD vs. 89% for DBD, p = 0.72). For DCD cohort, there was no differences in MCS use postoperatively (29% in DPP vs. 24% in NRP, p = 0.75) but the NRP cohort was found to have shorter ventilator support compared to DPP group (0.5 days in NRP vs. 1.4 days in DPP, p < 0.01) [52].
6.11 “Extended criteria” cardiac donors
The demand for heart donors continues to increase but the supply has plateaued [1]. The term “extended heart donor criteria” refers to the expansion of the donor pool by using organs outside of standard categories and using the OCS as a tool to access heart function after explant [48].
The EXPAND trial was conducted to evaluate the safety and efficacy of the Organ Care System in assessing and preserving extended criteria donor hearts [53]. Inclusion criteria include donors with anticipated >4 hours of ischemic time or > 2 hours of ischemic time plus at least one of these following; age > 55 years, 40–50% of ejection fraction (EF), left ventricular hypertrophy, >20 minutes of donor down time. The study demonstrated short-term survival rates were 94.7 and 88% at 30 days and 6 months respectively. The incidence of primary graft dysfunction at 24 hours postoperatively was 10.7% [2, 20, 53, 54].
The limitations of using ex-vivo heart perfusion include higher cost compared to the NRP technique and myocardial edema associated with prolonged ex-vivo perfusion time, although this effect can be minimized by avoiding unnecessarily high aortic root pressure. Additionally, synchronized pulsatile aortic flow can be used to achieve peak coronary perfusion during the diastolic phase without excessive root pressure [48].
Heart transplantation remains the gold standard treatment for end-stage heart failure. Mechanical circulatory support with left ventricular assist devices (LVAD) can provide a bridge to transplantation but has not resulted in the best successful alternative treatment to heart transplantation but adding more risk and complexity during redo-surgery. The demand for heart donors continues to increase and extended criteria donors are being accepted more frequently. Continued research to develop new preservation techniques is crucial to the goals of increasing transport times and expanding the number of donors while preserving optimal allograft function.
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Written By
Chawannuch Ruaengsri, Daniel M. Bethencourt, Tiffany Koyano and Yasuhiro Shudo
Submitted: 24 August 2023Reviewed: 13 November 2023Published: 05 December 2023
Open access peer-reviewed chapter
