While there has been reports of living lung donation, deceased donors account for the vast majority of lung grafts. Deceased donors are categorised into DCD donors or donation after brainstem death donors (DBD). Currently, DCD donors account for approximately 20% of the lung transplant procedures worldwide. In this section, we will discuss the issues regarding lung graft from DCD and DBD donors, as well as the graft extraction process.
Ischaemia time represents the time between cessation of the donor circulation to the reperfusion of the graft in the recipient. This is divided into warm and cold ischaemia time. Warm ischaemia time refers to time with reduced organ perfusion starting before cardiac arrest to start of organ preservation and cooling with solutions [
56]. It is generally accepted that lowering the graft temperature reduces metabolic requirement, which reduces the extent of the graft injury under ischaemic condition [
57]. DCD lung allografts will usually have degree of warm ischaemia, as there will invariably be a time-window between inadequate organ perfusion and cessation of circulation. The process involves certain key time points which would benefit from standardisation to enable data comparison. Cypel et al. defined 5 time points starting with withdrawal of life sustaining treatment (T0), oxygen saturations < 80% (T1), systolic blood pressure < 50 mmHg (T2), cessation of cardiac output/asystole (T3), resumption of lung inflation/ventilation (T4), and start of pulmonary flush (T5) [
58]. It is generally accepted that warm ischaemia should be limited to less than 60 min [
59]. However, small studies have suggested that longer warm ischaemic time may not be associated with worse post-transplantation outcomes [
60,
61]. If this holds true, however, and longer intervals from withdrawal of life sustaining treatments to arrest result in acceptable transplant outcomes, it may be possible to significantly expand the donor pool [
58].
DBD lung allografts on the other hand have minimal warm ischaemic time as circulatory arrest is not required prior to organ procurement [
2]. Therefore, ischaemic time in DBD is primarily cold ischaemia. The 2017 ISHLT report examining lung transplants between 2009 and 2015 and found that cases with more than 6 h cold ischaemia time was associated with significantly lower 30-day survival rate. However, the difference in survival is not seen in beyond 1 year follow-up [
2,
4]. However, the report had a poor data completion rate with difficulty adjusting for potential confounders, hence long-term survival conclusions cannot be made yet without further research.
Donation after brainstem death
Most organ transplantations in the UK are performed using heart beating brain-dead organ donors.
The process of brainstem death is often associated with a predictable pattern of complex multiple organ failure which can result in rapid deterioration in the function of the transplantable organ prior to retrieval, unless these pathophysiological processes are actively managed. Clinically, the central nervous system induces a triad of physiological changes described by Cushing; namely hypertension, bradycardia and apnoea in response to raised intracranial pressure [
62]. Brainstem death results in a systemic pro-inflammatory environment mediated by cytokine release, which the body subsequently responds to by causing a surge in circulating catecholamine release, thus creating a concomitant ‘autonomic storm’ [
63‐
66]. The cytokine and catecholamine burden on organ tissues and vasculature can precipitate the development of adverse inflammatory, haemodynamic and endocrine deleterious sequelae, including intense vasoconstriction, tachycardia, pulmonary oedema, myocardial damage, as well as both microvascular and parenchymal damage to distant organs, including the transplantable graft [
66‐
71]. The period of profound autonomic activity is followed by a sudden drop in catecholamine release, which is associated with subsequent bradycardia, systemic vasodilation, and ultimately tissue hypoxia and necrosis [
72]. These deleterious processes are accentuated by a profound coagulopathy, which is theorized to be partly due to release of tissue thromboplastin from the necrotic brain with the subsequent development of disseminated intravascular coagulation, which can have a significant effect on graft viability [
73,
74].
Endocrine and metabolic changes have also been described. In humans, most commonly posterior pituitary function is lost and results in diabetes insipidus and the resultant fluid and electrolyte abnormalities, whilst anterior pituitary function may be preserved or minimally affected [
74,
75]. It has been theorized that this may be due to preservation of pituitary perfusion [
76]. Loss of hypothalamic function and central thermoregulation has also been observed, characterized by initial hyperpyrexia and subsequent hypothermia, whilst changes to thyroid function are characterized as ‘sick euthyroid syndrome’ [
77,
78]. Furthermore, metabolic changes have also been observed, such as hyperglycaemia secondary to a reduction in insulin release, as well as insulin resistance [
63,
64,
79].
Due to the pathophysiological changes described above, DBD organs are subject to a significant pro-inflammatory period associated with haemodynamic instability and autonomic dysfunction.
Finally, like all grafts, DBD organs experience a degree of subsequent ischaemia–reperfusion injury, which generates reactive oxygen species, activates the innate and adaptive immune systems and drives the release of cytokines resulting in inflammation, and potentially microvascular and parenchymal injury [
80,
81].
To maximize recipient outcomes, it is imperative that patient monitoring, treatment goals and specific therapies are optimized peri-operatively. Whilst the precise methods by which to optimize graft outcomes remain to be elucidated, numerous principles of donor management have been suggested. These include, but are not limited to, ICU management with early correction of hypothermia [
63,
64,
78], lung protective ventilation with a tidal volume of 6–8 ml kg
−1 with optimal PEEP [
82‐
84], close cardiac monitoring and inotrope support as required with active correction of hypovolaemia whilst avoiding overhydration and hypernatremia [
71,
78,
85‐
88]. Furthermore, administration of a methylprednisolone bolus immediately after brain death has demonstrated improved utilization of heart and lung grafts [
89,
90].
Managing donor complications associated with donation after brainstem death
Brainstem death is associated with a predictable cascade of systemic inflammation and multiple organ failure. Optimal donor management during this period is vital to mitigate graft injury and ensure short- and long-term graft viability. Complications that require monitoring and management are varied, such as hypotension, hypovolaemia, coagulopathy.
Brainstem death is associated with a dramatic loss of sympathetic tone, resulting in profound systemic vasodilation and reduced cardiac contractility. Whilst the optimum management of this cardiovascular instability remains to be elucidated, it has been postulated that restoration of euvolemia is associated with improved postoperative graft function. A combination of crystalloids, colloids and blood components have been used to achieve this, and it has been suggested that sensible therapeutic objectives include maintaining a haemoglobin concentration above 10 g/dL and restoring intravascular volume, and colloid oncotic pressure [
91].
Whilst the use of inotrope should be limited due to the risk of excessive vasoconstriction, as well as downregulation of adrenergic receptors, there is evidence to suggest that dopamine should be a first-choice inotrope [
92]. In contrast, the use of noradrenaline may compromise graft viability. During this period, pulmonary artery catheter monitoring is often used to ascertain precise measurements such as cardiac output and pre-load, alongside optimising oxygen delivery. The aim is to maintain a mean arterial pressure > 60 mmHg.
Coagulopathy is a common complication of brainstem death and is thought to occur due to the release of plasminogen activator, thrombocytopenia and hypothermia [
73]. Once again, there is no consensus as to the optimum management of this complication, however, a variety of blood products is often required and reasonable end points include a platelet account > 50,000 mm
3 and an international normalised ration below 2.0.
A variety of other complications ensue following brainstem death, such as hypernatremia, hypokalaemia, and hypovolaemia secondary to diabetes insipidus [
93], as well as arrhythmias [
75], neurogenic pulmonary oedema [
71], aspiration pneumonitis, hypothermia, and hyperglycaemia due to pancreatic insufficiency [
94].
Various agents have been used in murine studies and in humans that have demonstrated some improvement in clinical outcomes, such as a combination of corticosteroids, vasopressin, insulin and thyroid hormone. Further investigation into novel cytoprotective regimens, such as the use of ischaemic preconditioning, anti-C5a and selectin inhibitors, remains ongoing.
These numerous clinical effects of DBD on donor physiology demonstrates the importance of improving clinicians’ understanding of the pathophysiology underlying these complications to optimise donor graft viability.
Donation after circulatory death
DCD refers to the process of retrieving organs for transplantation that occurs following confirmation of death using circulatory criteria. The circulatory death refers to ceasing of brain perfusion [
56]. Organs, therefore, are harvested from donors who have died or are awaiting cardiac death, rather than from brain-dead patients with a cardiac output, as in typical organ donation. DCD donors are generally patients who have been unsuccessfully resuscitated or are awaiting cardiac death. This generally encompasses patients that have suffered catastrophic brain injuries but do not fulfil the neurological criteria for death. However, despite this, these patients are experiencing significant injuries that would justify the withdrawal of life-supporting cardiorespiratory management in the patient’s best interests.
Due to the widening discrepancy between organ supply and demand, with demand continuing to increase, there has been a re-introduction of DCD donor schemes for various forms of transplantation, including organs with a low tolerance for warm ischaemia, such as the lungs, pancreas and liver. For example, Belgium, the Netherlands and the United Kingdom have effective DCD donor schemes, with an estimated 7.0–9.5 DCD donors per million population in 2013 [
7]. This change in practice is particularly due to the finding that graft outcomes following selected DCD transplantations and DBD transplantations are similar [
95‐
97].
The most widely used classification to categorise DCD is the modified Maastricht classification [
98]. Category I describes patients who are dead on arrival to the hospital (therefore, not receiving cardiopulmonary resuscitation); Category II describes patients who have underwent unsuccessful resuscitation en-route to the hospital; Category III indicates awaiting cardiac or circulatory death, this is usually in cases of planned withdrawal of life-sustaining therapies; Category IV describes cardiac in a brain-dead donor (Table
1) [
99]. Controlled DCD describes DCD which occurs after a planned withdraw of life-support, i.e. Category III; whereas Categories I, II and IV are generally thought to be uncontrolled.
Table 1
Maastricht classification of donation after circulatory death
Category I: | Patients pronounced dead prior to arrival at the hospital, cardiopulmonary resuscitation abandoned |
Category II: | Patients with ongoing cardiopulmonary resuscitation on arrival, but unsuccessful |
Category III: | Patients with planned withdrawal of life-sustaining therapies (controlled) |
Category IV | Cardiac arrest after brain stem death |
Compared to DBD grafts, DCD grafts sustain a greater degree of ischaemic insult prior to harvesting, when they are subsequently cooled and perfused. This is because, during DBD, organs undergo cold perfusion prior to organ harvesting, whilst in DBD grafts there is a definitive period between cardiac arrest and organ retrieval. This period is known as the “warm ischaemic time” and has been shown to affect organ quality. Studies have theorized that ischaemia impairs organ recovery due to stimulation of innate and adaptive immune responses, the generation of reactive oxygen species and the induction of apoptosis, resulting in hypoxic injury, inflammation and graft vascular disease [
80,
81,
100‐
102]. In turn, these deleterious pathophysiological changes may increase the risk of delayed graft function (DGF), which has been shown to result in poor long-term graft function and patient survival [
103,
104]. Due to the innate susceptibility of the kidneys to hypoxia, secondary to the organ’s significant metabolic demand, the long-term effects of ischaemia–reperfusion injury has been predominantly studied in the context of renal transplantation. Hypoxic injury has been shown to initiate kidney allograft dysfunction, acute reject; this reduces graft survival [
96].
The most significant period of warm ischaemia occurs following the onset of asystole and the institution of cold perfusion, however, it is important to note that the initial period occurs as early as the preceding phase of cardiorespiratory deterioration. Once the procurement process has begun, extracorporeal membrane oxygenation (ECMO) is a critical technique that circulates blood to the transplantable organ, thereby limiting the duration of warm ischaemia. The period of warm ischaemia is higher in uncontrolled DCD donors, because by definition, the process of warm ischaemic injury has already been established by the time that the possibility for donation has been appreciated.
Overall, due to the prolonged warm ischaemic time observed in DCD donor transplantation, compared to DBD donation, the risk of ischaemic injury is significantly higher (Fig.
1). This may contribute to acute rejection, primary graft failure, delayed graft failure, as well as other ischaemic complications [
105‐
109], such as biliary strictures [
110]. As such, criteria for selecting viable DCD donors must be strict and adhered to, whilst limiting uncontrolled DCD donors and elderly DCD donors with co-morbidities such as hypertension, peripheral vascular disease and diabetes, as well as limiting warm ischaemic time with adjunctive therapies such as ECMO.
Donation after circulatory death vs brainstem death
DCD rates started increasing in 2007 and now make up 17.8% of all lung transplants in 2017/2018 in the UK [
15]. DCD is classified into Uncontrolled DCD (e.g. dead on arrival, patients with unsuccessful resuscitation post cardiac arrest) and Controlled DCD (inpatient withdrawal of life sustaining treatment and unexpected cardiac arrest in patients with known or suspected brain death) [
56]. In the largest registry review comparing DCD (
n = 306) and DBD (
n = 3,992) lung allograft outcomes, no significant difference was found in 30 day (96% vs 97%), 1 year (DCD 89% vs DBD 88%,
p = 0.59) or 5 year mortality (both groups 61%,
p = 0.87) between the groups [
58]. 94.8% of DCD donors in this review were Maastricht Category 3 where inpatient withdrawal of life sustaining treatment was performed [
111]. Interestingly, early 30-day survival was significantly affected by donor mechanism of death with head trauma patients having worse early outcomes possibly due to silent micro-aspirations [
58]. A meta-analysis of 6 observational cohort studies by Krutsinger et al. found no difference in 1-year mortality, acute cellular rejection and primary graft dysfunction between DCD and DBD allograft recipients [
112].
In a retrospective single centre study evaluating transplants between 2007 and 2013, DCD lung transplant recipients (
n = 59) were compared with DBD lung transplant recipients (
n = 331) [
61]. No significant difference was found between both groups with respect to primary graft dysfunction score (
p = 0.67), chronic lung allograft dysfunction free survival (
p = 0.86) and overall survival (
p = 0.15) [
61]. PGD was graded from 0–3 based on partial pressure of oxygen over fractional inspired oxygen concentration (Pa02/Fio2), chest X ray findings and need for ECMO at 72 h [
61]. This occurred despite the significantly longer ischaemia time and significantly more donors with smoking history in the DCD group [
61]. A prospective single centre study of 302 lung transplants of which 60 were from DCD donors showed no significant difference in acute rejection episodes (
p = 0.98) and overall cumulative survival compared to DBD lung transplants after up to 7 years of follow-up [
113]. However, the incidence of postoperative bronchiolitis obliterans syndrome (BOS) was significantly higher in DCD group (23.5%) than in DBD group (11.7%,
p = 0.049) with significantly shorter BOS-free survival in the former (
p = 0.028) [
113].
In summary, while DBD organ grafts are often associated with shorter warm ischaemic time, the exposure to cytokines, catecholamine and haemodynamic compromise may still result in significant graft injury. Current data suggest that careful selection of DCD candidates may yield long term prognosis comparable to that of DBD candidates (Table
2).
Table 2
Summary of the characteristics of donation after brainstem death and donation after circulatory death
Donation cohort | Patients that fulfil the criteria for brainstem death but maintain cardiac output | Donors who have died or are awaiting cardiac death |
Proportion of donors | ≈ 65% | ≈ 35% |
Warm ischaemic time | Minimal, due to maintenance of cardiac output | Usually prolonged, due to the interval after asystole where organs are not perfused and have not yet been cooled |
Pathophysiological insult | Brainstem death results in systemic cytokine and cathecholamine release associated with haemodynamic instability and graft insult | Prolonged warm ischaemia stimulates the activation of innate and adaptive immune responses, generation of reactive oxygen species and induction of apoptosis |
Graft outcomes | Current data suggest that careful selection of DCD candidates confers a long-term graft outcome that is comparable to DBD donors [ 60, 112] |