In Italy about 2300 patients per year are declared brain dead, out of around 5500 dying in ICUs from acute devastating cerebral lesions (i.e., brain trauma, hemorrhagic or ischemic stroke and anoxia). Currently, brain-dead consented organ donors number around 1100 with less than 300 hearts transplanted per year (data from the “Italian National Health Institute ”, 2011). This severe shortage in transplantable heart status depends on eligibility criteria based on the donor age, which is continuously increasing, and functionality, which may be acutely affected by the consequences of brain coning and hemodynamic instability. Thus, new strategies enhancing functional recovery and reliable prediction of successful heart transplantation are needed. In brain-dead potential donors with hemodynamic instability, echocardiographic serial assessment of LV function is feasible and shows, in 40 % of patients, a moderate-to-severe alteration in global and regional LV function. These alterations may be fully reversible upon intensive care, in a couple of days. In this setting, regional wall motion abnormalities can occur in the absence of underlying coronary artery stenoses, and also coronary artery stenoses can be present with normal regional wall motion [
12,
13]. In this single-center study, based on a limited number of potential donors, we showed that serial echocardiography is feasible and interpretable in the extreme setting of DBD potential donors, and at least as a proof-of-concept it can be helpful, together with coronary angiography, in selecting suitable heart donors otherwise dismissed on the basis of the initial assessment. When initial LVEF is impaired, the period of treatment after brain death can be intentionally prolonged towards the golden time for harvesting, facilitating recovery of stunned hearts and eventually improving the quality of the graft before transplantation. Early hormonal treatment may facilitate complete weaning from vasopressors, and the recovery of stunned hearts often occurs within the maintenance period. These potential donors can manifest ECG abnormalities, hemodynamic instability, increased troponin and left ventricular segmental wall motion abnormalities mainly due to adrenergic storm and not to intrinsic cardiac disease. However, according to current eligibility criteria [
4], the presence of segmental wall motion abnormalities of the left ventricle is an exclusion criterion for donation. In a large subset of brain-dead donor hearts left ventricular performance is reduced because the myocardium is regionally stunned or hibernating rather than irreversibly infarcted or fibrotic [
12,
13]. The detection of reversible dysfunctional myocardium is clinically relevant, as regional or global left ventricular function will improve after transplant [
14,
15]. Such recovery can be facilitated, elicited by cardiovascular targeted intensive treatment, including hormonal treatment and noradrenaline sparing strategy, lasting until 24–48 h before harvesting [
8‐
10,
16,
17]. Thus, the challenge is to identify markers that indicate which hearts are likely to have good function or be treated to satisfactory hemodynamic status and transplantation suitability.
Serial echocardiography in the stunned brain-dead potential donor
Standard rest echocardiography is a non-invasive, portable, and rapidly available investigation that is ideally suited to the accurate assessment of donor ventricular function. However, in the presence of left ventricular dysfunction, a “single spot” echocardiography does not predict reversibility or non-reversibility of ventricular function after heart transplant [
14]. If echocardiography is the initial assessment investigation, echocardiographically detected left ventricular systolic dysfunction in the absence of a history of heart disease is the single most common cause for non-transplantation of an organ [
15]. However, ventricular dysfunction may be transient [
14], occurs in 10% to 42% of donor hearts, and arbitrary thresholds of LV function may exclude hearts that could be resuscitated to transplantable status. Such limitations can be overcome with serial evaluations allowing us to identify those hearts with reversible dysfunction that may recover transplantation status.
Hormonal treatment in the stunned brain-dead potential donor
The brainstem ischemia occurring in the terminal phase of the pathophysiological process which leads to brain death may cause an “autonomic storm” with intensive sympathetic nervous system activity, followed by vasoparesis and hypotension [
13]. Such injury might be exacerbated by changes in endocrine homeostasis, metabolism, and the development of a proinflammatory state. In patients with subarachnoid hemorrhage, the catecholamine surge occurring at the time of cerebral bleeding may cause a severe cardiac and pulmonary reversible dysfunction. Similarly, the intensive sympathetic activity and catecholamine release associated with brain death may result in severe myocardial dysfunction [
5] originating from multiple factors: calcium overload [
18], a possible reduction in high-energy phosphates [
19], beta-adrenoreceptor desensitization, endothelial damage [
19,
20], and altered gene expression. Further decreased thyroid hormone (especially T3, insulin, and cortisol levels) are seen [
13]. Pituitary failure produces abnormal temperature homeostasis, and eventually a catecholamine-deficient vasoparetic state occurs. All these phenomena may further affect cardiac function.
Impact of ‘optimal donor management’
Management of ‘marginal’ hearts should include donor graft ‘resuscitation’ and re-evaluation [
3,
5], thus allowing potential organ rescue and utilization. Many authors and guidelines [
6] support treatment with insulin, corticosteroids [
21], T3 [
22] and arginine vasopressin [
23] which may improve ventricular performance, raise systolic blood pressure and reduce inotropic requirements, obtaining early and sufficient circulatory stabilization. Published controlled studies do not support HT treatment in stable potential donors but other prospective results are needed to investigate HT effects in hemodynamically unstable donors, considering longer duration of treatment [
24]. However, in non-randomized clinical studies, organs that were at first glance assessed as marginal and/or unacceptable had the potential to improve with such an integrated approach and thus be utilized, resulting in an increase of utilization rates from only 39% to 58% [
21], with excellent results in experienced centers.
Study limitations
This is a single-center experience with a relatively low sample size. In addition, the observational, not randomized, study design does not allow us to separate the effects of HT (treat-wait-and-see) vs simple wait-and-see strategy on the observed benefit. In fact, neurogenic stunning can also spontaneously disappear with time, as clearly shown in patients with subarachnoid hemorrhage and Takotsubo cardiomyopathy [
13]. We used visual assessment of left ventricular ejection fraction (LVEF) despite general recommendations to use quantitative biplane Simpsons (BPS) measurements. Although quantitative methods are well-validated and to be preferred in a research-oriented setting, visual assessment (eyeballing) is unquestionably easier and faster, and possibly even more accurate, especially in a technically demanding clinical setting such as the neurological intensive care unit with brain dead potential donors, with poor image quality, and when a well-trained observer blinded to the study condition performs the analysis [
11].
Clinical implications
This study shows that it is possible to provide long maintenance periods based on high quality intensive care management without losing the possibility of organ retrieval. Consequently, the concept of “maintenance” of potential organ donors could be extended to “treatment” of a malfunctioning graft in the potential donor before organ retrieval. Larger, multicenter, prospective studies are needed to evaluate the effects of hormonal treatment and timing on potential organ donors under conditions of hemodynamic instability. This approach can be added to other strategies proposed to expand the heart donor pool, such as the ADONHERS project, with stress echo-driven selection of old donor hearts for heart transplantation [
25‐
28]. Using stress echo, ADONHERS recruits hearts previously excluded from transplantation due to advanced age, whereas the approach proposed here utilizes serial TTE to rescue hearts previously excluded for resting left ventricular wall motion abnormalities. At least in theory, the stress echo approach might also be applied to these potential heart donors with left ventricular abnormalities, since viability response during stress echo effectively recognizes viable tissue with non-fixed response, as opposed to necrotic response with scar and fixed wall motion abnormalities following inotropic challenge with either dobutamine or dipyridamole [
29]. Information on resting function, viability and ischemia can all be obtained in a one-stop shop with pharmacologic stress echocardiography in a bedside, low-cost, and radiation-free approach [
30].
Donor hearts with recovered LV function can be eligible for uneventful heart transplant. A strategy based on a) longer interval of maintenance of the brain-dead potential donor (wait), b) a circulatory targeted treatment including HT (treat) and c) heart function monitoring by 2D echo (see) can help to rescue organs suitable for heart donation.