Marginal Donor Recruitment

The Aged Donor Heart Rescue by Stress Echo Project was approved by the ethics committee of the Emilia-Romagna and Tuscany regions of Italy in 2004 (number 142/2004/U/Oss, October 19, 2004). From April 2005 to April 2010, 39 “marginal” candidate donors (mean age, 56 ± 6 years; 21 men) were initially enrolled in seven neurologic intensive care units, without direct access to coronary angiography facilities.

Marginal candidate donors were defined as patients aged > 50 years or < 50 years with concomitant risk factors (history of cocaine use or three risk factors such as hypertension, diabetes, smoking history, dyslipidemia, or family history of premature coronary artery disease). After legal declaration of brain death, all marginal donors underwent baseline echocardiography for evaluation of regional wall motion, global ventricular function, and ventricular mass, according to American Society of Echocardiography recommendations.

Donor Selection by Resting Echocardiographic Criteria

Potential donors with the following modifications on resting echocardiography were excluded from the study: wall motion score index > 1.0, global LV dysfunction (ejection fraction < 45%), diastolic ventricular dysfunction (moderate or severe), significant (moderate or greater) valve disease (insufficiency or stenosis), and moderate or severe LV hypertrophy (LV mass index > 175 g/m ² ). The transthoracic approach can be difficult in ventilated, supine patients in the intensive care setting. In two patients with poor-quality transthoracic echocardiographic images, transesophageal echocardiography was performed. Contrast agents were not used in any patient.

Donor Selection by Stress Echocardiographic Criteria

When the results of resting echocardiography were normal, pharmacologic stress echocardiography was performed following the European Association of Echocardiography and American Society of Echocardiography protocol, using either dipyridamole (0.84 mg/kg over 6 min) or dobutamine (up to 40 μg/kg/min). Per protocol, we suggested dipyridamole as a first-line choice, with dobutamine as a second-line option when dipyridamole was not available, when the operator did not have extensive experience with this stress agent, or when the patient had contraindications to the use of dipyridamole, such as asthma. Contraindications to the use of dobutamine were preharvest high inotrope dose (dopamine or dobutamine > 10 μg/kg/min and/or adrenalin or noradrenalin > 6 μg/kg/min) and increased endogenous catecholamine release from sympathetic nerve endings in subarachnoid hemorrhage.

Echocardiographic images were continuously recorded and intermittently digitized. During the procedure, blood pressure was assessed and 12-lead electrocardiograms were recorded every minute. Brachial blood pressure was measured with a cuff sphygmomanometer.

Regional wall motion score index was assessed and graded on a scale from 1 (normal) to 4 (dyskinetic) in each of the 17 segments at rest and after stress. LV wall motion score index was calculated by summing the scores and dividing the sum by 17. By definition, patients with abnormal stress echocardiographic results had rest wall motion abnormalities and/or stress-induced wall motion abnormalities.

We also considered changes in LV volumes as an index of global dysfunction and pressure and volume changes as an index of LV elastance. At baseline and peak stress, the projections of the four chambers and of the two apical chambers were recorded to obtain LV end-systolic volume using the biplane Simpson rule to calculate LV elastance (the ratio of systolic pressure by cuff sphygmomanometry to LV end-systolic volume).

A decrease in LV elastance during stress was considered abnormal. In a previous study, this response was shown to be associated with moderate to severe coronary or myocardial abnormalities on cardiac autopsy verification.

We accepted a priori three stress echocardiographic criteria excluding a heart from eligibility as a donor: (1) new regional wall motion abnormalities (wall motion score index > 1.0), (2) negative LV elastance variation during stress (stress value less than resting value), and (3) submaximal stress prematurely stopped because of nondiagnostic limiting effects (e.g., hemodynamic instability or hypotension with a decrease > 40 mm Hg in systolic or diastolic blood pressure) before completion of the infusion.

Each of the three criteria had a different rationale and target: a new-onset regional wall motion abnormality is a highly specific sign of a significant epicardial artery stenosis, a lack of hyperkinetic response with no increase in pressure/volume index is a sensitive marker of underlying cardiomyopathy, and a submaximal test loses diagnostic and prognostic power and falls in a gray zone unacceptable in the transplantation setting. Eligible organs were considered for transplantation in recipients in emergency or suboptimal conditions (i.e., marginal recipients). Hearts considered eligible but not used because of the lack of a suitable recipient were subjected to pathologic examination as previously described for ineligible hearts.

Starting January 1, 2009, the informatics infrastructure ( http://adonhers.ifc.cnr.it ) became available for a core lab reading from the central Pisa stress echocardiography lab ; marginal donor stress echocardiograms were sent via the internet to the central core echocardiography lab in Pisa for a second opinion before HT.

The first reader was the cardiologist-echocardiographer, who had passed the specific accreditation on stress echocardiographic reading required to enter the multicenter stress echocardiography trial network. He or she performed the stress echocardiographic study at bedside and interpreted images on site. At the time of test execution, the Pisa core lab was immediately alerted (via e-mail or text message), and the second reader (R.Sicari or E.Picano or E.Pasanisi) was required to provide a response within 3 hours. Only tests with unanimous assessments of negative results received a green light for organ explantation and possible donation.

Intensive Care Treatment

All donors were managed according to standardized organizational guidelines, including the use of intravenous fluids and inotropic agents (preferably noradrenalin or dopamine) to maintain a systolic blood pressure > 90 mm Hg, central venous pressure of 4 to 12 mm Hg, and urine output of 1 to 2 mL/kg/hour; correct anemia to maintain hemoglobin ≥ 10 g/dL; electrolyte replacement; vasopressin drip for diabetes insipidus; ventilator management to achieve partial pressure of oxygen > 90 mm Hg; and pH from 7.35 to 7.45. Preharvest high inotrope dose was defined as dopamine or dobutamine > 10 μg/kg/min and/or adrenalin or noradrenalin > 6 μg/kg/min.

Transplantation of Eligible Hearts

Eligible hearts (with normal echocardiographic findings) were retrieved using a standard technique and preserved with cold cardioplegic arrest and topical hypothermia. All transplantations were performed using the bicaval anastomosis technique. Primary graft failure after HT was defined as need for immediate post-HT mechanical circulatory support. The recipients followed routine treatment and follow-up procedures. They underwent coronary angiography and intravascular ultrasound at the first month. Evaluation of graft coronaries by angiography or autopsy had to have been performed <2 months after transplantation to exclude lesions that developed after transplantation (transplant vasculopathy). Multiple angiographic views were obtained for optimal visualization of the coronary arteries. For each identifiable lesion, the angiographer determined vessel diameter at the stenosis and at an adjacent angiographically normal reference site to quantify the percentage of stenosis diameter. Intravascular ultrasound images were obtained using a commercially available intravascular ultrasound catheter placed under fluoroscopic control in the left anterior descending coronary arteries of patients with angiographically normal arteries to rule out angiographically occult coronary artery disease (and as a baseline to detect future graft vasculopathy). Focal and noncircumferential atherosclerosis with 50% stenosis in proximal segments of at least one coronary vessel was regarded as native and donor-transmitted coronary atherosclerosis. All transplanted hearts were followed, and any adverse event was monitored.

Anatomic-Pathologic Study of Nontransplanted Hearts

Hearts deemed suitable as a result of stress echocardiographic results but not transplanted because of the lack of matching recipients were removed from donors and sent to the Pathology Department Center for a very detailed macroscopic and microscopic study. Autopsies were performed by an experienced cardiac pathologist. Coronary atherosclerosis was graded as absent, subcritical, or significant. In accordance with the criteria of cardiac catheterization given above, significant atherosclerosis was defined as focal and noncircumferential atherosclerosis with 50% stenosis in proximal segments of at least one coronary vessel.

Statistical Analysis

SPSS version 11 for Windows (SPSS, Inc., Chicago, IL) was used for statistical analyses. The statistical analyses included descriptive statistics (frequencies and percentages for categorical variables and mean ± SD for continuous variables). Pearson’s χ ² with Fisher’s exact test for categorical variables and the Mann-Whitney U test for continuous variables for intergroup comparisons were performed to confirm significance (using the Monte Carlo method for small sample comparisons). One-way analysis of variance was used to compare continuous variables between groups. The follow-up analyses included Kaplan-Meier survival curves. P values < .05 were considered statistically significant.