Extracorporeal life support for primary graft dysfunction after heart transplantation

Extracorporeal life support for primary graft dysfunction after heart transplantation Abstract OBJECTIVES Survival after heart transplantation is steadily improving but primary graft dysfunction (PGD) is still a leading cause of death. Medical management seems useful in mild or moderate PGD, whereas extracorporeal life support (ECLS) could be suggested for severe PGD refractory to conventional treatment. Our aim is to present the results of ECLS for PGD after heart transplantation at a single-centre experience. METHODS We performed an observational analysis of our local database. According to the International Society for Heart and Lung Transplantation classification, patients were divided into a left and biventricular failure (PGD-LV) or isolated right ventricular failure (PGD-RV) group. The primary end point was survival to hospital discharge. RESULTS Between January 2010 and December 2016, 38 patients presented with PGD (PGD-LV n = 22, 58%; PGD-RV n = 16, 42%) requiring ECLS support. The mean age was 50.8 ± 12.4 years and 79% were males. Baseline characteristics were comparable between the 2 groups. PGD-LV patients displayed a significantly higher mortality rate on ECLS support as opposed to PGD-RV patients (46% vs 13%, P = 0.033). The rate of complications during ECLS support was comparable between the 2 groups. Twenty-three (61%) patients were successfully weaned from ECLS (PGD-LV = 50% vs PGD-RV = 75%, P = 0.111) after a mean support of 9.0 ± 6.4 days. Seventeen (45%) patients survived to hospital discharge (PGD-LV = 41% vs PGD-RV = 50%, P = 0.410). CONCLUSIONS In case of severe PGD with various manifestations of ventricular failure refractory to conventional treatment, ECLS can be considered as a feasible option with satisfactory survival in this critically ill population. Heart transplantation, Primary graft dysfunction, Left-sided heart failure, Right-sided heart failure, Extracorporeal membrane oxygenation INTRODUCTION Although overall survival after heart transplantation (HTx) has continued to improve in the last 3 decades, primary graft dysfunction (PGD) is still a leading cause of death in the early post-transplant period [1]. The relevant literature of PGD shows heterogeneous results and conclusions owing to inconsistent definitions of PGD used by different authors [2]. This lack of standardization of the definition, diagnostic criteria and treatment strategies led the International Society for Heart and Lung Transplantation (ISHLT) to develop a consensus document in 2014 [3]. PGD is now clearly differentiated by secondary graft dysfunction where a specific cause—i.e. hyper-acute rejection, pulmonary hypertension or surgical complications—could be recognized. Moreover, the diagnosis of PGD must be performed within 24 h after completion of HTx and should distinguish between left- and biventricular failure (PGD-LV) and isolated right ventricular failure (PGD-RV). Finally, the introduction of a grading system of PGD severity could guide the subsequent decision-making algorithm [3]. Medical management seems useful in mild or moderate PGD, while extracorporeal life support (ECLS) could be suggested as a therapeutic option for those severe cases of PGD that are refractory to maximal conventional treatment including inotropes, vasodilators and nitric oxide [4–15]. We aimed to report the results of ECLS for PGD after HTx according to the ISHLT classification. PATIENTS AND METHODS Study design We undertook an observational analysis of our local database of ECLS implantation for PGD after HTx. Authorization from an ethics committee and written informed consent from participants were not required owing to national regulations on ‘non-interventional clinical research’ (articles L0.1121-1 and R0.1121-2 of the French Public Health Code). Patient population Adult patients who received an ECLS for PGD after HTx at our institution from January 2010 to December 2016 were included in this study. We excluded patients (i) undergoing HTx and aged <18 years (n = 29), (ii) requiring ECLS for graft dysfunction secondary to isolated pulmonary hypertension (n = 2) and (iii) receiving ECLS more than 24 h after HTx completion (n = 4). PGD was defined according to the ISHLT criteria [3]. In particular, severe PGD-LV was defined as the need of left or biventricular mechanical circulatory support. Conversely, there were no grades for the severity of PGD-RV because PGD-RV can often be more difficult to quantify. Surgical technique ECLS was implanted in the event of (i) inability to wean the patient from cardiopulmonary bypass despite inotropic support and (ii) refractory cardiogenic shock in the postoperative period within 24 h after completion of HTx. Failure of weaning from cardiopulmonary bypass was assessed by intraoperative transoesophageal echocardiography (left ventricular ejection fraction ≤40% and/or evidence of right ventricular dysfunction) coupled to right heart catheterization (cardiac index <2 l/min/m2). Cardiogenic shock was defined as hypotension (systolic blood pressure <90 mmHg) despite adequate filling status with signs of hypoperfusion [16]. The implantation of ECLS could be performed in a peripheral or intrathoracic configuration, and the choice was left to the surgeon’s discretion. Peripheral ECLS was implanted surgically. Venous and arterial cannulae were placed using a modified Seldinger technique after surgical exposure of the femoral vessels at the groin. As per institutional policy, an arterial catheter was systematically placed distally to the entry site of the arterial cannula to prevent lower limb ischaemia. In the intrathoracic or central ECLS, venous drainage was obtained using either direct cannulation of the right atrium or a percutaneous femoral venous cannula. The arterial reinjection was placed in the ascending aorta. Left ventricular unloading, if necessary, was accomplished after the cannulation of the right superior pulmonary vein or left ventricular apex. The cannulae were tunnelled in the subxyphoid or subcostal region, and the sternum was completely closed. The ECLS circuit consisted also of venous and arterial heparin-bounded tubing, a membrane oxygenator (Quadrox Bioline, Jostra-Maquet, Orléans, France), a centrifugal pump (Rotaflow, Jostra-Maquet) and an oxygen/air blender (Sechrist Industries, Anaheim, CA, USA). Extracorporeal life support management As described previously [17], ECLS flow was initially set at the theoretical cardiac output owing to the body surface area of the patient. However, an inotropic support with dobutamine was used in order to maintain a left ventricular ejection with aortic valve opening. Moreover, vasopressor support with norepinephrine was usually added with a target mean blood pressure of 60–80 mmHg. After admission to our intensive care unit, anticoagulation with unfractioned heparin was usually started 6 h after the completion of HTx if the surgical bleeding from the chest drains was <50 ml/h. Target unfractionated heparin anti-Xa factor activity was maintained between 0.30 and 0.35 IU/ml during ECLS support. Serial transoesophageal echocardiography was performed after progressive reduction of ECLS flow to assess the myocardial recovery. Patients stable during reduction trials and with left ventricular ejection fraction >25% and time–velocity integral >10 cm were weaned from ECLS [18]. Right ventricular function was considered recovered when (i) systemic arterial pressure remained stable without the augmentation of central venous pressure, (ii) major inotropic support or the need for escalation of inotropic support was not required, and (iii) a transthoracic echocardiography showed satisfactory right ventricular systolic function without dilatation. Right-sided haemodynamic parameters were not considered, because their interpretation under ECLS support is complicated. If the weaning trial was haemodynamically tolerated and the echocardiographic criteria were fulfilled, the decannulation procedure was performed in a surgical manner with reopening of the operative field at the groin or chest depending on the ECLS configuration. Successful weaning was defined as ECLS decannulation without the need for ECLS reinsertion or mortality within 48 h. In patients without complete myocardial recovery, cardiac retransplantation could be considered as a rescue therapeutic option. Conversely, ECLS support was considered futile and then stopped in the presence of multiple organ failure or brain death. Outcome and statistical analysis Preoperative, perioperative and postoperative data were retrieved from the computerized medical charts of our hospital. Moreover, the data of heart donors were collected from the French regulatory agency of transplantation (The Agency of Biomedecine). Patients were divided into a PGD-LV or PGD-RV group according to the echocardiographic and haemodynamic parameters defined in the ISHLT classification [3]. The secondary end points were complications rate during ECLS support, successful weaning rate from ECLS and short-term outcomes. Neurological complications included seizure, cerebral infarction and intracerebral haemorrhage. Only infections occurring >24 h after ECLS initiation and within 48 h after ECLS discontinuation were defined as ECLS associated [19]. Statistical analysis was performed with SPSS software, version 24.0 (IBM Corp., Armonk, NY, USA). Categorical variables were presented as counts and percentages and compared using the Pearson’s χ2 test or Fisher’s exact test (>20% of expected counts with <5 counts). Continuous variables were presented as mean ± standard deviation and compared using Student’s t-test or Mann–Whitney U-test depending on their normality, which was assessed by the Kolmogorov–Smirnov test. Survival was calculated with the use of Kaplan–Meier analysis and compared using the log-rank test. A level of 0.05 was used to test for significance. RESULTS Baseline characteristics Of the 212 patients who had orthotopic HTx, 38 (18%) patients developed PGD (PGD-LV n = 22, 58%; PGD-RV n = 16, 42%) requiring ECLS support and met our selection criteria. The mean age was 50.8 ± 12.4 (range 22–64) years and 79% were males. Table 1 shows the preoperative characteristics. Ischaemic cardiomyopathy was the most frequent (48%) diagnosis leading to HTx, and 14 (38%) patients were bridged to HTx with a temporary (n = 6, 16%) or long-term (n = 8, 21%) mechanical circulatory support. Baseline characteristics were comparable between both groups. The mean age of heart donors was 41.3 ± 12.6 (range 21–63) years and 68% were males. Table 2 summarizes the characteristics of heart donors. The characteristics of the heart donors were comparable between both groups. In particular, there was no difference in terms of sex mismatch (donor female to recipient male). Table 3 displays the baseline biological and haemodynamic evaluation of our patient population. The biological profile was typical of end-stage heart failure patients. PGD-LV patients showed numerically higher total bilirubin levels compared to PGD-RV patients, but the difference did not reach statistical significance (28.4 vs 16.9 μmol/l, P = 0.069). Table 1: Preoperative characteristics Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Age (years), mean ± SD 50.8 ± 12.4 50.4 ± 10.5 51.4 ± 14.9 0.814 Male sex, n (%) 30 (79) 18 (82) 12 (75) 0.453b BSA (m2), mean ± SD 1.8 ± 0.2 1.8 ± 0.2 1.7 ± 0.2 0.265 BMI (kg/m2), mean ± SD 24.7 ± 3.8 25.4 ± 3.5 23.7 ± 4.1 0.196 CV risk factors, n (%)  Hypertension 10 (26) 6 (27) 4 (25) 0.589b  Diabetes 8 (21) 6 (27) 2 (13) 0.245b  Dyslipidaemia 11 (29) 6 (27) 5 (31) 0.790a  History of smoking 20 (53) 11 (50) 9 (56) 0.480a  Obesity 4 (11) 3 (14) 1 (6) 0.433b Previous cardiac surgery, n (%) 17 (45) 9 (41) 8 (50) 0.578 ICD, n (%) 23 (61) 12 (55) 11 (69) 0.376a CRT, n (%) 10 (26) 6 (27) 4 (25) 0.589b Diagnosis, n (%) 0.369b  ICM 18 (48) 11 (50) 7 (44)  DCM 10 (26) 4 (18) 6 (38)  Other 10 (26) 7 (32) 3 (19) Waiting list time (months), mean ± SD 41.1 ± 207.2 5.5 ± 7.7 13.3 ± 24.2 0.228 High emergency waiting list, n (%) 25 (66) 14 (64) 11 (69) 0.743a Clinical status, n (%)  Inotropes 15 (39) 9 (41) 6 (38) 0.832a  Mechanical ventilation 5 (13) 4 (18) 1 (6) 0.286b  IABP 10 (26) 6 (27) 4 (25) 0.589b  ECLS 6 (16) 5 (23) 1 (6) 0.180b  Long-term MCS 8 (21) 6 (27) 2 (13) 0.245b Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Age (years), mean ± SD 50.8 ± 12.4 50.4 ± 10.5 51.4 ± 14.9 0.814 Male sex, n (%) 30 (79) 18 (82) 12 (75) 0.453b BSA (m2), mean ± SD 1.8 ± 0.2 1.8 ± 0.2 1.7 ± 0.2 0.265 BMI (kg/m2), mean ± SD 24.7 ± 3.8 25.4 ± 3.5 23.7 ± 4.1 0.196 CV risk factors, n (%)  Hypertension 10 (26) 6 (27) 4 (25) 0.589b  Diabetes 8 (21) 6 (27) 2 (13) 0.245b  Dyslipidaemia 11 (29) 6 (27) 5 (31) 0.790a  History of smoking 20 (53) 11 (50) 9 (56) 0.480a  Obesity 4 (11) 3 (14) 1 (6) 0.433b Previous cardiac surgery, n (%) 17 (45) 9 (41) 8 (50) 0.578 ICD, n (%) 23 (61) 12 (55) 11 (69) 0.376a CRT, n (%) 10 (26) 6 (27) 4 (25) 0.589b Diagnosis, n (%) 0.369b  ICM 18 (48) 11 (50) 7 (44)  DCM 10 (26) 4 (18) 6 (38)  Other 10 (26) 7 (32) 3 (19) Waiting list time (months), mean ± SD 41.1 ± 207.2 5.5 ± 7.7 13.3 ± 24.2 0.228 High emergency waiting list, n (%) 25 (66) 14 (64) 11 (69) 0.743a Clinical status, n (%)  Inotropes 15 (39) 9 (41) 6 (38) 0.832a  Mechanical ventilation 5 (13) 4 (18) 1 (6) 0.286b  IABP 10 (26) 6 (27) 4 (25) 0.589b  ECLS 6 (16) 5 (23) 1 (6) 0.180b  Long-term MCS 8 (21) 6 (27) 2 (13) 0.245b Obesity was defined as BMI >30 kg/m2. For categorical variables, P-values were obtained using athe χ2 test and bthe Fisher’s exact test. BMI: body mass index; BSA: body surface area; CRT: cardiac resynchronization therapy; CV: cardiovascular; CVA: cerebrovascular accident; DCM: dilated cardiomyopathy; ECLS: extracorporeal life support; IABP: intra-aortic balloon pump; ICD: implantable cardioverter-defibrillator; ICM: ischaemic cardiomyopathy; MCS: mechanical circulatory support; PGD-LV: left and biventricular primary graft dysfunction; PGD-RV: isolated right ventricular primary graft dysfunction; SD: standard deviation. Table 1: Preoperative characteristics Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Age (years), mean ± SD 50.8 ± 12.4 50.4 ± 10.5 51.4 ± 14.9 0.814 Male sex, n (%) 30 (79) 18 (82) 12 (75) 0.453b BSA (m2), mean ± SD 1.8 ± 0.2 1.8 ± 0.2 1.7 ± 0.2 0.265 BMI (kg/m2), mean ± SD 24.7 ± 3.8 25.4 ± 3.5 23.7 ± 4.1 0.196 CV risk factors, n (%)  Hypertension 10 (26) 6 (27) 4 (25) 0.589b  Diabetes 8 (21) 6 (27) 2 (13) 0.245b  Dyslipidaemia 11 (29) 6 (27) 5 (31) 0.790a  History of smoking 20 (53) 11 (50) 9 (56) 0.480a  Obesity 4 (11) 3 (14) 1 (6) 0.433b Previous cardiac surgery, n (%) 17 (45) 9 (41) 8 (50) 0.578 ICD, n (%) 23 (61) 12 (55) 11 (69) 0.376a CRT, n (%) 10 (26) 6 (27) 4 (25) 0.589b Diagnosis, n (%) 0.369b  ICM 18 (48) 11 (50) 7 (44)  DCM 10 (26) 4 (18) 6 (38)  Other 10 (26) 7 (32) 3 (19) Waiting list time (months), mean ± SD 41.1 ± 207.2 5.5 ± 7.7 13.3 ± 24.2 0.228 High emergency waiting list, n (%) 25 (66) 14 (64) 11 (69) 0.743a Clinical status, n (%)  Inotropes 15 (39) 9 (41) 6 (38) 0.832a  Mechanical ventilation 5 (13) 4 (18) 1 (6) 0.286b  IABP 10 (26) 6 (27) 4 (25) 0.589b  ECLS 6 (16) 5 (23) 1 (6) 0.180b  Long-term MCS 8 (21) 6 (27) 2 (13) 0.245b Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Age (years), mean ± SD 50.8 ± 12.4 50.4 ± 10.5 51.4 ± 14.9 0.814 Male sex, n (%) 30 (79) 18 (82) 12 (75) 0.453b BSA (m2), mean ± SD 1.8 ± 0.2 1.8 ± 0.2 1.7 ± 0.2 0.265 BMI (kg/m2), mean ± SD 24.7 ± 3.8 25.4 ± 3.5 23.7 ± 4.1 0.196 CV risk factors, n (%)  Hypertension 10 (26) 6 (27) 4 (25) 0.589b  Diabetes 8 (21) 6 (27) 2 (13) 0.245b  Dyslipidaemia 11 (29) 6 (27) 5 (31) 0.790a  History of smoking 20 (53) 11 (50) 9 (56) 0.480a  Obesity 4 (11) 3 (14) 1 (6) 0.433b Previous cardiac surgery, n (%) 17 (45) 9 (41) 8 (50) 0.578 ICD, n (%) 23 (61) 12 (55) 11 (69) 0.376a CRT, n (%) 10 (26) 6 (27) 4 (25) 0.589b Diagnosis, n (%) 0.369b  ICM 18 (48) 11 (50) 7 (44)  DCM 10 (26) 4 (18) 6 (38)  Other 10 (26) 7 (32) 3 (19) Waiting list time (months), mean ± SD 41.1 ± 207.2 5.5 ± 7.7 13.3 ± 24.2 0.228 High emergency waiting list, n (%) 25 (66) 14 (64) 11 (69) 0.743a Clinical status, n (%)  Inotropes 15 (39) 9 (41) 6 (38) 0.832a  Mechanical ventilation 5 (13) 4 (18) 1 (6) 0.286b  IABP 10 (26) 6 (27) 4 (25) 0.589b  ECLS 6 (16) 5 (23) 1 (6) 0.180b  Long-term MCS 8 (21) 6 (27) 2 (13) 0.245b Obesity was defined as BMI >30 kg/m2. For categorical variables, P-values were obtained using athe χ2 test and bthe Fisher’s exact test. BMI: body mass index; BSA: body surface area; CRT: cardiac resynchronization therapy; CV: cardiovascular; CVA: cerebrovascular accident; DCM: dilated cardiomyopathy; ECLS: extracorporeal life support; IABP: intra-aortic balloon pump; ICD: implantable cardioverter-defibrillator; ICM: ischaemic cardiomyopathy; MCS: mechanical circulatory support; PGD-LV: left and biventricular primary graft dysfunction; PGD-RV: isolated right ventricular primary graft dysfunction; SD: standard deviation. Table 2: Characteristics of heart donors Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Age (years), mean ± SD 41.3 ± 12.6 41.7 ± 12.8 40.9 ± 12.8 0.841 Male sex, n (%) 26 (68) 15 (68) 11 (69) 0.970a BSA (m2), mean ± SD 1.9 ± 0.2 1.9 ± 0.2 1.8 ± 0.2 0.450 BMI (kg/m2), mean ± SD 25.3 ± 4.8 25.2 ± 4.1 25.5 ± 5.7 0.838 Vasopressor support, n (%) 34 (90) 20 (91) 14 (88) 0.567b LVEF (%), mean ± SD 62.1 ± 6.2 61.3 ± 5.5 63.0 ± 7.2 0.424 Sex mismatch (recipient male, donor female), n (%) 9 (24) 5 (23) 4 (25) 0.584b Cause of death, n (%) 0.447b  Trauma 15 (39) 10 (45) 5 (31)  CVA 11 (29) 7 (32) 4 (25)  Other 12 (32) 5 (23) 7 (44) Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Age (years), mean ± SD 41.3 ± 12.6 41.7 ± 12.8 40.9 ± 12.8 0.841 Male sex, n (%) 26 (68) 15 (68) 11 (69) 0.970a BSA (m2), mean ± SD 1.9 ± 0.2 1.9 ± 0.2 1.8 ± 0.2 0.450 BMI (kg/m2), mean ± SD 25.3 ± 4.8 25.2 ± 4.1 25.5 ± 5.7 0.838 Vasopressor support, n (%) 34 (90) 20 (91) 14 (88) 0.567b LVEF (%), mean ± SD 62.1 ± 6.2 61.3 ± 5.5 63.0 ± 7.2 0.424 Sex mismatch (recipient male, donor female), n (%) 9 (24) 5 (23) 4 (25) 0.584b Cause of death, n (%) 0.447b  Trauma 15 (39) 10 (45) 5 (31)  CVA 11 (29) 7 (32) 4 (25)  Other 12 (32) 5 (23) 7 (44) For categorical variables, P-values were obtained using athe χ2 test and bthe Fisher’s exact test. BMI: body mass index; BSA: body surface area; CVA: cerebrovascular accident; LVEF: left ventricular ejection fraction; PGD-LV: left and biventricular primary graft dysfunction; PGD-RV: isolated right ventricular primary graft dysfunction; SD: standard deviation. Table 2: Characteristics of heart donors Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Age (years), mean ± SD 41.3 ± 12.6 41.7 ± 12.8 40.9 ± 12.8 0.841 Male sex, n (%) 26 (68) 15 (68) 11 (69) 0.970a BSA (m2), mean ± SD 1.9 ± 0.2 1.9 ± 0.2 1.8 ± 0.2 0.450 BMI (kg/m2), mean ± SD 25.3 ± 4.8 25.2 ± 4.1 25.5 ± 5.7 0.838 Vasopressor support, n (%) 34 (90) 20 (91) 14 (88) 0.567b LVEF (%), mean ± SD 62.1 ± 6.2 61.3 ± 5.5 63.0 ± 7.2 0.424 Sex mismatch (recipient male, donor female), n (%) 9 (24) 5 (23) 4 (25) 0.584b Cause of death, n (%) 0.447b  Trauma 15 (39) 10 (45) 5 (31)  CVA 11 (29) 7 (32) 4 (25)  Other 12 (32) 5 (23) 7 (44) Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Age (years), mean ± SD 41.3 ± 12.6 41.7 ± 12.8 40.9 ± 12.8 0.841 Male sex, n (%) 26 (68) 15 (68) 11 (69) 0.970a BSA (m2), mean ± SD 1.9 ± 0.2 1.9 ± 0.2 1.8 ± 0.2 0.450 BMI (kg/m2), mean ± SD 25.3 ± 4.8 25.2 ± 4.1 25.5 ± 5.7 0.838 Vasopressor support, n (%) 34 (90) 20 (91) 14 (88) 0.567b LVEF (%), mean ± SD 62.1 ± 6.2 61.3 ± 5.5 63.0 ± 7.2 0.424 Sex mismatch (recipient male, donor female), n (%) 9 (24) 5 (23) 4 (25) 0.584b Cause of death, n (%) 0.447b  Trauma 15 (39) 10 (45) 5 (31)  CVA 11 (29) 7 (32) 4 (25)  Other 12 (32) 5 (23) 7 (44) For categorical variables, P-values were obtained using athe χ2 test and bthe Fisher’s exact test. BMI: body mass index; BSA: body surface area; CVA: cerebrovascular accident; LVEF: left ventricular ejection fraction; PGD-LV: left and biventricular primary graft dysfunction; PGD-RV: isolated right ventricular primary graft dysfunction; SD: standard deviation. Table 3: Baseline biological and haemodynamic evaluation Variables Overall (n = 38), mean ± SD PGD-LV (n = 22), mean ± SD PGD-RV (n = 16), mean ± SD P-value Haemoglobin (g/dl) 11.5 ± 2.3 11.3 ± 2.5 11.7 ± 2.0 0.588 Platelets (109/l) 201.0 ± 90.2 202.0 ± 95.7 199.6 ± 85.2 0.937 WBC (109/l) 9.3 ± 4.2 9.2 ± 3.1 9.3 ± 5.4 0.990 INR 1.8 ± 1.0 1.9 ± 1.0 1.8 ± 0.9 0.605 BUN (mmol/l) 12.5 ± 9.0 11.9 ± 8.1 13.4 ± 10.3 0.611 Creatinine (μmol/l) 116.6 ± 15.5 110.4 ± 40.3 124.5 ± 61.9 0.430 Total bilirubin (μmol/l) 23.6 ± 21.6 28.4 ± 26.9 16.9 ± 7.7 0.069 ASAT (U/l) 83.0 ± 137.0 79.2 ± 130.9 88.1 ± 149.1 0.847 ALAT (U/l) 81.5 ± 169.2 95.0 ± 209.6 63.1 ± 92.1 0.573 sPAP (mmHg) 46.3 ± 16.7 44.7 ± 18.5 48.6 ± 13.8 0.552 mPAP (mmHg) 30.3 ± 11.4 29.8 ± 12.4 31.0 ± 10.5 0.798 TPG (mmHg) 11.6 ± 6.7 11.4 ± 8.3 11.8 ± 3.1 0.929 PVR (Wood units) 2.5 ± 1.5 2.3 ± 1.4 2.9 ± 1.7 0.337 Variables Overall (n = 38), mean ± SD PGD-LV (n = 22), mean ± SD PGD-RV (n = 16), mean ± SD P-value Haemoglobin (g/dl) 11.5 ± 2.3 11.3 ± 2.5 11.7 ± 2.0 0.588 Platelets (109/l) 201.0 ± 90.2 202.0 ± 95.7 199.6 ± 85.2 0.937 WBC (109/l) 9.3 ± 4.2 9.2 ± 3.1 9.3 ± 5.4 0.990 INR 1.8 ± 1.0 1.9 ± 1.0 1.8 ± 0.9 0.605 BUN (mmol/l) 12.5 ± 9.0 11.9 ± 8.1 13.4 ± 10.3 0.611 Creatinine (μmol/l) 116.6 ± 15.5 110.4 ± 40.3 124.5 ± 61.9 0.430 Total bilirubin (μmol/l) 23.6 ± 21.6 28.4 ± 26.9 16.9 ± 7.7 0.069 ASAT (U/l) 83.0 ± 137.0 79.2 ± 130.9 88.1 ± 149.1 0.847 ALAT (U/l) 81.5 ± 169.2 95.0 ± 209.6 63.1 ± 92.1 0.573 sPAP (mmHg) 46.3 ± 16.7 44.7 ± 18.5 48.6 ± 13.8 0.552 mPAP (mmHg) 30.3 ± 11.4 29.8 ± 12.4 31.0 ± 10.5 0.798 TPG (mmHg) 11.6 ± 6.7 11.4 ± 8.3 11.8 ± 3.1 0.929 PVR (Wood units) 2.5 ± 1.5 2.3 ± 1.4 2.9 ± 1.7 0.337 ALAT: alanine aminotransferase; ASAT: aspartate aminotransferase; BUN: blood urea nitrogen; INR: international normalized ratio; mPAP: mean pulmonary artery pressure; PGD-LV: left and biventricular primary graft dysfunction; PGD-RV: isolated right ventricular primary graft dysfunction; PVR: pulmonary vascular resistance; SD: standard deviation; sPAP: systolic pulmonary artery pressure; TPG: transpulmonary gradient; WBC: white blood cells. Table 3: Baseline biological and haemodynamic evaluation Variables Overall (n = 38), mean ± SD PGD-LV (n = 22), mean ± SD PGD-RV (n = 16), mean ± SD P-value Haemoglobin (g/dl) 11.5 ± 2.3 11.3 ± 2.5 11.7 ± 2.0 0.588 Platelets (109/l) 201.0 ± 90.2 202.0 ± 95.7 199.6 ± 85.2 0.937 WBC (109/l) 9.3 ± 4.2 9.2 ± 3.1 9.3 ± 5.4 0.990 INR 1.8 ± 1.0 1.9 ± 1.0 1.8 ± 0.9 0.605 BUN (mmol/l) 12.5 ± 9.0 11.9 ± 8.1 13.4 ± 10.3 0.611 Creatinine (μmol/l) 116.6 ± 15.5 110.4 ± 40.3 124.5 ± 61.9 0.430 Total bilirubin (μmol/l) 23.6 ± 21.6 28.4 ± 26.9 16.9 ± 7.7 0.069 ASAT (U/l) 83.0 ± 137.0 79.2 ± 130.9 88.1 ± 149.1 0.847 ALAT (U/l) 81.5 ± 169.2 95.0 ± 209.6 63.1 ± 92.1 0.573 sPAP (mmHg) 46.3 ± 16.7 44.7 ± 18.5 48.6 ± 13.8 0.552 mPAP (mmHg) 30.3 ± 11.4 29.8 ± 12.4 31.0 ± 10.5 0.798 TPG (mmHg) 11.6 ± 6.7 11.4 ± 8.3 11.8 ± 3.1 0.929 PVR (Wood units) 2.5 ± 1.5 2.3 ± 1.4 2.9 ± 1.7 0.337 Variables Overall (n = 38), mean ± SD PGD-LV (n = 22), mean ± SD PGD-RV (n = 16), mean ± SD P-value Haemoglobin (g/dl) 11.5 ± 2.3 11.3 ± 2.5 11.7 ± 2.0 0.588 Platelets (109/l) 201.0 ± 90.2 202.0 ± 95.7 199.6 ± 85.2 0.937 WBC (109/l) 9.3 ± 4.2 9.2 ± 3.1 9.3 ± 5.4 0.990 INR 1.8 ± 1.0 1.9 ± 1.0 1.8 ± 0.9 0.605 BUN (mmol/l) 12.5 ± 9.0 11.9 ± 8.1 13.4 ± 10.3 0.611 Creatinine (μmol/l) 116.6 ± 15.5 110.4 ± 40.3 124.5 ± 61.9 0.430 Total bilirubin (μmol/l) 23.6 ± 21.6 28.4 ± 26.9 16.9 ± 7.7 0.069 ASAT (U/l) 83.0 ± 137.0 79.2 ± 130.9 88.1 ± 149.1 0.847 ALAT (U/l) 81.5 ± 169.2 95.0 ± 209.6 63.1 ± 92.1 0.573 sPAP (mmHg) 46.3 ± 16.7 44.7 ± 18.5 48.6 ± 13.8 0.552 mPAP (mmHg) 30.3 ± 11.4 29.8 ± 12.4 31.0 ± 10.5 0.798 TPG (mmHg) 11.6 ± 6.7 11.4 ± 8.3 11.8 ± 3.1 0.929 PVR (Wood units) 2.5 ± 1.5 2.3 ± 1.4 2.9 ± 1.7 0.337 ALAT: alanine aminotransferase; ASAT: aspartate aminotransferase; BUN: blood urea nitrogen; INR: international normalized ratio; mPAP: mean pulmonary artery pressure; PGD-LV: left and biventricular primary graft dysfunction; PGD-RV: isolated right ventricular primary graft dysfunction; PVR: pulmonary vascular resistance; SD: standard deviation; sPAP: systolic pulmonary artery pressure; TPG: transpulmonary gradient; WBC: white blood cells. Short-term outcomes Table 4 shows the operative and postoperative outcomes of our study population. ECLS was implanted directly in the operating theatre when weaning from cardiopulmonary bypass was not possible in 30 (79%) patients (PGD-LV = 86% vs PGD-RV = 69%, P = 0.189). No patients underwent ECLS implantation during cardiopulmonary resuscitation. Peripheral ECLS was used in 25 (66%) patients (PGD-LV = 64% vs PGD-RV = 69%, P = 0.743). PGD-LV patients displayed a significantly higher mortality rate on ECLS support compared to those with PGD-RV patients (46 vs 13%, P = 0.033). The rate of complications during ECLS support was comparable between both groups. Twenty-three (61%) patients were successfully weaned from ECLS (PGD-LV = 50% vs PGD-RV = 75%, P = 0.111) after a mean support of 9.0 ± 6.4 (range 3–32) days (PGD-LV = 7.5 days vs PGD-RV = 9.3 days, P = 0.429). One (3%) patient died in the first 24 h after ECLS weaning for multiorgan failure, while 2 (5%) patients were bridged to cardiac retransplantation owing to the absence of myocardial recovery. Seventeen (45%) patients survived to hospital discharge (PGD-LV = 41% vs PGD-RV = 50%, P = 0.410). Figure 1 depicts the outcome of our study population. Overall survival was 43% [95% confidence interval (CI) 27.2–59.4%; 13 remaining observations] at 1 year. The log-rank test showed no significant difference on overall survival between the 2 groups (median overall survival in the PGD-LV group = 11 days, 95% CI 0–39; median overall survival in the PGD-RV group = 201 days, 95% CI 0–796; P = 0.315; Fig. 2). Table 4: Operative and postoperative outcomes Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Total ischaemic time (min), mean ± SD 273.6 ± 57.8 280.9 ± 66.4 263.6 ± 43.2 0.369 Mortality on ECLS, n (%) 12 (32) 10 (45) 2 (13) 0.033 Complications on ECLS, n (%)  Lower limb ischaemia 3 (8) 2 (9) 1 (6) 0.621  Neurological 5 (13) 3 (14) 2 (13) 0.654  Renal replacement therapy 25 (66) 14 (64) 11 (69) 0.743  Surgical re-exploration 20 (53) 12 (55) 8 (50) 0.520  Infection 14 (37) 7 (32) 7 (44) 0.452 Successful weaning rate, n (%) 23 (61) 11 (50) 12 (75) 0.111 Survival to hospital discharge, n (%) 17 (45) 9 (41) 8 (50) 0.410 Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Total ischaemic time (min), mean ± SD 273.6 ± 57.8 280.9 ± 66.4 263.6 ± 43.2 0.369 Mortality on ECLS, n (%) 12 (32) 10 (45) 2 (13) 0.033 Complications on ECLS, n (%)  Lower limb ischaemia 3 (8) 2 (9) 1 (6) 0.621  Neurological 5 (13) 3 (14) 2 (13) 0.654  Renal replacement therapy 25 (66) 14 (64) 11 (69) 0.743  Surgical re-exploration 20 (53) 12 (55) 8 (50) 0.520  Infection 14 (37) 7 (32) 7 (44) 0.452 Successful weaning rate, n (%) 23 (61) 11 (50) 12 (75) 0.111 Survival to hospital discharge, n (%) 17 (45) 9 (41) 8 (50) 0.410 Bold value indicates P-value <0.05. ECLS: extracorporeal life support; PGD-LV: left and biventricular primary graft dysfunction; PGD-RV: isolated right ventricular primary graft dysfunction; SD: standard deviation. Table 4: Operative and postoperative outcomes Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Total ischaemic time (min), mean ± SD 273.6 ± 57.8 280.9 ± 66.4 263.6 ± 43.2 0.369 Mortality on ECLS, n (%) 12 (32) 10 (45) 2 (13) 0.033 Complications on ECLS, n (%)  Lower limb ischaemia 3 (8) 2 (9) 1 (6) 0.621  Neurological 5 (13) 3 (14) 2 (13) 0.654  Renal replacement therapy 25 (66) 14 (64) 11 (69) 0.743  Surgical re-exploration 20 (53) 12 (55) 8 (50) 0.520  Infection 14 (37) 7 (32) 7 (44) 0.452 Successful weaning rate, n (%) 23 (61) 11 (50) 12 (75) 0.111 Survival to hospital discharge, n (%) 17 (45) 9 (41) 8 (50) 0.410 Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Total ischaemic time (min), mean ± SD 273.6 ± 57.8 280.9 ± 66.4 263.6 ± 43.2 0.369 Mortality on ECLS, n (%) 12 (32) 10 (45) 2 (13) 0.033 Complications on ECLS, n (%)  Lower limb ischaemia 3 (8) 2 (9) 1 (6) 0.621  Neurological 5 (13) 3 (14) 2 (13) 0.654  Renal replacement therapy 25 (66) 14 (64) 11 (69) 0.743  Surgical re-exploration 20 (53) 12 (55) 8 (50) 0.520  Infection 14 (37) 7 (32) 7 (44) 0.452 Successful weaning rate, n (%) 23 (61) 11 (50) 12 (75) 0.111 Survival to hospital discharge, n (%) 17 (45) 9 (41) 8 (50) 0.410 Bold value indicates P-value <0.05. ECLS: extracorporeal life support; PGD-LV: left and biventricular primary graft dysfunction; PGD-RV: isolated right ventricular primary graft dysfunction; SD: standard deviation. Figure 1: View largeDownload slide Flow diagram of the outcome of the study population. ECLS: extracorporeal life support; HTx: heart transplantation; PGD: primary graft dysfunction; PGD-LV: left and biventricular primary graft dysfunction; PGD-RV: isolated right ventricular primary graft dysfunction. Figure 1: View largeDownload slide Flow diagram of the outcome of the study population. ECLS: extracorporeal life support; HTx: heart transplantation; PGD: primary graft dysfunction; PGD-LV: left and biventricular primary graft dysfunction; PGD-RV: isolated right ventricular primary graft dysfunction. Figure 2: View largeDownload slide Survival of extracorporeal life support for primary graft dysfunction after heart transplantation. (A) Group analysis. (B) Total population. PGF-D: isolated right ventricular primary graft dysfunction; PGF-G: left and biventricular primary graft dysfunction. Figure 2: View largeDownload slide Survival of extracorporeal life support for primary graft dysfunction after heart transplantation. (A) Group analysis. (B) Total population. PGF-D: isolated right ventricular primary graft dysfunction; PGF-G: left and biventricular primary graft dysfunction. DISCUSSION PGD is a life-threatening complication after HTx that negatively affects short- and long-term outcomes. It accounts for ∼40% of deaths within 30 days of cardiac transplantation [20]. Moreover, overall late survival is significantly lower in patients experiencing PGD [7, 8, 10, 11, 14, 21]. The pathophysiology is multifactorial, and several risk factors involving the donor, recipient and surgical procedure have been identified over time [3, 14, 21]. The incidence of severe PGD requiring ECLS was quite high (18%) during our experience. Although the definitions of PGD were heterogeneous making comparisons difficult to carry out, this incidence was consistent with previous reports. In articles providing detailed information, the incidence of PGD supported with ECLS ranged between 7% and 23% [5, 7–15, 21]. Interestingly, D’Alessandro et al. [7] found a temporal trend of PGD after HTx. The raising of incidence in more recent years was explained by an evolving profile of recipients and donors, with more critically ill patients transplanted with marginal donors. This increasing rate of PGD after HTx reflects a more general effort of every transplant team to overcome the shortage of heart donors. This effort is also witnessed by our prolonged total ischaemic time. Allograft ischaemic time predominantly affects early outcomes, and ischaemic time <4 h is associated with considerably higher survival [22]. The high incidence of severe PGD requiring ECLS in our series could be partially explained by the presence of several well-known risk factors, such as older donor age [22], longer total ischaemic time and high rate of preoperative short- and long-term mechanical circulatory support, previous sternotomy and emergency transplant [3]. Our analysis showed that ECLS provided a survival to hospital discharge of 45%. These results compare favourably with other previous series that reported survivals to hospital discharge between 44% and 81% [5, 7, 8, 10–15, 21]. In only 1 small study (11 patients), this outcome improved to 91% [6] while other investigators reached a survival to hospital discharge of 82% adopting a systematic ECLS implantation in the setting of known preceding donor cardiac dysfunction [9]. This extreme variability in survival across studies could be partially explained by the complex and multifactorial physiopathology of PGD after HTx, as opposed to other conditions with a high potential of myocardial recovery and more reproducible ECLS results such as drug intoxication and myocarditis. ECLS was most frequently implanted directly in the operating theatre and in a peripheral configuration. Our institutional policy is to be as aggressive as possible in the implantation of ECLS before the onset of end-organ dysfunction. Interestingly, of the 8 patients who were not implanted directly in the operating theatre, 6 (75%) patients did not survive to hospital discharge. Prompt ECLS implantation could reduce the dose of inotropic support, which increases myocardial oxygen consumption and limits the chances of myocardial recovery. Moreover, we prefer a femoro-femoral rather than a central ECLS as its decannulation does not need a sternal re-entry, which has a potentially increased risk of bleeding and infection. However, any previous attempt to compare central and peripheral ECLS failed to find any significant difference in outcomes with the only exception of an increased rate of lower limb ischaemia in the femoral group [7, 21]. Lower limb ischaemia was encountered in 12% of our peripheral ECLS subgroup, and this complication rate is comparable with that reported in the literature [23–25] and in previous reports of ECLS for PGD after HTx [7, 8]. We observed a disproportionate rate (∼50%) of surgical re-exploration for bleeding. This complication rate was experienced in 26–38% of patients in previous analyses [7, 8, 14]. A possible explanation for this bleeding complication could be the higher proportion (21%) of patients bridged to HTx with a long-term mechanical circulatory support. In our study population, PGD-LV was the leading (58%) manifestation of PGD after HTx. Despite a comparable preoperative profile between both groups, PGD-LV patients displayed a significantly higher mortality rate on ECLS support as opposed to PGD-RV patients. The main cause of death (6 of 10 patients) in the PGD-LV group was multiorgan failure. However, there was no difference on overall survival between both groups at hospital discharge and short-term follow-up. In fact, 4 patients in the PGD-RV group were weaned from ECLS support but did not survive to hospital discharge. Conversely in a recent study by Loforte et al. [14] evaluating early graft failure (primary and secondary according to the ISHLT consensus document) after HTx, the ECLS group was characterized mainly by biventricular dysfunction (93%) and, rarely, by PGD-RV (7%). Based on our results and those from previous reports [4–15], ECLS can be considered as a feasible option in the setting of PGD after HTx as (i) the implantation—especially in the peripheral configuration—is easy and quick, (ii) it allows rapid haemodynamic stabilization with progressive end-organ function improvement, and (iii) it represents a reasonable solution in terms of cost-effectiveness in such a critically ill population. Cardiac retransplantation could no more be considered an acceptable option because of the shortage of donors entailing ethical considerations and the dismal survival. In our study, 2 patients were addressed to cardiac retransplantation in the absence of myocardial recovery during ECLS support and died. Recently, Takeda et al. [15] conducted a comparative analysis between ECLS (n = 27) and temporary ventricular assist devices (n = 17) in patients with severe PGD: ECLS was associated with fewer postoperative complications, higher graft recovery rate and lower in-hospital mortality compared with ventricular assist devices. Taghavi et al. [26] analysed retrospectively their experience with either right ventricular assist device (n = 15) or ECLS (n = 13) to treat acute right ventricular failure after HTx. Although no difference in survival to hospital discharge was observed between the 2 groups, the weaning rate and graft survival were significantly better in the ECLS group. In fact, right ventricular assist devices could not allow a successful recovery of graft function, and most patients either died during mechanical support (47%) or underwent urgent heart retransplantation (40%). Limitations The present study displays several limitations. The small sample size represents a limiting factor that could undermine the statistical power of our analysis. Our conclusions are gathered from a single-centre observational experience and thus may not be generalizable to other settings. The ISHLT criteria for the definition and classification of PGD were applied retrospectively to our local database with obvious intrinsic limitations. We did not consider as a comparison group patients with PGD not requiring ECLS or supported with other types of mechanical circulatory support. From a statistical standpoint, the survival estimates have been evaluated from a very limited sample size of patients, which leads to wide 95% confidence intervals around the estimates overlapping between both groups. The absence of statistical difference using the log-rank test translates the lack of power of our study. With regard to survival analysis, our results can be considered as inconclusive. CONCLUSION PGD is still a serious complication in the immediate postoperative period of cardiac transplantation. In case of severe PGD refractory to conventional treatment, ECLS can be considered as a feasible option with an acceptable rate of complications and a satisfactory survival in this critically ill population. Further studies with larger study populations are, however, mandatory to best define the prognostic role of the ISHLT classification. Conflict of interest: none declared. REFERENCES 1 Lund LH , Edwards LB , Kucheryavaya AY , Benden C , Dipchand AI , Goldfarb S et al. The Registry of the International Society for Heart and Lung Transplantation: thirty-second Official Adult Heart Transplantation Report–2015; Focus Theme: early Graft Failure . J Heart Lung Transplant 2015 ; 34 : 1244 – 54 . Google Scholar CrossRef Search ADS PubMed 2 Iyer A , Kumarasinghe G , Hicks M , Watson A , Gao L , Doyle A et al. Primary graft failure after heart transplantation . 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The Registry of the International Society for Heart and Lung Transplantation: thirty-fourth Adult Heart Transplantation Report-2017; Focus Theme: allograft ischemic time . J Heart Lung Transplant 2017 ; 36 : 1037 – 46 . Google Scholar CrossRef Search ADS PubMed 23 Bisdas T , Beutel G , Warnecke G , Hoeper MM , Kuehn C , Haverich A et al. Vascular complications in patients undergoing femoral cannulation for extracorporeal membrane oxygenation support . Ann Thorac Surg 2011 ; 92 : 626 – 31 . Google Scholar CrossRef Search ADS PubMed 24 Tanaka D , Hirose H , Cavarocchi N , Entwistle JW. The Impact of vascular complications on survival of patients on venoarterial extracorporeal membrane oxygenation . Ann Thorac Surg 2016 ; 101 : 1729 – 34 . Google Scholar CrossRef Search ADS PubMed 25 Vallabhajosyula P , Kramer M , Lazar S , McCarthy F , Rame E , Wald J et al. Lower-extremity complications with femoral extracorporeal life support . J Thorac Cardiovasc Surg 2016 ; 151 : 1738 – 44 . Google Scholar CrossRef Search ADS PubMed 26 Taghavi S , Zuckermann A , Ankersmit J , Wieselthaler G , Rajek A , Laufer G et al. Extracorporeal membrane oxygenation is superior to right ventricular assist device for acute right ventricular failure after heart transplantation . Ann Thorac Surg 2004 ; 78 : 1644 – 9 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Interactive CardioVascular and Thoracic Surgery Oxford University Press

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
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1569-9293
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Abstract

Abstract OBJECTIVES Survival after heart transplantation is steadily improving but primary graft dysfunction (PGD) is still a leading cause of death. Medical management seems useful in mild or moderate PGD, whereas extracorporeal life support (ECLS) could be suggested for severe PGD refractory to conventional treatment. Our aim is to present the results of ECLS for PGD after heart transplantation at a single-centre experience. METHODS We performed an observational analysis of our local database. According to the International Society for Heart and Lung Transplantation classification, patients were divided into a left and biventricular failure (PGD-LV) or isolated right ventricular failure (PGD-RV) group. The primary end point was survival to hospital discharge. RESULTS Between January 2010 and December 2016, 38 patients presented with PGD (PGD-LV n = 22, 58%; PGD-RV n = 16, 42%) requiring ECLS support. The mean age was 50.8 ± 12.4 years and 79% were males. Baseline characteristics were comparable between the 2 groups. PGD-LV patients displayed a significantly higher mortality rate on ECLS support as opposed to PGD-RV patients (46% vs 13%, P = 0.033). The rate of complications during ECLS support was comparable between the 2 groups. Twenty-three (61%) patients were successfully weaned from ECLS (PGD-LV = 50% vs PGD-RV = 75%, P = 0.111) after a mean support of 9.0 ± 6.4 days. Seventeen (45%) patients survived to hospital discharge (PGD-LV = 41% vs PGD-RV = 50%, P = 0.410). CONCLUSIONS In case of severe PGD with various manifestations of ventricular failure refractory to conventional treatment, ECLS can be considered as a feasible option with satisfactory survival in this critically ill population. Heart transplantation, Primary graft dysfunction, Left-sided heart failure, Right-sided heart failure, Extracorporeal membrane oxygenation INTRODUCTION Although overall survival after heart transplantation (HTx) has continued to improve in the last 3 decades, primary graft dysfunction (PGD) is still a leading cause of death in the early post-transplant period [1]. The relevant literature of PGD shows heterogeneous results and conclusions owing to inconsistent definitions of PGD used by different authors [2]. This lack of standardization of the definition, diagnostic criteria and treatment strategies led the International Society for Heart and Lung Transplantation (ISHLT) to develop a consensus document in 2014 [3]. PGD is now clearly differentiated by secondary graft dysfunction where a specific cause—i.e. hyper-acute rejection, pulmonary hypertension or surgical complications—could be recognized. Moreover, the diagnosis of PGD must be performed within 24 h after completion of HTx and should distinguish between left- and biventricular failure (PGD-LV) and isolated right ventricular failure (PGD-RV). Finally, the introduction of a grading system of PGD severity could guide the subsequent decision-making algorithm [3]. Medical management seems useful in mild or moderate PGD, while extracorporeal life support (ECLS) could be suggested as a therapeutic option for those severe cases of PGD that are refractory to maximal conventional treatment including inotropes, vasodilators and nitric oxide [4–15]. We aimed to report the results of ECLS for PGD after HTx according to the ISHLT classification. PATIENTS AND METHODS Study design We undertook an observational analysis of our local database of ECLS implantation for PGD after HTx. Authorization from an ethics committee and written informed consent from participants were not required owing to national regulations on ‘non-interventional clinical research’ (articles L0.1121-1 and R0.1121-2 of the French Public Health Code). Patient population Adult patients who received an ECLS for PGD after HTx at our institution from January 2010 to December 2016 were included in this study. We excluded patients (i) undergoing HTx and aged <18 years (n = 29), (ii) requiring ECLS for graft dysfunction secondary to isolated pulmonary hypertension (n = 2) and (iii) receiving ECLS more than 24 h after HTx completion (n = 4). PGD was defined according to the ISHLT criteria [3]. In particular, severe PGD-LV was defined as the need of left or biventricular mechanical circulatory support. Conversely, there were no grades for the severity of PGD-RV because PGD-RV can often be more difficult to quantify. Surgical technique ECLS was implanted in the event of (i) inability to wean the patient from cardiopulmonary bypass despite inotropic support and (ii) refractory cardiogenic shock in the postoperative period within 24 h after completion of HTx. Failure of weaning from cardiopulmonary bypass was assessed by intraoperative transoesophageal echocardiography (left ventricular ejection fraction ≤40% and/or evidence of right ventricular dysfunction) coupled to right heart catheterization (cardiac index <2 l/min/m2). Cardiogenic shock was defined as hypotension (systolic blood pressure <90 mmHg) despite adequate filling status with signs of hypoperfusion [16]. The implantation of ECLS could be performed in a peripheral or intrathoracic configuration, and the choice was left to the surgeon’s discretion. Peripheral ECLS was implanted surgically. Venous and arterial cannulae were placed using a modified Seldinger technique after surgical exposure of the femoral vessels at the groin. As per institutional policy, an arterial catheter was systematically placed distally to the entry site of the arterial cannula to prevent lower limb ischaemia. In the intrathoracic or central ECLS, venous drainage was obtained using either direct cannulation of the right atrium or a percutaneous femoral venous cannula. The arterial reinjection was placed in the ascending aorta. Left ventricular unloading, if necessary, was accomplished after the cannulation of the right superior pulmonary vein or left ventricular apex. The cannulae were tunnelled in the subxyphoid or subcostal region, and the sternum was completely closed. The ECLS circuit consisted also of venous and arterial heparin-bounded tubing, a membrane oxygenator (Quadrox Bioline, Jostra-Maquet, Orléans, France), a centrifugal pump (Rotaflow, Jostra-Maquet) and an oxygen/air blender (Sechrist Industries, Anaheim, CA, USA). Extracorporeal life support management As described previously [17], ECLS flow was initially set at the theoretical cardiac output owing to the body surface area of the patient. However, an inotropic support with dobutamine was used in order to maintain a left ventricular ejection with aortic valve opening. Moreover, vasopressor support with norepinephrine was usually added with a target mean blood pressure of 60–80 mmHg. After admission to our intensive care unit, anticoagulation with unfractioned heparin was usually started 6 h after the completion of HTx if the surgical bleeding from the chest drains was <50 ml/h. Target unfractionated heparin anti-Xa factor activity was maintained between 0.30 and 0.35 IU/ml during ECLS support. Serial transoesophageal echocardiography was performed after progressive reduction of ECLS flow to assess the myocardial recovery. Patients stable during reduction trials and with left ventricular ejection fraction >25% and time–velocity integral >10 cm were weaned from ECLS [18]. Right ventricular function was considered recovered when (i) systemic arterial pressure remained stable without the augmentation of central venous pressure, (ii) major inotropic support or the need for escalation of inotropic support was not required, and (iii) a transthoracic echocardiography showed satisfactory right ventricular systolic function without dilatation. Right-sided haemodynamic parameters were not considered, because their interpretation under ECLS support is complicated. If the weaning trial was haemodynamically tolerated and the echocardiographic criteria were fulfilled, the decannulation procedure was performed in a surgical manner with reopening of the operative field at the groin or chest depending on the ECLS configuration. Successful weaning was defined as ECLS decannulation without the need for ECLS reinsertion or mortality within 48 h. In patients without complete myocardial recovery, cardiac retransplantation could be considered as a rescue therapeutic option. Conversely, ECLS support was considered futile and then stopped in the presence of multiple organ failure or brain death. Outcome and statistical analysis Preoperative, perioperative and postoperative data were retrieved from the computerized medical charts of our hospital. Moreover, the data of heart donors were collected from the French regulatory agency of transplantation (The Agency of Biomedecine). Patients were divided into a PGD-LV or PGD-RV group according to the echocardiographic and haemodynamic parameters defined in the ISHLT classification [3]. The secondary end points were complications rate during ECLS support, successful weaning rate from ECLS and short-term outcomes. Neurological complications included seizure, cerebral infarction and intracerebral haemorrhage. Only infections occurring >24 h after ECLS initiation and within 48 h after ECLS discontinuation were defined as ECLS associated [19]. Statistical analysis was performed with SPSS software, version 24.0 (IBM Corp., Armonk, NY, USA). Categorical variables were presented as counts and percentages and compared using the Pearson’s χ2 test or Fisher’s exact test (>20% of expected counts with <5 counts). Continuous variables were presented as mean ± standard deviation and compared using Student’s t-test or Mann–Whitney U-test depending on their normality, which was assessed by the Kolmogorov–Smirnov test. Survival was calculated with the use of Kaplan–Meier analysis and compared using the log-rank test. A level of 0.05 was used to test for significance. RESULTS Baseline characteristics Of the 212 patients who had orthotopic HTx, 38 (18%) patients developed PGD (PGD-LV n = 22, 58%; PGD-RV n = 16, 42%) requiring ECLS support and met our selection criteria. The mean age was 50.8 ± 12.4 (range 22–64) years and 79% were males. Table 1 shows the preoperative characteristics. Ischaemic cardiomyopathy was the most frequent (48%) diagnosis leading to HTx, and 14 (38%) patients were bridged to HTx with a temporary (n = 6, 16%) or long-term (n = 8, 21%) mechanical circulatory support. Baseline characteristics were comparable between both groups. The mean age of heart donors was 41.3 ± 12.6 (range 21–63) years and 68% were males. Table 2 summarizes the characteristics of heart donors. The characteristics of the heart donors were comparable between both groups. In particular, there was no difference in terms of sex mismatch (donor female to recipient male). Table 3 displays the baseline biological and haemodynamic evaluation of our patient population. The biological profile was typical of end-stage heart failure patients. PGD-LV patients showed numerically higher total bilirubin levels compared to PGD-RV patients, but the difference did not reach statistical significance (28.4 vs 16.9 μmol/l, P = 0.069). Table 1: Preoperative characteristics Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Age (years), mean ± SD 50.8 ± 12.4 50.4 ± 10.5 51.4 ± 14.9 0.814 Male sex, n (%) 30 (79) 18 (82) 12 (75) 0.453b BSA (m2), mean ± SD 1.8 ± 0.2 1.8 ± 0.2 1.7 ± 0.2 0.265 BMI (kg/m2), mean ± SD 24.7 ± 3.8 25.4 ± 3.5 23.7 ± 4.1 0.196 CV risk factors, n (%)  Hypertension 10 (26) 6 (27) 4 (25) 0.589b  Diabetes 8 (21) 6 (27) 2 (13) 0.245b  Dyslipidaemia 11 (29) 6 (27) 5 (31) 0.790a  History of smoking 20 (53) 11 (50) 9 (56) 0.480a  Obesity 4 (11) 3 (14) 1 (6) 0.433b Previous cardiac surgery, n (%) 17 (45) 9 (41) 8 (50) 0.578 ICD, n (%) 23 (61) 12 (55) 11 (69) 0.376a CRT, n (%) 10 (26) 6 (27) 4 (25) 0.589b Diagnosis, n (%) 0.369b  ICM 18 (48) 11 (50) 7 (44)  DCM 10 (26) 4 (18) 6 (38)  Other 10 (26) 7 (32) 3 (19) Waiting list time (months), mean ± SD 41.1 ± 207.2 5.5 ± 7.7 13.3 ± 24.2 0.228 High emergency waiting list, n (%) 25 (66) 14 (64) 11 (69) 0.743a Clinical status, n (%)  Inotropes 15 (39) 9 (41) 6 (38) 0.832a  Mechanical ventilation 5 (13) 4 (18) 1 (6) 0.286b  IABP 10 (26) 6 (27) 4 (25) 0.589b  ECLS 6 (16) 5 (23) 1 (6) 0.180b  Long-term MCS 8 (21) 6 (27) 2 (13) 0.245b Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Age (years), mean ± SD 50.8 ± 12.4 50.4 ± 10.5 51.4 ± 14.9 0.814 Male sex, n (%) 30 (79) 18 (82) 12 (75) 0.453b BSA (m2), mean ± SD 1.8 ± 0.2 1.8 ± 0.2 1.7 ± 0.2 0.265 BMI (kg/m2), mean ± SD 24.7 ± 3.8 25.4 ± 3.5 23.7 ± 4.1 0.196 CV risk factors, n (%)  Hypertension 10 (26) 6 (27) 4 (25) 0.589b  Diabetes 8 (21) 6 (27) 2 (13) 0.245b  Dyslipidaemia 11 (29) 6 (27) 5 (31) 0.790a  History of smoking 20 (53) 11 (50) 9 (56) 0.480a  Obesity 4 (11) 3 (14) 1 (6) 0.433b Previous cardiac surgery, n (%) 17 (45) 9 (41) 8 (50) 0.578 ICD, n (%) 23 (61) 12 (55) 11 (69) 0.376a CRT, n (%) 10 (26) 6 (27) 4 (25) 0.589b Diagnosis, n (%) 0.369b  ICM 18 (48) 11 (50) 7 (44)  DCM 10 (26) 4 (18) 6 (38)  Other 10 (26) 7 (32) 3 (19) Waiting list time (months), mean ± SD 41.1 ± 207.2 5.5 ± 7.7 13.3 ± 24.2 0.228 High emergency waiting list, n (%) 25 (66) 14 (64) 11 (69) 0.743a Clinical status, n (%)  Inotropes 15 (39) 9 (41) 6 (38) 0.832a  Mechanical ventilation 5 (13) 4 (18) 1 (6) 0.286b  IABP 10 (26) 6 (27) 4 (25) 0.589b  ECLS 6 (16) 5 (23) 1 (6) 0.180b  Long-term MCS 8 (21) 6 (27) 2 (13) 0.245b Obesity was defined as BMI >30 kg/m2. For categorical variables, P-values were obtained using athe χ2 test and bthe Fisher’s exact test. BMI: body mass index; BSA: body surface area; CRT: cardiac resynchronization therapy; CV: cardiovascular; CVA: cerebrovascular accident; DCM: dilated cardiomyopathy; ECLS: extracorporeal life support; IABP: intra-aortic balloon pump; ICD: implantable cardioverter-defibrillator; ICM: ischaemic cardiomyopathy; MCS: mechanical circulatory support; PGD-LV: left and biventricular primary graft dysfunction; PGD-RV: isolated right ventricular primary graft dysfunction; SD: standard deviation. Table 1: Preoperative characteristics Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Age (years), mean ± SD 50.8 ± 12.4 50.4 ± 10.5 51.4 ± 14.9 0.814 Male sex, n (%) 30 (79) 18 (82) 12 (75) 0.453b BSA (m2), mean ± SD 1.8 ± 0.2 1.8 ± 0.2 1.7 ± 0.2 0.265 BMI (kg/m2), mean ± SD 24.7 ± 3.8 25.4 ± 3.5 23.7 ± 4.1 0.196 CV risk factors, n (%)  Hypertension 10 (26) 6 (27) 4 (25) 0.589b  Diabetes 8 (21) 6 (27) 2 (13) 0.245b  Dyslipidaemia 11 (29) 6 (27) 5 (31) 0.790a  History of smoking 20 (53) 11 (50) 9 (56) 0.480a  Obesity 4 (11) 3 (14) 1 (6) 0.433b Previous cardiac surgery, n (%) 17 (45) 9 (41) 8 (50) 0.578 ICD, n (%) 23 (61) 12 (55) 11 (69) 0.376a CRT, n (%) 10 (26) 6 (27) 4 (25) 0.589b Diagnosis, n (%) 0.369b  ICM 18 (48) 11 (50) 7 (44)  DCM 10 (26) 4 (18) 6 (38)  Other 10 (26) 7 (32) 3 (19) Waiting list time (months), mean ± SD 41.1 ± 207.2 5.5 ± 7.7 13.3 ± 24.2 0.228 High emergency waiting list, n (%) 25 (66) 14 (64) 11 (69) 0.743a Clinical status, n (%)  Inotropes 15 (39) 9 (41) 6 (38) 0.832a  Mechanical ventilation 5 (13) 4 (18) 1 (6) 0.286b  IABP 10 (26) 6 (27) 4 (25) 0.589b  ECLS 6 (16) 5 (23) 1 (6) 0.180b  Long-term MCS 8 (21) 6 (27) 2 (13) 0.245b Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Age (years), mean ± SD 50.8 ± 12.4 50.4 ± 10.5 51.4 ± 14.9 0.814 Male sex, n (%) 30 (79) 18 (82) 12 (75) 0.453b BSA (m2), mean ± SD 1.8 ± 0.2 1.8 ± 0.2 1.7 ± 0.2 0.265 BMI (kg/m2), mean ± SD 24.7 ± 3.8 25.4 ± 3.5 23.7 ± 4.1 0.196 CV risk factors, n (%)  Hypertension 10 (26) 6 (27) 4 (25) 0.589b  Diabetes 8 (21) 6 (27) 2 (13) 0.245b  Dyslipidaemia 11 (29) 6 (27) 5 (31) 0.790a  History of smoking 20 (53) 11 (50) 9 (56) 0.480a  Obesity 4 (11) 3 (14) 1 (6) 0.433b Previous cardiac surgery, n (%) 17 (45) 9 (41) 8 (50) 0.578 ICD, n (%) 23 (61) 12 (55) 11 (69) 0.376a CRT, n (%) 10 (26) 6 (27) 4 (25) 0.589b Diagnosis, n (%) 0.369b  ICM 18 (48) 11 (50) 7 (44)  DCM 10 (26) 4 (18) 6 (38)  Other 10 (26) 7 (32) 3 (19) Waiting list time (months), mean ± SD 41.1 ± 207.2 5.5 ± 7.7 13.3 ± 24.2 0.228 High emergency waiting list, n (%) 25 (66) 14 (64) 11 (69) 0.743a Clinical status, n (%)  Inotropes 15 (39) 9 (41) 6 (38) 0.832a  Mechanical ventilation 5 (13) 4 (18) 1 (6) 0.286b  IABP 10 (26) 6 (27) 4 (25) 0.589b  ECLS 6 (16) 5 (23) 1 (6) 0.180b  Long-term MCS 8 (21) 6 (27) 2 (13) 0.245b Obesity was defined as BMI >30 kg/m2. For categorical variables, P-values were obtained using athe χ2 test and bthe Fisher’s exact test. BMI: body mass index; BSA: body surface area; CRT: cardiac resynchronization therapy; CV: cardiovascular; CVA: cerebrovascular accident; DCM: dilated cardiomyopathy; ECLS: extracorporeal life support; IABP: intra-aortic balloon pump; ICD: implantable cardioverter-defibrillator; ICM: ischaemic cardiomyopathy; MCS: mechanical circulatory support; PGD-LV: left and biventricular primary graft dysfunction; PGD-RV: isolated right ventricular primary graft dysfunction; SD: standard deviation. Table 2: Characteristics of heart donors Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Age (years), mean ± SD 41.3 ± 12.6 41.7 ± 12.8 40.9 ± 12.8 0.841 Male sex, n (%) 26 (68) 15 (68) 11 (69) 0.970a BSA (m2), mean ± SD 1.9 ± 0.2 1.9 ± 0.2 1.8 ± 0.2 0.450 BMI (kg/m2), mean ± SD 25.3 ± 4.8 25.2 ± 4.1 25.5 ± 5.7 0.838 Vasopressor support, n (%) 34 (90) 20 (91) 14 (88) 0.567b LVEF (%), mean ± SD 62.1 ± 6.2 61.3 ± 5.5 63.0 ± 7.2 0.424 Sex mismatch (recipient male, donor female), n (%) 9 (24) 5 (23) 4 (25) 0.584b Cause of death, n (%) 0.447b  Trauma 15 (39) 10 (45) 5 (31)  CVA 11 (29) 7 (32) 4 (25)  Other 12 (32) 5 (23) 7 (44) Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Age (years), mean ± SD 41.3 ± 12.6 41.7 ± 12.8 40.9 ± 12.8 0.841 Male sex, n (%) 26 (68) 15 (68) 11 (69) 0.970a BSA (m2), mean ± SD 1.9 ± 0.2 1.9 ± 0.2 1.8 ± 0.2 0.450 BMI (kg/m2), mean ± SD 25.3 ± 4.8 25.2 ± 4.1 25.5 ± 5.7 0.838 Vasopressor support, n (%) 34 (90) 20 (91) 14 (88) 0.567b LVEF (%), mean ± SD 62.1 ± 6.2 61.3 ± 5.5 63.0 ± 7.2 0.424 Sex mismatch (recipient male, donor female), n (%) 9 (24) 5 (23) 4 (25) 0.584b Cause of death, n (%) 0.447b  Trauma 15 (39) 10 (45) 5 (31)  CVA 11 (29) 7 (32) 4 (25)  Other 12 (32) 5 (23) 7 (44) For categorical variables, P-values were obtained using athe χ2 test and bthe Fisher’s exact test. BMI: body mass index; BSA: body surface area; CVA: cerebrovascular accident; LVEF: left ventricular ejection fraction; PGD-LV: left and biventricular primary graft dysfunction; PGD-RV: isolated right ventricular primary graft dysfunction; SD: standard deviation. Table 2: Characteristics of heart donors Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Age (years), mean ± SD 41.3 ± 12.6 41.7 ± 12.8 40.9 ± 12.8 0.841 Male sex, n (%) 26 (68) 15 (68) 11 (69) 0.970a BSA (m2), mean ± SD 1.9 ± 0.2 1.9 ± 0.2 1.8 ± 0.2 0.450 BMI (kg/m2), mean ± SD 25.3 ± 4.8 25.2 ± 4.1 25.5 ± 5.7 0.838 Vasopressor support, n (%) 34 (90) 20 (91) 14 (88) 0.567b LVEF (%), mean ± SD 62.1 ± 6.2 61.3 ± 5.5 63.0 ± 7.2 0.424 Sex mismatch (recipient male, donor female), n (%) 9 (24) 5 (23) 4 (25) 0.584b Cause of death, n (%) 0.447b  Trauma 15 (39) 10 (45) 5 (31)  CVA 11 (29) 7 (32) 4 (25)  Other 12 (32) 5 (23) 7 (44) Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Age (years), mean ± SD 41.3 ± 12.6 41.7 ± 12.8 40.9 ± 12.8 0.841 Male sex, n (%) 26 (68) 15 (68) 11 (69) 0.970a BSA (m2), mean ± SD 1.9 ± 0.2 1.9 ± 0.2 1.8 ± 0.2 0.450 BMI (kg/m2), mean ± SD 25.3 ± 4.8 25.2 ± 4.1 25.5 ± 5.7 0.838 Vasopressor support, n (%) 34 (90) 20 (91) 14 (88) 0.567b LVEF (%), mean ± SD 62.1 ± 6.2 61.3 ± 5.5 63.0 ± 7.2 0.424 Sex mismatch (recipient male, donor female), n (%) 9 (24) 5 (23) 4 (25) 0.584b Cause of death, n (%) 0.447b  Trauma 15 (39) 10 (45) 5 (31)  CVA 11 (29) 7 (32) 4 (25)  Other 12 (32) 5 (23) 7 (44) For categorical variables, P-values were obtained using athe χ2 test and bthe Fisher’s exact test. BMI: body mass index; BSA: body surface area; CVA: cerebrovascular accident; LVEF: left ventricular ejection fraction; PGD-LV: left and biventricular primary graft dysfunction; PGD-RV: isolated right ventricular primary graft dysfunction; SD: standard deviation. Table 3: Baseline biological and haemodynamic evaluation Variables Overall (n = 38), mean ± SD PGD-LV (n = 22), mean ± SD PGD-RV (n = 16), mean ± SD P-value Haemoglobin (g/dl) 11.5 ± 2.3 11.3 ± 2.5 11.7 ± 2.0 0.588 Platelets (109/l) 201.0 ± 90.2 202.0 ± 95.7 199.6 ± 85.2 0.937 WBC (109/l) 9.3 ± 4.2 9.2 ± 3.1 9.3 ± 5.4 0.990 INR 1.8 ± 1.0 1.9 ± 1.0 1.8 ± 0.9 0.605 BUN (mmol/l) 12.5 ± 9.0 11.9 ± 8.1 13.4 ± 10.3 0.611 Creatinine (μmol/l) 116.6 ± 15.5 110.4 ± 40.3 124.5 ± 61.9 0.430 Total bilirubin (μmol/l) 23.6 ± 21.6 28.4 ± 26.9 16.9 ± 7.7 0.069 ASAT (U/l) 83.0 ± 137.0 79.2 ± 130.9 88.1 ± 149.1 0.847 ALAT (U/l) 81.5 ± 169.2 95.0 ± 209.6 63.1 ± 92.1 0.573 sPAP (mmHg) 46.3 ± 16.7 44.7 ± 18.5 48.6 ± 13.8 0.552 mPAP (mmHg) 30.3 ± 11.4 29.8 ± 12.4 31.0 ± 10.5 0.798 TPG (mmHg) 11.6 ± 6.7 11.4 ± 8.3 11.8 ± 3.1 0.929 PVR (Wood units) 2.5 ± 1.5 2.3 ± 1.4 2.9 ± 1.7 0.337 Variables Overall (n = 38), mean ± SD PGD-LV (n = 22), mean ± SD PGD-RV (n = 16), mean ± SD P-value Haemoglobin (g/dl) 11.5 ± 2.3 11.3 ± 2.5 11.7 ± 2.0 0.588 Platelets (109/l) 201.0 ± 90.2 202.0 ± 95.7 199.6 ± 85.2 0.937 WBC (109/l) 9.3 ± 4.2 9.2 ± 3.1 9.3 ± 5.4 0.990 INR 1.8 ± 1.0 1.9 ± 1.0 1.8 ± 0.9 0.605 BUN (mmol/l) 12.5 ± 9.0 11.9 ± 8.1 13.4 ± 10.3 0.611 Creatinine (μmol/l) 116.6 ± 15.5 110.4 ± 40.3 124.5 ± 61.9 0.430 Total bilirubin (μmol/l) 23.6 ± 21.6 28.4 ± 26.9 16.9 ± 7.7 0.069 ASAT (U/l) 83.0 ± 137.0 79.2 ± 130.9 88.1 ± 149.1 0.847 ALAT (U/l) 81.5 ± 169.2 95.0 ± 209.6 63.1 ± 92.1 0.573 sPAP (mmHg) 46.3 ± 16.7 44.7 ± 18.5 48.6 ± 13.8 0.552 mPAP (mmHg) 30.3 ± 11.4 29.8 ± 12.4 31.0 ± 10.5 0.798 TPG (mmHg) 11.6 ± 6.7 11.4 ± 8.3 11.8 ± 3.1 0.929 PVR (Wood units) 2.5 ± 1.5 2.3 ± 1.4 2.9 ± 1.7 0.337 ALAT: alanine aminotransferase; ASAT: aspartate aminotransferase; BUN: blood urea nitrogen; INR: international normalized ratio; mPAP: mean pulmonary artery pressure; PGD-LV: left and biventricular primary graft dysfunction; PGD-RV: isolated right ventricular primary graft dysfunction; PVR: pulmonary vascular resistance; SD: standard deviation; sPAP: systolic pulmonary artery pressure; TPG: transpulmonary gradient; WBC: white blood cells. Table 3: Baseline biological and haemodynamic evaluation Variables Overall (n = 38), mean ± SD PGD-LV (n = 22), mean ± SD PGD-RV (n = 16), mean ± SD P-value Haemoglobin (g/dl) 11.5 ± 2.3 11.3 ± 2.5 11.7 ± 2.0 0.588 Platelets (109/l) 201.0 ± 90.2 202.0 ± 95.7 199.6 ± 85.2 0.937 WBC (109/l) 9.3 ± 4.2 9.2 ± 3.1 9.3 ± 5.4 0.990 INR 1.8 ± 1.0 1.9 ± 1.0 1.8 ± 0.9 0.605 BUN (mmol/l) 12.5 ± 9.0 11.9 ± 8.1 13.4 ± 10.3 0.611 Creatinine (μmol/l) 116.6 ± 15.5 110.4 ± 40.3 124.5 ± 61.9 0.430 Total bilirubin (μmol/l) 23.6 ± 21.6 28.4 ± 26.9 16.9 ± 7.7 0.069 ASAT (U/l) 83.0 ± 137.0 79.2 ± 130.9 88.1 ± 149.1 0.847 ALAT (U/l) 81.5 ± 169.2 95.0 ± 209.6 63.1 ± 92.1 0.573 sPAP (mmHg) 46.3 ± 16.7 44.7 ± 18.5 48.6 ± 13.8 0.552 mPAP (mmHg) 30.3 ± 11.4 29.8 ± 12.4 31.0 ± 10.5 0.798 TPG (mmHg) 11.6 ± 6.7 11.4 ± 8.3 11.8 ± 3.1 0.929 PVR (Wood units) 2.5 ± 1.5 2.3 ± 1.4 2.9 ± 1.7 0.337 Variables Overall (n = 38), mean ± SD PGD-LV (n = 22), mean ± SD PGD-RV (n = 16), mean ± SD P-value Haemoglobin (g/dl) 11.5 ± 2.3 11.3 ± 2.5 11.7 ± 2.0 0.588 Platelets (109/l) 201.0 ± 90.2 202.0 ± 95.7 199.6 ± 85.2 0.937 WBC (109/l) 9.3 ± 4.2 9.2 ± 3.1 9.3 ± 5.4 0.990 INR 1.8 ± 1.0 1.9 ± 1.0 1.8 ± 0.9 0.605 BUN (mmol/l) 12.5 ± 9.0 11.9 ± 8.1 13.4 ± 10.3 0.611 Creatinine (μmol/l) 116.6 ± 15.5 110.4 ± 40.3 124.5 ± 61.9 0.430 Total bilirubin (μmol/l) 23.6 ± 21.6 28.4 ± 26.9 16.9 ± 7.7 0.069 ASAT (U/l) 83.0 ± 137.0 79.2 ± 130.9 88.1 ± 149.1 0.847 ALAT (U/l) 81.5 ± 169.2 95.0 ± 209.6 63.1 ± 92.1 0.573 sPAP (mmHg) 46.3 ± 16.7 44.7 ± 18.5 48.6 ± 13.8 0.552 mPAP (mmHg) 30.3 ± 11.4 29.8 ± 12.4 31.0 ± 10.5 0.798 TPG (mmHg) 11.6 ± 6.7 11.4 ± 8.3 11.8 ± 3.1 0.929 PVR (Wood units) 2.5 ± 1.5 2.3 ± 1.4 2.9 ± 1.7 0.337 ALAT: alanine aminotransferase; ASAT: aspartate aminotransferase; BUN: blood urea nitrogen; INR: international normalized ratio; mPAP: mean pulmonary artery pressure; PGD-LV: left and biventricular primary graft dysfunction; PGD-RV: isolated right ventricular primary graft dysfunction; PVR: pulmonary vascular resistance; SD: standard deviation; sPAP: systolic pulmonary artery pressure; TPG: transpulmonary gradient; WBC: white blood cells. Short-term outcomes Table 4 shows the operative and postoperative outcomes of our study population. ECLS was implanted directly in the operating theatre when weaning from cardiopulmonary bypass was not possible in 30 (79%) patients (PGD-LV = 86% vs PGD-RV = 69%, P = 0.189). No patients underwent ECLS implantation during cardiopulmonary resuscitation. Peripheral ECLS was used in 25 (66%) patients (PGD-LV = 64% vs PGD-RV = 69%, P = 0.743). PGD-LV patients displayed a significantly higher mortality rate on ECLS support compared to those with PGD-RV patients (46 vs 13%, P = 0.033). The rate of complications during ECLS support was comparable between both groups. Twenty-three (61%) patients were successfully weaned from ECLS (PGD-LV = 50% vs PGD-RV = 75%, P = 0.111) after a mean support of 9.0 ± 6.4 (range 3–32) days (PGD-LV = 7.5 days vs PGD-RV = 9.3 days, P = 0.429). One (3%) patient died in the first 24 h after ECLS weaning for multiorgan failure, while 2 (5%) patients were bridged to cardiac retransplantation owing to the absence of myocardial recovery. Seventeen (45%) patients survived to hospital discharge (PGD-LV = 41% vs PGD-RV = 50%, P = 0.410). Figure 1 depicts the outcome of our study population. Overall survival was 43% [95% confidence interval (CI) 27.2–59.4%; 13 remaining observations] at 1 year. The log-rank test showed no significant difference on overall survival between the 2 groups (median overall survival in the PGD-LV group = 11 days, 95% CI 0–39; median overall survival in the PGD-RV group = 201 days, 95% CI 0–796; P = 0.315; Fig. 2). Table 4: Operative and postoperative outcomes Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Total ischaemic time (min), mean ± SD 273.6 ± 57.8 280.9 ± 66.4 263.6 ± 43.2 0.369 Mortality on ECLS, n (%) 12 (32) 10 (45) 2 (13) 0.033 Complications on ECLS, n (%)  Lower limb ischaemia 3 (8) 2 (9) 1 (6) 0.621  Neurological 5 (13) 3 (14) 2 (13) 0.654  Renal replacement therapy 25 (66) 14 (64) 11 (69) 0.743  Surgical re-exploration 20 (53) 12 (55) 8 (50) 0.520  Infection 14 (37) 7 (32) 7 (44) 0.452 Successful weaning rate, n (%) 23 (61) 11 (50) 12 (75) 0.111 Survival to hospital discharge, n (%) 17 (45) 9 (41) 8 (50) 0.410 Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Total ischaemic time (min), mean ± SD 273.6 ± 57.8 280.9 ± 66.4 263.6 ± 43.2 0.369 Mortality on ECLS, n (%) 12 (32) 10 (45) 2 (13) 0.033 Complications on ECLS, n (%)  Lower limb ischaemia 3 (8) 2 (9) 1 (6) 0.621  Neurological 5 (13) 3 (14) 2 (13) 0.654  Renal replacement therapy 25 (66) 14 (64) 11 (69) 0.743  Surgical re-exploration 20 (53) 12 (55) 8 (50) 0.520  Infection 14 (37) 7 (32) 7 (44) 0.452 Successful weaning rate, n (%) 23 (61) 11 (50) 12 (75) 0.111 Survival to hospital discharge, n (%) 17 (45) 9 (41) 8 (50) 0.410 Bold value indicates P-value <0.05. ECLS: extracorporeal life support; PGD-LV: left and biventricular primary graft dysfunction; PGD-RV: isolated right ventricular primary graft dysfunction; SD: standard deviation. Table 4: Operative and postoperative outcomes Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Total ischaemic time (min), mean ± SD 273.6 ± 57.8 280.9 ± 66.4 263.6 ± 43.2 0.369 Mortality on ECLS, n (%) 12 (32) 10 (45) 2 (13) 0.033 Complications on ECLS, n (%)  Lower limb ischaemia 3 (8) 2 (9) 1 (6) 0.621  Neurological 5 (13) 3 (14) 2 (13) 0.654  Renal replacement therapy 25 (66) 14 (64) 11 (69) 0.743  Surgical re-exploration 20 (53) 12 (55) 8 (50) 0.520  Infection 14 (37) 7 (32) 7 (44) 0.452 Successful weaning rate, n (%) 23 (61) 11 (50) 12 (75) 0.111 Survival to hospital discharge, n (%) 17 (45) 9 (41) 8 (50) 0.410 Variables Overall (n = 38) PGD-LV (n = 22) PGD-RV (n = 16) P-value Total ischaemic time (min), mean ± SD 273.6 ± 57.8 280.9 ± 66.4 263.6 ± 43.2 0.369 Mortality on ECLS, n (%) 12 (32) 10 (45) 2 (13) 0.033 Complications on ECLS, n (%)  Lower limb ischaemia 3 (8) 2 (9) 1 (6) 0.621  Neurological 5 (13) 3 (14) 2 (13) 0.654  Renal replacement therapy 25 (66) 14 (64) 11 (69) 0.743  Surgical re-exploration 20 (53) 12 (55) 8 (50) 0.520  Infection 14 (37) 7 (32) 7 (44) 0.452 Successful weaning rate, n (%) 23 (61) 11 (50) 12 (75) 0.111 Survival to hospital discharge, n (%) 17 (45) 9 (41) 8 (50) 0.410 Bold value indicates P-value <0.05. ECLS: extracorporeal life support; PGD-LV: left and biventricular primary graft dysfunction; PGD-RV: isolated right ventricular primary graft dysfunction; SD: standard deviation. Figure 1: View largeDownload slide Flow diagram of the outcome of the study population. ECLS: extracorporeal life support; HTx: heart transplantation; PGD: primary graft dysfunction; PGD-LV: left and biventricular primary graft dysfunction; PGD-RV: isolated right ventricular primary graft dysfunction. Figure 1: View largeDownload slide Flow diagram of the outcome of the study population. ECLS: extracorporeal life support; HTx: heart transplantation; PGD: primary graft dysfunction; PGD-LV: left and biventricular primary graft dysfunction; PGD-RV: isolated right ventricular primary graft dysfunction. Figure 2: View largeDownload slide Survival of extracorporeal life support for primary graft dysfunction after heart transplantation. (A) Group analysis. (B) Total population. PGF-D: isolated right ventricular primary graft dysfunction; PGF-G: left and biventricular primary graft dysfunction. Figure 2: View largeDownload slide Survival of extracorporeal life support for primary graft dysfunction after heart transplantation. (A) Group analysis. (B) Total population. PGF-D: isolated right ventricular primary graft dysfunction; PGF-G: left and biventricular primary graft dysfunction. DISCUSSION PGD is a life-threatening complication after HTx that negatively affects short- and long-term outcomes. It accounts for ∼40% of deaths within 30 days of cardiac transplantation [20]. Moreover, overall late survival is significantly lower in patients experiencing PGD [7, 8, 10, 11, 14, 21]. The pathophysiology is multifactorial, and several risk factors involving the donor, recipient and surgical procedure have been identified over time [3, 14, 21]. The incidence of severe PGD requiring ECLS was quite high (18%) during our experience. Although the definitions of PGD were heterogeneous making comparisons difficult to carry out, this incidence was consistent with previous reports. In articles providing detailed information, the incidence of PGD supported with ECLS ranged between 7% and 23% [5, 7–15, 21]. Interestingly, D’Alessandro et al. [7] found a temporal trend of PGD after HTx. The raising of incidence in more recent years was explained by an evolving profile of recipients and donors, with more critically ill patients transplanted with marginal donors. This increasing rate of PGD after HTx reflects a more general effort of every transplant team to overcome the shortage of heart donors. This effort is also witnessed by our prolonged total ischaemic time. Allograft ischaemic time predominantly affects early outcomes, and ischaemic time <4 h is associated with considerably higher survival [22]. The high incidence of severe PGD requiring ECLS in our series could be partially explained by the presence of several well-known risk factors, such as older donor age [22], longer total ischaemic time and high rate of preoperative short- and long-term mechanical circulatory support, previous sternotomy and emergency transplant [3]. Our analysis showed that ECLS provided a survival to hospital discharge of 45%. These results compare favourably with other previous series that reported survivals to hospital discharge between 44% and 81% [5, 7, 8, 10–15, 21]. In only 1 small study (11 patients), this outcome improved to 91% [6] while other investigators reached a survival to hospital discharge of 82% adopting a systematic ECLS implantation in the setting of known preceding donor cardiac dysfunction [9]. This extreme variability in survival across studies could be partially explained by the complex and multifactorial physiopathology of PGD after HTx, as opposed to other conditions with a high potential of myocardial recovery and more reproducible ECLS results such as drug intoxication and myocarditis. ECLS was most frequently implanted directly in the operating theatre and in a peripheral configuration. Our institutional policy is to be as aggressive as possible in the implantation of ECLS before the onset of end-organ dysfunction. Interestingly, of the 8 patients who were not implanted directly in the operating theatre, 6 (75%) patients did not survive to hospital discharge. Prompt ECLS implantation could reduce the dose of inotropic support, which increases myocardial oxygen consumption and limits the chances of myocardial recovery. Moreover, we prefer a femoro-femoral rather than a central ECLS as its decannulation does not need a sternal re-entry, which has a potentially increased risk of bleeding and infection. However, any previous attempt to compare central and peripheral ECLS failed to find any significant difference in outcomes with the only exception of an increased rate of lower limb ischaemia in the femoral group [7, 21]. Lower limb ischaemia was encountered in 12% of our peripheral ECLS subgroup, and this complication rate is comparable with that reported in the literature [23–25] and in previous reports of ECLS for PGD after HTx [7, 8]. We observed a disproportionate rate (∼50%) of surgical re-exploration for bleeding. This complication rate was experienced in 26–38% of patients in previous analyses [7, 8, 14]. A possible explanation for this bleeding complication could be the higher proportion (21%) of patients bridged to HTx with a long-term mechanical circulatory support. In our study population, PGD-LV was the leading (58%) manifestation of PGD after HTx. Despite a comparable preoperative profile between both groups, PGD-LV patients displayed a significantly higher mortality rate on ECLS support as opposed to PGD-RV patients. The main cause of death (6 of 10 patients) in the PGD-LV group was multiorgan failure. However, there was no difference on overall survival between both groups at hospital discharge and short-term follow-up. In fact, 4 patients in the PGD-RV group were weaned from ECLS support but did not survive to hospital discharge. Conversely in a recent study by Loforte et al. [14] evaluating early graft failure (primary and secondary according to the ISHLT consensus document) after HTx, the ECLS group was characterized mainly by biventricular dysfunction (93%) and, rarely, by PGD-RV (7%). Based on our results and those from previous reports [4–15], ECLS can be considered as a feasible option in the setting of PGD after HTx as (i) the implantation—especially in the peripheral configuration—is easy and quick, (ii) it allows rapid haemodynamic stabilization with progressive end-organ function improvement, and (iii) it represents a reasonable solution in terms of cost-effectiveness in such a critically ill population. Cardiac retransplantation could no more be considered an acceptable option because of the shortage of donors entailing ethical considerations and the dismal survival. In our study, 2 patients were addressed to cardiac retransplantation in the absence of myocardial recovery during ECLS support and died. Recently, Takeda et al. [15] conducted a comparative analysis between ECLS (n = 27) and temporary ventricular assist devices (n = 17) in patients with severe PGD: ECLS was associated with fewer postoperative complications, higher graft recovery rate and lower in-hospital mortality compared with ventricular assist devices. Taghavi et al. [26] analysed retrospectively their experience with either right ventricular assist device (n = 15) or ECLS (n = 13) to treat acute right ventricular failure after HTx. Although no difference in survival to hospital discharge was observed between the 2 groups, the weaning rate and graft survival were significantly better in the ECLS group. In fact, right ventricular assist devices could not allow a successful recovery of graft function, and most patients either died during mechanical support (47%) or underwent urgent heart retransplantation (40%). Limitations The present study displays several limitations. The small sample size represents a limiting factor that could undermine the statistical power of our analysis. Our conclusions are gathered from a single-centre observational experience and thus may not be generalizable to other settings. The ISHLT criteria for the definition and classification of PGD were applied retrospectively to our local database with obvious intrinsic limitations. We did not consider as a comparison group patients with PGD not requiring ECLS or supported with other types of mechanical circulatory support. From a statistical standpoint, the survival estimates have been evaluated from a very limited sample size of patients, which leads to wide 95% confidence intervals around the estimates overlapping between both groups. The absence of statistical difference using the log-rank test translates the lack of power of our study. With regard to survival analysis, our results can be considered as inconclusive. CONCLUSION PGD is still a serious complication in the immediate postoperative period of cardiac transplantation. In case of severe PGD refractory to conventional treatment, ECLS can be considered as a feasible option with an acceptable rate of complications and a satisfactory survival in this critically ill population. Further studies with larger study populations are, however, mandatory to best define the prognostic role of the ISHLT classification. Conflict of interest: none declared. REFERENCES 1 Lund LH , Edwards LB , Kucheryavaya AY , Benden C , Dipchand AI , Goldfarb S et al. The Registry of the International Society for Heart and Lung Transplantation: thirty-second Official Adult Heart Transplantation Report–2015; Focus Theme: early Graft Failure . J Heart Lung Transplant 2015 ; 34 : 1244 – 54 . Google Scholar CrossRef Search ADS PubMed 2 Iyer A , Kumarasinghe G , Hicks M , Watson A , Gao L , Doyle A et al. Primary graft failure after heart transplantation . 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The Registry of the International Society for Heart and Lung Transplantation: thirty-fourth Adult Heart Transplantation Report-2017; Focus Theme: allograft ischemic time . J Heart Lung Transplant 2017 ; 36 : 1037 – 46 . Google Scholar CrossRef Search ADS PubMed 23 Bisdas T , Beutel G , Warnecke G , Hoeper MM , Kuehn C , Haverich A et al. Vascular complications in patients undergoing femoral cannulation for extracorporeal membrane oxygenation support . Ann Thorac Surg 2011 ; 92 : 626 – 31 . Google Scholar CrossRef Search ADS PubMed 24 Tanaka D , Hirose H , Cavarocchi N , Entwistle JW. The Impact of vascular complications on survival of patients on venoarterial extracorporeal membrane oxygenation . Ann Thorac Surg 2016 ; 101 : 1729 – 34 . Google Scholar CrossRef Search ADS PubMed 25 Vallabhajosyula P , Kramer M , Lazar S , McCarthy F , Rame E , Wald J et al. Lower-extremity complications with femoral extracorporeal life support . J Thorac Cardiovasc Surg 2016 ; 151 : 1738 – 44 . Google Scholar CrossRef Search ADS PubMed 26 Taghavi S , Zuckermann A , Ankersmit J , Wieselthaler G , Rajek A , Laufer G et al. Extracorporeal membrane oxygenation is superior to right ventricular assist device for acute right ventricular failure after heart transplantation . Ann Thorac Surg 2004 ; 78 : 1644 – 9 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Interactive CardioVascular and Thoracic SurgeryOxford University Press

Published: May 17, 2018

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