T. Siemeni

Aortic valve replacement in geriatric patients with small aortic roots: are sutureless valves the future?

OBJECTIVES Aortic valve replacement (AVR) in geriatric patients (>75 years) with small aortic roots is a challenge. Patient-prosthesis mismatch and the long cross-clamp time necessary for stentless valves or root enlargement are matters of concern. We compared the results of AVR with sutureless valves (Sorin Perceval), against those with conventional biological valves. METHODS Between April 2007 and December 2012, 120 isolated AVRs were performed in patients with a small annulus (<22 mm) at our centre. In 70 patients (68 females, age 77.4 ± 5.5 years), conventional valves (C group) and in 50 patients (47 females, age 79.8 ± 4.5 years), sutureless valves (P group) were implanted. The Logistic EuroSCORE of the C group was 16.7 ± 10.4 and that of the P group 20.4 ± 10.7, (P = 0.054). Minimal-access surgery was performed in 4.3% (3/70) patients in the C group and 72% (36/50) patients in the P group. RESULTS The cardiopulmonary bypass (CPB) and cross-clamp times of the C group were 75.3 ± 23 and 50.3 ± 14.2 min vs 58.7 ± 20.9 and 30.1 ± 9 min in the P group, (P < 0.001). In the C group, two annulus enlargements were performed. Thirty-day mortality was 4.3% (n = 3) in the C group and 0 in the P group, (n.s.). At follow-up (up to 5 years), mortalities were 17.4% (n = 12) in the C group and 14% (n = 7) in the P group, (n.s.). CONCLUSIONS This study highlights the advantages of sutureless valves for geriatric patients with small aortic roots reflected by shorter cross-clamp and CPB times, even though most of these patients were operated on via a minimally invasive access. Moreover, due to the absence of a sewing ring, these valves are also almost stentless, with greater effective orifice area (EOA) for any given size. This may potentially result in better haemodynamics even without the root enlargement. This is of advantage, as several studies have shown that aortic root enlargement can significantly increase the risks of AVR. Moreover, as seen in this series, these valves may also enable a broader application of minimally invasive AVR.

Early donor-specific antibodies in lung transplantation: risk factors and impact on survival.

BACKGROUND The impact of early donor-specific anti-HLA antibodies (DSA) on patient and graft survival after lung transplantation remains controversial. In this study we analyzed risk factors for DSA that developed before initial hospital discharge after lung transplantation (early DSA) and compared mid-term outcomes in patients with or without DSA. METHODS Between January 2009 and August 2013, 546 patients underwent lung transplantation at our institution. One hundred (18%) patients developed early DSA (Group A) and 446 (82%) patients (Group B) did not. Patient records were retrospectively reviewed. RESULTS Retransplantation (odds ratio [OR] = 2.7, 95% confidence interval [CI] 1.1 to 6.5, p = 0.03), pre-operative HLA antibodies (OR = 2.1, 95% CI 1.2 to 3.4, p = 0.003) and primary graft dysfunction (PGD) score Grade 2 or 3 at 48 hours (OR = 2.6, 95% CI 1.5 to 4.6, p = 0.001) were associated with early DSA development. Overall, 1- and 3-year survival in Group A and B patients was 79 ± 4% vs 88 ± 2% and 57 ± 8% vs 74 ± 3%, respectively (p = 0.019). Eleven Group A (11%) and 32 Group B (7%) patients died before hospital discharge (p = 0.34). Among patients surviving beyond discharge, 1- and 3-year survival in Group A and B patients was 89 ± 4% vs 95 ± 1% and 65 ± 8% vs 80 ± 3% in Group A and B patients, respectively (p = 0.04). Multivariate analysis identified early anti-HLA Class II DSA (OR = 1.9, 95% CI 1.0 to 3.4, p = 0.04) as an independent risk factor for post-discharge mortality but not for in-hospital mortality. CONCLUSIONS Pre-operative HLA antibodies, retransplantation or post-operative PGD increase the risk of developing early DSA, which were independently associated with an increased risk for mortality.

Five-year experience with intraoperative extracorporeal membrane oxygenation in lung transplantation: Indications and midterm results

BACKGROUND Since April 2010, extracorporeal membrane oxygenation (ECMO) has replaced cardiopulmonary bypass for intraoperative support during lung transplantation at our institution. The aim of this study was to present our 5-year experience with this technique. METHODS Records of patients who underwent transplantation between April 2010 and January 2015 were retrospectively reviewed. Patients who underwent transplantation without ECMO formed Group A. Patients in whom the indication for ECMO support was set a priori before the beginning of the operation formed Group B. The remaining patients in whom the indication for ECMO support was set during transplantation formed Group C. RESULTS Among 595 patients, 425 (71%) patients (Group A) did not require intraoperative ECMO; the remaining 170 (29%) patients did. Among these patients, 95 (56%) patients formed Group B, and the remaining 75 (44%) patients comprised Group C. Pulmonary fibrosis and pre-operative dilated or hypertrophied right ventricle emerged as risk factors for the indication of non-a priori intraoperative ECMO. Patients in Groups B and C showed a higher pre-operative risk profile and higher prevalence of post-operative complications than patients in Group A. Overall survival at 1 year was 93%, 83%, and 82% and at 4 years was 73%, 68%, and 69% in Groups A, B, and C (p = 0.11). The intraoperative use of ECMO did not emerge as a risk factor for in-hospital mortality or mortality after hospital discharge. CONCLUSIONS Intraoperative ECMO filled the gap between pre-operative and post-operative ECMO in lung transplantation. Although complications and in-hospital mortality were higher in patients who received ECMO, survival was similar among patients who underwent transplantation with or without ECMO.

Preemptive treatment with therapeutic plasma exchange and rituximab for early donor-specific antibodies after lung transplantation.

OBJECTIVE De novo donor-specific anti-human leukocyte antigen antibodies develop in a high proportion of lung transplant recipients early after lung transplantation. We recently showed that de novo donor-specific antibodies (DSA) occurrence is associated with significantly increased mortality. Here, we studied the efficacy of a preemptive treatment protocol. METHODS A retrospective observational study was conducted on all lung transplantations at Hanover Medical School between January 2009 and May 2013. RESULTS Among the 500 transplant recipients, early DSA developed in 86 (17%). Of these, 56 patients (65%; Group A) received therapeutic plasma exchange, and 30 patients (35%; Group B) did not. Among Group A patients, 51 also received rituximab. Between groups, there was no statistically significant difference in mortality, incidence of pulsed steroid therapies, rejections diagnosed by biopsy specimen, incidence of bronchitis obliterans syndrome (BOS), or infections requiring hospitalization at 1 year and 3 years. Also, there were no statistically significant differences after matching 21 Group A with 21 Group B patients through propensity score analysis. Significantly more Group A patients (65%) than Group B patients (34%) cleared DSA at hospital discharge (p = 0.01). At the last control after transplantation (median, 14 months; interquartile range, 5-24 months), 11 Group A (22%) and 9 Group B patients (33%) still showed DSA (p = 0.28). CONCLUSIONS Preemptive treatment with therapeutic plasma exchange and rituximab led to improved elimination of DSA early after lung transplantation (p = 0.01). However, spontaneous elimination in untreated Group B patients also occurred frequently. This treatment protocol was not associated with significantly improved outcome.

Veno-veno-arterial extracorporeal membrane oxygenation for respiratory failure with severe haemodynamic impairment: technique and early outcomes

OBJECTIVES Patients with respiratory failure may benefit from veno-venous and veno-arterial extracorporeal membrane oxygenation (ECMO) support. We report on our initial experience of veno-veno-arterial (v-v-a) ECMO in patients with respiratory failure. METHODS Between January 2012 and February 2014, 406 patients required ECMO support at our institution. Here, we retrospectively analysed the characteristics and outcomes of patients commenced on either veno-venous or veno-arterial ECMO due to respiratory failure, and then switched to v-v-a ECMO. RESULTS Ten (2%) patients proceeded to v-v-a ECMO. The underlying conditions were acute respiratory distress syndrome (n = 3), end-stage pulmonary fibrosis (n = 5) and respiratory failure after major thoracic surgery (n = 1) and Caesarean section (n = 1). In all of these patients, ECMO was initially started as veno-venous (n = 9) or veno-arterial (n = 1) ECMO but was switched to a veno-veno-arterial (v-v-a) approach after a mean of 2 (range, 0-7) days. Reasons for switching were: haemodynamic instability (right heart failure, n = 5; pericardial tamponade, n = 1; severe mitral valve regurgitation, n = 1; haemodynamic instability following cardiopulmonary resuscitation, n = 1 and evidence of previously unknown atrial septal defect with pulmonary hypertension and Eisenmenger syndrome, n = 1) and upper-body hypoxaemia (n = 1). ECMO-related complications were bleeding (n = 3) and leg ischaemia (n = 2). Seven patients were successfully taken off ECMO with 4 being bridged to recovery and a further 3 to lung transplantation after a mean of 11 (range, 9-18) days. Five patients survived until hospital discharge and all of them were alive at the end of the follow-up. CONCLUSIONS Veno-veno-arterial ECMO is a technically feasible rescue strategy in treating patients presenting with combined respiratory and haemodynamic failure.

IgM-Enriched Human Intravenous Immunoglobulin-Based Treatment of Patients With Early Donor Specific Anti-HLA Antibodies After Lung Transplantation.

Background At our institution, until April 2013, patients who showed early donor specific anti-HLA antibodies (DSA) after lung transplantation were preemptively treated with therapeutic plasma exchange (tPE) and a single dose of Rituximab. In April 2013, we moved to a therapy based on IgM-enriched human immunoglobulins (IVIG), repeated every 4 weeks, and a single dose of Rituximab. Methods This observational study was designed to evaluate the short-term patient and graft survival in patients who underwent IVIG-based DSA treatment (group A, n = 57) versus contemporary patients transplanted between April 2013 and January 2015 without DSA (group C, n = 180), as well as to evaluate DSA clearance in IVIG-treated patients versus historic patients who had undergone tPE-based treatment (group B, n = 56). Patient records were retrospectively reviewed. Follow-up ended on April 1, 2015. Results At 6 months and 1 year of follow-up, group A had a survival similar to group C (P = 0.81) but better than group B (P = 0.008). Group A showed statistically nonsignificant trends toward improved freedom from pulsed-steroid therapy and biopsy-confirmed rejection over groups B and C. The DSA clearance was better in group A than group B at treatment end (92% vs 64%; P = 0.002) and last DSA control (90% vs 75%; P = 0.04). Conclusions Patients with new early DSA but without graft dysfunction that are treated with IVIG and Rituximab have similarly good early survival as contemporary lung transplant recipients without early DSA. The IVIG yielded increased DSA clearance compared with historic tPE-based treatment, yet spontaneous clearance of new DSA also remains common.

Mid-term results of bilateral lung transplant with postoperatively extended intraoperative extracorporeal membrane oxygenation for severe pulmonary hypertension

OBJECTIVES In severe pulmonary hypertension, diastolic dysfunction of the left ventricle causes significant morbidity and mortality after lung transplantation, which may be successfully reversed using a protocol based on perioperative veno-arterial extracorporeal membrane oxygenation (ECMO) and early extubation. Here, we present echocardiographic data and mid-term outcomes. METHODS The records of lung transplanted patients at our institution between May 2010 and January 2016 were retrospectively reviewed. Echocardiography data were collected preoperatively, at discharge, 3 and 12 months after transplantation. RESULTS During the study period, 717 patients underwent lung transplantation at our institution, 38 (5%) patients being transplanted for severe pulmonary hypertension. All patients underwent bilateral lung transplantation on veno-arterial ECMO cannulated in the groin, through a sternum sparing thoracotomy in 36 (95%) patients. Extubation was performed early, after a median of 2 days, and awake ECMO was extended for at least 5 days after transplantation. The survival at 3 months, 1 year and 5 years was not different in comparison to patients transplanted for other underlying diseases ( P  = 0.45). At 1 year, tricuspid valve regurgitation had disappeared in all patients. The median of the left ventricular end-diastolic dimension improved from 40 (32-44) mm preoperatively to 45 (44-47) mm at 12 months after lung transplantation ( P  < 0.05). The median of the proximal right ventricular outflow diameter decreased to 25 (23-27) mm after 12 months, compared to 48 (43-51) mm preoperatively ( P  < 0.05). CONCLUSIONS The routine application of a prophylactic postoperative veno-arterial ECMO protocol in patients with severe pulmonary hypertension undergoing lung transplantation decreases postoperative mortality and favours achievement of normal cardiac function after 1 year.

Extracorporeal membrane oxygenation as a bridge to lung transplantation may not impact overall mortality risk after transplantation: results from a 7-year single-centre experience

OBJECTIVES Extracorporeal membrane oxygenation (ECMO) has an important role in bridging patients to lung transplantation. In this study, we present our experience with pretransplant ECMO during the last 7 years and investigate its impact on graft outcomes. METHODS Records of all lung-transplanted patients at our institution between January 2010 and April 2017 were retrospectively reviewed. Graft survival was compared between patients who required pretransplant ECMO (pre-Tx ECMO+) and patients who did not (pre-Tx ECMO-). Risk factors for in-hospital mortality and graft survival were identified using a binary logistic regression and the Cox regression analyses, respectively. RESULTS Among the 917 patients transplanted during the study period, 68 (7%) required ECMO as a bridge to transplantation [awake strategy, n = 57 (84%) patients]. Median bridging time was 9 days. Among pre-Tx ECMO+ patients, the need for haemodialysis at any point during bridging emerged as an independent risk factor for in-hospital mortality (odds ratio 7.79, 95% confidence interval 1.21-50.24; P = 0.031). Although in-hospital mortality was significantly higher in pre-Tx ECMO+ versus pre-Tx ECMO- patients (15% vs 5%, P = 0.003), overall graft survival did not differ between groups (79% vs 90% and 61% vs 68% at 1 and 5 years, respectively, P = 0.13). Pretransplant ECMO did not emerge as a risk factor for graft survival in the multivariable analysis. CONCLUSIONS If applied in selected patients in a high-volume centre, pretransplant ECMO as a bridge to transplantation results in impaired, but still high in-hospital, survival and does not impact graft survival.

Splenocyte Infusion and Whole-Body Irradiation for Induction of Peripheral Tolerance in Porcine Lung Transplantation: Modifications of the Preconditioning Regime for Improved Clinical Feasibility

Background Preoperative low-dose whole-body irradiation (IRR) with 1.5 and 7 Gy thymic IRR of the recipient, combined with a perioperative donor splenocyte infusion lead to reliable donor specific peripheral tolerance in our allogeneic porcine lung transplantation model. To reduce the toxicity of this preconditioning regime, modifications of the IRR protocol and their impact on allograft survival were assessed. Methods Left-sided single lung transplantation from major histocompatibility complex and sex mismatched donors was performed in 14 adult female minipigs. Recipient animals were exposed to 3 different protocols of nonmyeloablative IRR within 12 hours before transplantation. All animals were administered a donor splenocyte infusion on the day of lung transplantation. Intravenous pharmacologic immunosuppression was withdrawn after 28 postoperative days. Allograft survival was monitored by chest radiographs and bronchoscopy. Results IRR prolonged transplant survival in a dose- and field-dependent manner. Shielding of the bone marrow from IRR (total lymphoid IRR at 1.5 and 7 Gy thymic IRR) significantly reduced protocol toxicity defined as thrombocytopenia and consecutive increased bleeding propensity, but had a less effective impact on graft survival. Whole-body IRR at 0.5 and 7 Gy thymic IRR proved to be ineffective for reliable tolerance induction. Eventually, high levels of circulating CD4+CD25high regulatory T cells were present in long-term survivors. Conclusions These data show that the infusion of donor-specific alloantigen in combination with IRR is efficient once a threshold dose is exceeded.

Irradiation before and donor splenocyte infusion immediately after transplantation induce tolerance to lung, but not heart allografts in miniature swine

Solid organs may differ in their potential to induce and maintain a state of donor‐specific tolerance. Previously, we induced stable immunological tolerance in a lung transplantation model in miniature swine. Here, we wished to transfer this established protocol into a heart transplantation model in miniature swine. Heterotopic heart transplantation (HTX) was performed in four and left‐sided lung transplantation (LTX) in seven minipigs from gender‐ and SLA‐mismatched donors. All recipients received nonmyeloablative irradiation, donor splenocyte infusion and intravenous pharmacologic immunosuppression for 28 postoperative days. All transplanted hearts were rejected within 95 days. In contrast, four animals of the LTX group developed stable tolerance surviving beyond 500 days, and three further animals rejected 119, 239 and 360 days post‐transplantation. In both groups, peripheral blood donor leucocyte chimerism peaked 1 h after reperfusion of the allograft. Importantly, the early chimerism level in the LTX group was significantly higher compared to the HTX group and remained detectable throughout the entire observation period. In conclusion, lungs and hearts vary in their potential to induce a state of tolerance after transplantation in a protocol with pre‐operative recipient irradiation and donor splenocyte co‐transplantation. This could be due to differential early levels of passenger leucocyte chimerism.