Canada's First Successful Paediatric Total Artificial Heart Implant.

Cardiac allograft vasculopathy (CAV) and antibody mediated rejection (AMR) after heart transplant result in an inflammatory process that can cause systolic and diastolic dysfunction, and recalcitrant arrhythmias. Hemodynamic supports in this context are challenging as re-transplant is not always feasible with active rejection. Standard mechanical circulatory supports (MCS) in the form of left ventricular assist device (LVAD) supports systolic function but is higher risk with arrhythmias and diastolic dysfunction. Ongoing immunosuppression adds to infection risk. Therefore, total artificial heart (TAH) support has been used in failing allografts. We present the first Canadian pediatric TAH as successful bridge to re-transplantation. The patient was an 11-year-old female, 3 years after heart transplant for history of Ebstein's anomaly with left ventricular non-compaction, who presented with persistent tachycardia, diastolic dysfunction, mildly reduced systolic function (ejection fraction 48%) and severe mitral regurgitation. Clinical course after her initial transplant was unremarkable despite slightly longer total ischemic time of 5 hours 14 minutes. Crossmatch at the time of transplant was negative and there was no cytomegalovirus (CMV) mismatch. Following admission on this occasion, her hemodynamics revealed raised right and left sided filling pressures (left ventricular end-diastolic pressure 27 mmHg, right atrial pressure 17 mmHg). Coronary angiography showed moderate CAV with no narrowing in the left main coronary artery and mild stenosis in the proximal left anterior descending and circumflex arteries. Biopsy findings were consistent with pAMR2 (histology and immuno-pathological positivity) with no evidence of cellular rejection. De novo class II donor specific antibody (DSA), DQ6, developed during this time. Findings were consistent with severe antibody mediated rejection (AMR) and moderate CAV. She received pulse intravenous steroids, thymoglobulin, and plasmapheresis. She was also given intravenous immunoglobulin (IVIG) and Rituximab and maintenance immunosuppression was augmented to combination Tacrolimus and Sirolimus with mycophenolate mofetil (MMF). She was discharged with weekly plasmapheresis cycles, tapering dose of steroids, and outpatient follow up. However, despite these therapies, she represented 1 month later with an out-of-hospital cardiac arrest with rapid response to bystander cardiopulmonary resuscitation (CPR). Repeat angiography demonstrated significant progression of CAV, with diffuse distal disease in all branches and paucity/absence of distal branches in some regions. She was admitted to intensive care unit (ICU) and required milrinone and epinephrine infusion to maintain cardiac output and developed a secondary acute kidney injury necessitating dialysis which improved over the following week. Despite the augmented immunosuppression, she remained in a marginal state and experienced a brief arrest with pulseless electrical activity (PEA) 1 week after admission with rapid return of spontaneous circulation (ROSC). Following multidisciplinary discussion, she was assessed for a potential total artificial heart (TAH) implant to allow for stable cardiac output and end-organ perfusion, with cessation of anti-rejection medications and resolution of the overall inflammatory state prior to re-transplantation. Given borderline age and size (BSA 1.16m2Kobashigawa J.A. Katznelson S. Laks H. Johnson J.A. Yeatman L. Wang X.M. Chia D. Terasaki P.I. Sabad A. Cogert G.A. et al.EFFECT OF PRAVASTATIN ON OUTCOMES AFTER CARDIAC TRANSPLANTATION.NEJM. 1995; 333: 621-627Crossref PubMed Scopus (0) Google Scholar), a virtual fit test for TAH was reviewed and it was determined that a 50cc pump should suitably fit based on the 3D modeling (Figure 1).She proceeded to TAH insertion with 50cc Syncardia device 2 weeks following admission. Despite extensive dissection of the mediastinal space after explanation of the heart, including taking down the left sided pleura and pericardium, and anterior part of the diaphragm, there was anterior compression of inferior vena cava (IVC) and left pulmonary vein due to stiff nature of device compared to native cardiac tissue. Intra-operative course was complicated by lung reperfusion injury coming off cardiopulmonary bypass (CPB) with difficult oxygenation which improved with inhaled nitric oxide (iNO). There were additional challenges high central venous pressure (20-25mmHg) and fluctuating pump flow necessitating frequent volume infusion to maintain cardiac output through the pump. Post implantation cardiac output was ∼2.5-3 liters/minute. After prolonged hemostasis, she returned to ICU with sternum stented open. Her initial post-operative course was complicated by hemodynamic instability, manifested by low urine output, and lactic acidosis (peak 11mmol/L), attributed to profound systemic inflammatory response. She required volume resuscitation and vasopressors to maintain systemic perfusion. Oxygenation slowly improved with high ventilatory pressures. Immunosuppression was discontinued on the day of TAH insertion. She received antibiotic and antifungal prophylaxis for cardiac surgery and delayed sternal closure. Anticoagulation was initiated on day 1 post-operatively with therapeutic heparin. Sternum was closed on post-operative day 4 with some fluctuation of hemodynamics with residual moderate lower left pulmonary vein and IVC compression and 1-2 cm of lower sternum left open. Follow up CT to delineate extent of venous compression showed a large mediastinal hematoma. As such, she returned to OR on day 10 for mediastinal exploration and hematoma evacuation. The posterior aspect of the sternum was also thinned by cautery as it was noted to be tight between the device and chest wall to allow for chest closure. No additional interventions were required to address IVC or pulmonary veins. The subsequent ICU course was marked by hypertension and one episode of pulmonary hemorrhage which was likely related to the TAH ‘full filling’. She was extubated 2 weeks post-operatively and transitioned to the ward 4 weeks post-operatively. Following a period of rehabilitation with physiotherapy and improved nutritional intake she was activated on the waitlist and received a second heart transplant 2 months following TAH insertion. TAH removal at the time of re-transplant necessitated careful planning for sternal re-entry and dissection. Additional challenges included presence of old thrombus and adhesions in chest cavity, difficulty visualizing IVC due to right sided pump and challenges establishing plane between aorta and pulmonary artery due to existing pulmonary artery graft. Cardiopulmonary bypass was initiated ascending aortic and 2 venous cannulae. The air tube for the right pump was transected which allowed us to cannulate the IVC, then both pumps were completely explanted. Intra-operative course thereafter was otherwise unremarkable. Our patient remained off immunosuppression for the course of her TAH support. At the time of re-transplant she had one Class II donor-specific antibody (DR4). She received routine peri-operative steroids and one volume of plasma exchange while on pump. Remarkably, she was discharged home only 9 days after the transplant. She was treated with pulse steroids for AMR but remains well at home 18 months after re-transplant. This case documents the first pediatric use of Total Artificial Heart in Canada, with successful bridge to retransplant. End stage heart failure and refractory arrhythmias due to CAV presented a significant management dilemma for which the 50cc SynCardia TAH represented a unique opportunity to provide durable MCS. Specific challenges in this case included inotrope dependance, recalcitrant arrhythmias, small body size and need for ongoing immunosuppression. CAV involves a complex multifactorial inflammatory process, contributed to by ischemia reperfusion injury, cellular rejection, DSA and lifestyle mediated disease such as hyperlipidemia, hypertension and diabetes and remains the primary indication for re-transplant in pediatrics 1Vazquez C. Cantor R. Koehl D. et al.The evolution of pediatric heart retransplantation over three decades : An analysis from the PHTS.J Hear Lung Transplant. 2022; 41: 791-801https://doi.org/10.1016/j.healun.2022.02.018Abstract Full Text Full Text PDF Scopus (3) Google Scholar. Our patient had early onset aggressive CAV in association with AMR despite relatively low risk profile; with the only risk factor of note being a prolonged ischemic time after her initial transplant. Despite her previous surgeries, she was not sensitized prior to her initial transplant, had a negative retrospective crossmatch, no CMV mismatch, no prior rejection episodes, no additional lifestyle risk factors and had been managed with statin therapy prior to her graft failure. However, managing our patient's combination of AMR and severe CAV was additionally challenging due to the potential for immunosuppressive agents to potentiate vasculopathy2Kobashigawa J.A. Katznelson S. Laks H. Johnson J.A. Yeatman L. Wang X.M. Chia D. Terasaki P.I. Sabad A. Cogert G.A. et al.EFFECT OF PRAVASTATIN ON OUTCOMES AFTER CARDIAC TRANSPLANTATION.NEJM. 1995; 333: 621-627Crossref PubMed Scopus (0) Google Scholar. The deleterious consequences of CAV in association with rejection have been well described, with studies demonstrating a significant increase in risk of mortality in those with AMR and CAV versus AMR without CAV3Kleinmahon J.A. Gralla J. Kirk R. Auerbach S.R. Henderson H.T. Wallis G.A. Ramakrishnan K. Singh R.K. Caldwell R.L. Savage A.J.E.M. Cardiac allograft vasculopathy and graft failure in pediatric heart transplant recipients after rejection with severe hemodynamic compromise b.JHLT. 2019; 38: 277-284https://doi.org/10.1016/j.healun.2018.12.011Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar. Our patient had been treated with standard maintenance immunosuppression with MMF and Tacrolimus. Sirolimus was added after diagnosis of CAV, as mTOR inhibition has demonstrated slower disease progression4Keogh A. Richardson M. Ruygrok P. et al.Sirolimus in De Novo Heart Transplant Recipients Reduces Acute Rejection and Prevents Coronary Artery Disease at 2 Years A Randomized Clinical Trial.Circulation. 2010; 110: 2694-2700https://doi.org/10.1161/01.CIR.0000136812.90177.94Crossref Scopus (400) Google Scholar. Selection criteria for cardiac re-transplantation remain controversial with many centers not offering pediatric re-transplant for early graft failure due to low likelihood of long-term survival1Vazquez C. Cantor R. Koehl D. et al.The evolution of pediatric heart retransplantation over three decades : An analysis from the PHTS.J Hear Lung Transplant. 2022; 41: 791-801https://doi.org/10.1016/j.healun.2022.02.018Abstract Full Text Full Text PDF Scopus (3) Google Scholar. However, recent adult data has demonstrated improvements in outcomes post re-transplant in those who can achieve rehabilitation on MCS. More-over, survival after retransplant was superior in those bridged with VAD or TAH than extracorporeal membranous oxygenation (ECMO) or medical management1Vazquez C. Cantor R. Koehl D. et al.The evolution of pediatric heart retransplantation over three decades : An analysis from the PHTS.J Hear Lung Transplant. 2022; 41: 791-801https://doi.org/10.1016/j.healun.2022.02.018Abstract Full Text Full Text PDF Scopus (3) Google Scholar. During support, our patient demonstrated good end-organ function and remained a reasonable candidate for retransplant. However, supporting her to re-transplant and facilitating rehabilitation presented a unique challenge. Historically, Berlin Heart EXCOR has been a mainstay support for children requiring durable long-term biventricular support, although data supports an increase in mortality for this cohort. Thus, over the last decade, the frequency of use of biventricular support has declined as implant strategies have evolved including timing of implant and supportive measures based on specific patient characteristics and severity of illness 5Morales D.L.S. Adachi I. Peng D.M. et al.Fourth Annual Pediatric Interagency Registry for Mechanical Circulatory Support ( Pedimacs ) Report.Ann Thorac Surg. 2020; 110: 1819-1831https://doi.org/10.1016/j.athoracsur.2020.09.003Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar. However, conventional VAD support in the context of active rejection in our patient would have necessitated continued high levels of immunosuppression, with significant associated infection risk, and likely ongoing inflammation. MCS in pediatric populations presents the additional challenge of smaller patient size relative to device size. The development of the Syncardia 50cc device designed to support patients with BSA as low as 1.2m2 has expanded opportunities for viable biventricular MCS support. Since the advent of the 50cc Syncardia device, TAH has been successfully used in paediatric patients as bridge to transplant with BSA as small as 0.9m26Villa C.R. Moore R.A. Morales D.L. Lorts A. The total artificial heart in pediatrics : outcomes in an evolving field.Ann Cardiothorac Surg. 2020; 9: 104-109https://doi.org/10.21037/acs.2020.02.15Crossref Google Scholar. The largest pediatric case series to date describes 15 cases of which 2 were inserted for cardiac allograft failure 7Wells D. Villa C.R. Luís D. Morales S. The 50 / 50 cc Total Artificial Heart Trial : Extending the Benefits of the Total Artificial Heart to Underserved Populations.Pediatr Card Surg Annu. 2017; : 16-19https://doi.org/10.1053/j.pcsu.2016.09.004Abstract Full Text Full Text PDF Scopus (24) Google Scholar. Given our patient’s borderline BSA and chest size, a virtual fit test was completed accurately predicting device fit prior to surgery. This case supports the effective use of the 50cc Syncardia TAH as bridge to retransplant, providing a unique option for biventricular MCS and cessation of immunosuppression with resolution of the inflammatory process in this case. •Syncardia 50cc TAH allows for durable biventricular MCS in patients with low BSA•The use of Syncardia TAH provides unique opportunity for durable MCS with cessation of immunosuppression in the context of rejection. None. Funding sources: No relevant funding sources. Disclosures: Dr. Jeewa is a Medical monitor for the Pumpkin trial and consultant for Abbott. All other authors have no disclosures. Dr Lynch is supported by a Heart Failure Research Fellowship from Bristol-Myers Squibb, Mitacs and Myant. Patient Consent: The authors confirm that a patient consent form(s) has been obtained for this article.