Paediatric mechanical circulatory support with Berlin Heart EXCOR: development and outcome of a 23-year experience

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1 European Journal of Cardio-Thoracic Surgery 50 (2016) doi: /ejcts/ezw011 Advance Access publication 22 February 2016 Cite this article as: Hetzer R, Kaufmann F, Delmo Walter EM. Paediatric mechanical circulatory support with Berlin Heart EXCOR: development and outcome of a 23-year experience. Eur J Cardiothorac Surg 2016;50: a Paediatric mechanical circulatory support with Berlin Heart EXCOR: development and outcome of a 23-year experience Roland Hetzer a, Friedrich Kaufmann a and Eva Maria Delmo Walter b, * Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Berlin, Germany b Trauma Surgery Center Berlin, Berlin, Germany * Corresponding author. Trauma Surgery Centre Berlin, Warenerstrasse 7, Berlin, Germany. Tel: ; fax: ; eva.delmowalter@googl .com (E.M. Delmo Walter). Received 24 August 2015; received in revised form 18 December 2015; accepted 11 January 2016 Summary This paper reviews the development and establishment of the Berlin Heart EXCOR (BHE ) as a paediatric mechanical circulatory support and reports our entire experience with regard to indications, timing of implantation and explantation and outcome. The Berlin group reported the first successful paediatric bridge to transplantation using a pulsatile pneumatic paracorporeal biventricular assist device, the BHE, in 1990 in an 8-year-old boy with end-stage heart failure and coarctation of the aorta. This experience prompted them to develop miniaturized pump systems for children through the company Berlin Heart Mediproduct GmbH. The development and production of BHE to support paediatric patients with heart failure then began. Between 1990 and 2013, the BHE has been implanted in 122 patients (median age 8.64 years, range 3 days to 17 years) with heart failure, who were inotrope-dependent or switched from extracorporeal membrane oxygenation support or had postcardiotomy low-output syndrome. Thirty-five patients were <1 year old (median 125 days). The aetiology of heart failure included cardiomyopathy in 56 (median age 9.14 years), fulminant myocarditis in 17 (median age 8.2 years), end-stage congenital heart disease in 18 (median age 6.4 years), postcardiotomy heart failure (after correction of congenital heart disease) in 28 (median age 9.6 years) and transplant graft failure in 3 (median age 12.5 years). The overall median duration of implantation was 63.6 (range 1 841) days. Fifty-six children eventually underwent orthotopic heart transplantation. Eighteen patients had myocardial recovery and were weaned successfully. They had entirely normal cardiac function after a range of 4 10 years after surgery. At the time of this report, five patients were still on support, with a duration of days. Forty-three patients died on the system from loss of peripheral circulatory resistance, multiorgan damage, sepsis or haemorrhagic or thrombotic complications. Re-exploration because of bleeding was necessary in 22 patients. Pump exchange because of thrombus formation in the valves was necessary 35 times. With the introduction of a modified anticoagulation regimen in 2000, the pump exchange rate has decreased. The BHE can reliably support the circulation at any age for long periods with good results. It is now an established treatment for children with heart failure of any aetiology. Keywords: Mechanical circulatory support Ventricular assist device Heart failure Myocardial recovery Heart transplantation INTRODUCTION Tremendous progress has been made in paediatric mechanical circulatory assist devices since the Berlin group reported the first successful paediatric bridge to transplantation using a pulsatile pneumatic paracorporeal biventricular assist device (BVAD), the Berlin Heart EXCOR (BHE ), implanted by Warnecke et al. [1] in 1990 in an 8-year-old boy with end-stage heart failure and coarctation of the aorta [1]. Although he was supported with an adult-sized (50 ml) BHE, he was successfully bridged to heart transplantation. This experience prompted our group to develop miniaturized pump systems for infants and children through the company then named Presented at the 28th Annual Meeting of the European Association for Cardio- Thoracic Surgery, Milan, Italy, October Berlin Heart Mediproduct GmbH [2]. The development and commercial production of BHE as a paracorporeal ventricular assist device (VAD) and driving units to support paediatric patients with heart failure began in this way. The Berlin group has helped to revolutionize the use of the specially miniaturized BHE pulsatile VADs in children, and this may now be considered a significant contribution to heart failure therapy in this population. In 1992, the BHE was implanted in an infant using the newly designed paediatric blood pump system with a 10 ml stroke volume [2, 3], In 1994, the first blood pumps with a stroke volume of 25 and 30 ml for small children became available and were implanted [4]. Together with these pumps, designed to close the gap between the baby pump and the adult-sized pumps of 50, 60 and 80 ml, appropriate BHE silicone cannulae of various sizes and tip configurations were available, whereas conventional The Author Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

2 204 R. Hetzer et al. / European Journal of Cardio-Thoracic Surgery heart lung machine cannulae were used for implantation of the 10 ml pump before In the late 1990s, there had been a few unreported cases of BHE implantation in Phoenix, AZ, USA; however, its use found its way in the USA 14 years later, when the BHE was implanted in a 4-month-old infant suffering from acute myocarditis, about whom a story appeared on the front page of the New York Times [3] before its US Food and Drug Administration (FDA) approval for use under the Humanitarian Device exemption for the US market. Our centre has been making further improvements and advances [4 6], and during the subsequent 20 years, we have used the BHE assist device in children in profound heart failure as a bridge to transplantation or as a bridge to myocardial recovery [6 9]. In 2012, the BHE 15 ml blood pump received US FDA approval, and the 500th BHE patient was treated in the USA. In 2014, the BHE blood pump with bileaflet valves was also granted US FDA approval for use, and in this year the 1500th BHE implantation was performed. In the early years, modifications of the original heart lung machine circuit, such as extracorporeal membrane oxygenation (ECMO) [10 12] and extracorporeal centrifugal pumps [13], were widely used to support the failing heart in children. Paediatric-size pneumatically driven extracorporeal assist devices for infants and small children were introduced into clinical practice in The development of such miniaturized pump systems followed the experience of the first reported case [1]. Although 10 ml pumps for newborns and infants then became available, results during the early years in this age group were unfavourable. Until 1998, no infant was discharged home after such treatment at our institution [5]. Since then, several improvements have been introduced with regard to system design, postoperative management and, primarily, decision-making in favour of earlier pump implantation before irreversible shock has set in. At present, our longest duration of support with the BHE is 841 days [14] before heart transplantation became possible in a 5-year-old boy after Norwood and Glenn procedures for hypoplastic left heart syndrome, mitral valve dysplasia and aortic atresia. Another patient, a 14-month-old boy with decompensated dilated cardiomyopathy, remained stable with the BVAD for 547 days until heart transplantation [13]. This report reviews the development of the paediatric mechanical circulatory support device, the BHE, and reports the outcome of our entire 23-year experience of its use in infants and children, with regard to indications, timing of implantation and outcome. PATIENTS AND METHODS Since April 1988, 2361 VADs have been implanted at our institution, among which were 168 paediatric mechanical circulatory support systems. Part of this series ( , n = 34) was reported in 1999 [3, 15], in 2004 ( , n = 68) [7] and in 2011 ( , = 94) [9], with fairly satisfactory outcomes. Between 1990 and 2013, BHE devices were implanted in 122 patients (median age 8.6 years, range 3 days to 17 years) with heart failure; these patients were inotrope dependent or switched from ECMO support or suffering from postcardiotomy low-output syndrome. Thirty-five patients were <1 year old (median 125 days). The median weight of these children was 20.5 (range ) kg. Twenty-four children underwent cardiopulmonary resuscitation before BHE implantation, whereas 15 were brought to the operating room under resuscitative measures until the extracorporeal circulation was established. The aetiology of heart failure included cardiomyopathy (dilated, restrictive from endocardial fibrosis, idiopathic or toxic) seen in 56 (45.9%; median age 9.14 years, range 2 months to 17 years), fulminant myocarditis in 17 (13.9%; median age 8.2, range 3 days to 14 years), end-stage congenital heart disease in 18 (14.7%; median age 6.4 years, range 6 days to 17 years) postcardiotomy heart failure (after correction of congenital heart disease) in 28 (22.9%; median age 9.6 years, range 13 days to 17 years) and graft failure in 3 (2.4%; median age 12.5 years, range 10 months to 16 years; Table 1). The Berlin Heart EXCOR The Berlin Heart EXCOR (Berlin Heart AG, Berlin, Germany) system consists of a paracorporeal, pneumatic compressor-operated diaphragm pump with polyurethane valves (10, 15, 25 or 30 ml stroke volume) and silicon cannulae [8, 16, 17]. The larger pumps (50, 60 and 80 ml) are equipped with mechanical valves (Sorin, Milan, Italy). The stationary driving unit (IKUS) may be used in all pumps and in all circumstances. The BHE mobile driving unit (Berlin Heart AG, Berlin, Germany) was used when driving pressures <250 mmhg were required. The blood pumps with volumes of 10, 25, 30, 50, 60 and 80 ml were available in As previously mentioned, in 2012 the BHE 15 ml blood pump received the US FDA approval and has been widely used since then. Indications, timing of implantation, choice of pumps and techniques The BHE was implanted in patients with the following indications: (i) low cardiac output associated with metabolic acidosis; (ii) rapid deterioration of the circulation with cardiac index <2.0 l/min/m² with inotrope dependence, especially on epinephrine; (iii) mixed venous saturation <40%; (iv) oliguria (<1 ml/kg/min); (v) critical peripheral perfusion; and (vi) echocardiographically confirmed massive impairment of cardiac function despite maximal pharmacological treatment, signs of early renal, hepatic and respiratory failure and high or progressive increase in B-type natriuretic peptide (BNP) or N-terminal probnp level. Table 1: Patient data before Berlin Heart EXCOR implantation Diagnosis n = 122 Median age [years (range)] Cardiomyopathy Dilated (2 months to 17 years) Toxic 2 Restrictive 3 Myocarditis Fulminant (3 days to 14 years) Chronic 1 End-stage congenital heart (6 days to 17 years) disease After correction of congenital (13 days to 17 years) heart disease Graft failure after heart transplantation (10 months to 16 years)

3 R. Hetzer et al. / European Journal of Cardio-Thoracic Surgery 205 Over time, the criteria for BHE implantation have been modified and changed towards earlier BHE implantation before irreversible organ damage sets in or after a few days on ECMO to avoid coagulation disorders and infection. Likewise, several progressive technical steps, such as development of apical and modified arterial cannulae, advanced coagulation monitoring and individual anticoagulation, have been conceived. The decision regarding whether to implant a left ventricular assist device (LVAD) or BVAD was made in the operating theatre. The primary goal was to implant an LVAD. When patients failed to stabilize with an LVAD after coming off cardiopulmonary bypass with signs of refractory right ventricular (RV) failure, the right VAD was added. The choice of pump size was based on the weight of the patient. The calculated pump flow for children is ml/kg, and for adolescents, 100 ml/kg. The implantation guidelines were as follows: in patients weighing <9 kg, pumps with a stroke volume of 10 ml; in patients weighing between 10 and 25 kg, pumps with a stroke volume of 25 or 30 ml; and in patients weighing >30 kg, adult pumps with a stroke volume of 50 ml. In patients for whom the stroke volume of the pump was insufficient, the pump was easily replaced either in the operating theatre or at the bedside. The surgical technique of BHE implantation has been reported previously by our group [8, 9]. Implantation of the BVAD in infants and small children has been challenging because of the small pericardial space, and positioning of the four cannulae after reconstructive operations could then become complex. As more experience was gained in children, it became apparent that left ventricular (LV) apical cannulation does not only improve left ventricular emptying but also decreases right ventricular afterload, leading to significant improvement of the biventricular unloading; therefore, only a left ventricular external pump is necessary in most cases. The main step forward made by our group over time was the introduction of apical cannulae. Before that development, the drainage of the heart was performed through the atrial cannulae on the left, inserted through Sondegaard s groove directly to the right. This setting did not result in complete drainage of the ventricle, and biventricular support became obligatory in almost all cases. With the introduction of apical cannulation of the left ventricle, complete drainage of the left heart became feasible and, thus, biventricular support became necessary only in patients with more advanced heart failure. Anticoagulation postimplantation Management of anticoagulation has been modified since the year Before 2000, heparin activity was monitored using the activated clotting time to keep the activated clotting time between 140 and 160 s, and antithrombin III substitution was performed if the activated clotting time fell below 70%. At present, no postoperative anticoagulation is given for the first 8 24 h. The effect is monitored two to four times daily, if necessary. For the next 48 h, continuous and unfractionated heparin infusion is administered to keep the activated partial thromboplastin time between 60 and 80 s. Thromboelastography, performed twice a week after BHE implantation, helps to identify the coagulation status and impact of heparin. It is very useful to evaluate hypo- or hypercoagulation and to adjust the target value of activated partial thromboplastin time. Antithrombin III is substituted if activated partial thromboplastin time falls below 70%. When oral feeding has been started and chest tubes have been removed, treatment with acetylsalicylic acid combined with dipyridamol (assuming a normal platelet number and function) in a weight-adjusted dose is started 1 week after implantation. Platelet aggregation tests are performed at least weekly, with target activation of 30%. L-Hirudin or argatroban is used in patients with heparin-induced thrombocytopenia type II. This is monitored by the platelet aggregation test with arachidonic acid [17]. Children remaining in hospital on the BHE receive low molecular weight heparin for long-term anticoagulation under monitoring of anti-xa activity. After treatment with acetylsalicylic acid and dipyridamol is initiated, platelet aggregation tests are performed at least weekly, with target activation of 30% [18]. Phenprocoumon with a target international normalized ratio of is given to adolescents who are discharged home on the BHE. Pump operation is monitored daily and, if necessary, readjusted to achieve optimal diaphragm movement. Daily transillumination of the pump chambers is a very important practice for early detection of the formation of small thrombi. In the presence of larger thrombi, the pump is exchanged in sterile conditions, in the operating theatre. Our current criteria for pump exchange are any thrombus formation in the left pump or in the left-side cannulae and thrombus of more than a few millimetres or free-floating thrombi of any size in the right pump and cannulae. Echocardiography is performed daily to monitor cardiac function, especially during weaning. A prophylactic antibiotic with adequate antistaphylococcal coverage (generally a second-generation cephalosporine) is administered in the preoperative, intraoperative and postoperative phases. Dressings are regularly changed around the cutaneous lines in sterile conditions. All transparent parts of the pumps and cannulae are examined for thrombus formation. Haemofiltration or peritoneal dialysis as performed in cases of severe renal dysfunction. Respirator therapy as continued until clinical, radiological, blood gas and breathing parameters have normalized. In most patients, our experience has shown that restoration of adequate circulation by the BHE leads to recovery of previously dysfunctional organs. Mobilization Infants and older children are mobilized as soon as their condition allows. After extubation, children are transferred to an intermediate ward for recovery. Small children dependent on the powerful, stationary IKUS driver are kept in hospital, whereas older children in whom the portable BHE driver could be operated are discharged home whenever possible; these children go to school with the device. Indications for weaning and explantation Daily echocardiography was performed routinely. Weaning was considered in patients with continuous improvement of myocardial function. The decision to explant the BHE was made in the operating room, where the pump flow was then decreased, and blood pressure and ventricular filling were monitored. Weaning was then performed with the pump being stopped for 20 min when the following criteria were achieved: (i) LV end diastolic dimension <98th percentile (Z score < +2); (ii) ejection fraction 45% (i.e. no more than mild LV dysfunction); (iii) normotensive on milrinone only (no other inotropes); (iv) lactate <3 mmol/l; (v) LV end diastolic pressure <12 mmhg; and (vi) resting cardiac index of >2.8 l/min/m 2.

4 206 R. Hetzer et al. / European Journal of Cardio-Thoracic Surgery Additionally, stable central venous saturation and low pulmonary artery pressure (estimated by echocardiography) during pump stops were considered to be good prognostic parameters, as was normalization of the level of BNP or NT-proBNP during the whole weaning phase. In cases of borderline myocarditis or unclear diagnosis, an additional biopsy could be helpful [9]. Statistical analysis All data were analysed with the SPSS statistical program for Windows, version 22.0 (SPSS Inc., Chicago, IL, USA). Data are expressed as absolute and percentage frequency values and continuous data as the mean ± standard deviation or median and range, as appropriate. Competing risk outcomes for time-related events were analysed according to Kaplan Meier estimates. their cardiac function, and were taken off BHE support. It was possible to explant the BHE between days 10 and 42. These children have made an excellent recovery, are at present fully active and have entirely normal heart function after a range of 4 10 years after surgery. Two children (aged 0.3 and 14 years) with cardiomyopathy had successful mycardial recovery on days 17 and 125, respectively (see Fig. 2A). Another five patients (aged years) with heart failure resulting from congenital heart disease likewise experienced myocardial recovery after 6 60 days of support with the BHE (see Fig. 2B). A patient with end-stage congenital heart disease experienced myocardial recovery after BHE support of 63 days. Interestingly, the BHE was implanted in a 16-year-old boy who underwent heart transplantation but eventually had graft failure. He experienced successful myocardial recovery on the 76th day. RESULTS The overall median duration of implantation was 63.6 (range 1 841) days (Table 2). Figure 1 shows the overall competing outcomes of 122 patients supported with BHE, and the details are as follows. Ongoing support At the time of this report, five patients are still on BHE support with a median duration of 354 days. Bridge to transplantation Fifty-six (45.9%) children eventually underwent orthotopic heart transplantation. As previously mentioned, our longest duration of support with the BHE was 841 days [14] in a 5-year-old boy after Norwood and Glenn procedures for hypoplastic left heart syndrome, mitral valve dysplasia and aortic atresia. Likewise, it is also worth mentioning a 14-month-old boy with decompensated dilated cardiomyopathy who remained stable with the BVAD for 547 days until heart transplantation. In both these patients, the original BHE pump was swapped with a larger pump to accommodate somatic growth and haemodynamic demands. However, mortality occured in five (8.7%) children after heart transplantation. Bridge to myocardial recovery Eighteen (14.7%) patients were weaned successfully from the BHE. Among these, nine patients (age range 1 6 years) with heart failure owing to myocarditis recovered, displaying rapid restoration of Figure 1: Competing risk outcome in 122 children supported with Berlin Heart EXCOR. HTx: heart transplantation. Table 2: Duration and outcome of support with Berlin Heart EXCOR Diagnosis Duration of support [days; median (range)] Heart transplantation (n) and duration of support (median, range) Myocardial recovery (n) and duration of support (median, range) On assist (n) and duration of support (median, range) Mortality (n) and duration of support (median, range) Cardiomyopathy 60.3 (1 547) 36 (72.5, 1 547) 2 (69.5, ) 3 (360.5, ) 15 (25.2, 1 69) Myocarditis (1 100) 5 (42, 5 100) 9 (24.9, 10 42) 3 (6.3, 1 5) End-stage congenital heart disease 16.4 ( (159.6, 5 841) 1 (63) 1 (375) 7 (45.4, 1 286) After correction of congenital heart 17.7 (2 1129) 6 (59.5, 7 112) 4 (23.25, 6 60) 1 (159) 17 (15.4, 1 48) heart disease Graft failure after heart transplantation 94 (10 196) 1 (196) 1 (76) 1 (10)

5 R. Hetzer et al. / European Journal of Cardio-Thoracic Surgery 207 introduction of a modified anticoagulation regimen in 2000, the rate of pump exchange has decreased despite significantly longer support times. The main reason for pump exchange was thrombus formation in the valves. Pump exchange, performed in the operating theatre, has been proved to be a safe procedure; no complications occurred during pump changes in 23 years of experience with the BHE in paediatric patients and even in adults. Except for those patients who died very early from circulatory failure, none suffered from mediastinitis, even in those who required re-exploration.there was no instance of technical failure, either of the blood pump components or of the driving system. However, skin infections around the cannulae occured in 67%, pulmonary infections occuring early postimplantation in 23%, and adverse neurological symptoms, such as thromboembolism (22%) and cerebral haemorrhage (47%) confirmed by cerebal computerized tomography, likewise occured. These rates remain a troubling aspect generally associated with any kind of VAD support. DISCUSSION Figure 2: Competing risk outcomes in relation to diagnosis. (A) Dilated cardiomyopathy. (B) After correction of congenital heart diseases. HTx: heart transplantation. Mortality Forty-three (35.2%) patients died on the system from loss of peripheral circulatory resistance (unresponsive to α-receptor stimulants), multiorgan damage, sepsis or from haemorrhagic or thrombotic complications with the BHE system. Children with congenital heart diseases had the highest mortality rate, i.e. 53.3% (end-stage congenital heart disease, 41.7%; and after correction of congenital heart disease, 60.7%). Those children with cardiomyopathy and myocarditis fared relatively well, with mortality rates of of 26.8 and 17.6%, respectively (Table 2). Morbidity Re-exploration because of bleeding was necessary in 22 patients. Overall, pump exchange was necessary 35 times. With the With increasing experience in the use of BHE, it has evolved to be the most widely used mechanical circulatory support system in infants and children with heart failure. The first experience with a child supported by a Berlin Heart VAD [1] has led to the subsequent development of miniaturized systems. Over time, several changes and modifications in clinical decision-making and patient care resulted in the achievment of confidence that the BHE system can support the failing heart for a longer duration, which eventually led to an improvement in the survival rate. The BHE is able to keep children alive to be bridged to transplantation over long periods with satisfactory outcome [19]. Such prolonged support time allows those children being treated for malignancy to reach a transplantable status by documentation of a sufficiently long tumour-free period to justify listing for heart transplantation [20]. Likewise, transplantable status may be reached after prolonged support in children with adequate regression of preoperatively elevated pulmonary vascular resistance [9, 21]. Since 1988 and until June 2014, there have been operations for congenital heart defects, with 189 paediatric heart transplantations and 167 implantations of a VAD performed at our institution. Short-term mechanical circulatory support systems, such as centrifugal pumps and ECMO, were implanted in patients with potential for fast myocardial recovery and expected short-term support [22, 23]. In comparison to patients supported with these short-term assist device systems, those supported with the BHE can be mobilized, extubated and fed orally. This is advantageous when a waiting period of more than 3 or 4 weeks is anticipated [12, 15, 24]. Eight patients were supported by ECMO before BHE implantation, with a discharge rate of 60%. The decision to switch from ECMO to BHE was made when it became clear that longer-term support was necessary and the patient had not suffered severe organ damage, particularly to the brain, before or during ECMO. Another indication for BHE implantation was continuous bleeding on ECMO. In contrast to ECMO patients, those on BHE required less transfusion of blood products, with a correspondingly decreased risk of infection and of developing HLA antibodies [9, 25, 26]. The advantage of long-term mechanical circulatory support with BHE is also seen in terms of a better cost effectiveness ratio [26]. The quality-adjusted life years saved have been fully recognized, and an increasing number of centres are now using this type of circulatory support system in children with failing hearts [3, 25 29].

6 208 R. Hetzer et al. / European Journal of Cardio-Thoracic Surgery Regulation of the pump flow and the patient s systemic and pulmonary circulation was extremely difficult in the presence of intracardiac shunts. Such patients were treated with ECMO, if necessary. However, there are some reports of successful implantation of the BHE for single-ventricle physiology [30 32] and in some cases with aortopulmonary shunts [30]. In children who underwent staged single-ventricle palliation, including the Norwood stage 1 procedure, bidirectional cavopulmonary anastomosis and repair of obstructed pulmonary veins, the VAD could be used without an oxygenator while keeping the aortopulmonary shunt open and maintaining high pump flow. Clipping of the shunt then seemed unnecessary [33]. Fortunately, there were no patients with persistent intracardiac shunts implanted with BHE in this series. Generally, as with any kind of mechanical circulatory support system, earlier implantation has yielded better results. This effect was most pronounced in infants. During our early experience, the majority of these patients were placed on the BHE in a state of advanced circulatory failure, characterized by irreversible organ shock sequelae and unresponsiveness of the peripheral circulation to α-stimulants (vasoplegia). We then observed that no patient <1 year of age survived for longer than 30 days after BHE implantation. Later on, >75% of infants could finally leave the hospital alive when the BHE was implanted early. Earlier implantation of mechanical circulatory support has taken on an important role in patients with heart failure immediately after correction of congenital heart diseases. With a staged concept of immediate ECMO institution and later VAD implantation when it becomes apparent that the cardiac function cannot be stabilized postoperatively, catastrophic courses have been avoided. A similar concept is applied for decompensated chronic heart failure requiring resuscitation. This strategy is evident in the significantly increased number of patients supported by ECMO before VAD implantation. In patients with chronic end-stage heart failure, measurement of levels of natriuretic peptides and inflammatory markers could guide the timing of VAD implantation and weaning [34]. The introduction into the paediatric population of the implantation criteria, i.e. implantation of BHE before shock-induced organ failure sets in or, at the latest, at the very first signs of such organ failure [11, 35 38], has fulfilled its promise of better survival. At present, we adhere to the criteria listed in the Patients and Methods section, with utmost consideration that the speed of deterioration plays an important role. With more confidence gained in the mechanical circulatory support system, these criteria may be applied less restrictively in the future. However, increased survival and the fact that more patients were treated with an LVAD alone, were extubated on the assist device and did not require delayed sternum closure indicate the significance of adherence to these criteria. Anticoagulation and its monitoring remain a major problem despite significant progress [17, 39 43]. Heparin coating alone has not solved all the problems. Pumps had to be exchanged when significant thrombus formation became visible. In one particular case, following a frustrating period of multiple pump thrombi under intravenous unfractionated heparin, we switched to low molecular weight heparin with monitoring of heparin anti-xa activity. Since then, children requiring long-term anticoagulation on a VAD have been treated with low molecular weight heparin, allowing a more stable level of anticoagulation without thromboembolic events. The reported high rates of device-related morbidity in children, particularly the thromboembolic and haemorrhagic events, are of concern. It is likely that management of anticoagulation is the most important causal factor. Achieving effective anticoagulation in the smallest children is very difficult, because of both intrinsic factors related to maturation of the coagulation cascade and reasons related to the logistics of drug administration and frequent blood sampling. Noteworthy in the experience with the BHE was the observation that by unloading the ventricle with mechanical circulatory support, complete myocardial recovery has been demonstrated in acute myocarditis and even in dilated cardiomyopathy, as our group initially demonstrated in 1995 in the adult population. However, there no factors have been found that could predict the potential for recovery. Likewise, if recovery occurs, there is no guarantee that it will last after explanting the mechanical circulatory support system. In addition, it appears that younger age is a factor in plasticity of the myocardium,aswehaveshownandasseeninotherreports[44, 45]. Several medical concepts to support the mechanisms of myocardial recovery have been tried; however, there is no reported evidence to prove their efficacy. The mechanism of cellular recovery still remains unknown. Research must be focused on addressing this issue. The durability of all the currently available VADs is limited to a number of years. Therefore, in children and young adults presenting with end-stage heart failure and contraindications for heart transplantation, such as high pulmonary vascular resistance or uncertain freedom from malignancy after tumour treatment, there are no long-term options available. In these cases, the BHE may bridge children to the status of transplantability, and these children will require long-term support. For such long-term support, smaller and implantable devices would be a better choice in terms of quality of life than extracorporeal devices. Summary The BHE can reliably support the circulation in children with failing hearts, with equally good results for weeks, months and even years. In newborns and small children, the BHE remains the only reliable option. In some patients with myocarditis and with dilated cardiomyopathy, ventricular unloading may lead to complete myocardial recovery. Patients with end-stage congenital heart disease primarily uncorrected or after surgery show the lowest survival rate. Recent results show significant improvements in the survival and discharge rate, especially in children <1 year of age. The BHE is now an established treatment for children suffering from cardiogenic shock or from end-stage heart failure of any aetiology. ACKNOWLEDGEMENTS We appreciate the help of Julia Stein with statistical analysis and Carla Weber and Helge Haselbach with graphics. We appreciate the support of the staff of the Berlin Heart GmbH, who provided the necessary historical information on Berlin Heart EXCOR. Conflict of interest: none declared. REFERENCES [1] Warnecke H, Berdjis F, Hennig E, Lange P, Schmitt D, Hummel M et al. Mechanical left ventricular support as a bridge to transplantation. Eur J Cardiothorac Surg 1991;5: [2] Hennig E. Design criteria for pediatric mechanical circulatory support systems (PMCSS). In: Ferrazzi P, Parenzan L (eds). Annals of the Concerted Action HEART Bergamo, Italy: Commission of the European Communities, 1991,

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Impact of heparin-induced thrombocytopenia on outcome in patients with ventricular assist device support: single-institution experience in 358 consecutive patients. Ann Thorac Surg 2007;83:72 6. [18] Potapov EV, Ignatenko S, Nasseri BA, Loebe M, Harke C, Bettmann M et al. Clinical significance of PlA polymorphism of platelet GP IIb/IIIa receptors during long-term VAD support. Ann Thorac Surg 2004;77:869 74; discussion 874. [19] Cassidy J, Haynes S, Kirk R, Crossland D, Smith JH, Hamilton L et al. Changing patterns of bridging to heart transplantation in children. J Heart Lung Transplant 2009;28: [20] Potapov EV, Weng Y, Jurmann M, Lehmkuhl H, Hetzer R. Bridging to transplantability with a ventricular assist device. J Thorac Cardiovasc Surg 2005; 130:930. [21] Schulze-Neick I, Luther YC, Ewert P, Lehmkuhl HB, Hetzer R, Lange PE. End-stage heart failure with pulmonary hypertension: levosimendan to evaluate for heart transplantation alone versus combined heart-lung transplantation. Transplantation 2004;78: [22] Alexi-Meskishvili V, Hetzer R, Weng Y, Ishino K, Potapov E, Loebe M et al. Extracorporeal circulatory support in pediatric cardiac patients the Berlin Experience. In: Hetzer R, Hennig E, Loebe M (eds). Mechanical Circulatory Support. Darmstadt: Springer and Steinkopff, 1997, [23] Huebler M, Koster A, Redlin M, Boettcher W, Stiller B, Nurnberg I et al. Repair of ALCAPA in a 4-kg patient followed by successful weaning and off-pump explantation of an apical venting pulsatile LVAD. J Card Surg 2005;20: [24] Hendry PJ, Masters RG, Davies RA, Mesana T, Struthers C, Mussivand T et al. Mechanical circulatory support for adolescent patients: the Ottawa Heart Institute experience. Can J Cardiol 2003;19: [25] Arabia FA, Tsau PH, Smith RG, Nolan PE, Paramesh V, Bose RK et al. Pediatric bridge to heart transplantation: application of the Berlin Heart, Medos and Thoratec ventricular assist devices. J Heart Lung Transplant 2006;25: [26] Laliberte E, Cecere R, Tchervenkov C, Wan C, Bittira B, Calaritis C et al. The combined use of extracorporeal life support and the Berlin Heart pulsatile pediatric ventricular assist device as a bridge to transplant in a toddler. J Extra Corpor Technol 2004;36: [27] Mahle WT, Ianucci G, Vincent RN, Kanter KR. Costs associated with ventricular assist device use in children. Ann Thorac Surg 2008;86: [28] Rockett SR, Bryant JC, Morrow WR, Frazier EA, Fiser WP, McKamie WA et al. Preliminary single center North American experience with the Berlin Heart pediatric EXCOR device. ASAIO J 2008;54: [29] Gandhi SK, Huddleston CB, Balzer DT, Epstein DJ, Boschert TA, Canter CE. Biventricular assist devices as a bridge to heart transplantation in small children. Circulation 2008;118:S [30] Pearce FB, Kirklin JK, Holman WL, Barrett CS, Romp RL, Lau YR. Successful cardiac transplant after Berlin Heart bridge in a single ventricle heart: use of aortopulmonary shunt as a supplementary source of pulmonary blood flow. J Thorac Cardiovasc Surg 2009;137:e40 2. [31] Russo P, Wheeler A, Russo J, Tobias JD. Use of a ventricular assist device as a bridge to transplantation in a patient with single ventricle physiology and total cavopulmonary anastomosis. Paediatr Anaesth 2008;18: [32] Pretre R, Haussler A, Bettex D, Genoni M. Right-sided univentricular cardiac assistance in a failing Fontan circulation. Ann Thorac Surg 2008;86: [33] Hoskote A, Bohn D, Gruenwald C, Edgell D, Cai S, Adatia I et al. Extracorporeal life support after staged palliation of a functional single ventricle: subsequent morbidity and survival. J Thorac Cardiovasc Surg 2006;131: [34] Heise G, Lemmer J, Weng Y, Hubler M, Alexi-Meskishvili V, Bottcher W et al. Biomarker responses during mid-term mechanical cardiac support in children. J Heart Lung Transplant 2008;27: [35] Loebe M, Hennig E, Müller J, Spiegelsberger S, Weng Y, Hetzer R. Long-term mechanical circulatory support as a bridge to transplantation, for recovery from cardiomyopathy, and for permanent replacement. Eur J Cardiothorac Surg 1997;11(Suppl):S [36] Deng MC, Weyand M, Hammel D, Schmid C, Kerber S, Schmidt C et al. Selection and management of ventricular assist device patients: the Muenster experience. J Heart Lung Transplant 2000;19:S [37] El-Banayosy A, Arusoglu L, Kizner L, Tenderich G, Boethig D, Minami K et al. Predictors of survival in patients bridged to transplantation with the Thoratec VAD device: a single-center retrospective study on more than 100 patients. J Heart Lung Transplant 2000;19: [38] Deng MC, Loebe M, El-Banayosy A, Gronda E, Jansen PG, Vigano M et al. Mechanical circulatory support for advanced heart failure: effect of patient selection on outcome. Circulation 2001;103: [39] Stiller B, Lemmer J, Merkle F, Alexi-Meskishvili V, Weng Y, Hubler M et al. Consumption of blood products during mechanical circulatory support in children: comparison between ECMO and a pulsatile ventricular assist device. Intensive Care Med 2004;30: [40] Takahama T, Kanai F, Onishi K. Anticoagulation during use of a left ventricular assist device. ASAIO J 2000;46: [41] Spanier T, Oz M, Levin H, Weinberg A, Stamatis K, Stern D et al. Activation of coagulation and fibrinolytic pathways in patients with left ventricular assist devices. J Thorac Cardiovasc Surg 1996;112: [42] Schmid C, Weyand M, Hammel D, Deng MC, Nabavi D, Scheld HH. Effect of platelet inhibitors on thromboembolism after implantation of a Novacor N100 preliminary results. Thorac Cardiovasc Surg 1998;46: [43] Koster A, Loebe M, Sodian R, Potapov EV, Hansen R, Müller J et al. Heparin antibodies and thromboembolism in heparin-coated and noncoated ventricular assist devices. J Thorac Cardiovasc Surg 2001;121: [44] Birks EJ. Myocardial recovery in patients with chronic heart failure: is it real? J Card Surg 2010;25: [45] Potapov EV, Stiller B, Hetzer R. Ventricular assist devices in children: current achievements and future perspectives. Pediatr Transplant 2007;11: APPENDIX. CONFERENCE DISCUSSION Scan to your mobile or go to to search for the presentation on the EACTS library Dr M. Griselli (Newcastle upon Tyne, UK): You are the pioneer of mechanical support in children and, as you remember, as a group from Freeman we visited you on several occasions at the beginning of our experience.

8 210 R. Hetzer et al. / European Journal of Cardio-Thoracic Surgery I want to ask you something which I think has become a problem in our unit, and I want to hear your opinion about mechanical support in children. I asked several times, particularly the cardiologists and intensivists, to develop a ventricular assist device team, and this has been already established at the adult level but it has not been established yet for the paediatric team. What do you think about this? Who is looking after anticoagulation in your institution? Is it the anaesthetist on call, is it the intensivist on call, is it the cardiologist on call or the surgeon? Secondly, I would like to ask you, what do you think about single-ventricle mechanical cardiac support? Thirdly, these machines are good but, as we know, in the best series the risk of thromboembolic complications is up to 30%. We know there are new devices, different generation devices, and the last paper from John Kirklin showed, for example, HeartWare, an incidence about 5 10%. Have these machines changed what you do in your institution, how you approach maybe bigger children? Dr Hetzer: Dr Griselli, these are very important questions; actually, they are most important in this whole field. The questions which you have raised I think are most important. One is, of course, the question of anticoagulation. It has also been our experience that thrombus formation and thromboembolism is the greatest risk in those patients. Over the years, we, together with the company, have developed quite some steps forward to modify the anticoagulation, which now I think has resulted in a much lower thromboembolism rate than it was in the beginning. Also, the anticoagulation schematic that you have seen obviously now is much more successful in the early postoperative phase, but it does not mean that thrombus formation does not happen, particularly in small pumps, in small babies. I think there is still room for improvement. The other question, applying our systems in single-ventricle pathophysiology, is certainly a very important question. Dr Pretre has published one of the first cases where he modified the anatomy of the heart in such a way that he could support the heart with one pump alone. This was a very successful single case. We had also a patient, in a second stage Norwood operation, who has been on the Berlin Heart EXCOR system for two and a half years before heart transplantation. I think we were lucky enough to, let s say, run the pump in such a way that no unequal perfusion happens. I agree, this is still a huge field of modifications and further development, and I think, of course, if you have a two-chamber system it is much better to support such a heart. Dr Griselli: Will the new generation of pumps change anything? Dr Hetzer: The topic of this presentation did not include the pumps that we have been introducing in older children. We have implanted HeartWare pumps, the youngest of whom was 5 years old, and this was the smallest pump that we could house in such a chest cavity. To my knowledge, there is no smaller pump available at the moment. The smallest Jarvik pump, as I have been told, has been implanted in Italy in two or three cases, but I have not heard anything about results and there is no published report about that. All the other attempts within the paediatric programmes in the United States to my knowledge have not reached clinical application. Dr B. Maruszewski (Warsaw, Poland): I would like to ask you about your experience with weaning from support, because you have 16% of patients where you managed to wean them off, not transplant them. First, what are your criteria for weaning? Are they the same as suggested by the company, because there are serious differences between criteria for weaning of the company and, for example, of the Newcastle group? The second question is, did you observe that in the recent era the proportion of patients that you manage to wean off is increasing and why is it true? Dr Hetzer: The first cases where we have observed recovery and on whom we could wean the pump off were myocarditis cases. We had the first case in the world with such a system in 1994, where we could take the pump off even after 12 days of support, although the child had gone to the operating room under chest massage. This was a very surprising recovery. You have seen in the list which Dr Delmo Walter has shown you that the largest number of patients with myocardial recovery are those with myocarditis. So I think, as with any other system, myocarditis is the optimal condition for weaning for recovery. You can even achieve it with extracorporeal membrane oxygenation, for instance, but one doesn t know how long one needs it. We had also patients with dilated cardiomyopathy whom we could successfully wean off, and a few others. Now, the protocol that we have developed is already pretty old with respect to the late 1990s or early 2000s. That means when we see on echocardiogram that the heart is beginning to function, of course we can turn down the pump, we can even stop the pump, and see after more or less half an hour or so whether the heart is still functioning well. I think that is the minimal test one needs to be able to wean the patient off the pump. Now, as you know, we have also a large experience with weaning adults with dilated cardiomyopathy off the pump. We had the first case in I must say neither in the children nor in the adults have we any criteria on hand which would clearly tell us whether there is a potential of recovery and, if the heart recovers, whether this will be sustained over many years. There are many, many questions, which have not yet been answered. I think acute viral myocarditis is probably the best case for weaning off pump. However, one can always try it in dilated cardiomyopathy, but it is not sure whether recovery can be reached to allow pump explantation. Dr Maruszewski: If I may just add one comment, we had the experience of weaning a 17 kg 9-year-old boy off support after 1 year, but unfortunately after 8 days we had to go back. I think it is still worth a try. Dr Hetzer: Yes. European Journal of Cardio-Thoracic Surgery 50 (2016) doi: /ejcts/ezw114 EDITORIAL COMMENT Cite this article as: Kirklin JK. Transformational trajectory of paediatric circulatory support: the impact of a unique vision. Eur J Cardiothorac Surg 2016;50: Transformational trajectory of paediatric circulatory support: the impact of a unique vision James K. Kirklin* Division of Cardiothoracic Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA * Corresponding author. Division of Cardiothoracic Surgery, Department of Surgery, University of Alabama at Birmingham, 1900 University Blvd., 760 THT, Birmingham, AL 35294, USA. Tel: ; jkirklin@uab.edu ( J.K. Kirklin). Keywords: Mechanical circulatory support Ventricular assist device Heart failure Myocardial recovery Heart transplantation In this issue, Hetzer et al. describe their remarkable journey with the Berlin Heart Excor ventricular assist device in infants and children. The Berlin group has pioneered the application of durable mechanical circulatory support in the paediatric population. Following their initial pioneering experience in 1990 [1], it would be a decade before the Berlin Heart would be introduced into the USA.