Initial in vitro testing of a paediatric continuous-flow total artificial heart

Initial in vitro testing of a paediatric continuous-flow total artificial heart Abstract OBJECTIVES Mechanical circulatory support has become standard therapy for adult patients with end-stage heart failure; however, in paediatric patients with congenital heart disease, the options for chronic mechanical circulatory support are limited to paracorporeal devices or off-label use of devices intended for implantation in adults. Congenital heart disease and cardiomyopathy often involve both the left and right ventricles; in such cases, heart transplantation, a biventricular assist device or a total artificial heart is needed to adequately sustain both pulmonary and systemic circulations. We aimed to evaluate the in vitro performance of the initial prototype of our paediatric continuous-flow total artificial heart. METHODS The paediatric continuous-flow total artificial heart pump was downsized from the adult continuous-flow total artificial heart configuration by a scale factor of 0.70 (1/3 of total volume) to enable implantation in infants. System performance of this prototype was evaluated using the continuous-flow total artificial heart mock loop set to mimic paediatric circulation. We generated maps of pump performance and atrial pressure differences over a wide range of systemic vascular resistance/pulmonary vascular resistance and pump speeds. RESULTS Performance data indicated left pump flow range of 0.4–4.7 l/min at 100 mmHg delta pressure. The left/right atrial pressure difference was maintained within ±5 mmHg with systemic vascular resistance/pulmonary vascular resistance ratios between 1.4 and 35, with/without pump speed modulation, verifying expected passive self-regulation of atrial pressure balance. CONCLUSIONS The paediatric continuous-flow total artificial heart prototype met design requirements for self-regulation and performance; in vivo pump performance studies are ongoing. Anatomical fit, Congenital cardiomyopathy, Congenital heart disease, Paediatric devices, Paediatric transition to adult care INTRODUCTION Mechanical circulatory support is now standard therapy for adult patients with end-stage heart failure [1, 2]. In paediatric patients with congenital heart disease (CHD), however, the options for chronic mechanical circulatory support are limited to paracorporeal devices [3] or off-label use of implantable adult devices, as no implantable devices have yet been approved by the US Food and Drug Administration for patients younger than 18 years. CHD often involves both the left and right ventricles; thus, for CHD patients, left ventricular assist devices (VADs) are not always optimal because they may not adequately sustain both pulmonary and systemic circulations. In such cases, heart transplantation might be an ideal therapy, but donor hearts for infants and small children are extremely limited [4]. We have developed a continuous-flow total artificial heart (CFTAH) for adult patients and have demonstrated its stable haemodynamics and good biocompatibility without anticoagulation in 3 long-term calf experiments up to 90 days [5]. We are currently developing a paediatric version (paediatric continuous-flow total artificial heart [P-CFTAH]; Fig. 1), downsizing the adult device by a scale factor of 0.70 (1/3 of total volume). This strategy makes implantation possible in the infant chest. The pump flow range (1.5–4.5 l/min) is intended to support patients weighing up to 50 kg (average weight of 14-year-olds). The purpose of this in vitro study is to evaluate the system performance of the initial working prototype of the P-CFTAH. Figure 1: View largeDownload slide A cartoon of paediatric continuous-flow total artificial heart in the chest of a baby (aged <1 year); inset: size of the paediatric continuous-flow total artificial heart working prototype (68.9 mm in length, 43.4 mm diameter, 167 g) vs a golf ball. Figure 1: View largeDownload slide A cartoon of paediatric continuous-flow total artificial heart in the chest of a baby (aged <1 year); inset: size of the paediatric continuous-flow total artificial heart working prototype (68.9 mm in length, 43.4 mm diameter, 167 g) vs a golf ball. MATERIALS AND METHODS Device fabrication Similar to the adult CFTAH, the P-CFTAH uses a single, centrally located, rotating assembly that has impellers for both left and right centrifugal pumps (Fig. 2). The P-CFTAH is valveless and sensorless, and the position of the centrally located rotating assembly is primarily determined by the differential force between the right and left pump filling pressures acting on this part to balance left and right circulations without electronic intervention [6]. A pulsatile flow can be produced with speed modulation [7], and an algorithm allows the controller to adjust speed automatically. The nominal external dimensions of the P-CFTAH design used in this study were 68.9 mm (length), 43.4 mm (diameter), 54.9 ml (volume displacement) and 167 g (weight). Figure 2: View largeDownload slide Enlarged view of paediatric continuous-flow total artificial heart prototype. Figure 2: View largeDownload slide Enlarged view of paediatric continuous-flow total artificial heart prototype. The prototype P-CFTAH was primarily made using 3D-printed and machinable materials. The inlet and outlet port diameters were the same as for the adult CFTAH, allowing common assemblies and mounting on the same CFTAH mock circulatory loop [7]. In vitro evaluation The system performance of the P-CFTAH was evaluated using the CFTAH mock circulatory loop (Fig. 3), which can also mimic paediatric circulation. A mixture of water and glycerin (specific gravity 1.060) was used as the working fluid. The left atrial pressure (LAP) and right atrial pressure (RAP) and systemic and pulmonary arterial pressures were directly measured by fluid-filled pressure transducers, and the left and right pump flows were measured with ultrasonic flow probes; all data were recorded simultaneously. The left pump pressure–flow curves at various pump speeds (3000, 3500, 4000, 4500 and 5000 rpm) were obtained with various delta pressures (10–160 mmHg) by adjusting the resistance on the outflow conduits. Our proposed pump flow requirement is 1.5–4.5 l/min. Figure 3: View largeDownload slide Schematic of the mock circulatory loop. P-CFTAH: paediatric continuous-flow total artificial heart. Figure 3: View largeDownload slide Schematic of the mock circulatory loop. P-CFTAH: paediatric continuous-flow total artificial heart. To evaluate passive self-regulation left/right balance under both physiological and extreme conditions, the left and right atrial pressure difference (LAP-RAP) was obtained using various pump speeds and a wide range of systemic-to-pulmonary vascular resistance (SVR/PVR) ratios that extend beyond normal physiological conditions. To manipulate SVR/PVR ratio, the outflow pressures were varied by changing the systemic and pulmonary resistance with tube clamps. This range was intentionally implemented to account for the known sudden, acute and profound increases in PVR. LAP-RAP data were taken with and without pump speed modulation (sinusoidal speed change at a frequency of 1 Hz and an amplitude of ±25% of the mean speed). Our proposed system requirement for self-regulation is maintenance of LAP-RAP within −5 to +10 mmHg for SVR/PVR ≥2.0. RESULTS The pressure–flow curves indicated a broad range of left pump flow (Fig. 4). At the delta pressure of 100 mmHg, the left pump flow ranged from 0.4 to 4.7 l/min with pump speeds between 3500 and 5000 rpm. LAP-RAP was maintained within ±5 mmHg with a wide range of SVR/PVR ratios (between 1.4 and 35) with and without pump speed modulation (Fig. 5). These data met the proposed design requirements for pump flow range (1.5–4.5 l/min) and self-regulation (LAP-RAP within −5 to +10 mmHg). Figure 4: View largeDownload slide Left pump pressure–flow curves of paediatric continuous-flow total artificial heart. AoP: aortic pressure; LAP: left atrial pressure. Figure 4: View largeDownload slide Left pump pressure–flow curves of paediatric continuous-flow total artificial heart. AoP: aortic pressure; LAP: left atrial pressure. Figure 5: View largeDownload slide Atrial balance with and without pump speed modulation. LAP: left atrial pressure; PVR: pulmonary vascular resistance; RAP: right atrial pressure; SVR: systemic vascular resistance. Figure 5: View largeDownload slide Atrial balance with and without pump speed modulation. LAP: left atrial pressure; PVR: pulmonary vascular resistance; RAP: right atrial pressure; SVR: systemic vascular resistance. DISCUSSION CHD, a major cause of infant death during the first year, accounts for the largest proportion of mortality (30–50%) resulting from birth defects [8]. From 1999 to 2006, infant mortality accounted for 48.1% (69 252 deaths in the USA) of all mortality from CHD. Cardiac surgery for neonates and infants with CHD usually addresses complex cardiac anomalies such as hypoplastic left heart syndrome and transposition of the great artery. Complicated surgical procedures (e.g., the Norwood procedure and the Jatene (arterial switch) procedure) can be complicated by severe heart failure postoperatively, with failure to thrive. Persistent residual cyanosis and incomplete correction by these palliative procedures often result in unsatisfactory haemodynamic status after surgery. Options for mechanical circulatory support modalities are limited to external devices: temporary extracorporeal membrane oxygenation, temporary extracorporeal centrifugal VADs and the EXCOR® VAD (Berlin Heart GmbH, Berlin, Germany). The EXCOR VAD, a paracorporeal pneumatic pump, is currently the only VAD available to provide long-term support to small children awaiting heart transplantation. The Infant Jarvik 2000 (Jarvik Heart, Inc., New York, NY, USA) [9], a downsized version of the adult Jarvik 2000®, was used in a 5.7-kg baby in Italy. In October 2016, the Food and Drug Administration granted conditional approval to conduct an Investigational Device Exemption study of the Jarvik 2015, a 40% larger version of the Infant Jarvik 2000. The study [Pumps for Kids, Infants, and Neonates (PumpKIN) Clinical Trial: NCT02954497] which began in 19 June 2017 compares the implanted, portable electrically powered Jarvik 2015 left VAD System with the Berlin Heart EXCOR Paediatric System. CHD and cardiomyopathy often involve both ventricles, and in such cases, heart transplantation, a BiVAD or a total artificial heart (TAH) is needed. TAHs are more appropriate than BiVADs for patients born with a single ventricle, thrombosed ventricles, restrictive cardiomyopathy, cardiac tumours, severe ventricular septal defects, frail ventricles causing difficult cannulation and intractable arrhythmias. Device size is critically important to achieve chest closure and optimal fit for chronic implantation in small children. The only paediatric TAH under Investigational Device Exemption clinical study is SynCardia’s 50-cc TAH-t (SynCardia 50-cc TAH-t as a bridge to transplant: Clinical Trial NCT02459054). This 50-cc model is smaller than their 70-cc model but much larger than our P-CFTAH (∼3 times larger in total displacement volume). The 50-cc TAH-t is designed for use in patients with a body surface area of ≥1.2 m2 (average body surface area of 11-year-old children) [10], clearly indicating that that device is not intended for newborns or infants. On the basis of our preliminary human anatomical fitting study [11], we predict a good anatomical fit of P-CFTAH if patients have a vertebra-to-sternum distance (at the junction of the right atrium to the inferior vena cava) ≥5.25 cm, which corresponds to a body surface area of ≥0.3 m2 (height ≥55 cm; age 1 month). Further anatomical fitting studies (in patients undergoing open heart surgery and/or in cadavers) will be necessary to evaluate the models of the pumps inside the patient’s chest to determine the smallest patient size/critical dimensions and device port configurations. Penn State University has begun to develop a TAH for infants and small children, using 2 pneumatically driven infant VADs as a bridge to heart transplant (Weiss WJ, NIH grant 5R01HL131921-02, 2016–2020). Both SynCardia’s and Penn State’s TAHs are pneumatically driven, pulsatile devices with multiple moving parts (4 valves, 2 diaphragms and an external pneumatic driver). In the past 5 years, continuous-flow rotary VADs have totally replaced volume-displacement pulsatile-flow VADs because of their simplicity, greater mechanical reliability, improved durability, smaller size and better outcomes [2]. A similar trend is likely to be seen with the increasing adoption of CFTAHs over existing and emerging pulsatile technologies. Limitations This preliminary report has study limitations. As the first prototype was created using 3D-printed materials, we have not yet been able to show any haemolysis data, which is very important. We are planning to perform a haemolysis test on the next version of P-CFTAH with titanium housings and impellers. A series of chronic animal experiments will also be needed to evaluate its biocompatibility, especially in vivo haemolysis and thrombogenicity. In addition, device durability will be evaluated on the bench in the future. Second, if we use this device as a destination therapy, the device design cannot accommodate to the child’s growth. However, the pump flow range of up to 4.5 l/min will support patients weighing up to 50 kg (average weight of 14-year-olds). For destination therapy, when the patient grows beyond the requirement of 4.5 l/min, the P-CFTAH could be replaced by the adult version, with an overlapping pump flow range (3–9 l/min). We envision that replacement surgery can be done under cardiopulmonary bypass, by disconnecting the inflow/outflow ports of the P-CFTAH from their respective inflow cuffs and outflow grafts and connecting an adult CFTAH. CONCLUSIONS The initial in vitro study of the P-CFTAH prototype met the proposed design requirements for pump flow range and self-regulation. The in vivo experiments, currently ongoing, will be essential for refining the design of the P-CFTAH, validating the device’s overall system performance and its hydraulic performance and self-regulating mechanical design under specific haemodynamic conditions. Future chronic experiments are also necessary to evaluate biocompatibility, especially the risk of thrombosis, which is the major Achilles heel of paediatric support devices. ACKNOWLEDGEMENTS We thank our Cleveland Clinic colleagues Raymond Dessoffy of the Department of Biomedical Engineering and Shengqiang Gao of Medical Device Solutions (Polymer Core), both at the Lerner Research Institute, for their significant efforts, valuable help and technical assistance in carrying out these studies. Funding This study was supported by Cleveland Clinic’s internal fund (Kaufman Center for Heart Failure at the Miller Family Heart and Vascular Institute). All the authors had freedom of investigation and full control of the design of the study, methods used, outcome parameters and results, analysis of data and production of the written report. Conflict of interest: David J. Horvath and Barry D. Kuban are coinventors of the adult continuous-flow total artificial heart. The technology was licensed to Cleveland Heart, Inc., a Cleveland Clinic spin-off company. REFERENCES 1 Mancini D , Colombo PC. Left ventricular assist devices: a rapidly evolving alternative to transplant . J Am Coll Cardiol 2015 ; 65 : 2542 – 55 . Google Scholar CrossRef Search ADS PubMed 2 Moazami N , Hoercher KJ , Fukamachi K , Kobayashi M , Smedira NG , Massiello A et al. . Mechanical circulatory support for heart failure: past, present and a look at the future . Expert Rev Med Devices 2013 ; 10 : 55 – 71 . Google Scholar CrossRef Search ADS PubMed 3 De Rita F , Griselli M , Sandica E , Miera O , Karimova A , D’Udekem Y et al. . Closing the gap in paediatric ventricular assist device therapy with the Berlin Heart EXCOR(R) 15-ml pump . Interact CardioVasc Thorac Surg 2017 ; 24 : 768 – 71 . Google Scholar PubMed 4 Zafar F , Castleberry C , Khan MS , Mehta V , Bryant R 3rd , Lorts A et al. . Pediatric heart transplant waiting list mortality in the era of ventricular assist devices . J Heart Lung Transplant 2015 ; 34 : 82 – 8 . Google Scholar CrossRef Search ADS PubMed 5 Karimov JH , Moazami N , Kobayashi M , Sale S , Such K , Byram N et al. . First report of 90-day support of 2 calves with a continuous-flow total artificial heart . J Thorac Cardiovasc Surg 2015 ; 150 : 687 – 93.e1 . Google Scholar CrossRef Search ADS PubMed 6 Fukamachi K , Horvath DJ , Massiello AL , Fumoto H , Horai T , Rao S et al. . An innovative, sensorless, pulsatile, continuous-flow total artificial heart: device design and initial in vitro study . J Heart Lung Transplant 2010 ; 29 : 13 – 20 . Google Scholar CrossRef Search ADS PubMed 7 Shiose A , Nowak K , Horvath DJ , Massiello AL , Golding LA , Fukamachi K. Speed modulation of the continuous-flow total artificial heart to simulate a physiologic arterial pressure waveform . ASAIO J 2010 ; 56 : 403 – 9 . Google Scholar CrossRef Search ADS PubMed 8 Gilboa SM , Salemi JL , Nembhard WN , Fixler DE , Correa A. Mortality resulting from congenital heart disease among children and adults in the United States, 1999 to 2006 . Circulation 2010 ; 122 : 2254 – 63 . Google Scholar CrossRef Search ADS PubMed 9 Kirklin JK. Advances in mechanical assist devices and artificial hearts for children . Curr Opin Pediatr 2015 ; 27 : 597 – 603 . Google Scholar CrossRef Search ADS PubMed 10 Moore RA , Lorts A , Madueme PC , Taylor MD , Morales DL. Virtual implantation of the 50cc SynCardia total artificial heart . J Heart Lung Transplant 2016 ; 35 : 824 – 7 . Google Scholar CrossRef Search ADS PubMed 11 Fukamachi K , Karimov JH , Byram N , Sunagawa G , Dessoffy R , Miyamoto T et al. . Virtual fitting study of the Cleveland Clinic continuous-flow total artificial heart in adult and pediatric configurations. [Abstract]. Program and Abstract issue for the 2017 International Society for Mechanical Circulatory Support (formerly International Society for Rotary Blood Pumps) Houston, TX, USA, 16–18 October 2017. © 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

Initial in vitro testing of a paediatric continuous-flow total artificial heart

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Abstract

Abstract OBJECTIVES Mechanical circulatory support has become standard therapy for adult patients with end-stage heart failure; however, in paediatric patients with congenital heart disease, the options for chronic mechanical circulatory support are limited to paracorporeal devices or off-label use of devices intended for implantation in adults. Congenital heart disease and cardiomyopathy often involve both the left and right ventricles; in such cases, heart transplantation, a biventricular assist device or a total artificial heart is needed to adequately sustain both pulmonary and systemic circulations. We aimed to evaluate the in vitro performance of the initial prototype of our paediatric continuous-flow total artificial heart. METHODS The paediatric continuous-flow total artificial heart pump was downsized from the adult continuous-flow total artificial heart configuration by a scale factor of 0.70 (1/3 of total volume) to enable implantation in infants. System performance of this prototype was evaluated using the continuous-flow total artificial heart mock loop set to mimic paediatric circulation. We generated maps of pump performance and atrial pressure differences over a wide range of systemic vascular resistance/pulmonary vascular resistance and pump speeds. RESULTS Performance data indicated left pump flow range of 0.4–4.7 l/min at 100 mmHg delta pressure. The left/right atrial pressure difference was maintained within ±5 mmHg with systemic vascular resistance/pulmonary vascular resistance ratios between 1.4 and 35, with/without pump speed modulation, verifying expected passive self-regulation of atrial pressure balance. CONCLUSIONS The paediatric continuous-flow total artificial heart prototype met design requirements for self-regulation and performance; in vivo pump performance studies are ongoing. Anatomical fit, Congenital cardiomyopathy, Congenital heart disease, Paediatric devices, Paediatric transition to adult care INTRODUCTION Mechanical circulatory support is now standard therapy for adult patients with end-stage heart failure [1, 2]. In paediatric patients with congenital heart disease (CHD), however, the options for chronic mechanical circulatory support are limited to paracorporeal devices [3] or off-label use of implantable adult devices, as no implantable devices have yet been approved by the US Food and Drug Administration for patients younger than 18 years. CHD often involves both the left and right ventricles; thus, for CHD patients, left ventricular assist devices (VADs) are not always optimal because they may not adequately sustain both pulmonary and systemic circulations. In such cases, heart transplantation might be an ideal therapy, but donor hearts for infants and small children are extremely limited [4]. We have developed a continuous-flow total artificial heart (CFTAH) for adult patients and have demonstrated its stable haemodynamics and good biocompatibility without anticoagulation in 3 long-term calf experiments up to 90 days [5]. We are currently developing a paediatric version (paediatric continuous-flow total artificial heart [P-CFTAH]; Fig. 1), downsizing the adult device by a scale factor of 0.70 (1/3 of total volume). This strategy makes implantation possible in the infant chest. The pump flow range (1.5–4.5 l/min) is intended to support patients weighing up to 50 kg (average weight of 14-year-olds). The purpose of this in vitro study is to evaluate the system performance of the initial working prototype of the P-CFTAH. Figure 1: View largeDownload slide A cartoon of paediatric continuous-flow total artificial heart in the chest of a baby (aged <1 year); inset: size of the paediatric continuous-flow total artificial heart working prototype (68.9 mm in length, 43.4 mm diameter, 167 g) vs a golf ball. Figure 1: View largeDownload slide A cartoon of paediatric continuous-flow total artificial heart in the chest of a baby (aged <1 year); inset: size of the paediatric continuous-flow total artificial heart working prototype (68.9 mm in length, 43.4 mm diameter, 167 g) vs a golf ball. MATERIALS AND METHODS Device fabrication Similar to the adult CFTAH, the P-CFTAH uses a single, centrally located, rotating assembly that has impellers for both left and right centrifugal pumps (Fig. 2). The P-CFTAH is valveless and sensorless, and the position of the centrally located rotating assembly is primarily determined by the differential force between the right and left pump filling pressures acting on this part to balance left and right circulations without electronic intervention [6]. A pulsatile flow can be produced with speed modulation [7], and an algorithm allows the controller to adjust speed automatically. The nominal external dimensions of the P-CFTAH design used in this study were 68.9 mm (length), 43.4 mm (diameter), 54.9 ml (volume displacement) and 167 g (weight). Figure 2: View largeDownload slide Enlarged view of paediatric continuous-flow total artificial heart prototype. Figure 2: View largeDownload slide Enlarged view of paediatric continuous-flow total artificial heart prototype. The prototype P-CFTAH was primarily made using 3D-printed and machinable materials. The inlet and outlet port diameters were the same as for the adult CFTAH, allowing common assemblies and mounting on the same CFTAH mock circulatory loop [7]. In vitro evaluation The system performance of the P-CFTAH was evaluated using the CFTAH mock circulatory loop (Fig. 3), which can also mimic paediatric circulation. A mixture of water and glycerin (specific gravity 1.060) was used as the working fluid. The left atrial pressure (LAP) and right atrial pressure (RAP) and systemic and pulmonary arterial pressures were directly measured by fluid-filled pressure transducers, and the left and right pump flows were measured with ultrasonic flow probes; all data were recorded simultaneously. The left pump pressure–flow curves at various pump speeds (3000, 3500, 4000, 4500 and 5000 rpm) were obtained with various delta pressures (10–160 mmHg) by adjusting the resistance on the outflow conduits. Our proposed pump flow requirement is 1.5–4.5 l/min. Figure 3: View largeDownload slide Schematic of the mock circulatory loop. P-CFTAH: paediatric continuous-flow total artificial heart. Figure 3: View largeDownload slide Schematic of the mock circulatory loop. P-CFTAH: paediatric continuous-flow total artificial heart. To evaluate passive self-regulation left/right balance under both physiological and extreme conditions, the left and right atrial pressure difference (LAP-RAP) was obtained using various pump speeds and a wide range of systemic-to-pulmonary vascular resistance (SVR/PVR) ratios that extend beyond normal physiological conditions. To manipulate SVR/PVR ratio, the outflow pressures were varied by changing the systemic and pulmonary resistance with tube clamps. This range was intentionally implemented to account for the known sudden, acute and profound increases in PVR. LAP-RAP data were taken with and without pump speed modulation (sinusoidal speed change at a frequency of 1 Hz and an amplitude of ±25% of the mean speed). Our proposed system requirement for self-regulation is maintenance of LAP-RAP within −5 to +10 mmHg for SVR/PVR ≥2.0. RESULTS The pressure–flow curves indicated a broad range of left pump flow (Fig. 4). At the delta pressure of 100 mmHg, the left pump flow ranged from 0.4 to 4.7 l/min with pump speeds between 3500 and 5000 rpm. LAP-RAP was maintained within ±5 mmHg with a wide range of SVR/PVR ratios (between 1.4 and 35) with and without pump speed modulation (Fig. 5). These data met the proposed design requirements for pump flow range (1.5–4.5 l/min) and self-regulation (LAP-RAP within −5 to +10 mmHg). Figure 4: View largeDownload slide Left pump pressure–flow curves of paediatric continuous-flow total artificial heart. AoP: aortic pressure; LAP: left atrial pressure. Figure 4: View largeDownload slide Left pump pressure–flow curves of paediatric continuous-flow total artificial heart. AoP: aortic pressure; LAP: left atrial pressure. Figure 5: View largeDownload slide Atrial balance with and without pump speed modulation. LAP: left atrial pressure; PVR: pulmonary vascular resistance; RAP: right atrial pressure; SVR: systemic vascular resistance. Figure 5: View largeDownload slide Atrial balance with and without pump speed modulation. LAP: left atrial pressure; PVR: pulmonary vascular resistance; RAP: right atrial pressure; SVR: systemic vascular resistance. DISCUSSION CHD, a major cause of infant death during the first year, accounts for the largest proportion of mortality (30–50%) resulting from birth defects [8]. From 1999 to 2006, infant mortality accounted for 48.1% (69 252 deaths in the USA) of all mortality from CHD. Cardiac surgery for neonates and infants with CHD usually addresses complex cardiac anomalies such as hypoplastic left heart syndrome and transposition of the great artery. Complicated surgical procedures (e.g., the Norwood procedure and the Jatene (arterial switch) procedure) can be complicated by severe heart failure postoperatively, with failure to thrive. Persistent residual cyanosis and incomplete correction by these palliative procedures often result in unsatisfactory haemodynamic status after surgery. Options for mechanical circulatory support modalities are limited to external devices: temporary extracorporeal membrane oxygenation, temporary extracorporeal centrifugal VADs and the EXCOR® VAD (Berlin Heart GmbH, Berlin, Germany). The EXCOR VAD, a paracorporeal pneumatic pump, is currently the only VAD available to provide long-term support to small children awaiting heart transplantation. The Infant Jarvik 2000 (Jarvik Heart, Inc., New York, NY, USA) [9], a downsized version of the adult Jarvik 2000®, was used in a 5.7-kg baby in Italy. In October 2016, the Food and Drug Administration granted conditional approval to conduct an Investigational Device Exemption study of the Jarvik 2015, a 40% larger version of the Infant Jarvik 2000. The study [Pumps for Kids, Infants, and Neonates (PumpKIN) Clinical Trial: NCT02954497] which began in 19 June 2017 compares the implanted, portable electrically powered Jarvik 2015 left VAD System with the Berlin Heart EXCOR Paediatric System. CHD and cardiomyopathy often involve both ventricles, and in such cases, heart transplantation, a BiVAD or a total artificial heart (TAH) is needed. TAHs are more appropriate than BiVADs for patients born with a single ventricle, thrombosed ventricles, restrictive cardiomyopathy, cardiac tumours, severe ventricular septal defects, frail ventricles causing difficult cannulation and intractable arrhythmias. Device size is critically important to achieve chest closure and optimal fit for chronic implantation in small children. The only paediatric TAH under Investigational Device Exemption clinical study is SynCardia’s 50-cc TAH-t (SynCardia 50-cc TAH-t as a bridge to transplant: Clinical Trial NCT02459054). This 50-cc model is smaller than their 70-cc model but much larger than our P-CFTAH (∼3 times larger in total displacement volume). The 50-cc TAH-t is designed for use in patients with a body surface area of ≥1.2 m2 (average body surface area of 11-year-old children) [10], clearly indicating that that device is not intended for newborns or infants. On the basis of our preliminary human anatomical fitting study [11], we predict a good anatomical fit of P-CFTAH if patients have a vertebra-to-sternum distance (at the junction of the right atrium to the inferior vena cava) ≥5.25 cm, which corresponds to a body surface area of ≥0.3 m2 (height ≥55 cm; age 1 month). Further anatomical fitting studies (in patients undergoing open heart surgery and/or in cadavers) will be necessary to evaluate the models of the pumps inside the patient’s chest to determine the smallest patient size/critical dimensions and device port configurations. Penn State University has begun to develop a TAH for infants and small children, using 2 pneumatically driven infant VADs as a bridge to heart transplant (Weiss WJ, NIH grant 5R01HL131921-02, 2016–2020). Both SynCardia’s and Penn State’s TAHs are pneumatically driven, pulsatile devices with multiple moving parts (4 valves, 2 diaphragms and an external pneumatic driver). In the past 5 years, continuous-flow rotary VADs have totally replaced volume-displacement pulsatile-flow VADs because of their simplicity, greater mechanical reliability, improved durability, smaller size and better outcomes [2]. A similar trend is likely to be seen with the increasing adoption of CFTAHs over existing and emerging pulsatile technologies. Limitations This preliminary report has study limitations. As the first prototype was created using 3D-printed materials, we have not yet been able to show any haemolysis data, which is very important. We are planning to perform a haemolysis test on the next version of P-CFTAH with titanium housings and impellers. A series of chronic animal experiments will also be needed to evaluate its biocompatibility, especially in vivo haemolysis and thrombogenicity. In addition, device durability will be evaluated on the bench in the future. Second, if we use this device as a destination therapy, the device design cannot accommodate to the child’s growth. However, the pump flow range of up to 4.5 l/min will support patients weighing up to 50 kg (average weight of 14-year-olds). For destination therapy, when the patient grows beyond the requirement of 4.5 l/min, the P-CFTAH could be replaced by the adult version, with an overlapping pump flow range (3–9 l/min). We envision that replacement surgery can be done under cardiopulmonary bypass, by disconnecting the inflow/outflow ports of the P-CFTAH from their respective inflow cuffs and outflow grafts and connecting an adult CFTAH. CONCLUSIONS The initial in vitro study of the P-CFTAH prototype met the proposed design requirements for pump flow range and self-regulation. The in vivo experiments, currently ongoing, will be essential for refining the design of the P-CFTAH, validating the device’s overall system performance and its hydraulic performance and self-regulating mechanical design under specific haemodynamic conditions. Future chronic experiments are also necessary to evaluate biocompatibility, especially the risk of thrombosis, which is the major Achilles heel of paediatric support devices. ACKNOWLEDGEMENTS We thank our Cleveland Clinic colleagues Raymond Dessoffy of the Department of Biomedical Engineering and Shengqiang Gao of Medical Device Solutions (Polymer Core), both at the Lerner Research Institute, for their significant efforts, valuable help and technical assistance in carrying out these studies. Funding This study was supported by Cleveland Clinic’s internal fund (Kaufman Center for Heart Failure at the Miller Family Heart and Vascular Institute). All the authors had freedom of investigation and full control of the design of the study, methods used, outcome parameters and results, analysis of data and production of the written report. Conflict of interest: David J. Horvath and Barry D. Kuban are coinventors of the adult continuous-flow total artificial heart. The technology was licensed to Cleveland Heart, Inc., a Cleveland Clinic spin-off company. REFERENCES 1 Mancini D , Colombo PC. Left ventricular assist devices: a rapidly evolving alternative to transplant . J Am Coll Cardiol 2015 ; 65 : 2542 – 55 . Google Scholar CrossRef Search ADS PubMed 2 Moazami N , Hoercher KJ , Fukamachi K , Kobayashi M , Smedira NG , Massiello A et al. . Mechanical circulatory support for heart failure: past, present and a look at the future . Expert Rev Med Devices 2013 ; 10 : 55 – 71 . Google Scholar CrossRef Search ADS PubMed 3 De Rita F , Griselli M , Sandica E , Miera O , Karimova A , D’Udekem Y et al. . Closing the gap in paediatric ventricular assist device therapy with the Berlin Heart EXCOR(R) 15-ml pump . Interact CardioVasc Thorac Surg 2017 ; 24 : 768 – 71 . Google Scholar PubMed 4 Zafar F , Castleberry C , Khan MS , Mehta V , Bryant R 3rd , Lorts A et al. . Pediatric heart transplant waiting list mortality in the era of ventricular assist devices . J Heart Lung Transplant 2015 ; 34 : 82 – 8 . Google Scholar CrossRef Search ADS PubMed 5 Karimov JH , Moazami N , Kobayashi M , Sale S , Such K , Byram N et al. . First report of 90-day support of 2 calves with a continuous-flow total artificial heart . J Thorac Cardiovasc Surg 2015 ; 150 : 687 – 93.e1 . Google Scholar CrossRef Search ADS PubMed 6 Fukamachi K , Horvath DJ , Massiello AL , Fumoto H , Horai T , Rao S et al. . An innovative, sensorless, pulsatile, continuous-flow total artificial heart: device design and initial in vitro study . J Heart Lung Transplant 2010 ; 29 : 13 – 20 . Google Scholar CrossRef Search ADS PubMed 7 Shiose A , Nowak K , Horvath DJ , Massiello AL , Golding LA , Fukamachi K. Speed modulation of the continuous-flow total artificial heart to simulate a physiologic arterial pressure waveform . ASAIO J 2010 ; 56 : 403 – 9 . Google Scholar CrossRef Search ADS PubMed 8 Gilboa SM , Salemi JL , Nembhard WN , Fixler DE , Correa A. Mortality resulting from congenital heart disease among children and adults in the United States, 1999 to 2006 . Circulation 2010 ; 122 : 2254 – 63 . Google Scholar CrossRef Search ADS PubMed 9 Kirklin JK. Advances in mechanical assist devices and artificial hearts for children . Curr Opin Pediatr 2015 ; 27 : 597 – 603 . Google Scholar CrossRef Search ADS PubMed 10 Moore RA , Lorts A , Madueme PC , Taylor MD , Morales DL. Virtual implantation of the 50cc SynCardia total artificial heart . J Heart Lung Transplant 2016 ; 35 : 824 – 7 . Google Scholar CrossRef Search ADS PubMed 11 Fukamachi K , Karimov JH , Byram N , Sunagawa G , Dessoffy R , Miyamoto T et al. . Virtual fitting study of the Cleveland Clinic continuous-flow total artificial heart in adult and pediatric configurations. [Abstract]. Program and Abstract issue for the 2017 International Society for Mechanical Circulatory Support (formerly International Society for Rotary Blood Pumps) Houston, TX, USA, 16–18 October 2017. © 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)

Journal

Interactive CardioVascular and Thoracic SurgeryOxford University Press

Published: Jan 19, 2018

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