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Preclinical performance of a pediatric mechanical circulatory support device: The PediaFlow ventricular assist device

  • Salim E. Olia
    Affiliations
    Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pa

    McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pa

    Artificial Heart Program, University of Pittsburgh Medical Center, Pittsburgh, Pa
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  • Peter D. Wearden
    Affiliations
    Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pa

    McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pa

    Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pa

    Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pa
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  • Timothy M. Maul
    Affiliations
    Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pa

    McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pa

    Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pa

    Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pa
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  • Venkat Shankarraman
    Affiliations
    McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pa
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  • Ergin Kocyildirim
    Affiliations
    McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pa

    Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pa
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  • Shaun T. Snyder
    Affiliations
    LaunchPoint Technologies LLC, Goleta, Calif
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  • Patrick M. Callahan
    Affiliations
    McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pa

    Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pa

    Department of Anesthesiology, University of Pittsburgh, Pittsburgh, Pa
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  • Marina V. Kameneva
    Affiliations
    Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pa

    McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pa

    Department of Surgery, University of Pittsburgh, Pittsburgh, Pa
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  • William R. Wagner
    Affiliations
    Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pa

    McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pa

    Department of Surgery, University of Pittsburgh, Pittsburgh, Pa

    Department of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, Pa
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  • Harvey S. Borovetz
    Affiliations
    Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pa

    McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pa

    Department of Surgery, University of Pittsburgh, Pittsburgh, Pa

    Department of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, Pa
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  • James F. Antaki
    Correspondence
    Address for reprints: James F. Antaki, PhD, Cornell University, 109 Weill Hall, Ithaca, NY 14853.
    Affiliations
    McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pa

    Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, Pa
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Open ArchivePublished:April 20, 2018DOI:https://doi.org/10.1016/j.jtcvs.2018.04.062

      Abstract

      Objectives

      The PediaFlow (HeartWare International, Inc, Framingham, Mass) is a miniature, implantable, rotodynamic, fully magnetically levitated, continuous-flow pediatric ventricular assist device. The fourth-generation PediaFlow was evaluated in vitro and in vivo to characterize performance and biocompatibility.

      Methods

      Supported by 2 National Heart, Lung, and Blood Institute contract initiatives to address the limited options available for pediatric patients with congenital or acquired cardiac disease, the PediaFlow was developed with the intent to provide chronic cardiac support for infants as small as 3 kg. The University of Pittsburgh–led Consortium evaluated fourth-generation PediaFlow prototypes both in vitro and within a preclinical ovine model (n = 11). The latter experiments led to multiple redesigns of the inflow cannula and outflow graft, resulting in the implantable design represented in the most recent implants (n = 2).

      Results

      With more than a decade of extensive computational and experimental efforts spanning 4 device iterations, the AA battery–sized fourth-generation PediaFlow has an operating range of 0.5 to 1.5 L/min with minimal hemolysis in vitro and excellent hemocompatibility (eg, minimal hemolysis and platelet activation) in vivo. The pump and finalized accompanying implantable components demonstrated preclinical hemodynamics suitable for the intended pediatric application for up to 60 days.

      Conclusions

      Designated a Humanitarian Use Device for “mechanical circulatory support in neonates, infants, and toddlers weighing up to 20 kg as a bridge to transplant, a bridge to other therapeutic intervention such as surgery, or as a bridge to recovery” by the Food and Drug Administration, these initial results document the biocompatibility and potential of the fourth-generation PediaFlow design to provide chronic pediatric cardiac support.

      Abbreviations and Acronyms:

      CF (continuous-flow), FDA (Food and Drug Administration), LV (left ventricle), MCS (mechanical circulatory support), NIH (normalized index of hemolysis), NHLBI (National Heart Lung and Blood Institute), PF3 (third-generation PediaFlow), PF4 (fourth-generation PediaFlow), RBP (rotary blood pump), RPM (revolutions per minute), VAD (ventricular assist device)

      Key Words

      Figure thumbnail fx1
      The PediaFlow pediatric VAD described in this article.
      The PediaFlow pediatric VAD has the potential to provide long-term cardiac support safely in pediatric patients.
      Limited options exist, associated with serious neurologic and coagulation-related adverse events, for pediatric patients (body surface area <1.5 m2) requiring chronic MCS. The results of our PediaFlow design highlight the potential to safely provide long-term pediatric cardiac support using a magnetically levitated, fully implantable, CF RBP.
      See Editorial Commentary page 1652.
      See Editorial page 1642.

      Heart Failure in Adults

      Heart disease is the leading cause of mortality in adults internationally and domestically, responsible for 1 in every 7 deaths within the United States.
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      With circulatory assist device development spanning more than 5 decades for adults, multiple paradigm shifts from pulsatile total artificial hearts, to pulsatile (first generation) ventricular assist devices (VADs), to continuous-flow (CF) rotary blood pumps (RBPs) have revolutionized the field of mechanical circulatory support (MCS) in adults. By using centrifugal- or axial-flow designs with a single moving impeller, RBPs eliminate the flexible blood membranes, check valves, long cannulas, and tortuous blood paths required in prior pulsatile pumps. This increased simplicity allows for smaller blood-contacting surface area and reduced dead space, thereby reducing thrombosis potential and infection risks, in addition to decreasing the overall device size.
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      Likewise, controller size has been markedly reduced by the elimination of large percutaneous drivelines, compressors, vacuum pumps, solenoids, and large power supplies associated with positive-displacement VADs.
      • Lahpor J.R.
      State of the art: implantable ventricular assist devices.
      Supported by blood bearings/seals (second generation) or suspended by hydrodynamic or electromagnetic forces (third generation), RBPs are now the standard for chronic MCS support clinically.
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      With multiple adult CF VADs approved by the Food and Drug Administration (FDA) for bridge-to-transplant or destination therapy applications, these technologies have rescued thousands of adults with refractory end-stage heart failure with additional devices under development or in clinical trials.
      • Clegg A.J.
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      Pediatric Heart Failure

      Within the United States, 25% of all neonates born with a congenital heart defect will require invasive treatment within the first 12 months of life.
      • American Heart Association
      2005 Statistical Reference Book.
      Approximately 1800 infants die of congenital heart disease each year, and an additional 350 develop cardiomyopathy.
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      Children weighing less than 15 kg listed for cardiac transplantation have the highest waiting list mortality rate (17%) in all solid-organ transplantation categories.
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      • Blume E.D.
      • Bastardi H.J.
      • et al.
      Waiting list mortality among children listed for heart transplantation in the United States.
      Cardiac transplantation remains the standard of care for refractory heart failure, but with limited donor availability, only 56% of infants listed received an organ over the last decade.

      Organ Procurement and Transplantation Network. Vol 2015: US Department of Health & Human Services. Available at: https://optn.transplant.hrsa.gov. Accessed September 11, 2015.

      Although MCS has successfully decreased waiting list mortality and has been used as a bridge-to-recovery, availability of MCS devices for children remains limited.
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      • et al.
      The national heart, lung, and blood institute pediatric circulatory support program.
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      • et al.
      The waiting game: bridging to paediatric heart transplantation.

      Mechanical Circulatory Support for Pediatrics

      Extracorporeal membrane oxygenation is used extensively for providing temporary cardiac support to children from neonates to adolescents. Although resource intensive, it is cost-effective, institutionally available, and rapidly initiated.
      • Deiwick M.
      • Hoffmeier A.
      • Tjan T.D.
      Heart failure in children: mechanical assistance.
      However, extracorporeal membrane oxygenation is indicated only for short durations requiring immobilization and sedation, and has a high complication rate related to bleeding and thromboembolism proportional to support length.
      • Kulik T.J.
      • Moler F.W.
      • Palmisano J.M.
      Outcome-associated factors in pediatric patients treated with extracorporeal membrane oxygenator after cardiac surgery.
      For adolescents with sufficient body surface area, the use of adult-indicated durable CF-VADs is supported by the PediMACs registry with a 6-month survival approaching 90% (n = 126) since inception in 2012.
      • Kirklin J.K.
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      • Stevenson L.W.
      • Blume E.D.
      • et al.
      Seventh INTERMACS annual report: 15,000 patients and counting.
      The majority of CF-VADs were implanted in patients 6 years of age or older because of device size, although there is a growing off-label use of the smaller HeartWare HVAD (Framingham, Mass) typically implanted with an outflow graft constriction or operated at lower speeds (revolutions per minute [RPM]) to maintain pediatric-appropriate flow rates
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      • Pagani F.D.
      • Kormos R.L.
      • Stevenson L.W.
      • Blume E.D.
      • et al.
      Seventh INTERMACS annual report: 15,000 patients and counting.
      • Honjo O.
      • Rao V.
      Implantation of HeartWare left ventricular assist device in pediatric population.
      • VanderPluym C.J.
      • Fynn-Thompson F.
      • Blume E.D.
      Ventricular assist devices in children: progress with an orphan device application.
      in younger patients. Unlike adults, however, currently the only FDA-approved pediatric-specific bridge-to-transplant MCS device is the Berlin Heart EXCOR (Berlin, Germany), a paracorporeal, pneumatically driven, pulsatile VAD that provides extended support for the pediatric population through the use of varying volume-sized pumps coupled to a large pneumatic driver. The potential of the EXCOR as a lifesaving technology for children with heart failure is reflected in our center's experience since 2004.
      • Sharma M.S.
      • Webber S.A.
      • Morell V.O.
      • Gandhi S.K.
      • Wearden P.D.
      • Buchanan J.R.
      • et al.
      Ventricular assist device support in children and adolescents as a bridge to heart transplantation.
      However, the EXCOR has a substantial risk profile with approximately 80% of patients experiencing at least 1 significant adverse event, the majority (∼50%) from severe bleeding or infection, and is associated with frequent pump exchanges due to device thrombosis around the valve leaflets.
      • Fraser Jr., C.D.
      • Jaquiss R.D.B.
      • Rosenthal D.N.
      • Humpl T.
      • Canter C.E.
      • Blackstone E.H.
      • et al.
      Prospective trail of a pediatric ventricular assist device.

      Materials and Methods

      Government Initiatives

      Although there continues to be a need for next-generation pediatric MCS technology, the small market potential has limited commercial interest. Driven by the lack of progress for this underserved population, the National Heart, Lung, and Blood Institute's (NHLBI) Pediatric Circulatory Support Program awarded more than $22 million in 2004 to 5 separate consortia toward the development of novel pediatric MCS devices.
      • Baldwin J.T.
      • Borovetz H.S.
      • Duncan B.W.
      • Gartner M.J.
      • Jarvik R.K.
      • Weiss W.J.
      • et al.
      The national heart, lung, and blood institute pediatric circulatory support program.
      In 2010, NHLBI launched the Pumps for Kids, Infants, and Neonates (PumpKIN) – Pre-Clinical Program and awarded contracts ($24 million) to support 4 preclinical efforts (3 for pediatric devices funded under Pediatric Circulatory Support Program) to gain Investigational Device Exemption from the FDA.
      • Baldwin J.T.
      • Borovetz H.S.
      • Duncan B.W.
      • Gartner M.J.
      • Jarvik R.K.
      • Weiss W.J.
      The national heart, lung, and blood institute pediatric circulatory support program. A summary of the 5-year experience.
      The PediaFlow Consortium, consisting of the University of Pittsburgh, Children's Hospital of Pittsburgh, Carnegie Mellon University, and LaunchPoint Technologies (Goleta, Calif), received an award in both NHLBI Programs.

      PediaFlow Development

      As a participant in both NHLBI programs, we designed an implantable, mixed-flow, fully magnetically levitated (maglev), rotodynamic VAD to support the smallest (body surface area <0.5 m2 with a cardiac index >3.0 L/min/m2), and consequently most vulnerable, patients, for durations consistent with bridge-to-transplant wait list times, with the objective of minimizing MCS-associated serious adverse events.
      • Almond C.S.
      • Thiagarajan R.R.
      • Piercey G.E.
      • Gauvreau K.
      • Blume E.D.
      • Bastardi H.J.
      • et al.
      Waiting list mortality among children listed for heart transplantation in the United States.
      • Uber B.E.
      • Webber S.A.
      • Morell V.O.
      • Antaki J.F.
      Hemodynamic guidelines for design and control of a turbodynamic pediatric ventricular assist device.
      From the first prototype (PF1) demonstrating the feasibility and biocompatibility of a de novo, miniature maglev pump, the developmental evolution and miniaturization of the PediaFlow pediatric VAD (HeartWare International) summarized in Figure 1 involved implementation of turbomachinery principles outside of the usual operational ranges.
      • Maul T.M.
      • Kocyildirim E.
      • Johnson Jr., C.A.
      • Daly A.R.
      • Olia S.E.
      • Woolley J.R.
      • et al.
      In vitro and in vivo performance evaluation of the second developmental version of the PediaFlow pediatric ventricular assist device.
      • Antaki J.F.
      • Ricci M.R.
      • Verkaik J.E.
      • Snyder S.T.
      • Maul T.M.
      • Kim J.
      • et al.
      PediaFlow Maglev ventricular assist device: a prescriptive design approach.
      Designed to operate at supercritical speeds (RPMs above resonance frequencies), the third-generation PediaFlow (PF3) demonstrated excellent biocompatibility in vivo but maglev suspension instabilities limited flow rates to less than 1.0 L/min, necessitating further optimization and development.
      • Antaki J.F.
      • Ricci M.R.
      • Verkaik J.E.
      • Snyder S.T.
      • Maul T.M.
      • Kim J.
      • et al.
      PediaFlow Maglev ventricular assist device: a prescriptive design approach.
      Figure thumbnail gr1
      Figure 1Evolution and miniaturization of the PediaFlow from the PF1 to the PF4 pediatric VAD and pump topology (inset). PF1, First-generation PediaFlow; PF2, second-generation PediaFlow; PF3, third-generation PediaFlow; PF4, fourth-generation PediaFlow.
      Intended to provide up to 6 months of circulatory support for patients between 3 and 15 kg at flow rates of 0.3 to 1.5 L/min, the fourth-generation PediaFlow (PF4) pediatric VAD is the result of more than 10 years of biomedical, mechanical, electrical, and computational engineering. Representing the latest pump topology designed to achieve the target flow rates, the PF4's optimized blood-flow path consists of a tapered cylindrical impeller with 4 blades on the conical inlet face, leading to a single 1.5-mm annular fluid gap region, before passing through a 3-vane flow straightener machined into the aft-housing upon exit.
      • Wu J.
      • Antaki J.F.
      • Verkaik J.
      • Snyder S.
      • Ricci M.
      Computation fluid dynamics-based design optimization for an implantable miniature maglev pediatric ventricular assist device.
      Integrated “quick-connect” coupling mechanisms, recessed within the housing, enable direct attachment to the pump inlet and outlet (Figure 1, inset). Approximately the size of AA battery, a decrease in size of approximately 75% from the initial PF1 prototype (Figure 2, A), anatomic fit simulations suggest that the PF4 can be fully implanted in infants as small as 5 kg through placement behind the left rectus abdominus muscle with a single percutaneous driveline for electrical power.
      Figure thumbnail gr2
      Figure 2The PF4 prototype and implantable components: A, The PF4 pump and size comparison (AA battery). B, The parabolic-tip inflow cannula with detachable sewing ring. C, The preassembled 6-mm outflow graft assembly.

      In Vitro Assessment

      Benchtop evaluation of the PF4 was performed to confirm hemodynamic performance and characterize hemolysis potential. Physiologic flow rate and pressure measurements were simulated in a closed flow loop using a 2.39 centipoise blood analog glycerol-solution to generate characteristic pump “H-Q” curves following previously published methods.
      • Maul T.M.
      • Kocyildirim E.
      • Johnson Jr., C.A.
      • Daly A.R.
      • Olia S.E.
      • Woolley J.R.
      • et al.
      In vitro and in vivo performance evaluation of the second developmental version of the PediaFlow pediatric ventricular assist device.
      By using accepted standards, in vitro hemolysis testing was performed on several PF4 prototypes (Table E1 in Appendix E1) before in vivo implantation using purchased, citrated ovine whole blood (Lampire Inc, Ottsville, Pa) with a minimum total plasma protein concentration of 6.0 g/dL within 3 days of venipuncture.
      • Naito K.
      • Mizuguchi K.
      • Nose Y.
      The need for standardizing the index of hemolysis.
      • Maul T.M.
      • Kameneva M.V.
      • Wearden P.D.
      Mechanical Blood Trauma in Circulatory-Assist Devices.
      • Herbertson L.H.
      • Olia S.E.
      • Daly A.R.
      • Noatch C.P.
      • Smith W.A.
      • Kameneva M.V.
      • et al.
      Multi-laboratory study of flow-induced hemolysis using the FDA benchmark nozzle model.
      The clinically used, centrifugal PediMag (Thoratec, Pleasanton, Calif) pump served as a control for comparison. The Normalized Index of Hemolysis (NIH) was calculated for each pediatric hemodynamic test condition as follows
      • Naito K.
      • Mizuguchi K.
      • Nose Y.
      The need for standardizing the index of hemolysis.
      :
      NIH(g/100L)=ΔHbV(100Ht)/100[QT]/100


      where ΔHb is the measured change in plasma free hemoglobin (g/L), V is the total circuit volume (L), Ht is the blood hematocrit (%), Q is the flow rate (L/min), and T is the test duration (min).

      In Vivo Evaluation

      Under University of Pittsburgh Institutional Animal Care and Use Committee–approved protocols at the McGowan Institute's Center for Preclinical Studies, 6 PF4 prototypes were implanted in lambs (n = 11, 19.0-30.3 kg) without cardiopulmonary bypass to evaluate the chronic in vivo hemodynamic performance and biocompatibility of the PediaFlow and develop the implantable components (Table E2 in Appendix E1). Anesthesia, surgical approach, insertion, and postoperative management for the PF4 implants were similar to the 72-day PF3 implant described previously.
      • Maul T.M.
      • Kocyildirim E.
      • Johnson Jr., C.A.
      • Daly A.R.
      • Olia S.E.
      • Woolley J.R.
      • et al.
      In vitro and in vivo performance evaluation of the second developmental version of the PediaFlow pediatric ventricular assist device.
      • Antaki J.F.
      • Ricci M.R.
      • Verkaik J.E.
      • Snyder S.T.
      • Maul T.M.
      • Kim J.
      • et al.
      PediaFlow Maglev ventricular assist device: a prescriptive design approach.
      Three sham studies, in which the aforementioned implant procedure was followed without actual device placement, were performed to serve as complementary surgical controls (Appendix E2). Blood samples were drawn at regular intervals during the course of the studies for hematology and biocompatibility assessments, including plasma-free hemoglobin, fibrinogen concentration, and platelet activation and functionality assays, followed by a complete necropsy and pump component examination.
      • Maul T.M.
      • Kocyildirim E.
      • Johnson Jr., C.A.
      • Daly A.R.
      • Olia S.E.
      • Woolley J.R.
      • et al.
      In vitro and in vivo performance evaluation of the second developmental version of the PediaFlow pediatric ventricular assist device.
      • Johnson C.A.
      • Wearden P.D.
      • Kocyildirim E.
      • Maul T.M.
      • Woolley J.R.
      • Ye S.H.
      • et al.
      Platelet activation in ovines undergoing sham surgery or implant of the second generation PediaFlow pediatric ventricular assist device.
      A summary of the initial PF4 implant findings and design iterations, describing the concurrent development of the inflow cannula and outflow graft, can be found in Appendix E3.

      Fourth-Generation PediaFlow Implantable Design

      Detailed here are the most recent PF4 implants (n = 2) using the de novo designed 5-mm reinforced inflow cannula featuring a parabolic-shaped inlet entrance and detachable sewing ring to unload the left ventricle (LV) (Figure 2, B) and a 6-mm Gelweave (Vascutek Ltd, Renfrewshire, Scotland, UK) outflow graft with graduated strain relief to return blood to the aorta (Figure 2, C).
      • Griffin M.T.
      • Grzywinski M.F.
      • Voorhees H.J.
      • Kameneva M.V.
      • Olia S.E.
      Ex vivo assessment of a parabolic-tip inflow cannula for pediatric continuous-flow VADs.
      Surgical procedure with these implantable components varied only by first attaching the detachable sewing ring to the LV apex using pledgeted sutures after gaining access. After full anticoagulation with heparin, the outflow graft was anastomosed to the descending thoracic aorta and back-flushed before mating the graft connector to the pump outlet. The parabolic inflow cannula was inserted through the sewing ring after a cruciate incision without myocardium removal and a wet connection made to the pump inlet by the simultaneous removal of the inflow obturator and partial unclamping of the outflow graft. A perivascular ultrasonic probe (Transonic Systems, Ithaca, NY) was placed on the outflow graft to measure pump flow rate. Pump support was initiated and cannula depth optimized before thoracotomy closure. Rotational speed was adjusted as needed for a target flow rate of 1.5 L/min.

      Results

      Hemodynamic Performance In Vitro

      The characteristic performance curves of the PF4 highlighted an expanded operating range between 0.3 and 2.0 L/min at physiologically relevant pressure ranges, a marked improvement to PF3 (Figure 3, A). Hemolysis (NIH) varied somewhat among PF4 prototypes but was very low at the 3 pediatric flow rates tested and comparable to the PediMag control (Figure 3, B).
      Figure thumbnail gr3
      Figure 3A, PF4 characteristic H-Q pump curves using a blood analog (viscosity = 2.39 centipoise). B, The calculated in vitro NIH values (mean ± standard deviation) for the PF4 prototypes compared with the PediMag (Thoratec, Pleasanton, Calif) control. PF3, Third-generation PediaFlow; PF4, fourth-generation PediaFlow; NIH, normalized index of hemolysis.

      Implantation and Operation

      The last implants with the PF4 prototypes and implantable components were unremarkable for a study duration of 14 and 60 days. Pump support was initiated within 1 hour after first incision, achieving flow rates up to 2.0 L/min before reducing motor speed (RPM) to maintain a target flow rate of 1.5 L/min after chest closure (Figure 4, A). Because of the difficulty of titrating anticoagulation for an activated clotting time target of 180 to 200 seconds during the previous PF3 study, a continuous infusion of heparin was maintained at 20 UI/kg/h beginning on postoperative days 2 and 7 for PF4-S10 (60-day implant) and PF4-S11 (14-day implant), respectively (Figure 4, D).
      Figure thumbnail gr4
      Figure 4Results of the PF4 ovine studies using the current-design cannulae system (PF4-S10, PF4-S11), in comparison with the previous third-generation chronic implant (PF3-S01) and the nonimplanted surgical control shams (n = 3, mean ± standard deviation): A, Measured pump flow rate (Q) for the implanted animals (gaps indicate durations of signal loss during postoperative acoustic recoupling of the outflow graft probe). Hematologic and hemocompatibility measurements including plasma-free hemoglobin (B), fibrinogen (C), activated clotting time (D), and platelet biocompatibility (E) as determined by the time course of platelet activation by P-selectin expression and platelet functionality by agonist stimulation using platelet activating factor. ACT, Activated clotting time; FB, fibrinogen; PAF, platelet activating factor; PF3, third-generation PediaFlow; PF4, fourth-generation PediaFlow; plfHb, plasma-free hemoglobin; POD, postoperative day.

      In Vivo Biocompatibility

      During the PediaFlow implants, hemodynamic performance was within the pediatric physiologic range, whereas serum chemistry, hematology, and cellular biocompatibility parameters closely followed the trends observed in the 3 surgical control sham studies (Table E3 in Appendix E1). Plasma-free hemoglobin remained within preoperative levels and fibrinogen concentration values for the implants, and surgical control animals returned to baseline by postoperative day 14 (Figure 5, B and C). Platelet activation, measured by flow cytometry as percent of CD62p+ platelets, had a marked postsurgical response before returning to preoperative baseline values by postoperative day 10. Throughout the studies, platelets remained responsive to stimulation with platelet activating factor (Figure 4, E).
      Figure thumbnail gr5
      Figure 5Necropsy images of the PF3-S01 (72-day) implant. A, Pump placement in situ. B, The modified 18F fenestrated inflow cannula (Medtronic DLP, Minneapolis, Minn) free of thrombus within the LV. C, Left kidney with a minor and well-healed cortical infarction. D, Right kidney with a minor surface infarction that was not visible on sagittal dissection. The pump rotor (E) and stator (F) free of deposition.

      Necropsy

      Examination of the heart, lungs, liver, and spleen for both the PF3 and latest PF4 implants was unremarkable. The inflow cannulae were well healed within the LV apex with no myocardial injury evident, and the blood contacting surfaces of the pump, cannulae, and outflow grafts free of adherent thrombus (Figure 5, Figure 6, Figure 7). A well-healed, minor cortical infarction on the left kidney of the 72-day PF3 implanted animal was found, most likely from initial surgery (Figure 5, C). No surface lesions or infarcts were found on the kidneys of the 2 PF4 implants (Figures 6, D and E, and 7, G).
      Figure thumbnail gr6
      Figure 6Necropsy images of PF4-S11 (14-day) implant. A, The inflow cannula position in situ. B, Cannula body free of deposition. C, Adherent thrombus on the exterior of the outflow graft, outside of the blood flow path, possibly from the de-airing needle. D and E, Kidneys without evidence of infarcts. F-H, Rotor, impeller blading, and stator free of deposition.
      Figure thumbnail gr7
      Figure 7Explant photos of the PF4-S10 (60-day) implant. A, Well-encapsulated pump in situ. B, The inflow cannula tip position. C, The cannula body. Inflow (D) and outflow (E) connections free of deposition within the flow path. F, The pump rotor and stator (inset) free of deposits. G, Kidneys with no evidence of infarction.

      Discussion

      Implantable pediatric VADs have the potential to expand the number of children in heart failure rescued by MCS.
      • Webber S.
      Pediatric circulatory support contractors' meeting: report of the clinical trials working group.
      The use of RBPs for the treatment of pediatric heart failure is appealing by reducing the immobilization and inpatient restrictions that are currently associated with the EXCOR. Although the successful miniaturization of CF VADs will affect pediatric MCS options, the small market size and regulatory process create a significant entry barrier for this technology in the United States. Supported by the bench and preclinical findings reported in this article, the PediaFlow has the potential to serve as a bridge-to-transplant or bridge-to-recovery device.
      Consistent with the program goals for the 2 NHLBI contracts under which this work was conducted, the primary considerations for the design and development of the PediaFlow were miniaturization and reduction of serious adverse events by maximizing cellular biocompatibility, as judged on the bench and in situ.
      • Antaki J.F.
      • Ricci M.R.
      • Verkaik J.E.
      • Snyder S.T.
      • Maul T.M.
      • Kim J.
      • et al.
      PediaFlow Maglev ventricular assist device: a prescriptive design approach.
      • Borovetz H.S.
      • Badylak S.F.
      • Boston J.R.
      • Johnson C.A.
      • Kormos R.L.
      • Kameneva M.V.
      • et al.
      Towards the development of a pediatric ventricular assist device.
      • Wearden P.D.
      • Morell V.O.
      • Keller B.B.
      • Webber S.A.
      • Borovetz H.S.
      • Badylak S.F.
      • et al.
      The PediaFlow pediatric ventricular assist device.
      In silico optimization of the rotodynamics, magnetodynamics, heat transfer, and fluid dynamics yielded 4 successively smaller prototypes that were built and tested both in vitro and in vivo. Figure 1 displays the marked reduction in profile of the PediaFlow design in successive generations of prototypes (PF1-PF4), with the PF4 prototype approximating the size of an AA cell battery (Figure 2, A). By increasing the voice (levitation) coil to motor stator size-ratio to enhance rotor stability and optimizing the pump blading from PF3, flow rates were improved enabling PF4 to reach the target design goals. With an NIH of less than 0.02 g/100 L for the final PF4 prototypes, the PediaFlow PF4 device is nonhemolytic (eg, the NIH for the PF4 approximates that of the maglev PediMag) and less than published literature values for both adult and pediatric devices.
      • Naito K.
      • Mizuguchi K.
      • Nose Y.
      The need for standardizing the index of hemolysis.
      • Giridharan G.A.
      • Sobieski M.A.
      • Ising M.
      • Slaughter M.S.
      • Koenig S.C.
      Blood trauma testing for mechanical circulatory support devices.
      • Baldwin J.T.
      • Adachi I.
      • Teal J.
      • Almond C.A.
      • Jaquiss R.D.
      • Massicotte M.P.
      • et al.
      Closing in on the PumpKIN Trial of the Jarvik 2015 ventricular assist device.
      We attribute the absence of hemolysis to the fully magnetically levitated rotor design, the optimized single blood flow path, and the relatively large annular gap (1.5 mm), which eliminates the need for bearings or seals, thereby reducing hemolytic potential. Because each PF4 pump was hand-built, the variation in NIH among prototypes is likely due to assembly and polishing tolerances.
      Another design consideration for the PediaFlow technology is that pediatric MCS should be rapidly deployable and customizable to support the representative patient population. The use of cardiopulmonary bypass for VAD implantation is expected; however, limiting on-pump time remains ideal. Within this context, and for the PediaFlow inflow cannula, the removable sewing ring provides accurate and unencumbered placement onto the heart apex before allowing insertion and tool-less securement of the inflow body within the LV. The reinforced parabolic-shaped inflow tip (Figure 2, B) eases insertion and serves as a clinical marker for echocardiography perioperatively to adjust insertion depth and postoperatively when assessing cannula position. Along with the preassembled outflow graft and quick connect mechanisms (Figure 2, C), pump support was initiated in the latest studies in less than 1 hour from first incision without the use of cardiopulmonary bypass. Without any evidence of ventricular suction supported by explant analysis in the PF3 and PF4 implant studies, we hypothesize that the additional flow paths provided by the inlet shape geometry render the parabolic tip resistant to entrapment and less sensitive to positional variations.
      • Griffin M.T.
      • Grzywinski M.F.
      • Voorhees H.J.
      • Kameneva M.V.
      • Olia S.E.
      Ex vivo assessment of a parabolic-tip inflow cannula for pediatric continuous-flow VADs.
      Although in vivo analysis is performed in healthy animals and does not necessarily reflect the causes in children (ie, congenital, dilated, or restrictive cardiomyopathies), the results are nonetheless encouraging. The biocompatibility findings in vivo (Figure 5) and explant analyses (Figures 6 and 7) are consistent with the in vitro results demonstrating no hemolysis, platelet activation, or platelet dysfunction during implant periods up to 2 months. The lack of documented renal insufficiency or other evidence of thrombogenesis or thromboembolic events with only relatively low-dose heparin and subtherapeutic activated clotting times is especially promising toward the design goal for the PediaFlow pediatric VAD of solely antiplatelet therapies to minimize bleeding risk clinically.
      • Borovetz H.S.
      • Badylak S.F.
      • Boston J.R.
      • Johnson C.A.
      • Kormos R.L.
      • Kameneva M.V.
      • et al.
      Towards the development of a pediatric ventricular assist device.
      • Wearden P.D.
      • Morell V.O.
      • Keller B.B.
      • Webber S.A.
      • Borovetz H.S.
      • Badylak S.F.
      • et al.
      The PediaFlow pediatric ventricular assist device.
      Additional implants using the current PF4 design and components are necessary to demonstrate reproducibility of the preclinical assessment for Investigation Device Exemption application.

      Conclusions

      Figure thumbnail fx2
      Video 1Challenges to providing chronic MCS safely in pediatric patients with heart failure and the design features of the PediaFlow pediatric VAD to address these limitations. Video available at: https://www.jtcvs.org/article/S0022-5223(18)31049-3/fulltext.
      The data presented document the exceptional biocompatibility and the potential of safely providing chronic MCS to neonates and infants using a miniature, implantable, magnetically levitated, rotodynamic blood pump. Per the requirements of the NHLBI contract programs, the PediaFlow has been designated by the FDA as a Humanitarian Use Device for “mechanical circulatory support in neonates, infants, and toddlers weighing up to 20 kg as a bridge to transplant, a bridge to other therapeutic intervention such as surgery, or a bridge to recovery.” This important designation provides insight as to the remaining preclinical testing (both on the bench and in vivo) to be undertaken. Although accurate flow estimation has been achieved (Figure E1 in Appendix E1), work remains, including the final prototyping and testing of a clinical-use controller, which is required for the final preclinical studies in anticipation of submitting an Investigational Device Exemption application to the FDA.

      Conflict of Interest Statement

      The University of Pittsburgh, Carnegie Mellon University, and LaunchPoint Technologies, LLC, are co-inventors of the PediaFlow technology. The PediaFlow IP is licensed to HeartWare International, Inc (Framingham, Mass). Authors have nothing to disclose with regard to commercial support.
      The authors thank all of the members of the PediaFlow Consortium who participated in and contributed to the development of the PediaFlow pediatric VAD, including but not limited to Dr Gil Bearnson, Shawn Bengston, Dr Amanda Daly, Teri Dulak, Dr Antonio Ferreira, Joseph Hanke, Jal Jassawalla, Dr Carl Johnson, Dr Bradley Keller, Dr Pratap Khanwilkar, Dr Jeongho Kim, Phil Miller, Dr Brad Paden, Dave Paden, Michael Ricci, Dr Richard Schaub, Dr Fangjun Shu, Dr Trevor Snyder, Dr Dennis Trumble, Josiah Verkaik, Dr Stijn Vandenberghe, Andrew Wearden, Dr Steven Webber, Steven Winowich, Dr Joshua Woolley, and Dr Jingchun Wu. The PediaFlow is the culmination of work from our consortium beginning with the StreamLiner VAD, which was the world's first magnetically levitated axial/mixed flow VAD.

      Appendix E1

      Table E1Summary of the fourth-generation PediaFlow prototypes fabricated by the Consortium
      PrototypeExtent of testingModificationsManufacturing findings
      PF4.1Nonoperational
      PF4.2In vitroEpoxy-sealed feed-through assembly and printed circuit boardGround failure at feed-through requiring external grounding precluding in vivo assessment
      PF4.3In vivoImproved percutaneous cable feed-through attachment design
      PF4.4NonoperationalNoncompliant components
      PF4.5In vivo
      PF4.6In vivo
      PF4.7In vivoRevised stator housing to accommodate a Gelweave-compatible (Vascutek Ltd, Renfrewshire, Scotland, United Kingdom) outflow assembly connectionEpoxy infiltration into driveline during hermetic sealing leading to eventual fracture from fatigue
      PF4.6.1
      Used in the 60- and 14-day implants presented in the main text.
      In vivo1. Reduced-size driveline connector

      2. Smoothing filter on motor current signal
      PF4.8
      Used in the 60- and 14-day implants presented in the main text.
      In vivo(refurbished PF4.7)

      Copper-shielded percutaneous cable
      A total of 9 PF4 prototypes were fabricated, with 6 builds remitted for in vivo implantation and biocompatibility testing. Aside from variations due to manufacturing tolerances, the pump topologies (ie, blood flow paths) are identical across the PF4 generation. Instead, each hand-built pump represents the incorporation of incremental improvements based on fabrication or implant findings of the previous prototype. PF4, Fourth-generation PediaFlow.
      Used in the 60- and 14-day implants presented in the main text.
      Table E2Experimental details and relevant results of all fourth-generation PediaFlow ovine implants (n = 11) performed to develop, assess, and refine the implantable peripherals in addition to evaluating device hemodynamics and biocompatibility
      Study implantWeight (kg)PumpInflow cannula:

      Outflow assembly:
      Time (d)

      Intended/actual
      Average flow

      (L/min)
      Pertinent findings
      PF4-S0128.0PF4.3I: 22F Fenestrated

      O: Bard ePTFE
      4/141.21. Serosanguinous fluid collection

      2. Constricted outflow anastomosis
      PF4-S0227.9PF4.3I: 22F Fenestrated

      O: Bard ePTFE
      15/280.91. Detached pump inlet connection

      2. Fibrous deposition surrounding outflow graft along entire length

      3. Graft kink at pump attachment
      PF4-S0323.0PF4.5I: Bevel 1.0

      O: Bard ePTFE
      <1N/A1. Respiratory failure perioperatively after chest closure

      2. Nonseated outflow connector
      PF4-S0424.5PF4.5I: Bevel 1.1

      O: SEAL-PTFE
      4/281.51. Respiratory failure secondary to thoracic blood collection

      2. Outflow graft thrombus
      PF4-S0528.0PF4.6I: Bevel 1.1

      O: SEAL-PTFE
      4/281.01. Cardiac compression secondary to large thoracic hematoma

      2. Tissue entrapped on cannula tip

      3. Thrombus present at base of LV
      PF4-S0622.3PF4.7I: Bevel 1.1

      O: Gelweave
      28/281.31. Inflow cannula kink
      PF4-S0727.3PF4.7I: Bevel 1.1

      O: Gelweave
      12/281.51. Rotor position sensor failure secondary to driveline fracture

      2. Inflow cannula kink
      PF4-S0828.2PF4.6.1I: Bevel 2.0

      O: Gelweave
      9/282.01. Tamponade secondary to infectious pericarditis

      2. Large thoracic hematoma
      PF4-S0919.0PF4.8I: Bevel 2.0

      O: Gelweave
      15/281.01. Cardiovascular collapse

      2. Thoracic hematoma

      3. Inflow cannula kink
      PF4-S10
      The most recent implants presented in the main text using the parabolic-inflow cannula and Gelweave-based outflow graft assembly.
      28.7PF4.6.1I: Parabolic

      O: Gelweave
      60/601.61. Unremarkable
      PF4-S11
      The most recent implants presented in the main text using the parabolic-inflow cannula and Gelweave-based outflow graft assembly.
      Although initially implanted for an intended 30-day study, the study was electively terminated on postoperative day 14 because of irrecoverable de-levitation of the rotor. Although each PediaFlow prototype is indicated for single-use, the PF4 pump (PF4.8) implanted in PF4-S11 had been implanted and refurbished multiple times previously, leading to excessive wear, a failure mode that would not be expected clinically.
      30.3PF4.8I: Parabolic

      O: Gelweave
      14/281.41. Hemodynamic and biocompatibility design goals achieved until de-levitation due to wear from repeated refurbishments
      Bard ePTFE is a product of Bard Peripheral Vascular (Tempe, Ariz). SEAL-PTFE, and Gelweave are products of Vascutek Ltd (Renfrewshire, Scotland, UK). PF4, Fourth-generation PediaFlow; ePTFE, expanded polytetrafluoroethylene; NA, not available; LV, left ventricle.
      The most recent implants presented in the main text using the parabolic-inflow cannula and Gelweave-based outflow graft assembly.
      Although initially implanted for an intended 30-day study, the study was electively terminated on postoperative day 14 because of irrecoverable de-levitation of the rotor. Although each PediaFlow prototype is indicated for single-use, the PF4 pump (PF4.8) implanted in PF4-S11 had been implanted and refurbished multiple times previously, leading to excessive wear, a failure mode that would not be expected clinically.
      Table E3Additional blood parameters of the third- and fourth-generation PediaFlow and sham in vivo animal studies presented in the main article: All were within reference values
      PF3-S01 (72 d)PF4-S10 (14 d)PF4-S11 (60 d)Sham implants (n = 3, mean)Reference range
      Weight (kg)(24)(30)(28.7)(43.3 ± 12.7)
      WBC (×103/mm3)7.3 ± 1.2 (7.2)8.6 ± 2.8 (9.5)13.4 ± 3.4 (12.8)5.0 ± 0.5 (5.6)4-12
      RBC (×106/mm3)7.6 ± 0.5 (10.3)8.2 ± 0.7 (13.1)10.0 ± 0.7 (13.4)8.5 ± 0.7 (9.9)9-15
      Hgb (g/dL)8 ± 0.9 (9.9)7.7 ± 0.6 (12.3)10.7 ± 0.7 (14.2)9.6 ± 1.0 (10.0)9-15
      HCT (%)23.3 ± 2.7 (26.5)24.1 ± 1.3 (37.6)31.9 ± 1.9 (41.5)26.6 ± 2.2 (31.9)27-45
      Platelets (×103/mm3)626 ± 248 (2000)855 ± 477 (634)605 ± 306 (518)755 ± 571 (1406)250-750
      MCV (μm3)29.7 ± 1.8 (26)29.7 ± 1.5 (29)31.9 ± 1.0 (31)31.4 ± 2.3 (31)28-40
      MCH (pg)10.3 ± 0.6 (9.6)9.4 ± 0.3 (9.4)10.7 ± 0.3 (10.7)11.4 ± 0.3 (10.2)8-12
      MCHC (%)34.9 ± 1.2 (37.4)31.8 ± 1.3 (32.7)33.7 ± 0.9 (34.4)35.8 ± 4.6 (35.2)31-34
      Neutrophils (×103/mm3)3 ± 1.3 (1.7)3.8 ± 1.7 (3.2)3.7 ± 2.4 (4.3)2.2 ± 0.5 (1.9)0.7-6.0
      Lymphocytes (×103/mm3)3.7 ± 1.5 (4.6)4.5 ± 2.1 (6.2)9.2 ± 2.4 (8.2)2.4 ± 0.5 (3.2)2-9
      PT (s)22.1 ± 6.2 (26.6)16.5 ± 7.3 (15.2)16.9 ± 2.2 (16.2)17.1 ± 3.4 (20.0)N/A
      INR2.2 ± 3.5 (2.3)N/AN/AN/AN/A
      PTT (s)61.2 ± 22.7 (29.7)43.7 ± 8.2 (44.5)49.4 ± 12.8 (33.9)31.1 ± 7.7 (38.2)N/A
      BUN (mg/dL)21 ± 15.3 (16)16 ± 5.4 (12)11.2 ± 2.7 (13)14.3 ± 1.9 (16)10.3-26
      Glucose (mg/dL)91.9 ± 15.1 (88)96.5 ± 32.1 (74)77.9 ± 7.1 (86.5)75.2 ± 4.3 (77.3)44-81.2
      Creatinine (mg/dL)1.4 ± 1.5 (0.8)0.9 ± 0.3 (0.7)0.6 ± 0.1 (0.5)1.3 ± 1.1 (0.6)0.9-2.0
      Ca (mg/dL)10 ± 0.9 (10.5)8.8 ± 1.1 (10.8)10.1 ± 0.9 (10.9)9.9 ± 0.3 (10.2)9.3-11.7
      Mg (mEQ/L)1.1 ± 0.2 (1.6)1.4 ± 0.3 (1.5)1.6 ± 0.2 (1.8)1.6 ± 0.0 (1.6)2.0-2.7
      Cl (mmol/L)111 ± 4.7 (105)109 ± 5.5 (107)109 ± 3.3 (110)109 ± 2.7 (108)100.8-113.0
      K (mmol/L)6.1 ± 1.6 (4.4)4.3 ± 0.7 (5.2)5.2 ± 0.6 (4.7)5.5 ± 0.8 (4.3)4.3-6.3
      Na (mmol/L)143 ± 4 (144)144 ± 3.3 (144)145 ± 3.5 (150)144 ± 0.5 (148)141.6-159.6
      SGPT(ALT) (IU/L)11 ± 9 (13)12.3 ± 10.5 (9)10.4 ± 8.6 (10.5)21.0 ± 17.6 (27.8)14.8-43.8
      SGOT(AST) (IU/L)76 ± 46 (71)212 ± 127 (82)99 ± 67 (78)71 ± 30 (70)49.0-123.0
      Albumin (g/dL)2.7 ± 0.6 (3)2.2 ± 0.3 (3.2)2.8 ± 0.5 (3.4)2.9 ± 0.1 (2.9)2.4-3.0
      Total bilirubin (mg/dL)0.1 ± 0 (0.2)0.1 ± 0.1 (0.1)0.6 ± 1.6 (0.1)0.3 ± 0.2 (0.2)0.1-0.5
      GGT (IU/L)44 ± 13 (57)36.4 ± 6.0 (54)36 ± 3.6 (52)67 ± 25 (73)10-118
      LDH (IU/L)437 ± 146 (325)713 ± 355 (383)427 ± 115 (439)377 ± 8 (365)238-560
      Phosphorus (mg/dL)8.1 ± 1 (7.5)5.1 ± 2.0 (6.2)7.8 ± 1.3 (6.4)7.2 ± 1.1 (6.4)4.0-7.3
      Cholesterol (mg/dL)71.1 ± 26 (40)47.8 ± 26.2 (56)48.9 ± 13.8 (33.5)71.7 ± 19.3 (43)44.1-90.1
      ALP (IU/L)82.7 ± 23.6 (139)100.8 ± 26.2 (144)92.8 ± 17.7 (195.5)112.3 ± 47.1 (230)26.9-156.1
      CPK (IU/L)500 ± 1181 (111)642 ± 805 (145)613 ± 1678 (128)270.8 ± 147.4 (300)47-4212
      Total protein (g/dL)5.2 ± 0.4 (5.7)4.0 ± 0.5 (5.5)5.1 ± 0.7 (5.7)5.3 ± 0.2 (5.6)5.9-7.8
      Data presented as mean ± standard deviation (preoperative mean). PF3, Third-generation PediaFlow; PF4, fourth-generation PediaFlow; WBC, white blood cell; RBC, red blood cell; Hgb, hemoglobin; HCT, hematocrit; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; PT, prothrombin time; N/A, not available; INR, international normalized ratio; PTT, partial prothrombin time; BUN, blood urea nitrogen; Ca, calcium; Mg, magnesium; Cl, chlorine; K, potassium; Na, sodium; SGPT, serum glutamic pyruvic transaminase; ALT, alanine transaminase; SGOT, serum glutamic oxaloacetic transaminase; AST, aspartate transaminase; GGT, gamma-glutamyltransferase; LDH, lactate dehydrogenase; ALP, Alkaline phosphatase; CPK, creatine phosphokinase.
      Figure thumbnail fx3
      Figure E1Flow rate estimation accuracy using the PediaFlow rotor position signal, motor current, and motor speed. Because of the fully magnetically levitated suspension, the rotor position signal used for the virtual zero power levitation control is analogous to the pressure drop across the pump and therefore provides an additional parameter (in addition to pump speed and motor current) to enhance flow rate estimation. The estimated flow rate for the 60-day PF4-S10 implant was within 6% of the actual flow rate as measured by the perivascular ultrasonic flow probe on the pump outflow tract. This feature will greatly simplify the instrumentation required for physiologic (hemodynamic) control of the PediaFlow system when used clinically. RP, Rotor position; MC, motor current; POD, postoperative day; MS, motor speed.

      Appendix E2

      Third-Generation PediaFlow Surgical Methods

      The PF3 was implanted in a healthy lamb for 72 days in accordance with the Institutional Animal Care and Use Committee guidelines at the University of Pittsburgh.
      • Antaki J.F.
      • Ricci M.R.
      • Verkaik J.E.
      • Snyder S.T.
      • Maul T.M.
      • Kim J.
      • et al.
      PediaFlow Maglev ventricular assist device: a prescriptive design approach.
      The pump was introduced into the circulation as an LV assist device, interposed between the LV and descending thoracic aorta. Surgical access was gained through a left thoracotomy, followed by heparinization for a target activated clotting time greater than 300 seconds. A modified wire-reinforced polyurethane cannula (18F DLP, Medtronic, Minneapolis, Minn) was inserted into the apex of the LV through a stab incision and secured with a sewing ring fashioned from thick surgical felt (PTFE, C.R. Bard, Murray Hill, NJ). The outflow from the PF3 was 6-mm diameter polyester vascular graft (Vascutek Ltd, Renfrewshire, Scotland, UK) anastomosed to the descending thoracic aorta using a partial occlusion clamp. The pump was operated at a fixed speed of 14.5 kilo RPM. The flow rate was measured via an ultrasonic transit-time flow probe (Transonic Inc, Ithaca, NY) attached to the outflow graft. Throughout the study, pump flow, power consumption, and carotid blood pressure were recorded. Hemorheology and serum chemistry values were collected daily to assess the biological impact of the pump on blood damage and organ function.

      Surgical Sham (Control) Studies

      Three “sham” implants were performed for an intended 28-day duration for the purpose of obtaining “control” biocompatibility data for the PediaFlow implantations.
      • Johnson C.A.
      • Wearden P.D.
      • Kocyildirim E.
      • Maul T.M.
      • Woolley J.R.
      • Ye S.H.
      • et al.
      Platelet activation in ovines undergoing sham surgery or implant of the second generation PediaFlow pediatric ventricular assist device.
      These sham surgical implants mimic a full PediaFlow implant study with the exception of device insertion and allow us to account for surgery and postoperative recovery on rheology, platelet activation, and other biocompatibility indices of interest. Because preoperative jugular venipuncture samples are prone to artifact from needle sticking an awake animal,
      • Johnson C.A.
      • Wearden P.D.
      • Kocyildirim E.
      • Maul T.M.
      • Woolley J.R.
      • Ye S.H.
      • et al.
      Platelet activation in ovines undergoing sham surgery or implant of the second generation PediaFlow pediatric ventricular assist device.
      a jugular venous catheter was placed under general anesthesia 1 week before sham surgery for collection of baseline biocompatibility parameters (ie, platelet activation, plasma free hemoglobin, and fibrinogen).
      For the sham surgical procedure, after intubation and induction of anesthesia, the existing venous catheter in the left jugular vein was replaced and an arterial catheter was inserted in the left carotid artery. The thorax was entered via a left, fourth interspace thoracotomy, and the LV apex and descending aorta were exposed. The animal was anticoagulated with heparin to maintain the whole blood activated clotting time at 1.5 to 2.0 times baseline. A lubricated sewing ring was fixed on the LV apex and a stab incision was made in the LV apex, which was then sutured closed. A 3-cm length of 6-mm diameter Gelweave (Vascutek Ltd, Renfrewshire, Scotland, UK) graft was connected in an end-to-side fashion to the descending thoracic aorta to duplicate the pump outflow graft and anastomosis site. The graft was then “tied off” to prevent graft material being in contact with the blood.
      Surgery proceeded without any major complications, the animals recovered from anesthesia and were returned to the intensive care unit, where they were monitored for the duration of the study. Recovery and follow-up were uneventful with hemodynamic and respiratory parameters remaining within normal limits. During follow-up periods, the animals were cared for exactly as the 72-day animal implanted with the PF3. After meeting the intended 28-day study period, the 3 sham experiments were electively ended for gross necropsy examination (Table E4).
      Table E4Summary of the surgical sham (control) in vivo ovine studies
      Study animalWeight (kg)Length (d) actual/intendedNecropsy findings
      Sham-S014539/281. Two minor (<2 mm diameter), surface infarcts on left kidney

      2. Two minor (<2 mm diameter), surface infarcts on right kidney
      Sham-S025532/281. Single minor (<2 mm diameter), surface infarct on right kidney
      Sham-S033028/281. Unremarkable

      Appendix E3

      Fourth-Generation PediaFlow In Vivo Developmental Summary

      A total of 11 (n = 11) in vivo ovine studies were performed with the PF4 pumps to develop, assess, and refine the implantable peripherals in addition to evaluating device hemodynamics and biocompatibility (Table E2). The initial 9 implants led to the parabolic-inflow cannula and outflow graft assembly design used together in the most recent implants (PF4-S10, PF4-S11) that are presented in the article.

      Pump Connectors

      Introduced with the PF4 prototypes was a compact, tool-less, “quick-connect” coupling used with both the inflow cannula and the outflow graft assembly. Consisting of a nitinol-wire retaining clasp on the pump mating face and a flanged inlet/outlet adapter, attachment or removal of the cannula/graft is achieved by depressing the loop to concentrically deform the 2 guidewires that hold the radial flange in place (Figure E2, A). After initial wet-to-wet connections during surgical implantation were less than successful (Figure E2, B), a reduced flange diameter adapter was used for the PF4-S04 and subsequent implants that eliminated difficulties with nonseated pump connections (Figure E2, C).

      Outflow Tract Assembly

      As described in Table E5, 3 outflow assembly iterations were implanted in conjunction with the PF4 in vivo studies. Although previous-generation PediaFlow studies used polyester-based outflow grafts (including the 72-day PF3-S01 implant), concerns about commercial availability and patency led to the selection of an ePTFE-based graft for the initial PF4 implants. Despite evaluating 2 different ePTFE styles, continuing issues with excessive fluid and plasma protein loss (ie, “graft weep”) led to the decision to return to the Gelweave grafts previously used successfully.

      Inflow Cannula

      Continuing the transition from modified, off-the-shelf, commercial hardware to PediaFlow-specific implantable components, a bevel-type inflow cannula was developed, modeled after the EXCOR LV drainage cannula (Table E6). Limited by premature ventricular suction or myocardial occlusion of the inlet tip, perioperative efforts to gain adequate drainage led to kinking of the inflow cannula evident at study termination (Figure E3).
      After extensive redesign and ex vivo testing,
      • Griffin M.T.
      • Grzywinski M.F.
      • Voorhees H.J.
      • Kameneva M.V.
      • Olia S.E.
      Ex vivo assessment of a parabolic-tip inflow cannula for pediatric continuous-flow VADs.
      the new suction-resistant parabolic-type inflow cannula, depicted in Figure 2, B, in the main article, was used in studies PF4-S10 and PF4-S11 with great success.

      Hemocompatibility Findings

      Despite the repeated challenges with the implantable peripherals in vivo, hemocompatibility as measured by plasma-free hemoglobin remained below 20 mg/dL for 7 of the 9 preliminary implants (Figure E4).
      Figure thumbnail fx4
      Figure E2The PF4 quick-connect attachment mechanism: The initial full-flange design was difficult to attach (A) and prone to misalignment in vivo (B). C, The revised design with a smaller flange size to ease insertion past the guidewires.
      Table E5Outflow graft iterations used for the 11 fourth-generation PediaFlow implants
      PrototypeOutflow graftModifications/external strain relief
      ID (mm)Material
      Bard ePTFE5.0Thin-wall ePTFE-
      SEAL-PTFE6.0Dual-layer, extraluminally gelatin-sealed ePTFEReduced pump connector flange diameter

      8-mm MAXIFLO ePTFE Wrap
      Gelweave6.0Gelatin-impregnated polyester8-mm MAXIFLO ePTFE Wrap
      Bard ePTFE (5-mm Flex Thinwall Small Beading) is a product of Bard Peripheral Vascular (Tempe, Ariz). SEAL-PTFE (standard-wall, external spiral support), MAXIFLO (standard-wall, external solid-PTFE spiral support), and Gelweave are products of Vascutek Ltd (Renfrewshire, Scotland, UK). ePTFE, Expanded polytetrafluoroethylene.
      Table E6Inflow cannula prototypes used for the PF4 in vivo implants
      Prototype (inlet geometry)IterationDesign features
      Fenestrated-Modified 22F commercial venous drainage

      Custom glue-fixed apical sewing ring

      Single-stage multiport/caged-tip

      Right-angle wire-reinforced body
      Bevel1.0Nitinol, round-wire reinforced polyurethane

      Blunt-tip inlet opening

      Preattached, fixed-depth, rotating sewing ring
      Bevel1.1Reduced pump connection flange diameter
      Bevel2.0316 SS, flat-wire reinforcement

      Increased bend angle

      Graded strain relief at pump connector
      Parabolic316 SS reinforced U-shaped inlet opening

      Removable, variable depth, tool-less sewing ring
      Figure thumbnail fx5
      Figure E3Example images of the inflow kinking phenomenon experienced with the bevel-type inflow cannulae from PF4-S06 (left) and PF4-S09 (right).
      Figure thumbnail fx6
      Figure E4Plasma-free hemoglobin values for the initial in vivo PF4 implants. plfHb, Plasma-free hemoglobin; POD, postoperative day; PF4, fourth-generation PediaFlow.

      Supplementary Data

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      Linked Article

      • Overcoming bumps to build little pumps
        The Journal of Thoracic and Cardiovascular SurgeryVol. 156Issue 4
        • Preview
          Although heart transplantation is the gold standard treatment for end-stage heart failure, children have the highest waitlist mortality rate compared with adults and other solid organ transplantations.1 The mortality is especially high for neonates and infants who weigh less than 5 kg. Larger children and adults can be successfully bridged to heart transplantation with a suite of mechanical circulatory support (MCS) options, with continuous-flow devices incorporating magnetically-levitated rotors as being the current state of the art.
        • Full-Text
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        Open Archive
      • Alternatives to PumpKIN: The ongoing development of ventricular assist devices for infants
        The Journal of Thoracic and Cardiovascular SurgeryVol. 156Issue 4
        • Preview
          The availability and use of mechanical circulatory support devices in children has been expanding rapidly. There is still no option, however, for safe, durable, and dischargeable support in infants and small children weighing less than 15 to 20 kg. The development of extracorporeal centrifugal and paracorporeal pulsatile devices intended for use in children has resulted in a dramatic improvement in outcomes in these complex cases.1 Challenges remain, however, and outcomes are far from ideal.
        • Full-Text
        • PDF
        Open Archive