Ergin Kocyildirim

Extending the Boundaries of the Primary Arterial Switch Operation in Patients With Transposition of the Great Arteries and Intact Ventricular Septum

Background—We have previously suggested that the primary arterial switch operation is a feasible strategy for patients with transposition of the great arteries and intact ventricular septum (TGA-IVS) up to age 2 months. This study reports our current results with this approach and examines whether this policy could be extended beyond age 2 months. Methods and Results—380 patients who underwent arterial switch for TGA-IVS were reviewed. 275 patients were younger than 3 weeks at the time of surgery (early switch group); 105 patients were 3 weeks or older (range, 21 to 185 days) (late switch group). There was no difference in outcome in terms of in-hospital mortality (5.5% versus 3.8%) or need for mechanical circulatory support (3.6% versus 5.7%) between early and late switch groups. However, duration of postoperative ventilation (4.9 versus 7.1 days, P=0.012) and length of postoperative stay (12.5 versus 18.9 days, P<0.001) were significantly prolonged in the late switch group. Primary left ventricular failure resulting in death occurred in 2 patients in the late switch group, with no deaths in 9 patients aged 2 to 6 months. Conclusions—This experience confirms that in TGA-IVS, the left ventricle maintains the potential for systemic work well beyond the first month of life. Consequently, neonates at high risk or late referrals can benefit from delayed arterial switch, even beyond age 2 months. However, the need for mechanical support in some of the older patients may limit the widespread adoption of such a strategy.

Platelet activation in ovines undergoing sham surgery or implant of the second generation PediaFlow pediatric ventricular assist device.

The PediaFlow pediatric ventricular assist device (VAD) is a magnetically levitated turbodynamic pump under development for circulatory support of small children with a targeted flow rate range of 0.3-1.5 L/min. As the design of this device is refined, ensuring high levels of blood biocompatibility is essential. In this study, we characterized platelet activation during the implantation and operation of a second generation prototype of the PediaFlow VAD (PF2) and also performed a series of surgical sham studies to examine purely surgical effects on platelet activation. In addition, a newly available monoclonal antibody was characterized and shown to be capable of quantifying ovine platelet activation. The PF2 was implanted in three chronic ovine experiments of 17, 30, and 70 days, while surgical sham procedures were performed in five ovines with 30-day monitoring. Blood biocompatibility in terms of circulating activated platelets was measured by flow cytometric assays with and without exogenous agonist stimulation. Platelet activation following sham surgery returned to baseline in approximately 2 weeks. Platelets in PF2-implanted ovines returned to baseline activation levels in all three animals and showed an ability to respond to agonist stimulation. Late-term platelet activation was observed in one animal corresponding with unexpected pump stoppages related to a manufacturing defect in the percutaneous cable. The results demonstrated encouraging platelet biocompatibility for the PF2 in that basal platelet activation was achieved early in the pump implant period. Furthermore, this first characterization of the effect of a major cardiothoracic procedure on temporal ovine platelet activation provides comparative data for future cardiovascular device evaluation in the ovine model.

Platelet activation after implantation of the Levitronix PediVAS in the ovine model.

The Levitronix PediVAS is an extracorporeal magnetically levitated pediatric ventricular assist system with an optimal flow rate range of 0.3–1.5 L/min. The system is being tested in preclinical studies to assess hemodynamic performance and biocompatibility. The PediVAS was implanted in nine ovines for 30 days using either commercially available cannulae (n = 3) or customized Levitronix cannulae (n = 6). Blood biocompatibility in terms of circulating activated platelets was measured by flow cytometric assays to detect P-selectin. Platelet activation was further examined after exogenous agonist stimulation. Platelet activation increased after surgery and eventually returned to baseline in animal studies where minimal kidney infarcts were observed. Platelet activation remained elevated for the duration of the study in animals where a moderate number of kidney infarcts with or without thrombotic deposition in the cannulae were observed. When platelet activation did return to baseline, platelets appropriately responded to agonist stimulation, signifying conserved platelet function after PediVAS implant. Platelet activation returned to baseline in the majority of studies, representing a promising biocompatibility result for the Levitronix PediVAS.

Pre-Clinical Evaluation of an Adult Extracorporeal Carbon Dioxide Removal System with Active Mixing for Pediatric Respiratory Support:

The objective of this work was to conduct pre-clinical feasibility studies to determine if a highly efficient, active-mixing, adult extracorporeal carbon dioxide removal (ECCO2R) system can safely be translated to the pediatric population. The Hemolung Respiratory Assist System (RAS) was tested in vitro and in vivo to evaluate its performance for pediatric veno-venous applications. The Hemolung RAS operates at blood flows of 350-550 ml/min and utilizes an integrated pump-gas exchange cartridge with a membrane surface area of 0.59 m2 as the only component of the extracorporeal circuit. Both acute and seven-day chronic in vivo tests were conducted in healthy juvenile sheep using a veno-venous cannulation strategy adapted to the in vivo model. The Hemolung RAS was found to have gas exchange and pumping capabilities relevant to patients weighing 3-25 kg. Seven-day animal studies in juvenile sheep demonstrated that veno-venous extracorporeal support could be used safely and effectively with no significant adverse reactions related to device operation.

Preclinical Performance of a Pediatric Mechanical Circulatory Support Device: The PediaFlow® Ventricular Assist Device

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.

The Use of GMP-Produced Bone Marrow-Derived Stem Cells in Combination with Extracorporeal Membrane Oxygenation in ARDS: An Animal Model.

Acute respiratory distress syndrome (ARDS) is the result of a wide variety of disorders, which can be associated with different clinical disorders or systemic diseases directly affecting the lungs. Currently, the only existing therapy is limited to supportive care. In a 6 hour pilot study, we analyzed the use of the combination of both stem cell and extracorporeal membrane oxygenation (ECMO) strategies to prevent or treat severe lung injury. A total of 11 sheep were used. Five sheep received Escherichia coli endotoxin as a control group (group 1). Three sheep that received E. coli endotoxin were treated with veno-venous ECMO support in group 2. In group 3, 3 sheep received a dose of clinical grade good manufacturing practice (GMP)-produced MultiPotent Adult Progenitor cells (MAPC) intratracheally after the end of the infusion of E. coli endotoxin, followed by ECMO support. The respiratory parameters by means of blood gas results, measurements of lung injury, inflammatory responses, and integrity of the alveolar capillary barrier after the infusion of these cells were analyzed. Our data suggest that the combination of ECMO and stem cell therapy showed better histopathologic changes with less inflammation. We believe that the combination of stem cells with the ECMO treatment may be useful in future studies investigating the diagnosis, treatment, and prevention of ARDS.

Biocompatibility Assessment of the CentriMag-Novalung Adult ECMO Circuit in a Model of Acute Pulmonary Hypertension.

Extracorporeal membrane oxygenation (ECMO) is rarely used in patients with severe pulmonary hypertension (PH) as a bridge to lung transplantation. In this study, we assess the blood biocompatibility of the integrated CentriMag–Novalung ECMO system (venoarterial) in an acute model of PH. Severe PH (≥2/3 systemic) was induced in eight sheep through progressive ligation of the main pulmonary artery. System performance, platelet activation, thromboelastography (TEG) parameters, fibrinogen, plasma-free hemoglobin, and total plasma protein were measured at initiation, 3, and 6 hr of support in the ECMO (N = 4) and sham (N = 4) groups. A stable ECMO flow (2.2 ± 0.1 L/min), low transmembrane pressure gradient, and steady blood O2 and CO2 levels were maintained. Platelet activation was low (<4%) in both the groups, whereas platelet responsiveness to agonist (platelet activating factor) was reduced in the sham group when compared with the ECMO group. There were no differences in the TEG parameters, fibrinogen concentration, plasma-free hemoglobin (<10 mg/dl), and plasma total protein between the two groups. The findings of low levels of platelet activation and plfHb suggest adequate blood biocompatibility of the integrated CentriMag–Novalung circuit use for short-term support in a model of PH.

Effect of Caval Waveform on Energy Dissipation of Failing Fontan Patients

Last stage of the palliative surgical reconstruction (i.e. Fontan procedure) for the infants with functional single-ventricle is total cavopulmonary connection (TCPC), where the superior vena cavae (SVC) and inferior vena cavae (IVC) are routed directly into the pulmonary arteries. Limited pumping energy available due to the absence of right-ventricle and altered venous characteristics require optimized hemodynamics inside the TCPC pathway, which can be achieved by minimizing the power losses.Copyright

Intra-operative imaging in paediatric cardiac surgery: the reactions of parents who requested and watched a video of the surgery performed on their child

OBJECTIVE Our previous work demonstrated that digital video recording of operations is the best way to describe the morphological features and complex dynamic physiology of surgical treatment of congenitally malformed hearts. Parental consent is required for video recording, and some parents have requested, and obtained, a copy of the video of the operation performed on their child. Our present aim was to explore their feelings and opinions having viewed the recording of the surgical procedures. DESIGN AND PARTICIPANTS This exploratory study examined the views of 17 parents, comprising 7 couples, 2 mothers, and 1 father, after requesting, and then watching, the recording of the operation performed on their child. The audio-taped, semistructured interviews were analyzed for the thematic content. RESULTS All parents watched the videos at least once, and no parent exhibited distress as a result. Curiosity and desire for learning, and wanting to know what exactly happened to the child during the operation, were the most common reasons for requesting the video. Parents reported that the videos were also useful in sharing the experience with family and friends. The videos had no effect on the attitudes of the parents towards the surgical team. Parents made recommendations to increase the length of the edited videos and add labels and voice-overs. CONCLUSION Parents of children with congenitally malformed hearts want to watch the recording of the operation performed because of their need for information, and to understand the experience of their children when separated from them. Research is needed to assess the potential value of operative videos in facilitating parental knowledge and coping when children undergo major cardiac surgery.

Investigation of Pulsatile Hemodynamics in Patient-Specific Fontan Templates With Fenestration

The third stage for palliative surgical reconstruction for children with functional single-ventricle (SV) physiology is the completion of the total cavopulmonary connection (TCPC), where the superior vena cava (SVC) and inferior vena cava (IVC) are routed directly into the pulmonary arteries. Approximately 5000 newborns in the US each year join to the existing SV (or Fontan) patient population, along with increasing numbers of adult Fontan patients surviving longer due to the advances in surgical techniques and post-op management. Although most post-operative Fontan patients experience an acceptable quality of life, their lifespan is shorter than normal with a significant number of these patients developing late hemodynamic complications (failing Fontan) and requiring heart transplantation. Donor shortage and the high-risk nature of transplantation for these complex and often very ill patients demand alternative therapeutic options [1].Copyright