Short-term in vivo performance of the Cleveland clinic PediPump left ventricular assist device.

The PediPump was implanted in six healthy lambs (mean 25.6 ± 1.4 kg) between the left ventricular apex and the descending aorta to evaluate in vivo performance for up to 30 days. Anticoagulation was achieved by continuous heparin infusion. Three animals were euthanized prematurely, two because of respiratory dysfunction and one because of deteriorating pump performance resulting from thrombus formation inside the pump. Three lambs were electively sacrificed 30 days after implantation; all had stable hemodynamics and minimal hemolysis, as indicated by low plasma free hemoglobin (2.5 ± 3.1 mg/dL). Mean 30-day pump flow was 1.8 ± 0.1 L/min at a pump speed of 12 200 ± 400 rpm. Neither activated clotting time nor activated partial thromboplastin time followed the changes in heparin dose. At necropsy, depositions were observed at the front (n = 1) and rear rotor axial positioning stops (n = 4); improved polishing techniques on the stationary stop surfaces and the addition of a hard-carbon, thin-film coating on the rotating stop of the pumps used for the last two experiments addressed the deposition seen earlier. In conclusion, the PediPump showed excellent hydraulic performance and minimal hemolysis during support for up to 30 days. Depositions observed at the axial positioning stops in earlier experiments were addressed by design and material refinements. We continue to focus on developing effective anticoagulation management in the lamb model as well as on further evaluating and demonstrating pump biocompatibility.

Circulating blood volumes: a review of measurement techniques and a meta-analysis in children.

The accurate determination of circulating blood volume (CBV) in children has many clinical applications. The purposes of this article were to review currently available CBV measurement techniques and perform a meta-analysis using values from many small-scale studies that calculated CBV values for normal healthy children. A literature review demonstrated numerous methods by which to determine CBV. However, these methods necessitate repetitive blood sampling, require the introduction of foreign substances into the bloodstream, or address the uncertainty of substance distribution and clearance. Many small-scale studies have calculated CBV values for normal healthy children, and we performed a meta-analysis using these values. Age groups were defined, and within each group, means +/- 1 and 2 standard deviations were compared. A pooled estimate of mean blood volume and a 95% confidence interval was calculated after Q-statistics calculations indicated that the groups were homogeneous. Mean values showed agreement with typically accepted normal values. A large-scale study should be repeated when a gold standard for CBV measurements is developed.

Pathways to approval of pediatric cardiac devices in the United States: challenges and solutions.

Patients treated by pediatric interventional cardiologists and cardiac surgeons often have unmet medical device needs that pose a challenge to the current regulatory evaluation and approval process in the United States. In this report we review current US Food and Drug Administration regulatory processes, review some unique aspects of pediatric cardiology and cardiac surgery that pose challenges to these processes, and discuss possible alternate pathways to cardiac device evaluation and approval for children. Children deserve to benefit from new and refined cardiac devices and technology designed explicitly for their conditions.

The PediPump: a versatile, implantable pediatric ventricular assist device--update IV.

Cleveland Clinic's PediPump (Cleveland, OH, USA) is a ventricular assist device designed for the support of pediatric patients. The PediPump is a mixed-flow ventricular assist device with a magnetically suspended impeller measuring 10.5 mm in diameter by 64.5 mm in length. Progress and achievements for the PediPump program are considered according to the development project's three primary objectives: Basic engineering: along with size reductions, substantial design improvements have been incorporated in each design iteration including the motor, magnetic bearings, axial touch points, and heat transfer path; Anatomic modeling and device fitting studies: Techniques based on computed tomography and magnetic resonance imaging have been developed to create three-dimensional anatomic-modeling and device-fitting tools to facilitate device implantation and to assist in preoperative planning. For in vivo testing, to date, six acute (6-h duration) and nine chronic (30-day target duration) implantations have been performed in sheep; the implantation of the PediPump appears to be relatively easy with excellent hemodynamic performance and minimal hemolysis during support. Cleveland Clinic's PediPump program supported by the National Heart, Lung and Blood Institute's Pediatric Circulatory Support Program has led to the development of a pediatric ventricular assist device that has satisfactory performance in preclinical evaluation and appears to be ready to support a program of clinical testing.

Success and limitations of right ventricular sinus myectomy for pulmonary atresia with intact ventricular septum.

OBJECTIVES: Right ventricular sinus myectomy has been proposed for pulmonary atresia with intact ventricular septum for morphology falling within the uncertain area for eventual biventricular repair. Our objective was to evaluate right ventricular sinus myectomy by characterizing the morphologic spectrum of these patients, determining whether biventricular repair was achieved, ascertaining growth of right-sided structures, and assessing survival. METHODS: We evaluated medical records, all imaging studies, and follow-up data (complete in all but 1 patient) from 43 patients with pulmonary atresia with intact ventricular septum treated from October 1993 to July 2005, 16 of whom underwent right ventricular sinus myectomy. Serial echocardiographic measurements of right-sided cardiac structures were converted to Z values to estimate their growth relative to somatic growth. RESULTS: Patients undergoing right ventricular sinus myectomy had mild-to-moderate right ventricular size diminution (grade -1.2 +/- 3.2) and a tricuspid valve Z value of -4.9 +/- 1.9. Thirteen (87%) of the 16 patients achieved biventricular repair. After right ventricular sinus myectomy, mean right ventricular cavity size grade increased to 1.4 +/- 0.66, but the tricuspid valve Z value did not change appreciably over time. Five-year survival after sinus myectomy was 85%; late deaths were in patients with the smallest tricuspid valves at presentation (Z value < -7). CONCLUSIONS: Right ventricular sinus myectomy in the uncertain area for biventricular repair of pulmonary atresia with intact ventricular septum leads to immediate increase in right ventricular volume. It, in combination with establishing right ventricle-pulmonary trunk continuity, allowed early biventricular repair in 87% of patients. However, tricuspid valve growth in relation to somatic growth was minimal. Thus, small tricuspid valve size might limit the long-term success of biventricular repair achieved by means of right ventricular sinus myectomy.

Gene array analysis of a rat model of pulmonary arteriovenous malformations after superior cavopulmonary anastomosis.

OBJECTIVE: Pulmonary arteriovenous malformations commonly develop in children who have undergone a cavopulmonary anastomosis as part of the palliative sequence for single-ventricle physiology. METHODS: We developed a rat model of cavopulmonary anastomosis that results in pulmonary arteriovenous malformations that are angiographically and histologically similar to the human condition. We used this model to analyze the gene expression profile associated with pulmonary arteriovenous malformations developing after cavopulmonary anastomosis. RESULTS: Six Sprague-Dawley rats underwent right superior cavopulmonary anastomosis, allowing the left lung to serve as a control. Total RNA was isolated from each lung at death 8 months postoperatively and compared by using the Affymetrix Rat Microarray RAE230 2.0 GeneChip (Affymetrix, Santa Clara, Calif). One hundred thirty-seven genes demonstrated altered expression in the lungs after cavopulmonary anastomosis compared with that seen in the control lungs: 55 (40%) genes demonstrated increased expression, and 82 (60%) genes demonstrated decreased expression. Modulation of genes associated with angiogenesis and vascular remodeling was found, including angiopoietin-2, placental growth factor, several matrix metalloproteases, and several collagen subtypes. Genes with vasoactive properties, including endothelin 1 and endothelin receptor type B, demonstrated altered gene expression. Several members of the transforming growth factor beta superfamily signaling pathway also demonstrated altered expression. CONCLUSIONS: These changes in gene expression might have causative implications for pulmonary arteriovenous malformations that develop after cavopulmonary anastomosis.

Melbourne shunt promotes growth of diminutive central pulmonary arteries in patients with pulmonary atresia, ventricular septal defect, and systemic-to-pulmonary collateral arteries.

BACKGROUND: We manage patients with pulmonary atresia, ventricular septal defect, major systemic-to-pulmonary collateral arteries, and diminutive central pulmonary arteries with a staged approach. The first procedure is a central end-to-side aortopulmonary shunt (Melbourne shunt) intended to cause growth and development of the central pulmonary arteries. We subsequently measured central pulmonary artery growth after Melbourne shunt. METHODS: Forty consecutive patients were followed after Melbourne shunt. The maximum pulmonary artery diameter was measured at the time of surgery and at subsequent catheterizations or surgery. RESULTS: Median pulmonary artery size at surgery was 2 mm. The median pulmonary artery diameter was 5.5 mm at first assessment (median, 6.35 months) and 7 mm at most recent assessment (19.7 months). Mean modified Nakata index increased from 27 mm(2)/m(2) at surgery to 138 mm(2)/m(2) at first assessment, and 176 mm(2)/m(2) at final assessment. There was one acute shunt failure from anastomotic stenosis. Thirteen patients (32.5%) required 21 percutaneous interventions. There were 4 deaths during a median follow-up of 68 months. At the time of complete repair (n = 25) all patients required pulmonary artery augmentation, and 8 are in various stages of palliation. The remaining patients are considered not reparable owing to irreversible pulmonary hypertension (n = 4) or have required fenestration of ventricular septal defect after complete repair (n = 2). CONCLUSIONS: Melbourne shunt promotes modest growth of central pulmonary arteries leading to complete repair in the majority of patients. There is considerable need for further interventions in these patients to augment the size of the pulmonary arteries.

The Cleveland Clinic PediPump: virtual fitting studies in children using three-dimensional reconstructions of cardiac computed tomography scans.

The fitting of implantable ventricular assist devices (VADs) is a particular challenge for pediatric patients and patients with small body surface area. The purpose of this study was to determine optimal placement of the PediPump, a pediatric VAD currently under development at the Cleveland Clinic, using virtual three-dimensional (3D) on-screen models. Digital models were created from computed tomographic datasets of pediatric hearts using commercially available 3D image processing software. Pixels representing the myocardium, great vessels, sternum, and rib cage were selected and rendered as on-screen models (n = 13) from pediatric patients with or without congenital heart disease (median age 42 months; range 2 days to 13 years 11 months). Using 3D model manipulation software, virtual models of the PediPump (70 x 10 mm) were combined on-screen with the anatomic models. A variety of virtual fitting options were created, which allowed easy detection of device interference with surrounding tissues. Generation of 3D on-screen models of cardiac structures in relation to PediPump placement has provided useful preliminary fitting information, which is being used to guide further development of this device.

The Cleveland Clinic PediPump: anatomic modeling and virtual fitting studies in a lamb model.

Implantation of ventricular assist devices (VADs) is challenging in small patients with limited space in the chest. We created three-dimensional models of lambs to facilitate fitting of the PediPump, a pediatric VAD currently under development. Serial computed tomography (CT) scans were acquired at multiple time points (n = 8) for three lambs. Digital models were created using these CT datasets and three-dimensional image processing software (Mimics, Materialise). Pixels representing the heart and chest wall were rendered as three-dimensional models. Using three-dimensional model manipulation software (Magics RP, Materialise), on-screen models of extravascular and intravascular VADs were placed in right, left and biventricular support configurations to determine optimal placement. A cannulation strategy was established and in some cases three-dimensional models of the inflow and outflow grafts were created. After the final CT study, an open-chest fitting study was performed using rapid prototype models of the pediatric VAD and cannulas. The pump location and orientation predictions from the virtual fitting studies matched those determined at the time of the open-chest fitting studies. Using three-dimensional modeling, we have established a fitting protocol that facilitates animal implantations; the same modeling techniques may be useful for device fitting in humans.

The PediPump: a versatile, implantable pediatric ventricular assist device-update III.

The PediPump is a passive magnetic bearing, mixed flow, rotary ventricular assist device designed to provide support for the entire range of patient sizes encountered in pediatrics. Blood enters axially at the inlet and is accelerated and turned in the impeller to exit the pump at an intermediate angle. The size of the PediPump facilitates standard cannulation strategies with substantially downsized components. The program pursues three specific objectives: 1) System engineering: Progress within the last year has focused on the assembly and testing of PediPump prototypes. Initial in vitro hydraulic performance and hemolysis testing were judged satisfactory. 2) Anatomic fitting studies: As part of the PediPump program, three-dimensional modeling techniques based on routine, clinically obtained computerized tomography (CT) scans have been developed. During 2006, the same techniques developed for clinical scans were applied to CT scans obtained from sheep to guide the presurgical planning. 3) Animal studies: Animal implantation of PediPump prototypes commenced in July 2006. A total of four 6 hour acute studies were performed throughout the remainder of the year. In vivo performance was satisfactory and compared well with the in vitro results. Hemolysis levels were low.

Initial acute in vivo performance of the Cleveland Clinic PediPump left ventricular assist device.

The PediPump is a small ventricular assist device (VAD) with a hydraulic output range designed to support children from newborns to adolescents. The present report describes our initial evaluation of the PediPump as a left VAD in an acute sheep model. The PediPump was implanted in two sheep (50.8 and 62.7 kg). Pump speed was adjusted to achieve a flow of 2 L/min with the naturally occurring preload and afterload conditions to evaluate pump performance under a steady hemodynamic state for 4 hours. Upon completion, pump performance was evaluated under various blood pressure and heart rate conditions. During steady-state evaluations, the ascending aortic flow and pump speed varied slightly depending on systemic arterial pressure variations. During the hemodynamic manipulation studies, flows ranged between 0.5 and 3.2 L/min with pump speeds of 5,200-16,200 rpm and motor current of 0.06-0.75 A. The PediPump demonstrated good initial hemodynamic performance for use as an implantable left VAD. However, some depositions were detected at the time of explanation, mainly at the rear of the pump. We are continuing with further acute studies to evaluate pump performance in anticipation of beginning chronic studies to evaluate long-term biocompatibility.

Cleveland Clinic PediPump lamb cadaver fitting studies.

We are developing the PediPump, a magnetically suspended, mixed-flow pump, as an implantable pediatric ventricular assist device (VAD). Lamb cadaver fitting studies were performed to determine the optimal pump location and optimal design of the inflow and outflow conduits for chronic in vivo studies. A prototype of the PediPump right and left ventricular assist devices (RVAD and LVAD, respectively) were implanted via a sternotomy or left thoracotomy in four lamb cadavers (3.7-34.2 kg). Via a sternotomy, the RVAD and LVAD required long inflow cannulas when placed into the right or left thoracic cavities, respectively. Via a left thoracotomy, with both pumps implanted in the left thoracic cavity, the RVAD required a 70 degrees inflow cannula and a bent outflow graft while the LVAD required a 130 degrees inflow cannula and a straight outflow graft. In conclusion, left thoracotomy provided optimal fitting for both LVAD and RVAD for the small lamb model.

Transhepatic Broviac catheter placement for long-term central venous access in critically ill children with complex congenital heart disease.

OBJECTIVE: Critically ill children with cardiac disease often require prolonged central venous access. Thrombosis of systemic veins or the need to preserve vessels for future cardiac procedures limits sites for placement of central venous catheters in these patients. This study evaluates the use of Broviac placement via the transhepatic approach for this patient population. DESIGN: A retrospective review. SETTING: A tertiary care center. PATIENTS: All children with complex congenital heart disease who underwent transhepatic Broviac placement between May 2000 and April 2004. INTERVENTIONS: Transhepatic Broviac placement. MEASUREMENTS AND MAIN RESULTS: Thirty-two children with a median age of 5 months (20 days-5.3 yrs) and a median weight of 4.2 kg (2.2-24.9 kg) underwent 40 transhepatic Broviac placements. There were three (8.8%) procedural-related complications. One patient suffered an intra-abdominal bleed requiring an urgent laparotomy and removal of the Broviac, one patient required transfusion because of a mild self-contained intra-abdominal bleed, and one patient developed temporary complete heart block. There was one catheter infection. Thrombus was noted by echocardiography on the tip of two Broviacs; however, no intracardiac vegetations or embolic events occurred. There was no mortality related to the procedure. Broviacs remained in place for a median of 36 days (1 day-6 months). Five Broviacs were dislodged inadvertently (two during cardiac massage and three resulting from patient manipulation). The remaining Broviacs were electively removed safely without coil embolization. At a median follow-up of 3.5 months (10 days-3 yrs), there have been no long-term complications related to the Broviacs. CONCLUSIONS: Transhepatic Broviac catheters can be used safely in critically ill children with cardiac disease and remain indwelling for adequate periods of time. This modality of prolonged vascular access should be considered for children whose veins are occluded or need to be preserved for future procedures.

High-risk medical devices, children and the FDA: regulatory challenges facing pediatric mechanical circulatory support devices.

Pediatric mechanical circulatory support is a critical unmet need in the United States. Infant- and child-sized ventricular assist devices are currently being developed largely through federal contracts and grants through the National Heart, Lung, and Blood Institute (NHLBI). Human testing and marketing of high-risk devices for children raises epidemiologic and regulatory issues that will need to be addressed. Leaders from the US Food and Drug Administration (FDA), NHLBI, academic pediatric community, and industry convened in January 2006 for the first FDA Workshop on the Regulatory Process for Pediatric Mechanical Circulatory Support Devices. The purpose was to provide the pediatric community with an overview of the federal regulatory process for high-risk medical devices and to review the challenges specific to the development and regulation of pediatric mechanical circulatory support devices. Pediatric mechanical circulatory support present significant epidemiologic, logistic, and financial challenges to industry, federal regulators, and the pediatric community. Early interactions with the FDA, shared appreciation of challenges, and careful planning will be critical to avoid unnecessary delays in making potentially life-saving devices available for children. Collaborative efforts to address these challenges are warranted.

Matching the mechanical circulatory support device to the child with heart failure.

A number of mechanical circulatory support devices are currently available for the treatment of children with heart failure refractory to medical therapy. Patient size, the acute versus chronic nature of the heart failure that is present, and the underlying anatomy and physiology define the clinical setting in any given case. Determining which device most effectively meets the specific needs of the clinical setting requires an understanding of the characteristics of each of the available devices. This report describes a graphic representation of the clinical setting in which pediatric heart failure occurs to provide a decision-making framework for the selection of the most appropriate mechanical circulatory support device.

Pediatric mechanical circulatory support in the United States: past, present, and future.

Mechanical support of the failing myocardium has become standard therapy for adults who fail medical management. Historically, there have been fewer options for children with heart failure. Extracorporeal membrane oxygenation and centrifugal pump-based ventricular assist devices have been the most commonly used circulatory support modalities for pediatrics in the United States. During the last few years, substantial advances in pediatric circulatory support have been made, with greater availability of a number of devices suitable for pediatrics. For example, there has been increasing experience using the DeBakey VAD Child and the Berlin Heart VAD to provide circulatory support for children during this period. A number of innovative devices under development supported by the Pediatric Circulatory Support Program of the National Heart, Lung, and Blood Institute hold great promise for expanded options for pediatric mechanical circulatory support in the future.

The PediPump: development status of a new pediatric ventricular assist device: update II.

The PediPump is a new ventricular assist device with a hydraulic output range designed for children from newborn infants to adolescents. The design is based on a mixed-flow rotary pump; the rotating assembly consists of a front impeller, front and rear radial magnetic bearings, and a central motor magnet. Two different implantable pumps were designed initially: an intravascular pump measuring 7 x 75 mm and an extravascular pump measuring 14 x 85 mm. Current prototypes are substantially smaller: The current intravascular version measures 4.5 x 55 mm, whereas the current extravascular version measures 11 x 70 mm. Both devices provide pressure and flows capable of supporting adults, far exceeding the initially defined physiologic requirements for children weighing 2 to 25 kg. This basic pump design may be used in acute or chronic clinical settings to provide right ventricular, left ventricular, or biventricular support. There are three objectives for the PediPump development program: 1) determination of basic engineering requirements for hardware and control logic including design analysis for system sizing, evaluation of control concepts, and bench testing of prototypes; 2) performance of preclinical anatomic fitting studies using CT-based 3D modeling; and 3) animal studies to provide characterization and reliability testing of the device.