A novel restrainer device for acquistion of brain images in awake rats.

Functional neuroimaging methods like fMRI and PET are vital in neuroscience research, but require that subjects remain still throughout the scan. In animal research, anesthetic agents are typically applied to facilitate the acquisition of high-quality data with minimal motion artifact. However, anesthesia can have profound effects on brain metabolism, selectively altering dynamic neural networks and confounding the acquired data. To overcome the challenge, we have developed a novel head fixation device designed to support awake rat brain imaging. A validation experiment demonstrated that the device effectively minimizes animal motion throughout the scan, with mean absolute displacement and mean relative displacement of 0.0256 (SD: 0.001) and 0.009 (SD: 0.002), across eight evaluated subjects throughout fMRI image acquisition (total scanning time per subject: 31 min, 12 s). Furthermore, the awake scans did not induce discernable stress to the animals, with stable physiological parameters throughout the scan (Mean HR: 344, Mean RR: 56, Mean SpO2: 94 %) and unaltered serum corticosterone levels (p = 0.159). In conclusion, the device presented in this paper offers an effective and safe method of acquiring functional brain images in rats, allowing researchers to minimize the confounding effects of anesthetic use.

Continuous-flow total artificial heart: hemodynamic and pump-related changes associated with posture in a chronic calf model.

This study aimed to evaluate the effects of posture (sitting [lying down]/standing) on hemodynamic and pump-related parameters in calves implanted with our institution's continuous-flow total artificial heart (CFTAH). These parameters were analyzed with posture information in four calves that had achieved the intended 14-, 30-, or 90-day durations of implantation. In each animal, postoperative hourly data gathered throughout the study were used to compare average values with the animal sitting vs. standing. Pump flow became significantly higher in the standing than sitting position at the same pump speed (standing 7.9 ± 0.8, sitting 7.4 ± 1.0 L/min, p = 0.028). Systemic vascular resistance (SVR) and aortic pressure (AoP) were significantly lower in the standing than sitting position (SVR standing 779 ± 145, sitting 929 ± 206 dyne s/cm5, p = 0.027; AoP standing 93 ± 7, sitting 103 ± 7 mm Hg, p < 0.001). No substantial change occurred in pulmonary vascular resistance (PVR) or pulmonary arterial pressure (PAP) with posture (PVR standing 161 ± 39, sitting 164 ± 48 dyne s/cm5, p = 0.639; PAP standing 32 ± 3, sitting 33 ± 4 mm Hg, p = 0.340). Posture affected some hemodynamic and pump-related parameters in calves with CFTAH, with implications for patients with implanted pumps.

The design modification of advanced ventricular assist device to enhance pulse augmentation and regurgitant flow shut-off.

The new Advanced ventricular assist device (Advanced VAD) has many features such as improving pulsatility and preventing regurgitant flow during pump stoppage. The purpose of this study was to evaluate the effects of design modifications of the Advanced VAD on these features in vitro. Bench testing of four versions of the Advanced VAD was performed on a static or pulsatile mock loop with a pneumatic device. After pump performance was evaluated, each pump was run at 3000 rpm to evaluate pulse augmentation, then was stopped to assess regurgitant flow through the pump. There was no significant difference in pump performance between the pump models. The average pulse pressure in the pulsatile mock loop was 23.0, 34.0, 39.3, 33.8, and 37.3 mm Hg without pump, with AV010, AV020 3S, AV020 6S, and AV020 RC, respectively. The pulse augmentation factor was 48%, 71%, 47%, and 62% with AV010, AV020 3S, AV020 6S, and AV020 RC, respectively. In the pump stop test, regurgitant flow was -0.60 ± 0.70, -0.13 ± 0.57, -0.14 ± 0.09, and -0.18 ± 0.06 L/min in AV010, AV020 3S, AV020 6S, and AV020 RC, respectively. In conclusion, by modifying the design of the Advanced VAD, we successfully showed the improved pulsatility augmentation and regurgitant flow shut-off features.

Transient power elevation during iron dextran infusion in a patient with a continuous-flow left ventricular assist device.

Anemia is common in patients with mechanical circulatory support and is associated with increased morbidity. Repletion using parenteral iron infusions has been proven to be beneficial in patients with heart failure. In this report, we describe a case of increased power and flows of continuous-flow left ventricular assist device (LVAD) during an iron dextran infusion. We subsequently studied the effects of iron dextran infusion in an in vitro LVAD mock circulatory loop. The observed increase in flow and power was most likely due to drug-patient interaction rather than drug-LVAD interaction. Mock loops and in vivo animal models may be necessary for proactive evaluation of the safety of intravenous (IV) preparations in this patient population.

Simulated Performance of the Cleveland Clinic Continuous-Flow Total Artificial Heart Using the Virtual Mock Loop.

Our new Virtual Mock Loop (VML) is a mathematical model designed to simulate the human cardiovascular system and gauge performance of mechanical circulatory support devices. We aimed to mimic the hemodynamic performance of Cleveland Clinic's self-regulating continuous-flow total artificial heart (CFTAH) via VML and evaluate VML's accuracy versus bench data from our standard mock circulatory loop. The VML reproduced 23 hemodynamic conditions. Systemic/pulmonary vascular resistances and pump rotational speed were set for VML from bench test data. We compared outputs (pump flow, left/right pump pressure rise, normalized pump performance, and atrial pressure difference) of the two methods. Data from pump flow and left pump pressure rise were similar, but right pump pressure rise slightly differed. Left pump normalized pump performance curves were similar. Right pump VML results were within the same performance range indicated by bench tests. The plots of atrial pressure differences of VML versus bench-test data were similar, but slightly differed in the midrange of systemic/pulmonary gradients. Virtual Mock Loop successfully reproduced results from our mock circulatory loop of CFTAH test conditions. The CFTAH's self-regulation feature of right pump performance was also calculated effectively. We foresee using versions of the VML for training, simulating physiologic cardiac conditions, and patient monitoring.

Advantages of Integrating Pressure-Regulating Devices Into Mechanical Circulatory Support Pumps.

Control of mechanical circulatory support pump output typically requires that pressure-regulating functions be accomplished by active control of the speed or geometry of the device, with feedback from pressure or flow sensors. This article presents a different design approach, with a pressure-regulating device as the core design feature, allowing the essential control function of regulating pressure to be directly programmed into the hydromechanical design. We show the step-by-step transformation of a pressure-regulating device into a continuous-flow total artificial heart that passively balances left and right circulations without the need for pressure and flow sensors. In addition, we discuss a ventricular assist device that prevents backflow in the event of power interruption and also dynamically interacts with residual ventricle function to preserve pulsatility.

Use of a Mechanical Circulatory Support Simulation to Study Pump Interactions With the Variable Hemodynamic Environment.

The Virtual Mock Loop, a versatile virtual mock circulation loop, was developed using a lumped-parameter model of the mechanically assisted human circulatory system. Inputs allow specification of a variety of continuous-flow pumps (left, right, or biventricular assist devices) and a total artificial heart that can self-regulate between left and right pump outputs. Hemodynamic inputs were simplified using a disease-based input panel, allowing selection of a combination of cardiovascular disease states, including systolic and diastolic heart failure, stenosis, and/or regurgitation in each of the four valves, and high to low systemic and pulmonary vascular resistance values. The menu-driven output includes a summary of hemodynamic parameters and graphical output of selected flows, pressures, and volumes in the heart's four chambers as well as in the pulmonary artery and aorta. New tools to augment experimental research on implantable heart-assist devices and to increase our understanding of patient-specific pump interactions are in high demand. The purpose of this ongoing study is to demonstrate the use of a system analysis computer simulation to explore and better comprehend the interactions of mechanical circulatory support pumps with a more extensive combination of patient-specific or simulation conditions than can be established by practical experimentation. Usability is an important factor in constructing computer models for research purposes, and among our primary objectives in creating this simulation model were to make it as portable and useful as possible outside the lab environment, by people not involved in the creation of its operational software.

Anatomical study of the Cleveland Clinic continuous-flow total artificial heart in adult and pediatric configurations.

The purpose of this study was to assess the smallest possible body sizes of patients in whom the Cleveland Clinic continuous-flow total artificial heart for adult (CFTAH) and pediatric configurations (P-CFTAH) can fit. One of the most critical dimensions is the vertebra-to-sternum distance at the junction of the right atrium to the inferior vena cava (V-S distance). Our previous CFTAH anatomical fitting study suggested that the CFTAH would fit patients of V-S distance ≥ 7.5 cm and the P-CFTAH of V-S distance ≥ 5.25 cm (70% of 7.5 cm). To confirm this, we assessed the relationship between body surface area (BSA) and V-S distance in 15 adult patients (BSA 1.86-2.62 m2) and 31 pediatric patients (BSA 0.17-1.80 m2) whose computed tomography scans were available. We found a highly significant correlation between BSA and V-S distance (p < 1.0 × 10-25). It appears that the CFTAH will fit in most patients with BSA ≥ 1.0 m2 (corresponding height of ≥ 130 cm and age of 9 years) and the P-CFTAH in patients with BSA ≥ 0.3 m2 (corresponding height of ≥ 55 cm and age of 1 month). Further anatomical fitting studies are needed to evaluate the two pump models inside human chests to determine the smallest patient size/critical dimensions and device port configurations.

Early in vivo experience with the pediatric continuous-flow total artificial heart.

BACKGROUND: Heart transplantation in infants and children is an accepted therapy for end-stage heart failure, but donor organ availability is low and always uncertain. Mechanical circulatory support is another standard option, but there is a lack of intracorporeal devices due to size and functional range. The purpose of this study was to evaluate the in vivo performance of our initial prototype of a pediatric continuous-flow total artificial heart (P-CFTAH), comprising a dual pump with one motor and one rotating assembly, supported by a hydrodynamic bearing. METHODS: In acute studies, the P-CFTAH was implanted in 4 lambs (average weight: 28.7 ± 2.3 kg) via a median sternotomy under cardiopulmonary bypass. Pulmonary and systemic pump performance parameters were recorded. RESULTS: The experiments showed good anatomical fit and easy implantation, with an average aortic cross-clamp time of 98 ± 18 minutes. Baseline hemodynamics were stable in all 4 animals (pump speed: 3.4 ± 0.2 krpm; pump flow: 2.1 ± 0.9 liters/min; power: 3.0 ± 0.8 W; arterial pressure: 68 ± 10 mm Hg; left and right atrial pressures: 6 ± 1 mm Hg, for both). Any differences between left and right atrial pressures were maintained within the intended limit of ±5 mm Hg over a wide range of ratios of systemic-to-pulmonary vascular resistance (0.7 to 12), with and without pump-speed modulation. Pump-speed modulation was successfully performed to create arterial pulsation. CONCLUSION: This initial P-CFTAH prototype met the proposed requirements for self-regulation, performance, and pulse modulation.

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

OBJECTIVES: Mechanical circulatory support has become standard therapy for adult patients with end-stage heart failure; however, in paediatric patients with congenital heart disease, the options for chronic mechanical circulatory support are limited to paracorporeal devices or off-label use of devices intended for implantation in adults. Congenital heart disease and cardiomyopathy often involve both the left and right ventricles; in such cases, heart transplantation, a biventricular assist device or a total artificial heart is needed to adequately sustain both pulmonary and systemic circulations. We aimed to evaluate the in vitro performance of the initial prototype of our paediatric continuous-flow total artificial heart. METHODS: The paediatric continuous-flow total artificial heart pump was downsized from the adult continuous-flow total artificial heart configuration by a scale factor of 0.70 (1/3 of total volume) to enable implantation in infants. System performance of this prototype was evaluated using the continuous-flow total artificial heart mock loop set to mimic paediatric circulation. We generated maps of pump performance and atrial pressure differences over a wide range of systemic vascular resistance/pulmonary vascular resistance and pump speeds. RESULTS: Performance data indicated left pump flow range of 0.4-4.7 l/min at 100 mmHg delta pressure. The left/right atrial pressure difference was maintained within ±5 mmHg with systemic vascular resistance/pulmonary vascular resistance ratios between 1.4 and 35, with/without pump speed modulation, verifying expected passive self-regulation of atrial pressure balance. CONCLUSIONS: The paediatric continuous-flow total artificial heart prototype met design requirements for self-regulation and performance; in vivo pump performance studies are ongoing.

New Technology Mimics Physiologic Pulsatile Flow During Cardiopulmonary Bypass.

The VentriFlo True Pulse Pump (Design Mentor, Inc., Pelham, NH, USA) is the first blood pump designed to mimic human arterial waveforms in a standard oxygenation circuit. Our aim was to demonstrate the feasibility and safety of this pump in preparation for future studies to determine possible clinical advantages. We studied four piglets (41.4-46.2 kg): three with an implanted VentriFlo pulsatile pump and one with the nonpulsatile ROTAFLOW pump (MAQUET Holding B.V. & Co. KG, Rastatt, Germany) as a control. Hemodynamics was monitored during 6-h cardiopulmonary bypass (CPB) support and for 2 h after weaning off CPB. The VentriFlo demonstrated physiologic arterial waveforms with arterial pulse pressure of 24.6 ± 5.7 mm Hg. Pump flows (2.0 ± 0.1 L/min in ROTAFLOW; 1.9 ± 0.1 L/min in VentriFlo) and plasma free hemoglobin levels (27.9 ± 12.5 mg/dL in ROTAFLOW; 28.5 ± 14.2 mg/dL in VentriFlo) were also comparable, but systemic O2 extraction (as measured by arterial minus venous O2 saturation) registered slightly higher with the VentriFlo (63.2 ± 6.9%) than the ROTAFLOW (55.4 ± 6.5%). Histological findings showed no evidence of ischemic changes or thromboembolism. This pilot study demonstrated that the VentriFlo system generated pulsatile flow and maintained adequate perfusion of all organs during prolonged CPB.

Generating pulsatility by pump speed modulation with continuous-flow total artificial heart in awake calves.

The purpose of this study was to evaluate the effects of sinusoidal pump speed modulation of the Cleveland Clinic continuous-flow total artificial heart (CFTAH) on hemodynamics and pump flow in an awake chronic calf model. The sinusoidal pump speed modulations, performed on the day of elective sacrifice, were set at ±15 and ± 25% of mean pump speed at 80 bpm in four awake calves with a CFTAH. The systemic and pulmonary arterial pulse pressures increased to 12.0 and 12.3 mmHg (±15% modulation) and to 15.9 and 15.7 mmHg (±25% modulation), respectively. The pulsatility index and surplus hemodynamic energy significantly increased, respectively, to 1.05 and 1346 ergs/cm at ±15% speed modulation and to 1.51 and 3381 ergs/cm at ±25% speed modulation. This study showed that it is feasible to generate pressure pulsatility with pump speed modulation; the platform is suitable for evaluating the physiologic impact of pulsatility and allows determination of the best speed modulations in terms of magnitude, frequency, and profiles.

Moderate hypothermia technique for chronic implantation of a total artificial heart in calves.

The benefit of whole-body hypothermia in preventing ischemic injury during cardiac surgical operations is well documented. However, application of hypothermia during in vivo total artificial heart implantation has not become widespread because of limited understanding of the proper techniques and restrictions implied by constitutional and physiological characteristics specific to each animal model. Similarly, the literature on hypothermic set-up in total artificial heart implantation has also been limited. Herein we present our experience using hypothermia in bovine models implanted with the Cleveland Clinic continuous-flow total artificial heart.

Mechanism of Self-Regulation and In Vivo Performance of the Cleveland Clinic Continuous-Flow Total Artificial Heart.

Cleveland Clinic's continuous-flow total artificial heart (CFTAH) provides systemic and pulmonary circulations using one assembly (one motor, two impellers). The right pump hydraulic output to the pulmonary circulation is self-regulated by the rotating assembly's passive axial movement in response to atrial differential pressure to balance itself to the left pump output. This combination of features integrates a biocompatible, pressure-balancing regulator with a double-ended pump. The CFTAH requires no flow or pressure sensors. The only control parameter is pump speed, modulated at programmable rates (60-120 beats/min) and amplitudes (0 to ±25%) to provide flow pulses. In bench studies, passive self-regulation (range: -5 mm Hg ≤ [left atrial pressure - right atrial pressure] ≤ 10 mm Hg) was demonstrated over a systemic/vascular resistance ratio range of 2.0-20 and a flow range of 3-9 L/min. Performance of the most recent pump configuration was demonstrated in chronic studies, including three consecutive long-term experiments (30, 90, and 90 days). These experiments were performed at a constant postoperative mean speed with a ±15% speed modulation, demonstrating a totally self-regulating mode of operation, from 3 days after implant to explant, despite a weight gain of up to 40%. The mechanism of self-regulation functioned properly, continuously throughout the chronic in vivo experiments, demonstrating the performance goals.

Thrombotic Depositions on Right Impeller of Double-Ended Centrifugal Total Artificial Heart In Vivo.

The development of total artificial heart devices is a complex undertaking that includes chronic biocompatibility assessment of the device. It is considered particularly important to assess whether device design and features can be compatible long term in a biological environment. As part of the development program for the Cleveland Clinic continuous-flow total artificial heart (CFTAH), we evaluated the device for signs of thrombosis and biological material deposition in four animals that had achieved the intended 14-, 30-, or 90-day durations in each respective experiment. Explanted CFTAHs were analyzed for possible clot buildup at "susceptible" areas inside the pump, particularly the right pump impeller. Depositions of various consistency and shapes were observed. We here report our findings, along with macroscopic and microscopic analysis post explant, and provide computational fluid dynamics data with its potential implications for thrombus formation.

Deairing Techniques for Double-Ended Centrifugal Total Artificial Heart Implantation.

The unique device architecture of the Cleveland Clinic continuous-flow total artificial heart (CFTAH) requires dedicated and specific air-removal techniques during device implantation in vivo. These procedures comprise special surgical techniques and intraoperative manipulations, as well as engineering design changes and optimizations to the device itself. The current study evaluated the optimal air-removal techniques during the Cleveland Clinic double-ended centrifugal CFTAH in vivo implants (n = 17). Techniques and pump design iterations consisted of developing a priming method for the device and the use of built-in deairing ports in the early cases (n = 5). In the remaining cases (n = 12), deairing ports were not used. Dedicated air-removal ports were not considered an essential design requirement, and such ports may represent an additional risk for pump thrombosis. Careful passive deairing was found to be an effective measure with a centrifugal pump of this design. In this report, the techniques and design changes that were made during this CFTAH development program to enable effective residual air removal and prevention of air embolism during in vivo device implantation are explained.

The axial continuous-flow blood pump: Bench evaluation of changes in flow associated with changes of inflow cannula angle.

BACKGROUND: Changes in the geometry of the HeartMate II (HMII) inflow cannula have been implicated in device thrombosis post-implant. The purpose of this in vitro study was to evaluate what effects changing the angle of the cannula in relation to the pump may have on pump flow and arterial pressure, under simulated inflow conditions. METHODS: The HMII with an inflow cannula was mounted on a mock loop consisting of a pulsatile pneumatic ventricle to simulate the native ventricle. The angles of the HMII in relation to the inflow cannula were adjusted by separate fixed gooseneck holders. A custom-made miniature steerable camera was introduced into a flexible portion of the HMII inflow cannula. Endoscopic views of various types of inflow cannula constriction (bending, squeezing, stretching and twisting) were recorded, and pump flow and systemic arterial pressure (AoP) were assessed during each simulation. RESULTS: Baseline mean pump flow (3.5 liters/min) and mean AoP (91.5 mm Hg) were unchanged by bending maximally in 2 different directions, twisting up to 30°, stretching (compression or extension), or occluding the inflow graft <90%. However, mean pump flow and mean AoP decreased substantially when the inflow graft became occluded by ≥90% by sliding or squeezing. CONCLUSIONS: "Less-than-critical" obstruction (what we define here as <90%) of the HMII inflow cannula did not reveal substantial changes in pump flow or AoP. Data suggest that a major alteration to inflow cannula geometry is required to achieve clinically relevant hemodynamic changes. These data confirm that minor changes in angulation of the inflow cannula have no impact on flow through the device.

The Contribution to Hemodynamics Even at Very Low Pump Speeds in the HVAD.

BACKGROUND: We recently reported using bench testing that the Thoratec HeartMate II at 6,000 rpm contributed to hemodynamics when the heart had not recovered well, making weaning assessment questionable. In this bench study, we characterized hemodynamics and pump flow of the HeartWare HVAD at 1,800 rpm, the lowest speed commonly used to assess clinical recovery. METHODS: The HVAD was operated in a mock loop at 1,800, 2,400, and 3,000 rpm. We acquired pressure-flow curves in each steady state. In pulsatile mode with the pneumatic ventricle (heart simulator) activated, pump flow, total flow, and aortic pressure (AoP) data were obtained under conditions simulating normal heart function or heart failure. RESULTS: A large regurgitant flow during diastole was confirmed during normal heart function at 1,800 rpm support; however, the net flow was zero, and there was no difference in mean AoP between 1,800 rpm support and no HVAD support. In contrast, in the heart failure condition, HVAD flow at 1,800 rpm significantly contributed to mean AoP and total flow, because there was less regurgitant flow. CONCLUSIONS: Similar to the results for the HeartMate II at 6,000 rpm, we found that the net pump flow generated by the HeartWare HVAD at 1,800 rpm depends on the degree of residual left ventricular (LV) function. In the setting of improved LV function, at 1,800 rpm we noted a large regurgitant flow. Although this "marker" can serve as a useful indicator for recovery, assessing recovery at this speed is flawed unless measures are taken to prevent regurgitant flow.

Median Sternotomy or Right Thoracotomy Techniques for Total Artificial Heart Implantation in Calves.

The choice of optimal operative access technique for mechanical circulatory support device implantation ensures successful postoperative outcomes. In this study, we retrospectively evaluated the median sternotomy and lateral thoracotomy incisions for placement of the Cleveland Clinic continuous-flow total artificial heart (CFTAH) in a bovine model. The CFTAH was implanted in 17 calves (Jersey calves; weight range, 77.0-93.9 kg) through a median sternotomy (n = 9) or right thoracotomy (n = 8) for elective chronic implantation periods of 14, 30, or 90 days. Similar preoperative preparation, surgical techniques, and postoperative care were employed. Implantation of the CFTAH was successfully performed in all cases. Both methods provided excellent surgical field visualization. After device connection, however, the median sternotomy approach provided better visualization of the anastomoses and surgical lines for hemostasis confirmation and repair due to easier device displacement, which is severely limited following right thoracotomy. All four animals sacrificed after completion of the planned durations (up to 90 days) were operated through full median sternotomy. Our data demonstrate that both approaches provide excellent initial field visualization. Full median sternotomy provides larger viewing angles at the anastomotic suture line after device connection to inflow and outflow ports.