The role of diastolic pump flow in centrifugal blood pump hemodynamics.

We tried to verify the hypothesis that increases in pump flow during diastole are matched by decreases in left ventricular (LV) output during systole. A calf (80 kg) was implanted with an implantable centrifugal blood pump (EVAHEART, SunMedical Technology Research Corp., Nagano, Japan) with left ventricle to aorta (LV-Ao) bypass, and parameters were recorded at different pump speeds under general anesthesia. Pump inflow and outflow pressure, arterial pressure, systemic and pulmonary blood flow, and electrocardiogram (ECG) were recorded on the computer every 5 ms. All parameters were separated into systolic and diastolic components and analyzed. The pulmonary flow was the same as the systemic flow during the study (p > 0.1). Systemic flow consisted of pump flow and LV output through the aortic valve. The ratio of systolic pump flow to pulmonary flow (51.3%) did not change significantly at variable pump speeds (p > 0.1). The other portions of the systemic flow were shared by the left ventricular output and the pump flow during diastole. When pump flow increased during diastole, there was a corresponding decrease in the LV output (Y = -1.068X + 51.462; R(insert)(2) = 0.9501). These show that pump diastolic flow may regulate expansion of the left ventricle in diastole.

HeartMate III: pump design for a centrifugal LVAD with a magnetically levitated rotor.

A long-term, compact left ventricular assist device (LVAD), the HeartMate III, has been designed and fabricated, featuring a centrifugal pump with a magnetically levitated rotor. The pump has been optimized by in vitro testing to achieve a design point of 7 L/min against 135 mm Hg at high hydrodynamic efficiency (30%) and to be capable of up to 10 L/min under such a load. Furthermore, the pump has demonstrated no mechanical failures, low hemolysis (4-10 mg/dl plasma free Hb), and low thrombogenicity during six (40, 27, 59, 42, 27, and 49-day) in vivo bovine studies.

The Heartmate III: design and in vivo studies of a maglev centrifugal left ventricular assist device.

A compact implantable centrifugal left ventricular assist device (LVAD) (HeartMate III) featuring a magnetically levitated impeller is under development. The goal of our ongoing work is to demonstrate feasibility, low hemolysis, and low thrombogenicity of the titanium pump in chronic bovine in vivo studies. The LVAD is based on so-called bearingless motor technology and combines pump rotor, drive, and magnetic bearing functions in a single unit. The impeller is rotated (theta z) and levitated with both active (X, Y) and passive (Z, theta x, theta y) suspension. Six prototype systems have been built featuring an implantable titanium pump (69 mm diameter, 30 mm height) with textured blood contacting surfaces and extracorporeal electronics. The pumps were implanted in 9 calves (< or = 100 kg at implant) that were anticoagulated with Coumadin (2.5 < or = INR < or = 4.0) throughout the studies. Six studies were electively terminated (at 27-61 days), 1 study was terminated after the development of severe pneumonia and lung atelectasis (at 27 days) another study was terminated after cardiac arrest (at 2 days) while a final study is ongoing (at approximately 100 days). Mean pump flows ranged from 2 to 7 L/min, except for brief periods of exercise at 6 to 9 L/min. Plasma free hemoglobin ranged from 4 to 10 mg/dl. All measured biochemical indicators of end organ function remained within normal range. The pumps have met performance requirements in all 9 implants with acceptable hemolysis and no mechanical failures.

Relationship of blood pressure and pump flow in an implantable centrifugal blood pump during hypertension.

The purpose of this study was to evaluate the real time relationship between pump flow and pump differential pressure (D-P) during experimentally induced hypertension (HT). Two calves (80 and 68 kg) were implanted with the EVA-HEART centrifugal blood pump (SunMedical Technology Research Corp., Nagano, Japan) under general anesthesia. Blood pressure (BP) in diastole was increased to 100 mm Hg by norepinephrine to simulate HT. Pump flow, D-P, ECG, and BP were measured at pump speeds of 1,800, 2,100, and 2,300 rpm. All data were separated into systole and diastole, and pump flow during HT was compared with normotensive (NT) conditions at respective pump speeds. Diastolic BP was increased to 99.3+/-4.1 mm Hg from 66.5+/-4.4 mm Hg (p<0.01). D-P in systole was under 40 mm Hg (range of change was 10 to 40 mm Hg) even during HT. During NT, the average systolic pump flow volume was 60% of the total pump flow. However, during HT, the average systolic pump flow was 100% of total pump flow volume, although the pump flow volume in systole during HT decreased (33.1+/-5.7 vs. 25.9+/-4.0 ml/systole, p<0.01). In diastole, the average flow volume through the pump was 19.6+/-6.9 ml/diastole during NT and -2.2+/-11.1 ml/diastole during HT (p<0.01). The change in pump flow volume due to HT, in diastole, was greater than the change in pump flow in systole at each pump speed (p<0.001). This study suggests that the decrease of mean pump flow during HT is mainly due to the decrease of the diastolic pump flow and, to a much lesser degree, systolic pump flow.

Continuously maintaining positive flow avoids endocardial suction of a rotary blood pump with left ventricular bypass.

This study showed the usefulness of maintaining positive pump flow to avoid endocardial suction and as an assist bypass. Three calves were implanted with centrifugal pumps. Hemodynamics and pump parameters were measured at varying pump speeds (from 1,100 to 2,300 rpm). In each test pump, speed was adjusted to create 3 hemodynamic states: both positive and negative flow (PNF), positive and zero flow (PZF), and continuously positive flow (CPF). The pump flow volume was determined during systole (Vs) and diastole (Vd). Vs in PNF was 29.6 ml and was not significantly different from Vs in PZF (p > 0.15). Vd in PNF was significantly different from Vd in PZF (p < 0.05). All bypass rates of PNF were over 30% of pulmonary flow. All PZF bypass rates were between the PNF rate and the CPF rate. These data showed that PZF satisfied the minimum requirement of assist flow and was under 100% bypass. Thus, PZF may avoid endocardial suction.

Development of the Nimbus/University of Pittsburgh innovative ventricular assist system.

BACKGROUND: Nimbus Inc, and the University of Pittsburgh's McGowan Center for Artificial Organ Development have been collaborators on rotary blood pump technology initiatives since 1992. Currently, a major focus is an innovative ventricular assist system (IVAS) that features an implantable, electrically powered axial flow blood pump. In addition to the blood pump, a major development item is the electronic controller and the control algorithm for modulating pump speed in response to varying physical demand. METHODS: Methods used in developing the IVAS include computational fluid dynamic modeling of the pump's interior flow field, flow visualization of the flow field using laser-based imaging, computer simulation of blood pump-physiological interactions, vibroaccoustic monitoring, and an extensive in vivo test program. RESULTS: Results to date, which are presented below, include successful in vivo tests of blood pumps with blood-immersed bearings, and feasibility demonstration of vibroacoustic monitoring in this application. CONCLUSIONS: This unique blend of industrial experience and technologies with the University-based Research and Development Center has greatly enhanced the progress made on this IVAS project.

Rotary blood pump flow spontaneously increases during exercise under constant pump speed: results of a chronic study.

Many types of rotary blood pumps and pump control methods have recently been developed with the goal of clinical use. From experiments, we know that pump flow spontaneously increases during exercise without changing pump control parameters. The purpose of this study was to determine the hemodynamics associated with the long-term observation of calves implanted with centrifugal blood pumps (EVAHEART, Sun Medical Technology Research Corporation, Nagano, Japan). Two healthy female Jersey calves were implanted with devices in the left thoracic cavity. A total of 22 treadmill exercise tests were performed after the 50th postoperative day. During exercise, the following parameters were compared with conditions at rest: heart rate, blood pressure, central venous oxygen saturation (SvO2), pump speed, and pump flow. The pump flow in a cardiac cycle was analyzed by separating the systole and diastole. Compared to the base data, statistically significant differences were found in the following interrelated parameters: the heart rate (66.8 +/- 5.2 vs. 106 +/- 9.7 bpm), mean pump flow (4.8 +/- 0.2 vs. 7.0 +/- 0.3 L/min), and volume of pump flow in diastole (26.0 +/- 1.8 vs. 13.5 +/- 2.5 ml). During exercise, the volume of pump flow in systole was 3 times larger than that measured in diastole. Blood pressure, SvO2, and pump speed did not change significantly from rest to exercise. These results suggested that the mean pump flow depends on the systolic pump flow. Therefore, the increase in the mean pump flow during exercise under constant pump speed was caused by an increase in the heart rate.

Chronic animal health assessment during axial ventricular assistance: importance of hemorheologic parameters.

Chronic testing of the Nimbus/UOP Axial Flow Pump was performed on 22 calves for periods of implantation ranging from 27 to 226 days (average, 74 days). The following parameters were measured: plasma free hemoglobin, blood and plasma viscosity, erythrocyte deformability and mechanical fragility, oxygen delivery index (ODI), blood cell counts, hematocrit, hemoglobin, blood urea nitrogen, creatinine, bilirubin, total protein, fibrinogen, and plasma osmolality. Most of the above parameters were stable during the full course of support. Compared with baseline, statistically significant differences during the entire period of implantation were only found in: hematocrit (p<0.001), hemoglobin (p<0.005), red blood cell (RBC) count (p<0.001), and whole blood viscosity (p<0.01). Plasma viscosity and ODI were mostly stable during the period of implantation. In some animals, an acute increase in fibrinogen concentration, plasma and blood viscosity, and a decrease in ODI were found to be early signs of the onset of infection. A small (10%) decrease in deformability of RBCs was found during the first 2 weeks after implantation. This alteration in RBC deformability was highly correlated (r = 0.793) with changes in total plasma protein concentration that fell more than 15% (p<0.001) during the same period. Mechanical fragility of RBCs was found to be slightly increased after implantation. Plasma free hemoglobin remained close to baseline level (p>0.2). After the first 2 weeks of the postoperative period, pump performing parameters for all animals were consistent and stable. In general, the Nimbus/UOP Axial Flow Pump demonstrated basic reliability and biocompatibility and did not produce significant alterations in the mechanical properties of blood or animal health status. The pump provided adequate hemodynamics and was well tolerated by the experimental animal for periods as long as 7.5 months. Monitoring rheologic parameters of blood is very helpful for evaluation of health during heart-assist device application.

Progress on development of the Nimbus-University of Pittsburgh axial flow left ventricular assist system.

Nimbus Inc. (Rancho Cordova, CA) and the University of Pittsburgh have completed the second year of development of a totally implanted axial flow blood pump under the National Institutes of Health Innovative Ventricular Assist System Program. The focus this year has been on completing pump hydraulic development and addressing the development of the other key system components. Having demonstrated satisfactory pump hydraulic and biocompatibility performance, pump development has focused on design features that improve pump manufacturability. A controller featuring full redundancy has been designed and is in the breadboard test phase. Initial printed circuit layout of this circuit has shown it to be appropriately sized at 5 x 6 cm to be compatible with implantation. A completely implantable system requires the use of a transcutaneous energy transformer system (TETS) and a diagnostic telemetry system. The TETS power circuitry has been redesigned incorporating an improved, more reliable operating topography. A telemetry circuit is undergoing characterization testing. Closed loop speed control algorithms are being tested in vitro and in vivo with good success. Eleven in vivo tests were conducted with durations from 1 to 195 days. Endurance pumps have passed the 6 month interval with minimal bearing wear. All aspects of the program continue to function under formal quality assurance.

Induction of ventricular collapse by an axial flow blood pump.

An important consideration for clinical application of rotary blood pump based ventricular assist is the avoidance of ventricular collapse due to excessive operating speed. Because healthy animals do not typically demonstrate this phenomenon, it is difficult to evaluate control algorithms for avoiding suction in vivo. An acute hemodynamic study was thus conducted to determine the conditions under which suction could be induced. A 70 kg calf was implanted with an axial flow assist device (Nimbus/UoP IVAS; Nimbus Inc., Rancho Cordova, CA) cannulated from the left ventricular apex to ascending aorta. On initiation of pump operation, several vasoactive interventions were performed to alter preload, afterload, and contractility of the left ventricle. Initially, dobutamine increased contractility and heart rate ([HR] = 139; baseline = 70), but ventricular collapse was not achievable, even at the maximal pump speed of 15,000 rpm. Norepinephrine decreased HR (HR = 60), increased contractility, and increased systemic vascular resistance ([SVR] = 24; baseline = 15), resulting in ventricular collapse at a pump speed of 14,000 rpm. Isoproterenol (beta agonist) increased HR (HR = 103) and decreased SVR (SVR = 12), but ventricular collapse was not achieved. Inferior vena cava occlusion reduced preload, and ventricular collapse was achieved at speeds as low as 11,000 rpm. Esmolol (beta1 antagonist) decreased HR (HR = 55) and contractility, and ventricular collapse was achieved at 11,500 rpm. Episodes of ventricular collapse were characterized initially by the pump output exceeding the venous return and the aortic valve remaining closed throughout the cardiac cycle. If continued, the mitral valve would remain open throughout the cardiac cycle. Using these unique states of the mitral and aortic valves, the onset of ventricular collapse could reliably be identified. It is hoped that the ability to detect the onset of ventricular collapse, rather than the event itself, will assist in the development and the evaluation of control algorithms for rotary ventricular assist devices.

Assessment of bovine platelet life span with biotinylation and flow cytometry.

Reduced platelet life span is associated with the implantation of a variety of cardiovascular devices and may be used as a gauge of device biocompatibility. In the bovine model, platelet life span has previously been assessed with radioisotope labeling of removed platelets followed by reinjection and periodic gamma counting of blood samples. We report here the use of protein-reactive biotin (sulfo-N-hydroxysuccinimido [NHS]-biotin) as an alternative to radioisotope techniques whereby reinjected biotinylated platelets are subsequently detected in blood samples using phycoerythrin-streptavidin and flow cytometric techniques. Platelet life span was quantified in a normal calf (4.9 days) and in a calf prior to (6.1 days) and following (3.1 days) implantation of a Nimbus Axial Flow Pump ventricular assist device. The assessment of bovine platelet life span with biotinylation and flow cytometry avoids the technical, regulatory, and safety considerations associated with radioisotope usage and appears readily amenable to application in cardiovascular device testing.

An implantable centrifugal blood pump with a recirculating purge system (Cool-Seal system).

A compact centrifugal blood pump has been developed as an implantable left ventricular assist system. The impeller diameter is 40 mm, and pump dimensions are 55 x 64 mm. This first prototype, fabricated from titanium alloy, resulted in a pump weight of 400 g including a brushless DC motor. The weight of a second prototype pump was reduced to 280 g. The entire blood contacting surface is coated with diamond like carbon (DLC) to improve blood compatibility. Flow rates of over 7 L/min against 100 mm Hg pressure at 2,500 rpm with 9 W total power consumption have been measured. A newly designed mechanical seal with a recirculating purge system (Cool-Seal) is used for the shaft seal. In this seal system, the seal temperature is kept under 40 degrees C to prevent heat denaturation of blood proteins. Purge fluid also cools the pump motor coil and journal bearing. Purge fluid is continuously purified and sterilized by an ultrafiltration unit which is incorporated in the paracorporeal drive console. In vitro experiments with bovine blood demonstrated an acceptably low hemolysis rate (normalized index of hemolysis = 0.005 +/- 0.002 g/100 L). In vivo experiments are currently ongoing using calves. Via left thoracotomy, left ventricular (LV) apex descending aorta bypass was performed utilizing an expanded polytetrafluoroethylene (ePTFE) vascular graft with the pump placed in the left thoracic cavity. In 2 in vivo experiments, the pump flow rate was maintained at 5-9 L/min, and pump power consumption remained stable at 9-10 W. All plasma free Hb levels were measured at less than 15 mg/dl. The seal system has demonstrated good seal capability with negligible purge fluid consumption (<0.5 ml/day). In both calves, the pumps demonstrated trouble free continuous function over 6 month (200 days and 222 days).

Fine trabecularized carbon: ideal material and texture for percutaneous device system of permanent left ventricular assist device.

The development of a percutaneous artificial internal organ system requires a reliable biocompatible connection between the external environment and the inside of the human body. Such is necessary for the success of a permanent left ventricular assist device. However, the search for a satisfactory interface at the epidermal level has proven to be difficult. Carbon has been proposed for this application, but its texture does not typically promote ingrowth from surrounding tissue. We have therefore employed a new processing method to produce a fine trabecularized carbon implant. The method for preparing the implant involves infiltrating low temperature pyrolytic carbon into the surface of a carbon core which is wrapped with carbon fabric. This results in a tightly woven porous structure of carbon (carbon fiber diameter: 35-50 microm, maximal pore size >200 microm) with gradually increasing porosity from 15-75%. We implanted test samples percutaneously in a calf for in vivo histological evaluation. Thirty days after implantation epidermal downgrowth was minimal. Microscopic analysis revealed that a thin fibrous capsule surrounded the implant, and mature connective tissue with accompanying blood vessels filled the pores of the fine trabecularized carbon layer. From these results we suggest that fine trabecularized carbon is ideally suited for a percutaneous device system in a permanent left ventricular assist device.

Effect of pressure-flow relationship of centrifugal pump on in vivo hemodynamics: a consideration for design.

We have been developing centrifugal pumps for an implantable left ventricular assist device. We manufactured 2 prototype centrifugal pumps (PI, PII). These two have similar designs except for the PII having a volute casing and a large output port. To determine the differences in the hydraulic characteristics between the PI and PII, we carried out in vitro and in vivo experiments. In vitro study showed that the PII had a shallower H-Q curve than that of the PI, and the PII required a pump speed faster than the PI for the same flow rate and pressure head. On the other hand, in vivo study showed that the PII demonstrated a flow pulsatility greater than that of the PI at 1,900 rpm and 8 L/min although no significant change was observed at low pump speeds (< or = 1,500 rpm). This greater pulsatility consisted of a large discharge according to the small differential pressure during the systolic phase and a small discharge according to the large differential pressure during the diastolic phase. In contrast, the PI, having the steeper H-Q curve, showed a small discharge in the systolic phase and a large discharge in the diastolic phase. These results showed that pulsatility synchronized with the native heart beating depended on the slope of the H-Q curve. As a result, the slope of the H-Q curve is important to determine the component of pulsatility synchronized with native cardiac output. Regarding the slope of the H-Q curve, a pump having a volute casing and a large outlet port demonstrates a shallow slope in the H-Q curve. In conclusion, we suggest that a centrifugal pump for use in left ventricular aortic bypass should be designed considering the effect on the native heart pulsatility.

Flow cytometric assays to detect platelet activation and aggregation in device-implanted calves.

Cardiovascular device development often relies upon large-animal models to assess blood biocompatibility prior to initiating clinical trials. Unfortunately, the amount of information gleaned from such trials is limited by simple assays that do not take full advantage of immunotechnological advances that increasingly are applied in clinical studies. Thus we have developed and tested new flow cytometric techniques for measuring circulating activated bovine platelets and platelet microaggregates. Monoclonal antibodies (MAbs) raised against both activated and quiescent bovine platelets were incubated with control and PMA-or ADP-stimulated whole blood. Selected MAbs detected activated bovine platelets and platelet microaggregates in vitro with flow cytometry. Five calves implanted with one of two designs of nonpulsatile ventricular-assist devices (VADs) were followed with these assays prior to and during VAD implantation. Circulating activated bovine platelets and microaggregates increased after implantation in all animals and, alternatively, remained elevated or returned toward preimplant levels. Platelet activation percentages as detected temporally by three MAbs were correlated with one another, and platelet activation was correlated with microaggregate formation. In summary, these new methods for the sensitive measurement of circulating activated bovine platelets and microaggregates may provide valuable information for the development and assessment of future cardiovascular device designs.

Controller for an axial-flow blood pump.

An axial-flow ventricular assist device (VAD) under development at the authors' facility is intended for use as a long-term implantable device. At high speeds axial-flow VADs can collapse the native ventricle and damage the heart muscle, lung tissue, and blood. A prototype algorithm was developed to maintain physiologic perfusion to the vital organs while preventing ventricular collapse, through analysis of the electrical current waveform of the motor. The premise of the control algorithm is that the hemodynamics of the patient are reflected in the shape of this waveform. This approach is intended to eliminate the need for invasive sensors, thus effectively using the pump itself as a transducer. The control algorithm regulates the speed of the pump by comparing the motor-current waveform with reference waveforms using a matched filter. The matched filter was evaluated by its classification and differentiation performance. Thus far, the authors have been able to classify the waveforms into one of the four physiologic regions (below, within, or above the optimal range, and ventricular suction) with over 90% reliability. Ongoing work is directed toward improving the detection of ventricular suction, as this condition must be strictly avoided.

Continued development of the Nimbus/University of Pittsburgh (UOP) axial flow left ventricular assist system.

Nimbus and the University of Pittsburgh (UOP) have continued the development of a totally implanted axial flow blood pump under the National Institutes of Health (NIH) Innovative Ventricular Assist System (IVAS) program. This 62 cc device has an overall length of 84 mm and an outer diameter of 34.5 mm. The inner diameter of the blood pump is 12 mm. It is being designed to be a totally implanted permanent device. A key achievement during the past year was the completion of the Model 2 pump design. Ten of these pumps have been fabricated and are being used to conduct in vitro and in vivo experiments to evaluate the performance of different materials and hydraulic components. Efforts for optimizing the closed loop speed control have continued using mathematical modeling, computer simulations, and in vitro and in vivo testing. New hydraulic blade designs have been tested using computational fluid dynamics (CFD) and flow visualization. A second generation motor was designed with improved efficiency. To support the new motor, a new motor controller fabricated as a surface mount PC board has been completed. The program is now operating under a formal QA system.