Feasibility of a Composite Measure of Pulmonary Vascular Impedance and Application to Patients with Chronic RV Failure Post LVAD Implant.

Pulmonary vascular impedance (PVZ) describes RV afterload in the frequency domain and has not been studied extensively in LVAD patients. We sought to determine (1) feasibility of calculating a composite (c)PVZ using standard of care (SoC), asynchronous, pulmonary artery pressure (PAP) and flow (PAQ) waveforms; and (2) if chronic right ventricular failure (RVF) post-LVAD implant was associated with changes in perioperative cPVZ.PAP and PAQ were obtained via SoC procedures at three landmarks: T(1), Retrospectively, pre-operative with patient conscious; and T(2) and T(3), prospectively with patient anesthetized, and either pre-sternotomy or chest open with LVAD, respectively. Additional PAP's were taken at T(4), following chest closure; and T(5), 4-24 h post chest closure. Harmonics (z) were calculated by Fast Fourier Transform (FFT) with cPVZ(z) = FFT(PAP)/FFT(PAQ). Total pulmonary resistance Z(0); characteristic impedance Zc, mean of cPVZ(2-4); and vascular stiffness PVS, sum of cPVZ(1,2), were compared at T(1,2,3) between +/-RVF groups.Out of 51 patients, nine experienced RVF. Standard hemodynamics and changes in cPVZ-derived parameters were not significant between groups at any T.In conclusion, cPVZ calculated from SoC measures is possible. Although data that could be obtained were limited it suggests no difference in RV afterload for RVF patients post-implant. If confirmed in larger studies, focus should be placed on cardiac function in these subjects.

Hemodynamics and the vascular endothelial cytoskeleton.

Although there is considerable evidence to suggest that hemodynamics play an important role in vascular disease processes, the exact mechanisms are unknown. With this in mind, we have designed a pulsatile perfusion apparatus which reproducibly delivers pulsatile hemodynamics upon freshly excised canine carotid arteries in vitro. Quantifiable simulations included normotension with normal or lowered flow rates (120/80 mmHg, 120 and 40 ml/min), normotension with lowered or elevated transmural pressures (40-170 mmHg), and elevated pulse pressure (120 and 80 mmHg) with normal (150 ml/min) or elevated rates of flow (300 and 270 ml/min). Arterial biomechanical stresses and cellular behaviors were characterized biochemically and morphologically under all these stimulations which continued for 2-24 h. We found that increased pulse pressure alone had little effect on the total amount of radiolabeled [4-14C]cholesterol present within the medial compartment. However, normotension when coupled with altered transmural pressure yielded a three- to fourfold increase. Combinations of increased pulse pressure and flow potentiated cholesterol uptake by a factor of 10 when compared with normotension control values. Simulations that enhanced carotid arterial cholesterol uptake also influenced the endothelial cytoskeletal array of actin. Stress fibers were not present within the carotid endothelial cells of either the sham controls or the normotension and increased pulse pressure (normal flow) simulations. Endothelial cells lining carotids exposed to elevations in flow or those present within vessels perfused as per simulation b above assembled stress fibers (x = 4 and 10 per cell, respectively) within the time course of these studies. When endothelial cells were subjected to hemodynamic conditions that potentiated maximally cholesterol transport, no diffuse or stress fiber staining could be seen, but the cortical array of actin was intact. These results suggest that those biomechanical stresses that alter endothelial permeability and intimal integrity may do so via cytoskeletal actin signaling.

Arteriovenous ECMO for neonatal respiratory support. A study in perigestational lambs.

A study was undertaken to investigate the applicability of the arteriovenous mode of perfusion for partial support of neonatal respiration. Perigestational lambs, delivered by cesarean section, served as the animal model of respiratory distress. Arteriovenous flow was accomplished between a single umbilical artery and vein. A microchannel membrane oxygenator was used to provide partial respiratory support to the newborn lambs. Total systemic flow, pulmonary blood flow, and pulmonary vascular resistance were assessed at various rates of arteriovenous perfusion and correlated with systemic oxygenation. A reduction in right-to-left shunting of blood and pulmonary vascular resistance occurred as arterial oxygenation rose from conditions of hypoxemia to PaO2 values higher than 50 torr. Myocardial performance was not impaired at rates of arteriovenous perfusion below 30 percent of the total systemic flow, as evidenced by normal electrocardiographic tracings, pulmonary capillary wedge pressures, and central venous pressures. Arteriovenous extracorporeal membrane oxgenation (ECMO) may be particularly suitable for use in infants with hypoxia and high pulmonary vascular resistance.

Extracorporeal membrane oxygenation. Successful treatment of persistent fetal circulation following repair of congenital diaphragmatic hernia.

Four neonates (three having undergone repair of a congenital diaphragmatic hernia and developing a persistent fetal circulatory pattern and one having severe infant respiratory distress syndrome) have been supported with prolonged extracorporeal membrane oxygenation (ECMO) at Children's Hospital of Pittsburgh between December of 1979 and April of 1980. Three have survived. This encouraging experience indicates that the pattern of persistent fetal circulation in the newborn infant who has undergone repair of a diaphragmatic hernia can be successfully managed with ECMO even when efforts to lower pulmonary hypertension and improve oxygenation with vasodilators (tolazoline, phenothiazine, acetylcholine, or prostaglandin E1) and have been ineffective. The effectiveness and safety of ECMO is convincing enough to warrant its consideration as therapy for congenital diaphragmatic hernia and persistent fetal circulation prior to the use of vasodilators.

Measurement in vitro of pulsatile arterial diameter using a helium-neon laser.

A noncontacting in vitro measurement of pulsatile arterial diameter using a scanning optical micrometer is described. The major component of this system is a He-Ne laser whose beam scans the pulsating artery to be measured. The laser micrometer was integrated into a pulsatile perfusion apparatus that imposed various hemodynamic conditions on excised canine vessels. The laser system reliably tracked the pulsating arterial diameter at a particular longitudinal site as well as at various increments in the presence of an experimentally created stenosis. The He-Ne laser measured the radial motion of canine arteries and various vascular substitutes anastomosed in an end-to-end fashion. From these novel measurements, calculations were made of arterial compliance and bending stress, two biomechanical parameters that are implicated as potential causes of anastomotic intimal hyperplasia and graft failure. Although this device is inherently limited to in vitro use, it is a potentially useful instrument for vascular physiology and biophysics.

Clinical experience with pediatric microporous oxygenator for profound hypothermia.

The Travenol TMO Total Bypass Membrane Oxygenator-Pediatric satisfactorily transfers oxygen and carbon dioxide under standardized conditions of operation during total high-flow bypass at normothermia or moderate hypothermia. This oxygenator has not been used at rates of flow less than 1 L/min or at temperatures below 23 degrees C. The current technique requires a venous and arterial pump with 5% recirculation to assure that pressure in the blood phase does not exceed the pressure above which blood may seep through the adhesive seals into the gas envelope. Conventional methods of perfusion were modified for use at profound hypothermia (18 degrees C) with low-flow bypass or circulatory arrest. Clinical experience with 22 children, preceded by six laboratory experiments, indicates that satisfactory control of arterial gases can be achieved and maintained.

Hemodynamic effects on endothelial cell monolayer detachment from vascular prostheses.

The establishment of an early blood-contacting endothelialized surface may improve the graft-host relationship. This study evaluated the adherence of indium 111-radiolabeled endothelial cells that were cultured to confluence on fibronectin-treated polyester elastomer (Hytrel) grafts that were perfused for two hours on a pulse duplicator apparatus under high- and low-shear conditions. Perfusate samples were serially assayed for radioactivity. After perfusion, grafts were sectioned into four segments and assayed for retained radioactivity. All graft segments were hematoxylin stained and examined under light microscopy for evaluation of cell density. Excellent endothelial cell adherence (90%) was observed under both hemodynamic conditions at 120 minutes, with most losses occurring within the first 15 minutes. No differences were seen between high- and low-shear conditions or proximal vs distal graft segments.

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.

Cardiopulmonary dynamics during arteriovenous perfusion: cardiac output, pulmonary arterial resistance, and right venticular stroke work.

The effects of arteriovenous perfusion on myocardial performance, pulmonary circulatory dynamics, and organ preservation were studied in dogs in order to evaluate the applicability of arteriovenous extracorporeal membrane oxygenation for partial respiratory support. Studies were made on normally oxygenated dogs, on dogs made hypoxic by oxygen deprivation and ventilatory depression, and on dogs with pulmonary injury and moderate pulmonary hypertension induced by injection of oleic acid into the right ventricle. The latter two groups were included to assess the changes that occur in cardiopulmonary dynamics in the presence of hypoxia and pulmonary hypertension. A microchannel membrane oxygenator was employed to provide partial respiratory support to the group of animals with pulmonary injury. The results indicate that no deleterious hemodynamic changes occurred in any of the groups of animals with arteriovenous flow for periods of up to 5 hours at rates corresponding to 20 to 35% of the total cardiac output. Adequate systemic oxygenation was provided by the microchannel oxygenator at these rates of arteriovenous perfusion.

Experience with univentricular support in mortally ill cardiac transplant candidates.

Between July 1987 and March 1989, 11 patients underwent left ventricular support with the Novacor left ventricular assist system irrespective of apparent degree of right ventricular failure. The first 2 patients died of multisystem organ failure while on support. All the remaining patients survived the support period, and actuarial survival after transplantation was 100% at 6 months and 89% at 1 year. In no patient did bacterial infection develop during support or after transplantation. Right ventricular ejection fraction before implantation of the left ventricular assist system was lower than 15% in 6 of 8 patients, yet it increased twofold during left ventricular support. The need for excessive inotropic support (2 patients) or temporary (four days) mechanical right ventricular support (2 patients) while on the left ventricular support system appeared to be related to elevated pulmonary vascular resistance during support in association with large preimplantation ventricular volumes. It appears that even patients with compromised right ventricular performance can be supported long term with a left ventricular assist device. Patients with elevated pulmonary vascular resistance may require temporary right ventricular support.

HeartMate II left ventricular assist system: from concept to first clinical use.

The HeartMate II left ventricular assist device (LVAD) (ThermoCardiosystems, Inc, Woburn, MA) has evolved from 1991 when a partnership was struck between the McGowan Center of the University of Pittsburgh and Nimbus Company. Early iterations were conceptually based on axial-flow mini-pumps (Hemopump) and began with purge bearings. As the project developed, so did the understanding of new bearings, computational fluid design and flow visualization, and speed control algorithms. The acquisition of Nimbus by ThermoCardiosystems, Inc (TCI) sped developments of cannulas, controller, and power/monitor units. The system has been successfully tested in more than 40 calves since 1997 and the first human implant occurred in July 2000. Multicenter safety and feasibility trials are planned for Europe and soon thereafter a trial will be started in the United States to test 6-month survival in end-stage heart failure.

Chronic mechanical circulatory support: rehabilitation, low morbidity, and superior survival.

Because of donor scarcity, 12 (39%) of a series of 31 Novacor left ventricular assist system recipients required mechanical circulatory support for an average of 125 days before transplantation (range, 61 to 303 days). Ten received a heart transplant and all survived to discharge. Two died of infection before transplantation after 93 and 303 days of support. Significant reductions were noted from preimplantation values of right and left cardiac filling pressures. Right ventricular ejection fraction and cardiac index increased. The 4-month actuarial freedom from infection during support was 75%. Three patients benefited from chronic outpatient housing for 5, 18, and 131 days, respectively, with improvements in quality of life measures. Ten chronically supported patients participated in an intensive rehabilitative exercise program resulting in an improvement of New York Heart Association class from IV to I in 9 patients. Mean oxygen consumption, which was 10 mL.kg-1.min-1 30 days after implantation (mean exercise time, 10 minutes) had risen to 15 mL.kg-1.min-1 before transplantation (mean exercise time, 16 minutes). This series suggests that long-term circulatory support is compatible with low morbidity, significant physical and hemodynamic rehabilitation, and an outpatient setting.

Development and initial testing of a pediatric centrifugal blood pump.

BACKGROUND: We are developing a miniaturized centrifugal blood pump for use as a temporary cardiac assist device in neonatal and pediatric sized patients. This pump has a very low priming volume of 13 mL. A small motor stator has also been designed, which resulted in a device that can be placed very close to the patient, thereby minimizing overall circuit volume. METHODS: Testing to date has included in vitro hemodynamic performance, in vitro hemolysis generation, and in vivo evaluation in 5 lambs weighing 5.5 to 21 kg. Two lambs underwent peripheral cannulation from external jugular vein to carotid artery, whereas 3 others were cannulated from left atrium to carotid artery. RESULTS: In vitro data demonstrated pump capacity spanning 0.3 to 3.0 L/min and very low hemolysis generation at these conditions. In vivo, the pump functioned satisfactorily for periods up to 148 hours, and the bypass appeared to be well tolerated by the animals. Plasma free hemoglobin levels remained less than 25 mg/dL during all animal experiments. All devices were thrombus-free at explantation. CONCLUSIONS: We conclude that this device has merit as an alternative to current oversized systems used for neonatal and pediatric cardiac assistance. In addition, a chronic neonatal lamb model in which to evaluate pediatric circulatory assist devices has been developed successfully.

Clinical utilization of the artificial heart.

During the past 30 years the artificial heart has evolved from a bioengineering concept to clinical reality. To date four patients have had an artificial heart implanted as a permanent device, while over 150 artificial hearts have been utilized temporarily as a bridge to cardiac transplantation. Increased use of this device requires that a number of issues be critically addressed: (1) criteria for patient selection; (2) operative techniques for implantation including size of device and its position in the mediastinum; and (3) management of the patient in the intensive care unit (ICU), in particular, regimens of anticoagulation, assessment of adequacy of organ perfusion, and prevention of sepsis. This chapter is a discussion of these bioengineering and clinical concerns with respect to the Jarvik total artificial heart (TAH). Clinical data are presented which highlight the current problems with these devices and the areas of future research that need to be undertaken.

Characterisation of the unsteady transport of labelled species in permeable capillaries: role of convective dispersion.

A mathematical model of transcapillary exchange has been developed which considers in detail the contribution of Taylor dispersion (i.e., non-uniform velocity and inequalities in radial concentration) to the uptake and wash-out of multiple tracers from single capillaries. A numerical solution to the two-dimensional unsteady-state species continuity equation for a single capillary is obtained (by the use of an array processor) which simulates the convective dispersion of labelled indicators in permeable capillaries. Particular attention is directed toward an analysis of the roles of capillary permeability, transport regime as characterised by the Peclet number, velocity profile and the length of the exchange region on the development of time-concentration profiles and on the importance of convective dispersion. For the physiologic range of parameters consistent with pulmonary capillary transport of multiple indicators (e.g., labelled urea, albumin, etc.), we find that the magnitude of convective dispersion is insufficient to markedly affect the shapes of simulated tracer concentration profiles. The implication in these circumstances is that the use of one-dimensional models, which do not account for Taylor dispersion, does not lead to significant errors in parameter estimates derived from data of multiple indicator dilution.

Towards an evaluation of the accuracy of ventilatory rate constants derived from dynamic computer-assisted tomographic measurements.

Dynamic computer-assisted tomographic (CT) measurements using non-radioactive xenon gas have recently been employed along with a simple model of pulmonary transport to derive ventilation rate constants (K) in small tissue volumes. Inherent in the model description is the assumption that instantaneous diffusion equilibrium occurs between inhaled Xe gas and lung tissue. The validity of this assumption as it relates to the accuracy of the derived values of K has been considered for both normal and oedematous tissue, the latter characterised by a severe widening of the interstitial fluid space. It was found that only a small error in the predicted values for K results, when the simple model is applied to the dynamic cT measurements of xenon enhancement.

Numerical simulation of the transient transport of inert gases in lung tissue.

A numerical simulation of the transport of xenon gas into healthy and oedematous lung tissue is described. The lung is modelled as four parallel tissue layers; alveolar membrane, interstitial fluid, capillary membrane, and blood, surrounded by a uniform air space. Using a finite difference representation of the governing diffusion equations, the concentration distribution of Xe gas in each of the layers of tissue is obtained for a step change in the Xe concentration in the air space. The effect of a thickening of the interstitial fluid layer, found in pulmonary oedema, on the kinetics of Xe transport is also considered. Computational findings indicate that a good approximation to the steady state profiles for Xe in the layers of tissue can be obtained simply by assuming that instantaneous equilibrium exists (as described by Henry's Law) between the lung tissue and surrounding air space. This same finding is documented even when the thickness of the interstitial fluid layer is increased by a factor of 40 above baseline values. The results suggest that the reduction in gas exchange which occurs in pulmonary oedema is caused by fluid flow into the alveoli, rather than a true diffusion deficit caused by a thicker alveolar-capillary barrier. The relationship of the present findings to those which would be obtained for more physiological input functions of Xe gas into the air space in also discussed.

Role of longitudinal diffusion in the extravascular pulmonary space on parameter estimates derived from data of multiple indicator dilution.

A mathematical model of transcapillary exchange has been developed that considers in detail the role of axial diffusion in the extravascular tissue region on estimates of such physiological parameters as lung water (VE) and pulmonary capillary permeability-surface area products (PS), obtained from multiple indicator dilution studies. The experimental cases considered correspond to two animal models of pulmonary oedema in which the integrity of the pulmonary capillary membrane is disrupted and the effects of extravascular axial diffusion may be important. A novel feature of the computational scheme is the use of an Array Processor in the solution of the governing equations, initial and boundary conditions. Computer time is reduced to 2-3 min for parameter identification, thereby allowing a wide range of values for extravascular axial diffusion coefficients (D'/L2) to be studied at little computational expense. The results indicate that diffusion in the extravascular region does not influence parameter estimates for PS to urea. A statistical correlation is suggested between values for VE, PS to water, and D'/L2.

Experimental determination of mechanical shear stress about an anastomotic junction.

The present study is undertaken to determine whether the elastic tube model originally developed by Kuchar and Ostrach (Biomedical Fluid Mechanics Symposium, pp. 45-69, 1966) accurately provides a first approximation of the biomechanics of the anastomotic junction. The experimental protocol involves the use of canine carotid arteries as the host vessel and several graft materials including autogenous and prosthetic substitutes. The host artery-graft combinations are perfused in vitro in a pulsatile perfusion apparatus which simulates the natural hemodynamic environment. This apparatus provides accurate dynamic measurements of radial wall motion (measured at various longitudinal increments), associated pressures and rates of fluid flow. These data are then applied to the theoretical model for calculation of anastomotic induced bending stresses. The results indicate that the predictions derived from the elastic model consistently overestimate the measured radial change adjacent to the anastomotic junction. As a result shear stresses based on elastic theory deviate from values derived from a numerical curve fit to the experimental data.

A model of pulsatile flow in a uniform deformable vessel.

Simulations of blood flow in natural and artificial conduits usually require large computers for numerical solution of the Navier-Stokes equations. Often, physical insight into the fluid dynamics is lost when the solution is purely numerical. An alternative to solving the most general form of the Navier-Stokes equations is described here, wherein a functional form of the solution is assumed in order to simplify the required computations. The assumed forms for the axial pressure gradient and velocity profile are chosen such that conservation of mass is satisfied for fully established pulsatile flow in a straight, deformable vessel. The resulting equations are cast in finite-difference form and solved explicitly. Results for the limiting cases of rigid wall and zero applied pressure are found to be in good agreement with analytical solutions. Comparison with the experimental results of Klanchar et al. [Circ. Res. 66, 1624-1635 (1990]) also shows good agreement. Application of the model to realistic physiological parameter values provides insight as to the influence of the pulsatile nature of the flow field on wall shear development in the presence of a moving wall boundary. Specifically, the model illustrates the dependence of flow rate and shear rate on the amplitude of the vessel wall motion and the phase difference between the applied pressure difference and the oscillations of the vessel radius. The present model can serve as a useful tool for experimentalists interested in quantifying the magnitude and character of velocity profiles and shearing forces in natural and artificial biologic conduits.