A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy

Recent research on development of the implantable artificial pancreas for treatment of diabetes is reviewed, based on a Medline literature search that focused on glucose sensors, insulin pumps, and pump control systems. To achieve a closed feedback loop, a clinically applicable implantable artificial pancreas requires miniaturization and coordination of three components: an insulin pump, a blood glucose monitor, and a control system. Recent clinical studies have demonstrated that implantable insulin pumps are feasible for satisfactory control of diabetes for over a year, with the major complication being obstruction of the infusion catheter. Research on continuous glucose sensors has predominantly used the glucose-oxidase reaction or near-infrared light spectroscopy. Implantable glucose oxidase sensors have been limited by local factors causing unstable signal output, whereas optical sensors must overcome interference by substances with absorption spectra similar to glucose. Investigators have developed control algorithms in an effort to stabilize operation of the integrated artificial pancreas in the face of variations in sensor output and pump function. The ultimate goals of fully automatic glucose control by an artificial pancreas include prevention or delay of chronic complications of diabetes, lowered risk of hypoglycemia, and less patient inconvenience and discomfort than with multiple daily glucose self-tests and insulin injection. The recent developments of optical glucose sensing, radiotelemetry systems to link pump and sensor, and miniaturization and refinement of insulin pumps are significant steps toward a clinically applicable artificial pancreas.     

In vitro thrombogenicity testing of artificial organs

Thromboembolic complications remain as one of the main problems for blood contacting artificial organs such as heart valves, bloodpumps and others. In vitro evaluation of thrombogenesis in prototypes has not previously been part of the standard evaluation of these devices. In comparison to hemolysis testing, evaluation of the thrombogenic potential is more difficult to perform because of the complexity of the blood coagulation system. We present an in vitro testing procedure that allows the accelerated examination of the thrombogenic potential of different types of blood pumps. Additionally, first results are presented that indicate the reliability of the accelerated clotting test for mechanical heart valves. Results for the centrifugal pump BioMedicus and two microaxial pumps have shown typical thrombus formation at locations such as bearings. The results indicate that the accelerated clotting test is an excellent addition to the much more expensive animal testing of artificial organs or assist devices. In vitro testing permits studies of thrombus formation to be performed at an early stage and at low costs and also facilitates a more precise investigation of device areas known to be potential hot spots for thrombus formation.     

Continuous monitoring of autonomic nerve information for the control of an artificial heart

To drive an artificial heart system optimally, information from the autonomic nervous system may be needed; however, it is very difficult to monitor autonomic nerve discharges continuously. In this study, we propose a new automatic control algorithm for a total artificial heart (TAH) using fluctuations in the circulatory system. It was reported that fluctuations in hemodynamics reflect ongoing information from the autonomic nervous system. A Mayer wave at 0.1 Hz was reported to reflect sympathetic information. We observed fluctuations in vascular resistance, which can be measured during use of an artificial heart. Four adult goats were used for the experiments. Through a left thoracotomy, hemodynamic parameters were measured during chronic animal experiments. All time series data were recorded on magnetic tape. Quantitative analysis, statistics, and spectral analysis were carried out on a computer through an analog-digital (AD) converter. A Mayer wave peak was clearly recognized in all goats in the spectrum of vascular resistance. A band pass filter was used to convert this information to automatic control. Time series curves of the Mayer wave of vascular resistance were provided, and compared with the time series curve of the cardiac output. After a change in the Mayer wave, increase in cardiac output was observed. This phenomenon may be interpreted as sympathetic nervous control of changes in cardiac output. These results suggest that an artificial heart may be controlled by the measurement of the Mayer wave of vascular resistance, making it possible to control an artificial heart with neural information.     

Prolonged pulseless perfusion in unanesthetized calves

Nonpulsatile left ventricular (LV) bypass was achieved in nine alert, active calves for periods of up to two weeks using a centrifugal blood pump. Data were compared to prebypass control values and to results obtained from seven calves that underwent nonthoracotomy, retrograde LV cannulation, and pulsatile bypass for up to 35 days. Nonpulsatile flow produced an increase in heart rate of 20% (P less than .05) and an increase in aortic pressure of 10% (P less than .05). Cardiac output and systemic vascular resistance were similar in both groups for three days; thereafter, vascular resistance decreased as cardiac output progressively increased. Serum renin, lactate, and pyruvate values remained normal; creatinine clearances were not significantly different than control values, and there were no significant changes in body weight. These data indicate no untoward effects as a result of prolonged pulseless perfusion.     

The artificial heart and neuromonitoring? Technical and clinical aspects

There is a steady progress in the development of artificial heart and circulatory assist devices. There is also no doubt that further advances in energy systems, materials, and electronics will provide for smaller and more reliable electrically driven blood pumps, but the present engineering design appears to be adequate to provide devices satisfactory for initial clinical use. Due to problems in the availability of suitable donor hearts, the concept of replacing the natural heart with an artificial heart as a "bridge to transplantation" has gained attention in recent years. The present paper shows technical and clinical aspects of multivariable electrophysiologic neuromonitoring in a patient with an artificial heart assist device in the intensive care unit. The data (EEG, 40 Hz brain oscillations, brainstem auditory- and somatosensory evoked potentials) are discussed with respect to the influence of the artificial heart on their quality and reliability. Reasons for artifacts and problems of interpretation are shown.     

Monitoring of cardiac function in patients with a left ventricle assist device

In complex therapy of acute or chronic cardiac failure, the use of valve-free centrifugal pumps or artificial heart ventricles takes place. In these cases, simultaneous monitoring of cardiac and pump performance is very important. In this study, an ultrasound dilution method based on the registration of two dilution curves after intravenous injection of isotonic and hypertonic sodium solution was developed. Comparison of total cardiac output (TCO), which included pump and heart output measured by thermodilution and ultrasound (TCOus) dilution, yielded TCOus = 1.11TCOth - 0.54 (n = 13).     

Long-term in vivo left ventricular assist device study with a titanium centrifugal pump

A totally implantable centrifugal artificial heart has been developed. The plastic prototype, Gyro PI 601, passed 2 day hemodynamic tests as a functional total artificial heart, 2 week screening tests for antithrombogenicity, and 1 month system feasibility. Based on these results, a metallic prototype, Gyro PI 702, was subjected to in vivo left ventricular assist device (LVAD) studies. The pump system employed the Gyro PI 702, which has the same inner dimensions and the same characteristics as the Gyro PI 601, including an eccentric inlet port, a double pivot bearing system, and a magnet coupling system. The PI 702 is driven with the Vienna DC brushless motor actuator. For the in vivo LVAD study, the pump actuator package was implanted in the preperitoneal space in two calves, from the left ventricular apex to the descending aorta. Case 1 achieved greater than 9 month survival without any complications, at an average flow rate of 6.6 L/min with 10.2 W input power. Case 2 was killed early due to the excessive growth of the calf, which caused functional obstruction of the inlet port. There was no blood clot inside the pump. During these periods, neither case exhibited any physiologic abnormalities. The PI 702 pump gives excellent results as a long-term implantable LVAD.     

Artificial heart transplants

The use of a mechanical device to support a failing heart is one of the greatest challenges in cardiothoracic practice. Many different approaches are being considered, but they share the use of many advanced engineering principles. Power supplies and the interface between artificial surfaces and the blood remain areas of difficulty. The accent is moving from console driven devices with drive lines which must cross the body wall to reach the pump, towards smaller control packs, with inductive coupling to fully contained pumps. More attention is focused on the use of axial pumps lying within the lumena of the great vessels and the ventricles. Despite the wideheld belief that mechanical pumps must confer survival advantage to the recipients, there has been no prospective study demonstrating any advantage over medical management of the failing heart. Economic considerations must be taken into account if the technology is to be available to everyone with heart failure.     

The analysis of driving mode influence on energy dissipation in pneumatic artificial heart chambers

The energy dissipated in blood or on a total artificial heart (TAH) chamber's elements directly or indirectly decreases the biological or technical safety of the TAH's work. The energetic analysis of the Polish total artificial heart (POLTAH) external work with the objective of estimating the valve and membrane roles in energy dissipation has been performed. The simulation of left and right artificial heart chamber work under physiological conditions using a self-constructed physical model of the circulatory system has been performed for the full systole percent and frequency range and for different valves. The total energy dissipated on valves equals 15-30% of the chambers' work value. Energy losses on valves are influenced by the driving mode. The usage of inappropriate systolic and diastolic times increases the value of the energy dissipated on the membrane and on valves in the overall energy balance. The absolute value of the energy dissipated on the valves increases with the increase of the cycle time and depends on the valve type. The energy dissipated on the outlet valve decreases with the frequency (if the remaining driving parameters are kept constant) and for 150 bpm is nearly 3 times lower than that for 30 bpm. The energy dissipated on the membrane equals 10-50% of the TAH's work during systole, depending on the driving parameters. The filling process is assisted by the pressure from the atrium, and a great amount of energy during the diastolic period is consumed by the start of the membrane movement. We have also estimated the influence of the driving parameters on the valves' functions, measuring the acoustic wave intensity. The conclusions drawn are of a general character; they are applicable to all membrane, pneumatically powered blood pumps.     

A new design for a totally artificial heart: the ellipsoid heart (author's transl)]

Thromboembolic complications represent the main limiting factor in cardiac replacement by totally artificial hearts in calves at present. Thrombus formation within artificial hearts is caused by the appearance of stagnation areas. The ellipsoid heart eliminates stagnation areas by virtue of its production as a one-piece membrane. The heart is driven pneumatically and functions as a diaphragmatic blood pump. The stroke volume is 178 cm3 and the maximal cardiac output 15.8l/Min. Three acute experiments demonstrated a high degree of haemodynamic efficiency without compression of, or interference with surrounding structures, especially the inferior vena cava or the right atrium.     

Cora valveless pulsatile rotary pump: new design and control

For decades, research for developing a totally implantable artificial ventricle has been carried on. For 4 to 5 years, two devices have been investigated clinically. For many years, we have studied a rotary (but not centrifugal) pump that furnishes pulsatile flow without a valve and does not need external venting or a compliance chamber. It is a hypocycloidal pump based on the principle of the Maillard-Wankel rotary compressor. Currently made of titanium, it is activated by an electrical brushless direct-current motor. The motor-pump unit is totally sealed and implantable, without noise or vibration. This pump was implanted as a left ventricular assist device in calves. The midterm experiments showed good hemodynamic function. The hemolysis was low, but serious problems were encountered: blood components collecting on the gear mechanism inside the rotor jammed the pump. We therefore redesigned the pump to seal the gear mechanism. We used a double system to seal the open end of the rotor cavity with components polished to superfine optical quality. In addition, we developed a control system based on the study of the predicted shape of the motor current. The new design is now underway. We hope to start chronic experiments again in a few months. If the problem of sealing the bearing could be solved, the Cora ventricle could be used as permanent totally implantable left ventricular assist device.     

Origin of chaos in the circulation: open loop analysis with an artificial heart

To develop the optimal automatic control algorithm for an in vivo artificial heart system, investigation of the basic characteristics of the cardiovascular system may be important. The clinical significance of chaotic dynamics in the cardiovascular system has attracted attention. The circulation is a so-called complex system with many feedback circuits, making it very difficult to investigate the origin of chaos within the system. In this study, we investigated the origin of chaos by open loop analysis with an artificial heart (which has no fluctuation in pumping rate or contraction power) in chronic animal experiments with healthy adult goats. As a result, in the artificial heart circulatory time series data, low dimensional deterministic chaos was discovered by nonlinear mathematical analysis, suggesting the importance of blood vessels in the chaotic dynamics of the cardiovascular system. To investigate the origin of chaos further, sympathetic activity was directly measured in animals with artificial hearts. Chaotic dynamics was also recognized in sympathetic action potentials, even during artificial heart circulation. Coupling of the nonlinear information between blood vessels and sympathetic activity was suggested by analysis of mutual information. In chaotic dynamics, the central nervous system (CNS) played an important role through sympathetic activity. These findings may be useful for the development of an automatic control algorithm for an artificial heart.     

Peripheral vascular versus direct cardiac effects of calcium

Peripheral vascular and direct cardiac effects of calcium chloride were determined in a new animal model, the unanesthetized calf, before and after replacement of its natural heart (NH) with a pneumatically driven artificial heart (AH). Calcium (5 and 10 mg/kg) significantly increased cardiac output (Qt) and reduced systemic vascular resistance (SVR) before and after AH implantation. Increases in Qt in AH calves and reductions in SVR in both NH and AH calves were, however, transient, being present 5 minutes but not 15 minutes after both doses of calcium. Increases in Qt and reductions in SVR were significantly (P less than .05) greater after 10 mg/kg than after 5 mg/kg calcium in NH and AH calves. Both doses of calcium produced greater (P less than .05) increases of Qt in NH than in AH animals but similar reductions in SVR. Pulmonary vascular resitance, heart rate and pulmonary arterial and right atrial pressures were not significantly altered by either dose of calcium in NH or AH calves. Mean aortic pressure was influenced by 10 mg/kg calcium only, being transiently reduced in AH calves and increased in NH animals. Pulmonary shunt (QS/Qt) was increased by both doses of calcium in NH calves but only by 10 mg/kg in AH animals. Correlations of mean change in QS/Qt with mean change in Qt were high both before (r=.99) and after (r=.97) AH implantation. These data demonstrate that calcium significantly reduces SVR in a dose-related manner as well as exerting a positive inotropic effect on the myocardium.     

Mean systemic pressure and mean pulmonary pressure: their effects on the total artificial heart

Mean systemic pressure (MSP) and mean pulmonary pressure (MPF), which are mean driving pressures for venous return in the natural heart, were studied in 11 calves in which the natural heart had been replaced with a total artificial heart (TAH). They were measured simply by stopping the artificial heart pumping. Although blood translocation from the arterial to the venous side was not performed, the eventual right and left atrial pressures reached six to eight seconds after stopping the TAH would represent MSP and MPP with reasonable accuracy. The MSP varied from nine to 3k mmHg (20+/-6 mmHg), whereas the MPP varied from nine to 39 mmHg (22+/-7 mmHg). The MSP varied in close relation to the right atrial pressure prior to cessation of the TAH (r=0.9124). Increases in RAP and MSP were mainly attributed to an increase in circulating blood volume. In the performance of the TAH, MSP (or MPP), proper diastolic duration and vacuum application during diastole was of prime importance in determining the end-diastolic ventricular volume.     

Collaborative problem-solving in telemedicine and evidence interpretation in a complex clinical case

The objective of this study was to evaluate the effect of different infection levels of Ostertagia ostertagi and Cooperia oncophora in a simulated 'first grazing season' on the resistance of calves to an artificial challenge infection. The infection levels were determined by the infection schedules and the chemoprophylaxis used. Thirty six 7-11-month old Holstein-Friesian bull calves were randomly divided into four groups. The animals of group B received an ivermectin sustained release bolus (ISRB) on day 0. The calves of group D were treated on days 0 and 56 with a subcutaneous injection of doramectin (0.2 mg kg(-1) BW). Group C was the untreated control group. The calves of group N were used as helminth-naive controls, while the animals of groups B, C and D were trickle infected for 24 weeks. The infection schedules were designed to simulate the expected infection pattern for each treatment group under set-stocked conditions in temperate climate areas. After the last infection, all animals were treated with oxfendazole. One week later, all animals received a challenge infection of 50,000 O. ostertagi L3 and 100,000 C. oncophora L3, spread over 10 consecutive days. During the primary infection period the faecal egg output and the serum pepsinogen and antibody levels reflected the different levels of host-parasite contact between the groups (group C > group D > group B > group N). After the challenge infection, faecal egg counts, total Ostertagia burden, size of the adult worms and abomasal globule leucocyte counts all indicated a positive relationship between the level of Ostertagia infection during the primary infection period and the level of acquired resistance. A reduction of host-parasite contact during the primary infection period, as a consequence of the infection schedule and the chemoprophylaxis used, resulted in a diminished level of resistance to the artificial challenge infection with O. ostertagi. Faecal cultures and small intestine worm counts indicated that all previously infected groups had acquired a high degree of resistance to the Cooperia challenge infection.     

Circulatory support with pneumatic paracorporeal ventricular assist device in infants and children

BACKGROUND: Mechanical circulatory support in intractable heart failure in children has been limited to centrifugal pumps and extracorporeal membrane oxygenation: Since 1990 small adult-size pulsatile air-driven ventricular assist devices "Berlin Heart" (VAD) and, since 1992 miniaturized pediatric VAD (12, 15, 25, 30 mL pumps), have been used in our institution. Since 1994 the blood-contacting surfaces of the device system have been heparin-coated. In this report the experiences with VAD support in 28 children are presented. METHODS: In 28 children-ages between 6 days and 16 years-the Berlin Heart VAD has been applied for periods of between 12 hours and 98 days (mean, 16.9 days) aiming at keeping the patient alive and allowing for recovery from shock sequelae until later transplantation or myocardial recovery. There were three groups. Group I: with primary intention of "bridge-to-transplantation" in various forms of cardiomyopathy (n = 13) or chronic stages of congenital heart disease (n = 5). Group II: "Rescue" in intractable heart failure early after corrective surgery for congenital heart disease (n = 4) or in early graft failure after a heart transplantation (n = 1). Group III: "Acute myocarditis" (n = 5) aiming at either myocardial recovery or transplantation. Twelve were brought to the operating room under cardiac massage and 25 had been on the respirator for more than 24 hours. RESULTS: Twelve patients died on the system from sequelae of profound shock-multiorgan failure, sepsis, loss of peripheral circulatory resistance-or from hemorrhagic complications (n = 4) or brain death (n = 1). Thirteen patients (groups I and III) were transplanted after support periods of between 3 and 98 days with 7 long-term survivors living now up to 7.5 years (mean, 4.4 years). Three patients (groups II and III) were weaned from the system with two long-term survivors (both in group III). There were no patients in group II who survived and the "rescue" indication has been discarded for VAD since 1992. Such patients are since treated by extracorporeal membrane oxygenation (ECMO) in our institution. Out of the 8 patients placed on VAD during 1996 and 1997, 7 were successfully supported until transplantation or weaning. Thirteen patients were extubated and mobilized on the system. Whereas with the earlier systems thrombi in the blood pumps were seen in 15 instances and 2 patients suffered from thromboembolic complications, no thrombotic events occurred with the heparin-coated systems. CONCLUSIONS: After accumulating clinical experience and several technical improvements since 1990 the use of the pediatric Berlin Heart VAD has matured into a reliable and safe system to keep patients with otherwise intractable heart failure alive until complete myocardial recovery is reached or transplantation becomes feasible. Whereas heart failure early after cardiac operation is now primarily treated by ECMO, acute myocarditis appears to be a promising precondition for complete cardiac recovery during VAD support.     

Effects of FR167653 on ischemia-reperfusion injury: evaluation through preservation and transplantation in canine hearts

BACKGROUND: Ischemia-reperfusion injury may result in the local release of proinflammatory cytokines. A newly synthesized organic compound, FR167653, has been characterized as a potent suppressant of interleukin-1beta and tumor necrosis factor-alpha. We investigated the effects of FR 167653 on ischemia-reperfusion injury of canine hearts during preservation and transplantation. METHODS: Seventeen pairs of adult mongrel dogs were used. The donor heart was removed, stored in University of Wisconsin solution at 4 degrees C for 12 hours, and then transplanted orthotopically. Recipients were divided into the FR-treated group (FR167653 1 mg/kg/hr, 8 dogs) and the control group (9 dogs). Hemodynamic parameters, including cardiac output, left ventricular pressure (LVP), and the maximum rate of increase of LVP, were assessed after 120 minutes of reperfusion. The heart specimen was then harvested for histopathologic examination. RESULTS: The values of LVP (mm Hg) of the FR-treated and the control groups were 120+/-10 and 79+/-9, respectively. The values of LV dp/dt (mm Hg/sec) in the FR-treated and control groups were 4944+/-414 and 2292+/-380, respectively. There were significant differences in LVP (P < .05) and the maximum rate of increase of LVP (P < .01) between the two groups. The values of cardiac output (L/min) of the FR-treated and control groups were 1.27+/-0.12 and 0.71+/-0.11 of the baseline, respectively, showing a significant difference (P < .05) between the two groups. Histopathologic findings included irregular glycogen distribution in myocardial cells of the control group, although this change was less frequent in the FR-treated group. CONCLUSION: FR 167653 seems to have a protective effect on tissue subjected to ischemia-reperfusion injury during the acute phase after heart transplantation.     

Prevention of Eimeria alabamensis coccidiosis by a long-acting baquiloprim/sulphadimidine bolus

Twelve calves aged 6-10 months, and 12 calves aged 10-16 months were turned out onto a permanent pasture known to have been contaminated with oocysts of Eimeria alabamensis during the previous year. Two days after turnout, six of the older calves and six of the younger were each treated with one bolus per 200 kg bodyweight containing 1.6 g baquiloprim and 14.4 g sulphadimidine. The other 12 calves were left untreated. The excretion of Eimeria oocysts, the faecal dry matter and the weight gain of treated and untreated calves within each age group were compared during the first 3 weeks on pasture to assess the efficacy of the bolus in preventing E. alabamensis coccidiosis. All the older of the untreated calves and four of the younger developed gruel-like to watery diarrhoea 4-7 days after turnout. The faecal consistency of the treated calves remained firm and they lost significantly less weight than the control calves during the first 13 days on pasture. The treated calves also excreted significantly fewer oocysts during the first 20 days of grazing; their oocyst excretion remained low during days 8-10 when all but one of the diarrhoeic control calves excreted more than 850,000 oocysts per gram faeces (OPG). Starting on days 12 to 14 the oocyst excretion of 8 of the treated calves increased to 20,000-65,000 OPG and of 2 calves to 210,000-240,000 OPG. There was no difference in oocyst output between treated and untreated calves from the fourth week of grazing and no difference in weight gain among the younger calves. In the older calves there was a tendency for the untreated calves to gain more weight than treated calves.     

History of the Kolff Laboratory turbine driven electrohydraulic artificial heart

The concept of an electrically powered total artificial heart has been pursued by Dr. Kolff and his associates since the 1960s. Since the 1980s these efforts have been concentrated upon the development of the electrohydraulic total artificial heart, a turbine pump powered by a brushless DC motor. Dr. Kolff realized the benefits of pulsatile flow and device response to Starling's Law, and these concepts have formed the basis of subsequent design decisions. Design iterations have both solved existing problems and exposed new challenges. The current device design is greatly improved over early attempts due to the incorporation of technologies that have recently become available as the result of progress in the fields of materials and electronics and due to the lessons learned over many years of research under the guidance of Dr. Kolff. This article describes, from its inception, the last major research project of Dr. Kolff prior to his retirement. The discussion centers around development, problems and their solutions, and the reasoning for given solutions.     

Growth-induced haemodynamic changes in healthy Friesian calves

This study investigated the pattern of growth-induced haemodynamic changes in normal calves during their first year of life. The central venous pressure (CVP), the right ventricular pressure (RVP), the pulmonary arterial pressure (PAP), the pulmonary capillary wedge pressure (PW), the systemic arterial pressure (SAP) and the cardiac output (CO) were measured in 41 healthy Friesian calves. The heart rate (HR), the stroke volume (SV), the cardiac and stroke indices (CI and SI, respectively), the pulmonary and systemic vascular resistance (PVR and SVR, respectively), the right ventricular and left ventricular work (RVW and LVW, respectively) and their corresponding indices (PVRI, SVRI, RVWI and LVWI, respectively) were also measured or calculated. The cardiac output, SV, SAP, PVRI, SVRI, RVW and LVW increased significantly while the HR, CI, PVR, SVR, RVWI and LVWI decreased significantly with somatic growth. The right-sided vascular pressures did not change significantly. The significant increase in systemic arterial pressure may be due to the simultaneous increase in CO. The high CI observed in the first few weeks of life was attributed to a high metabolic rate and might induce a reduced cardiac pumping reserve in young calves. In consequence, a therapeutic inotropic intervention may have little potential benefit at this age.