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Ann Thorac Surg 2001;71:S125-S132
© 2001 The Society of Thoracic Surgeons
a Cullen Cardiovascular Surgical Research Laboratories, Texas Heart Institute, Houston, Texas, USA
b Jarvik Heart, Inc, New York, New York, USA
c Oxford Heart Centre, Oxford, England, United Kingdom
Address reprint requests to Dr Frazier, Texas Heart Institute, PO Box 20345, MC 3-147, Houston, TX 77225-0345
Presented at the Fifth International Conference on Circulatory Support Devices for Severe Cardiac Failure, New York, NY, Sept 15–17, 2000.
Abstract
Advances in technology and increased clinical need have led to the development of a new type of blood pump. The Jarvik 2000 Heart is an electrically powered, axial-flow left ventricular assist device that has been developed during the past 13 years. Unlike first-generation left ventricular assist devices, which were developed in the 1970s and were designed to totally capture the cardiac output, the Jarvik 2000 is designed to normalize the cardiac output by augmenting the function of the chronically failed heart for extended periods. Design iterations have been tested in 67 animals, and clinical trials have recently begun. Three patients have received the Jarvik 2000 as a bridge to transplantation, and 1 patient is being supported permanently outside the hospital. All 4 patients have improved from New York Heart Association functional class IV to class I, and 2 of them have been discharged from the hospital after heart transplantation. The experimental and clinical results indicate that the Jarvik 2000 can provide physiologic support with minimal complications and is reliable, biocompatible, and easy to implant.
Today’s mechanical circulatory support (MCS) systems for treating chronic heart failure were initially developed more than 25 years ago. During the past two decades, these systems have undergone extensive in vivo and in vitro testing. In the mid-1980s, clinical trials were initiated to evaluate these systems as bridges to transplantation. After their safety and efficacy was established, a number of these devices were approved by the U.S. Food and Drug Administration for commercialization during the mid-1990s [1–4].
Clinical experience with MCS systems has mainly been acquired in the setting of postcardiotomy heart failure or bridging to transplantation. Success with bridge devices is leading to clinical research targeted at identifying which patient populations may benefit from this technology. Specifically, active research programs are currently evaluating extended bridging to myocardial recovery [5] and long-term support [6] with implantable MCS devices. Both of these applications involve patients at high risk of death despite maximal temporary mechanical and pharmacologic support. Implantation of an MCS device requires a major surgical procedure and intensive care in these desperately ill patients. Recovery from the implant procedure is uncertain and presents a formidable challenge not only to the patients but also to their families and caregivers. The morbidity and mortality of MCS remains high. Despite successful support, complications may arise from the ravages of chronic heart failure. During the support period, many patients have serious complications that are mainly related to primary heart failure or secondary multiorgan failure.
In today’s climate of rapid technologic advancement, new MCS technology is emerging that should result in important advances in the treatment of severe heart failure [7]. During the past decade, a new generation of blood pumps has been developed to provide physiologic levels of cardiac support while minimizing device-related complications [8–10]. Technologic advances have allowed the miniaturization of blood pumps that can create satisfactory levels of cardiac support. An example of this technology is the Jarvik 2000 Heart (Jarvik Heart, Inc, New York, NY), an electrically powered, axial-flow left ventricular assist device (LVAD) that is small, durable, quiet, and easy to implant and operate [11]. The requirement for external venting in the current, clinically applied LVADs has resulted in the potential hazard of contamination and subsequent infection. This concern led us to experiment with implantable, continuous-flow, impeller-type pumps in 1981. Although the experiments were successful, a lack of funding prevented further experimentation with this type of pump. Owing to its small size, nonpulsatile flow, and intraventricular placement the Jarvik 2000 should minimize infection, thromboembolism, and severe bleeding [12]. When placed within the left ventricle, the device is exposed to continuous blood flow, which may optimize exposure to the immune properties of the blood. In addition, intraventricular placement obviates the need for an inlet cannula, thereby avoiding the potential adverse effects of negative pressure on the blood (eg, hemolysis and platelet adhesion and destruction). Because of the device’s small size and simplicity, less extensive surgical procedures are needed, thereby increasing the ease of implantation, reducing the likelihood of bleeding complications, and hastening surgical recovery.
The Texas Heart Institute and Jarvik Heart, Inc, began research on the Jarvik 2000 Heart in 1989 and achieved long-term, complication-free, in vivo support in 1994. Additional animal studies have been performed since that time, and clinical trials were begun in early 2000. This article presents an overview of the research and development efforts that this device has undergone during the past 10 years.
Material and methods
Device description
Since its inception, the Jarvik 2000 Heart has undergone several design iterations and improvements [13]. The original prototype weighed 260 g and displaced a volume of 60 mL. In contrast, the present blood pump (Fig 1) weighs 90 g, measures 2.5 cm in diameter, and displaces 25 mL. The blood pump is about the size of a common D-cell battery. The welded titanium pump shell is hermetically sealed and contains a brushless electromagnetic direct current motor. The rotor, which is held in place by two ceramic bearings, includes titanium impeller blades and a neodymium-iron-boron magnet. The pump also includes outflow stator blades downstream from the impeller. By means of electromagnetic force, the impeller rotates at 8,000 to 12,000 rpm, yielding a maximal blood flow of 7 L/min against physiologic resistance. All blood-contacting surfaces are made of smooth titanium. Power is transmitted by a bundle of extrusion-insulated cables, enclosed within a silicone tube. The blood pump may be controlled by either a fixed-rate analog system or a variable-speed microprocessor system.
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Implant procedure
The Jarvik 2000 blood pump is implanted through a left thoracotomy incision in the sixth intercostal space. Partial cardiopulmonary bypass support is used when the apex of the left ventricle is cored. To optimize exposure of the descending aorta, a double-lumen endotracheal tube is used for single-lung ventilation. Hemodynamic variables are monitored with a systemic arterial pressure catheter and a pulmonary artery catheter. Once the femoral artery and vein have been exposed for cardiopulmonary bypass access, a left thoracotomy is performed, and the heart and descending thoracic aorta are exposed. A 16-mm Hemashield graft is then anastomosed to the descending thoracic aorta with the aid of partial clamp occlusion. To secure the pump in place, a sewing cuff is anastomosed to the apex of the heart. Once the femoral artery and vein have been cannulated, partial cardiopulmonary bypass is initiated. Ventricular fibrillation is induced, and an opening is created in the left ventricle, through the cuff, with a circular knife. The blood pump is inserted into the left ventricle and secured, and a proper length is obtained. The heart is then defibrillated, and air is evacuated from the left ventricle and blood pump. The graft from the blood pump is anastomosed to the graft previously placed on the descending aorta. Any residual air is removed from the graft with a 19-gauge needle. An ultrasonic flow probe is placed on the outflow graft for pump flow measurement. The Jarvik 2000 pump is then activated, and the patient is weaned from cardiopulmonary bypass. Just before the thoracotomy incision is closed, the ultrasonic flow probe is removed.
Animal studies
From 1991 to 1999, the Texas Heart Institute tested the Jarvik 2000 LVAD in 37 healthy calves weighing 75 to 100 kg [13]. Twenty-three calves had the percutaneous system, and 14 calves had development-stage versions of the fully implantable system. Variations of the Jarvik 2000, including the skull-mounted pedestal, were tested by the Oxford group in 30 sheep. The 37 calves were supported for a mean of 70 days (range, 1 to 250 days). To verify the feasibility of the operation, we conducted two initial experiments that lasted for 2 days each and a third experiment that lasted for 1 day. (Unless otherwise noted, data from these three experiments are not included here.) As we gained experience with pump implantation and made improvements to the device, the support period lengthened. Three experiments exceeded 200 days, and six experiments exceeded 100 days. Calves that survived for more than 200 days were electively killed because they grew too large for the laboratory facilities. All of the animals underwent a complete postmortem examination.
The first and third calves had increased hemolysis, but the remainder had normal plasma hemoglobin values (baseline level, 7.0 ± 4.6 mg/dL; level during LVAD support, 8.2 ± 5.4 mg/dL; p = 0.136). Bleeding was not encountered. Combined heparin and warfarin were administered to maintain the clotting time at 1.5 to 2.0 times the baseline value. Antiplatelet therapy was achieved with aspirin and dipyridamole. The prothrombin time, partial thromboplastin time, and international normalized ratio were 1.0 to 1.5 times baseline values, thus failing to meet the target range (1.5 to 2.0 times baseline). Similar suboptimal anticoagulation occurred in the sheep but did not result in thrombosis of the device. Renal, hepatic, hematologic, pulmonary, and neurologic function was normal in all studies.
In 10 experiments, pump flow rates were continuously recorded throughout the support period. When the calves were inactive, the pump yielded flows of 4.23 ± 1.5 L/min at a constant rate of 10,000 rpm. In general, increasing the pump speed to between 8,000 and 14,000 rpm caused a linear response in pump flow (Fig 5), with a maximum of 8 L/min at 14,000 rpm. When either the manual or the automatic controller was used during treadmill exercise, the cardiac output showed a physiologic response. With the automatic controller, the pump speed depended on changes in the heart rate. At a fixed number of revolutions per minute, increasing the pump preload also increased pump flow against constant resistance.
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Clinical trials
Clinical trials to evaluate the safety and efficacy of the Jarvik 2000 LVAD as a temporary bridge to heart transplantation began in April 2000 at the Texas Heart Institute. Shortly thereafter, a clinical trial was begun in Oxford, United Kingdom, in collaboration with our program, using the model with a skull-mounted pedestal [18]. The Oxford protocol includes heart failure patients who are not transplantation candidates and who will be supported permanently. Both studies are feasibility studies that will eventually expand to become multicenter clinical trials.
The first 3 patients to receive the Jarvik 2000 Heart at the Texas Heart Institute under the U.S. Food and Drug Administration–approved investigational device exemption protocol were transplant candidates (Table 1). They included 2 men and 1 woman, all of whom had long-standing heart failure from cardiomyopathy. The first patient had an idiopathic dilated cardiomyopathy; the second patient had a form of cardiomyopathy known to occur with Noonan’s syndrome; and the third patient had an ischemic cardiomyopathy secondary to ischemic coronary disease. The first 2 patients underwent successful heart transplantation after 79 and 52 days of support, respectively, and the third patient continues to be supported at 60 days.
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During the support period, the patients’ hemodynamic status improved significantly. The average cardiac index increased from 1.9 L · min-1 · m-2 before LVAD implantation to 3.5 L · min-1 · m-2 48 hours after the implant. At the same time, the pulmonary capillary wedge pressure decreased from 19.7 mm Hg to 7.3 mm Hg. The arterial blood pressure and heart rate were within an acceptable range during the entire support period. All inotropic support was withdrawn within 48 hours after the implant operation. Hemodynamic and echocardiographic studies confirmed that the left ventricle was sufficiently unloaded by the Jarvik 2000. Figure 6 shows the hemodynamic effects of changing the pump speed and turning the pump off. As the pump speed increased, the pulse pressure narrowed because of the increase in diastolic pressure and unloading of the left ventricle (Fig 6A). The mean arterial pressure also consistently increased as the pump speed increased. With the pump off, the pulse pressure widened, and the cardiac index decreased (Fig 6B). Regurgitation through the pump was minimal. The pulmonary capillary wedge pressure decreased with increasing pump speeds and then rose by 7 mm Hg with the pump off (Fig 6C). Figure 7 shows the hemodynamic response to the changing pump speed, as assessed by echocardiographic data. As the pump speed increased, the time during which the aortic valve was open during systole decreased until the valve remained closed at the higher settings (Fig 7A). The left ventricular systolic and diastolic dimensions also decreased with the speed of the pump (Fig 7B). The amount of blood flow through the right ventricular outflow tract increased as expected with an increased total cardiac output, whereas the flow through the left ventricular outflow tract decreased until all flow occurred through the blood pump (Fig 7B). The point at which no flow was measured in the left ventricular outflow tract corresponded to the point at which the aortic valve remained closed.
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In the series as a whole, anticoagulation therapy was minimal, and no thromboembolism was observed. The first patient received daily warfarin, starting on the sixth postoperative day; the second patient received either heparin or warfarin throughout the support period, and the third patient received only three doses of warfarin. The average international normalized ratio for the 3 patients was 1.55. There was no evidence of thromboembolism in any patient. The devices retrieved from the 2 transplant recipients were free of thrombus. The third patient is essentially receiving no anticoagulation therapy and has had no evidence of thromboembolism.
The first permanent implantation of the Jarvik 2000 with the skull-mounted pedestal was performed in June 2000 at the Oxford Heart Center [19]. The patient was a 61-year-old man with a 3-year history of idiopathic dilated cardiomyopathy. Preoperatively, his cardiac index was 1.8 L · min-1 · m-2, his ejection fraction was 10%, and his maximum oxygen consumption was 5.7 mL · kg-1 · min-1. He had severe orthopnea, peripheral edema, and ascites. Postoperatively, the patient’s condition improved markedly, and his hemodynamic values normalized. He lost 12 kg of body weight, with a subsequent loss of ascites and peripheral edema. He underwent a 6-week rehabilitation program, was discharged from the hospital, and continues to do well.
Comment
On the basis of National Heart, Lung, and Blood Institute support, research on implantable long-term LVADs was introduced in the 1970s. The initial goal of this technology was to capture the entire cardiac output. The pumps were constructed to produce flows of up to 10 L/min against physiologic resistance. They were introduced clinically as bridges to transplantation in the 1980s and were approved for commercial use as bridging devices in the 1990s. The current clinical LVADs have resulted in a dramatic improvement in multiorgan function in numerous patients [20–22], most of whom have undergone successful heart transplantation [23–25]. As clinical experience with this technology has grown, it has become apparent that, in most instances of chronic heart failure, complete capture of the left ventricular output is not only unnecessary but may even be undesirable. Use of a continuous-flow pump allows more physiologic unloading of the failed left ventricle, particularly if the flow is limited to the amount necessary to result in optimal circulatory physiology.
The pathophysiology of patients with chronic heart failure is characterized by hypertrophy, which allows compensatory mechanisms to adjust to cardiac cellular impairment. As this compensation becomes inadequate for circulatory needs, symptoms of heart failure occur. The Jarvik intraventricular pump offers several primary mechanical advantages for surgical treatment of chronic heart failure. Initially, its flow can be adjusted so that only the flow necessary to normalize the left ventricular end-diastolic pressure and volume is used. This approach allows the native heart to respond more physiologically. Ejection of native heart flow through the aortic valve is preserved, resulting in a more normal physiology and a preservation of appropriate circulatory feedback mechanisms. The rheology of the blood is also maximized by the device’s position. The blood flow is never achieved by means of negative pressure. The end point of the circulatory cascade (the left ventricle in end diastole) is retained, so that the energy imparted to the blood is always positive. By placing the graft’s outlet in the descending thoracic aorta rather than in the ascending aorta above the aortic valve, one avoids stasis blood flow in the supraaortic position, when aortic valve opening is minimal (Fig 8). Experience with pulsatile pumps has shown that prolonged aortic valve closure can lead to aortic stenosis owing to fusion of the commissures. Because of the constant motion of the pulsatile pump, however, stasis is avoided. In contrast, continuous flow throughout the cardiac cycle raises concerns about supraaortic valve stasis and the potential for thrombosis. In the Jarvik 2000 Heart, this complication is avoided by pumping the blood into the descending aorta and maximizing left ventricular ejection and aortic valve opening.
Because the pump is positioned intraventricularly, surgical implantation is markedly simplified. Experience at the Texas Heart Institute has shown that implantation of the Jarvik 2000 Heart results in less operative trauma than that associated with conventional pulsatile LVADs. This decreased trauma has minimized blood loss and time in the intensive care unit.
Another advantage of this technology is the ease with which the pump’s output can be regulated. With a simple dial mechanism, available to both the patient and clinician, the speed can be increased from 8,000 to 12,000 rpm. The ease of outpatient use of this feature has been verified by the Oxford experience; in response to increased activity, patients were able to adjust the output so as to improve circulatory delivery. In addition, the pump is totally quiet, and its active function is unnoticed by the patient or anyone in the patient’s proximity.
Because of the small size of the Jarvik 2000, treatment has been extended to small patients, who would otherwise be unsuitable for an implantable pump. At the Texas Heart Institute, all of the bridge-to-transplant patients who have received this pump have had a body surface area of less than 2 m2. Therefore, this technology is lifesaving for smaller patients, especially women and children.
The Jarvik 2000 can be deactivated with little aortic regurgitation. There is no external pressure buildup, such as that produced by dead space when a pump is placed outside the ventricle. Patients tolerate deactivation of the pump without exhibiting symptoms. Because the pump has no valves and entails no blood stasis, anticoagulant therapy has been minimal and, in fact, may not be required clinically.
With the introduction of the Hemopump (DLP, Medtronic, Grand Rapids, MI) [26], researchers showed that a high-speed, continuous-flow pump could support the circulation without causing hemolysis or thrombosis. Our experience with the Jarvik 2000 has shown that a larger implantable pump can provide the same benefits. Moreover, this experience seems to justify the concept of normalizing the function of the failed heart physiologically. This approach can be expected to result in lower operative risk, better survival, more physiologic support of the circulation, and broader application of MCS.
Thus far, the clinical results of Jarvik 2000 implantation have been encouraging, as the pump has led to rapid recovery and stabilization of critically ill patients. Because of the vast experience accumulated during the past two decades with conventional MCS systems and because of the emerging systems that use advanced technology, implantable blood pumps have a promising future in the treatment of end-stage heart failure. The Jarvik 2000 axial-flow, intraventricular pump offers important physiologic and anatomic advantages, which were documented in the first patients to receive this device. The role of this pump will be further clarified by larger clinical trials. Meanwhile, its long-term use appears to be feasible and safe.
Footnotes
Dr Jarvik is President of Jarvik Heart, Inc.
References
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