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First successful bridge to cardiac transplantation using direct mechanical ventricular actuation
First Successful Bridge to Cardiac Transplantation Using Direct Mechanical Ventricular Actuation James E. Lowe, MD, Mark P. Anstadt, MD, Peter Van Trigt, MD, Peter K. Smith, MD, Paul J. Hendry, MD, Mark D. Plunkett, MD, and George L. Anstadt, VMD Department of Surgery, Duke University Medical Center, Durham, North Carolina
Currently available ventricular assist devices are technically difficult to implant, require continuous anticoagulation, and are associated with hemorrhagic and thromboembolic complications. Direct mechanical ventricular actuation is a biventricular assist device that can be applied in 3 to 5 minutes through a left anterior thoracotomy and has no direct blood contact or need for anticoagulation. The present study was designed to determine the effects of direct mechanical ventricular actuation in total biventricular circulatory support. Cardiogenic shack refractory to standard therapy developed in 2 patients awaiting cardiac transplantation. Direct mechanical ventricular actuation was applied and provided immediate hemodynamic stabilization in both. All inotropic agents and intraaortic balloon support were then discontinued. Fifty-six hours of circulatory support bridged the first patient to successful cardiac transplan-
tation without complication. The patient is alive and well more than 1 year later without incident of infection or rejection. The second patient suffered cardiac arrest and required closed chest cardiopulmonary resuscitation before device application. After 45 hours of support, it was determined that irreversible neurologic injury had occurred and direct mechanical ventricular actuation was discontinued. Neither patient’s native heart exhibited any histologic evidence of device-related trauma. Direct mechanical ventricular actuation has undergone limited clinical investigation since its original description 25 years ago, but in these initial trials, the device has proved effective. The concept of mechanically actuating the ventricles appears to be a valuable, yet under-utilized method of total circulatory support.
T
he concept of applying rhythmic, external mechanical compression and decompression to both ventricles of the failing heart was first described in 1965 [l].Extensive laboratory investigations have shown that direct mechanical ventricular actuation (DMVA) produces cardiac outputs of 80% to 110% of control values compared with outputs of 20% to 40% using open chest bimanual compression [l-61. Animal studies also have shown that DMVA results in minimal epicardial trauma, does not require sophisticated electrophysiologic timing, and can produce normal cardiac outputs in the failing, asystolic, and even fibrillating heart. Conceptually, this technology is simple and elegant, and offers several advantages compared with other existing ventricular assist devices as well as partial cardiopulmonary bypass. First, there is no blood contact or need for anticoagulation, which should reduce thromboembolic, hemorrhagic, and infectious complications. Second, the support cup can be rapidly applied through a left anterior thoracotomy to achieve biventricular support within 3 minutes [l-61. The anterior thoracotomy application preserves the sternal approach for subsequent cardiac operations including cardiac transplantation. Third, physiologic and pulsatile flow rates are rapidly achieved without the need for inotropic support.
Until the present study, clinical applications of DMVA were primarily limited to heroic efforts of resuscitation after prolonged periods of failed standard external cardiopulmonary resuscitation [2-61. These initial clinical applications did not result in long-term survivors but did convincingly demonstrate that previous experimental results could be duplicated in humans. The present investigation was designed to determine whether DMVA could be used to support patients with refractory cardiogenic shock who were otherwise candidates for cardiac transplantation. This particular group of patients was chosen to attempt to answer a number of important questions: can the technology provide prolonged circulatory support without systemic complications, is there serious trauma to the native heart, and finally, what are the present limitations in device design and construction that could lead to device failure? Based on extensive laboratory testing, the Institutional Review Board at Duke University Medical Center approved DMVA for use in patients with refractory cardiogenic shock or cardiac arrest including those awaiting cardiac transplantation.
Presented at the Twenty-seventh Annual Meeting of The Society of Thoracic Surgeons, San Francisco, CA, Feb 1%20, 1991.
Direct mechanical ventricular actuation employs an elliptically contoured cup which fits over both ventricles. The cup consists of an outer shell or housing and an inner flexible diaphragm. The housing can be made of either a
Address reprint requests to Dr Lowe, Duke University Medical Center, Box 3954, Durham, NC 27710.
0 1991 by The Society of Thoracic Surgeons
(Ann Tliorac Surg 1991;52:123745)
Material and Methods
0003-4975/91/$3.50
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Fig 1 . Schematic diagram of direct mechanical ventricular actuation drive system and cup. The cup is shown actuating the ventricles into both systolic (right) and diastolic (left) configurations.
hard translucent material (Pyrex) or a soft material (Dacron-reinforced Silastic) which produces a semirigid structure. The advantage of the soft shell is its ease of application through a smaller incision, while the rigid shell has the advantage of allowing visualization of the diaphragm’s action on the heart. The flexible diaphragm currently used in both the hard and soft cups is a Silastic membrane (Dow Corning Corp). The cup attaches itself to both ventricles via a continuous vacuum at the apex of the cup. Once the cup is in position, positive and negative pneumatic forces operate a diaphragm within the cup to ”actuate” the ventricles into their normal systolic and diastolic configurations. Appropriate delivery of uniform positive and negative forces to the ventricles rapidly returns the failing, asystolic, or fibrillating heart to its function as a blood pump (Fig 1). The apical vacuum source provides device attachment, but more importantly and critical to the concept, it seals the actuating diaphragm to the myocardial surface. Consequently, the device not only compresses the ventricles to create systole but also enhances cardiac filling by decompressing the ventricles into a diastolic configuration. The massaging action of DMVA is con;rolled by a pneumatic drive unit that has both pulsed pressure and sustained vacuum systems (see Fig 1). The vacuum system is responsible for device attachment and can be adjusted to the least degree of suction (approximately -70 mm Hg line pressure) that will maintain a constant diaphragm-to-epicardium seal. The pulsed pressure system consists of a positive pneumatic source for systolic
compression and a negative pneumatic source for diastolic filling. The internal diameter of each assist cup is identified by a numerical label in millimeters. An appropriate cup size is one that approximates the greatest transverse diameter of the unassisted heart. Cups varying in size from 90 to 150 mm in transverse diameter were prepared for the present study. This particular range was chosen by evaluation of chest radiographs of cardiac transplant candidates on the waiting list at Duke University Medical Center. Once a general size has been selected, the assist cup can rapidly be positioned through a small left anterior, sixth intercostal space thoracotomy. After the heart is adequately exposed, the device is positioned over the ventricular apex while set in a diastolic mode. The drive system’s continuous vacuum source causes the device to aspirate itself onto the heart. Once attached, the drive system is switched into an actuating mode which cycles positive and negative forces from the pulsed pressure source resulting in ventricular systole and diastole. The process of DMVA application takes seconds after adequate exposure. The entire procedure has been performed in less than 3 minutes for emergency resuscitation in both the clinical [3-61 and the laboratory setting [l]. After acute hemodynamic stabilization, systolic (+120 mm Hg to +130 mm Hg) a n d diastolic (-100 mm Hg to -115 mm Hg) forces and flow rates can be adjusted to maximize hemodynamics. Cycle rates are generally set between 80 per minute (large hearts) to 120 per minute (small hearts). Adequate left ventricular emptying is achieved by systolic durations set at 50% of the
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Fig 2 . Ciry apylicatiori is made hy exposing the heart through a left U I Z tcrior thoracotoiii~y;positioning the clip oiicr tl7e vciztricirlar apex rcwlts iiz self attachrirerit ( k j t ) . The chest is then closed after the d r i w lines arc broirght out through separate stah incisions (right).
DMVA actuating cycle. This is important to prevent any potential for pulmonary edema, which could result if an abbreviated systolic force effectively emptied the right ventricle but not the left. Assurance of avoiding this situation is possible by monitoring pulmonary wedge pressures. An increase in wedge pressures during support indicates the need for increased systolic durations. Other conceivable complications can be circumvented by the usual preparations for any mechanical failures. If a leak develops in the actuating diaphragm, it is easily detected by fluctuations in drive pressures and vacuum attachment pressures. Although such an event requires device replacement, initial hemodynamic stabilization can be maintained by increasing drive pressures. The possibility of a pneumothorax is prevented by placement of a chest tube at the time of initial thoracotomy. The pneumatic drive units are an unlikely source of mechanical failure but were monitored as with any other device. For these reasons, an additional drive unit and set of devices were available for emergency back-up in the present study. Institutional Review Board approval was obtained in August 1989. After informed consent, DMVA was applied to 2 patients in whom refractory cardiogenic shock developed while they were awaiting cardiac transplantation. Patients with preexisting infection and multiorgan failure were excluded from the investigation.
Patient 1 In January 1990, a 56-year-old woman, diagnosed 2 years previously with an idiopathic dilated cardiomyopathy, was seen in acute congestive failure. The patient had been previously approved as a candidate for cardiac transplantation. Cardiac catheterization revealed an ejection fraction of 0.08 with normal coronary arteries, 3+ mitral regurgitation, and a pulmonary vascular resistance of 3 Wood units. At the time of presentation to the emergency room, she was in pulmonary edema with a cardiac index
of less than 2.0 L/m2. After admission to the intensive care unit, the patient was successfully resuscitated with inotropic agents and vigorous diuresis. Shortly after being transferred to a step-down unit, the patient required readmission to the intensive care unit for hypotension and pulmonary edema. She was placed on a regimen of maximal doses of three inotropic agents yet continued to deteriorate hemodynamically; she became oliguric, and episodes of nonsustained ventricular tachycardia developed. Cardiac index dropped to 1.8 L/m2 with mean pulmonary artery pressures of more than 40 mm Hg and arterial pressures of 70140 mm Hg. After informed consent, the patient was taken on an emergency basis to the operating room for device application. During transport, cardiac index (<1.8 L/m2) and arterial pressures (60/40 mm Hg) fell further, with increases in pulmonary diastolic pressures to more than 45 mm Hg.
Patient 2 In November 1990, a 46-year-old man with no past medical history was seen at the emergency room with an acute, massive myocardial infarction. The patient was given thrombolytic therapy, which did not result in electrocardiographic evidence of reperfusion. Therefore, he was taken to the cardiac catheterization laboratory for emergency percutaneous transluminal coronary angioplasty. Catheterization revealed an ejection fraction of 0.10, severe global hypokinesis, and 100% occlusions of the proximal anterior descending and circumflex arteries with a 75% proximal right coronary occlusion. Multiple attempts to open the anterior descending artery using percutaneous transluminal coronary angioplasty techniques were unsuccessful and resulted in hernodynamic deterioration requiring placement of an intraaortic balloon pump and initiation of inotropic support. The patient’s condition stabilized over the next 24 hours, and he was placed on the active cardiac transplant list. The patient’s hemodynamic status subsequently deteriorated. Inotropic
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of larger size (125 mm) provided adequate support; however, a subsequent change to a slightly smaller size (120 mm) substantially improved hemodynamics.
Patient 1
Fig 3 . Systemic arterial and venous pressures before and during 56 hours of support in the first direct mechanical ventricular actuation recipient. The patient was weaned from all inotropic agents during the first 12 hours of support.
agents were increased to maximal doses along with continued intraaortic balloon pump support. However, the patient became oliguric with a cardiac index worsening to less than 1.8 L/m2. Systemic pressures fell to 80/60 mm Hg and pulmonary artery diastolic pressure was greater than 40 mm Hg. After informed consent, the patient was taken on an emergency basis to the operating room where he suffered cardiac arrest upon arrival. Cardiopulmonary resuscitation was begun using standard closed chest cardiac massage while the chest was prepared and draped. However, cardiac index (0.5 L/m2) and mean arterial pressures (40 mm Hg) were severely depressed for 15 minutes before device application.
Results Both patients had transesophageal echocardiography performed in the operating room immediately before device application. This allowed for determination of transverse cardiac dimensions, and an appropriate device size was estimated preoperatively. A 115-mm diameter cup was selected for the first patient based on a 115-mm transverse cardiac diameter. The device fit perfectly, and DMVA application through an anterior thoracotomy was completed in less than 3 minutes. In the second patient, a cup
Fig 4. Cardiac outputs and uenous oxygen saturations before and during 56 hours of support in the first direct mechanical ventricular actuation recipient.
After DMVA application, hemodynamics immediately improved to a cardiac output of 3.9 L/min (2.78 L/m2). Systemic arterial pressure increased to 100/60 mm Hg, and pulmonary pressure dropped to 24/8 mm Hg. Drive lines and a single chest tube exited the chest through separate intercostal incisions (Fig 2). The entire operation from skin incision to closure took 38 minutes. During the subsequent 12 hours administration of all inotropic agents was discontinued. The patient remained hemodynamically 1.0/63 -+ stable with normal systemic arterial (106 0.4 mm Hg) and venous pressures (12 k 0.3 mm Hg) (Fig 3). Cardiac outputs averaged 3.16 0.05 L/min (2.26 0.03 L/m2)during support, with adequate tissue perfusion as evidenced by normal venous saturations (Fig 4) and return of normal urine output. Pulmonary artery pressures (33 k 0.9/16 0.5 mm Hg) remained normal during the entire support period (Fig 5). All end organs demonstrated normal function during the period of DMVA support. After 56 hours, a donor heart became available and the patient was returned to the operating room where cardiopulmonary bypass was instituted through a virgin sternotomy. The device was easily removed after the patient was placed on cardiopulmonary bypass by cutting the sterile, intrathoracic portions of the drive and suction lines (Fig 6). Cardiac transplantation was then performed with a subsequent uncomplicated recovery. The patient is alive and in functional class I more than 1 year after transplantation without incidence of either infection or rejection.
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Patient 2 The heart could only be briefly defibrillated before cup application and remained fibrillating during the entire period of support. Initial cardiac outputs increased to 4.7 L/min (2.14 L/m2) upon placement of DMVA. These results were dramatic in comparison with the patient’s severely depressed outputs (approximately 1 L/min) during his resuscitation for cardiac arrest. Systemic arterial pressures increased to 120/80 mm Hg, whereas pulmo-
Fig 5. Pulmonary artery pressures before and during 56 hours of support in the first direct mechanical ventricular actuation recipient.
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Fig 6. Before cardiac transplantation in patient 1, cardiopulmonary bypass was instituted using standard cannulation techniques through a virgin sternotomy (left). Device removal was performed by cutting the sterile drive lines within the chest and removing the cup through the sternotomy (right).
nary diastolic pressures decreased from 45 mm Hg to 22 mm Hg. As in the first patient, the chest was closed and the patient transferred to the intensive care unit. Hemodynamics remained stable during circulatory support with a mean cardiac output of 6.2 0.3 L/min (2.8 ? 0.1 L/m2) (Fig 7). A gradual decline in cardiac output occurred after 6 hours of support owing to a leak in a defective diaphragm. Placement of a new device resulted in initial cardiac outputs of 11 L/min. Systemic pressures (110 5 2/66 ? 1 mm Hg) and central venous pressures (9.9 ? 1.5 mm Hg) remained adequate throughout support, despite the initial cup failure (Fig 8) and refractory ventricular fibrillation. Pulmonary diastolic pressures (21.3 k 0.9 mm Hg) remained below device implant values (Fig 9). Venous saturations averaged 0.57 k 0.04 during support, which indicated improved tissue perfusion (see Fig 7). Unfortunately, the patient remained neurologically unresponsive after his cardiac arrest and was pronounced brain-dead. Therefore, the device was removed after 45 hours of circulatory support, and the patient died.
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Histologic Examination Both patients' native hearts underwent extensive histologic examination. Despite the presence of recent un100 h
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derlying myocardial infarctions, neither heart showed any device-related trauma. In the first patient, myocardial infarction, predominantly in the right ventricle, was estimated to have occurred 3 to 4 days before device application. In the second patient, myocardial infarctions throughout both ventricles involved 60% of the myocardial mass. Approximately half of the infarcted myocardium was acute and represented two recent events that had occurred approximately 3 to 4 and 6 to 9 days before device implantation. The remaining infarctions appeared as well-defined scars that originated months to years earlier.
Complications There were no complications during the entire period of support in the first patient. However, in the second patient, defective material led to premature diaphragm fatigue and a small leak in the cup diaphragm where it was attached to the housing. Cardiac outputs gradually declined at a rate of approximately 0.5 L . min-' . h-' after onset of the leak. This slow clinical failure of the cup confirmed failures observed during prolonged experimental in vivo and in vitro studies. Because sudden, complete cup failure has not been encountered, there is adequate time for cup replacement while hemodynamic support is 150 130
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Fig 7. Cardiac outputs and venous oxygen saturations before and during 45 hours of support in the second direct mechanical ventricular actuation recipient. Use of the intraaortic balloon and all inotropic agents was discontinued immediately after direct mechanical ventricular actuation application. Arrow indicates the onset of a leak in the cup diaphragm at 6 hours of support. Replacement of a new cup at 14 hours resulted in return of normal hemodynamics.
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Fig 8. Systemic arterial and venous pressures before and during 45 hours of support in the second direct mechanical ventricular actuation recipient. Use of the intraaortic balloon and all inotropic agents was discontinued immediately after direct mechanical ventricular actuation application. Pressures remained relatively stable despite a device leak during the early support period.
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Fig 9. Pulmonary diastolic pressures before and during 45 hours of support in the second direct mechanical ventricular actuation recipient. Pulmonary systolic pressures could not be interpreted because of recording artifacts.
still adequately maintained. Furthermore, as demonstrated in the second patient, the cup can be replaced at the bedside using a standard thoracotomy tray. The initial hard-shell device was replaced in the second patient using a more pliable soft-shell device. The soft-shell device was very easy to apply through the small anterior thoracotomy.
Comment These initial clinical results show that DMVA can be successfully used in patients with biventricular failure and refractory cardiogenic shock as a means of total circulatory support while awaiting cardiac transplantation. Based on numerous experimental studies and the present clinical results, we believe that this technology deserves further human application. Direct mechanical ventricular actuation has many proven and theoretical advantages compared with current blood contacting assist devices. Because DMVA requires no anticoagulation or vascular cannulation, hemorrhagic and thromboembolic complications should theoretically be markedly reduced. In addition, implantation of DMVA does not require any vascular anastomoses. Reoperation for hemorrhage using current blood-contacting devices continues to be a major complication occurring in nearly 60% of patients [9-151. Although newer devices employ “antithrombogenic” surfaces, thromboembolism remains an often catastrophic complication. Often these thromboemboli arise at sites of anastomosis or from mechanical valves or sewing rings and not from the moving membrane used to create blood flow [16-181. In addition, DMVA application requires only a small left anterior thoracotomy, and complete biventricular support can be established in only 3 to 5 minutes. The installation of current blood-contacting univentricular and biventricular assist devices requires a major and timeconsuming operative intervention complicated at times by technical problems [9-11, 17, 191. These devices, unlike DMVA, also require an elaborate set-up and support team. Finally, as shown in the present study, DMVA can
restore physiologic, pulsatile flow rates even in the fibrillating heart, which is not possible with standard bloodcontacting ventricular assist devices. This technology does not require an elaborate set-up or support team and does not necessitate prolonged training courses. Once DMVA is applied, a number of options become available: (1) support can be provided to determine whether endorgan injury is reversible or irreversible, (2) the device can serve as a temporary circulatory support system to bridge to implantation of a total artificial heart, or ( 3 ) the device can provide a definitive bridge to cardiac transplantation. Through these options, DMVA can provide initial support and allow thorough patient assessment before committing to more elaborate and expensive devices. Such an approach may reduce early mortality and morbidity and minimize heroic and costly resuscitation efforts currently applied to patients who subsequently succumb early-on. For example, of those deaths occurring before transplantation while assist devices are being used, approximately 50% occur during the first hours to days of support [lo, 14, 181. Direct mechanical ventricular actuation may decrease early mortality by allowing rapid hemodynamic stabilization and avoidance of the complications associated with blood-contacting assist devices. In addition, if continued support is not justified secondary to end-organ failure, the unfortunate loss of the patient is not associated with tremendous expense. Direct mechanical ventricular actuation requires further evaluation to determine its potential for providing longterm circulatory support. On the other hand, its ability to serve as a valuable adjunct in this regard has been shown in the present study. There are a number of potential future applications for DMVA: Bridging to cardiac transplantation Bridging to any other cardiac assist devices Resuscitation from refractory cardiac arrest Circulatory support for cardiogenic shock Postcardiotomy circulatory support Resuscitation from profound hypothermia Noncardiac donor organ preservation after neurologic death In certain situations, the device may actually prove critical in determining a patient’s suitability for transplantation. For instance, some selection criteria for potential transplant candidates are difficult to adequately assess during acute cardiovascular collapse. Pulmonary vascular resistance is a particularly relevant example. Pulmonary vascular resistance is sometimes even more difficult to assess during conventional methods of circulatory support. This can be a major problem because substantial elevations in pulmonary vascular resistance have been found to be associated with right ventricular failure and subsequent mortality after transplantation [20]. Because DMVA creates hemodynamic conditions similar to the normal physiologic state, pulmonary vascular resistance can be calculated using standard techniques. A major drawback of DMVA is its current state of cup manufacture. Presently, all devices are hand-fabricated
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using Silastic (Dow Corning) diaphragms. Industrial fabrication with careful quality control must be accomplished before widespread application of this technology. Another potential drawback may be trauma to previously placed coronary artery bypass grafts. However, we have used DMVA after coronary artery bypass grafting in 1 patient [3] as well as in experimental animal studies. In the acute setting, there was no evidence of graft trauma or interference with graft flow after 4 hours of device application. However, further experimental work will be required to determine DMVA's effect on bypass grafts during prolonged periods of circulatory support. Finally, it is unknown whether this particular technology can be routinely applied in patients who have had previous cardiac operations. In those patients who have had previous cardiac operations, the heart would have to be totally dissected free before device application. This would require a median sternotomy instead of the preferred left anterior thoracotomy approach. In summary, we believe that our initial clinical results are most encouraging and justify further clinical application of this unique form of biventricular assistance. Although the technology was originally conceived to be applicable only to those patients who suffer acute refractory cardiac arrest, we believe that the technology can be perfected to provide a simple means for long-term circulatory support.
References 1. Anstadt GL, Blakemore WS, Baue AE. A new instrument for prolonged mechanical massage [Abstract]. Circulation 1965; 31(Suppl 2):43. 2. Anstadt MP, Anstadt GL, Lowe JE. Direct mechanical ventricular actuation: a review. Resuscitation 1991;21:7-23. 3. Anstadt MP, Bartlett RL, Malone JP, et al. Direct mechanical ventricular actuation for cardiac arrest in humans: a clinical feasibility trial. Chest 1991;100:86-92. 4. Skinner DB, Schechter E, Hood RH, Camp TF, Anstadt MP. Mechanical ventricular assistance in human beings. Ann Thorac Surg 1968;5:13140. 5. Baue AE, Tragus ET, Anstadt GL, Blakemore WS. Mechanical ventricular assistance in man. Circulation 1968;37(Suppl 2):3M.
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6 . Baue AE, Tragus ET, Anstadt GL, Blakemore WS. Resuscitation and circulatory support by mechanical cardiac massage in man. Biomed Sci Instrum 1969;5:69-74. 7. Skinner DB, Orringer MB, Williams GM. Successful kidney transplantation after 6 hours of cadaver organ preservation by mechanical ventricular assistance. J Surg Res 1987;lO: 287-90. 8. Skinner DB, Leonard LG, Cooke SAR. Resuscitation following prolonged cardiac arrest. Ann Thorac Surg 1971;11:201-9. 9. Hill JD. Bridging to cardiac transplantation. Ann Thorac Surg 1989;47167-71. 10. Gray LA Jr, Ganzel BL, Mavroudis C, Slater AD. The Pierce-Donachy ventricular assist device as a bridge to cardiac transplantation. Ann Thorac Surg 1989;48:222-7. 11. Kormos RL, Borovetz HS, Gasior T, et al. Experience with univentricular support in mortally ill cardiac transplant candidates. Ann Thorac Surg 1990;49:261-72. 12. Champsaur G, Ninet J, Vigneron M, et al. Use of the Abiomed BVS system 5000 as a bridge to cardiac transplantation. J Thorac Cardiovasc Surg 1990;100:122-8. 13. Kanter KR, McBride LR, Pennington DG, et al. Bridging to cardiac transplantation with pulsatile ventricular assist devices. Ann Thorac Surg 1988;46:13&40. 14. Brugger JP, Bonandi L, Meli M, et al. SWAT team approach to ventricular assistance. Ann Thorac Surg 1989;47:136-41. 15. Miller CA, Pae WE, Pierce WS. Combined registry for the clinical use of mechanical ventricular assist pumps and the total artificial heart in conjunction with cardiac transplantation: fourth official report. J Heart Transplant 1990;9:45W. 16. Joyce LD, Johnson KE, Toninato CJ, et al. Results of the first 100 patients who received Symbion total artificial hearts as a bridge to cardiac transplantation. Circulation 1989;8O(Suppl 3):192-201. 17. Copeland JG, Smith RG, Icenogle TB, et al. Early experience with the total artificial heart as a bridge to cardiac transplantation. Surg Clin North Am 1988;68:621-34. 18. Portner PM, Oyer PE, Pennington DG, et al. Implantable electrical left ventricular assist system: bridge to transplantation and the future. Ann Thorac Surg 1989;47:142-50. 19. Bolman RM 111, Cox JL, Marshall W, et al. Circulatory support with a centrifugal pump as a bridge to cardiac transplantation. Ann Thorac Surg 1989;47:108-12. 20. Kirklin JK, Naftel DC, Kirklin JW, et al. Pulmonary vascular resistance and the risk of heart transplantation. J Heart Transplant 1988;73314.
DISCUSSION DR DAVID B. SKINNER (New York, NY): I was delighted to
hear this report. Back in the late 1960s, beginning in 1966 on until about 1972, George Anstadt and I and others had a chance to explore this device extensively. We were able to support dogs up to 72 hours with a fibrillating heart followed by defibrillation and normal organ function throughout that time, including regional blood flow studies. We were able to study coronary circulation while the cup was in place and found that it was not diminished by the device itself, and based on that our initial hope was that it might be useful in cardiac resuscitation. There were initial clinical trials with this at the Wilford-Hall US Air Force Hospital and at Johns Hopkins Hospital in the late 1960s and early 1970s. We had patients maintained as described here with good hernodynamics
on the device but were unsuccessful in weaning anybody off the cup. We did not have the heart transplant option available at that time. So this heart transplant option is the necessary finish for this story. Other possible applications of the device that were explored included the use of the device in a patient who was brain-dead with heart failure to sustain the brain-dead cadaver, if you will, while other organs were being harvested for transplantation as the perfusion of the other organs with this device is quite good. Dr Lowe, did you consider that possibility in this second patient who, at his young age, might have been a good donor for another organ? We stopped the work in 1972 because the National Institutes of
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Health, who had been funding the work up until that time, decided not to fund this avenue of research anymore. We were at a point where there were problems with using hand-made devices that were not standardized and could not be of certain reliability. It appears that this still remains a problem. Dr Lowe, what plans are there to try to take this device beyond a handmade, experimental mode into something that can be standardized and reproducibly available for the rest of us? This is an excellent report. I am delighted to see the successful outcome after 20 years of hoping this would happen. Congratulations.
DR LOWE: Thank you very much, Dr Skinner, for your comments. Drs Skinner and Anstadt did indeed prove that this technology could be used to preserve a brain-dead patient so that a kidney could be harvested for successful transplantation. I believe bridging to cardiac transplantation has now been established as another application. Furthermore, in the immediate future, we hope to apply DMVA for resuscitation from refractory cardiac arrest. As Dr Skinner stated, however, before we can take this technology further, even within our own hospital, we must obtain appropriate industrial support. At the present time, all cups are handmade. We believe that industrial techniques including injection molding and application of new biomers will eliminate inner membrane rupture or leak. I personally believe that DMVA will become a means for long-term circulatory support. We plan to apply it for biventricular support in patients with cardiogenic shock after cardiac surgical operations. At the present time, we do not know whether or not we can apply DMVA technology in patients with recent coronary artery bypass grafts. We have done bypass grafts in animals and put the cup on for a number of hours and did not tear anastomoses or adversely affect blood flow. However, in a patient with a short or tight internal mammary artery, I would not recommend applying DMVA. DR STEVEN F. BOLLING (Ann Arbor, MI): I see Dr Pennington in the audience, who has tried virtually all of these devices at one time or another. Dr Pennington, have you had any experience with this type of device, and what do you think about its potential for long-term support? DR D . GLENN PENNINGTON (St. Louis, MO): Well, I have no experience whatsoever with this system. I suppose my own bias at this point would be to consider this as a bridge to a bridge. We have learned from our bridging experience that one of the major benefits is its great rehabilitative potential. This sort of short-term support you are reporting would not allow for that. The salvage rates now among bridged patients are almost as good as those among the nonbridged patients. And so what you would have to do is show that this device could last for weeks or months until one could have an elective transplantation under optimal circumstances. I suspect you are quite a way from that. But it is an exciting device, and I am looking forward to hearing more about it. DR VALAVANUR A. SUBRAMANIAN (New York, NY): Around the same time as Drs Skinner and Anstadt were developing the ventricular cup and trying in the laboratory for cardiogenic shock support, we at Dr C. Walton Lillehei's lab at The New York Hospital-Cornell Medical Center, developed a left ventricular direct mechanical assistance cup made from a blood pressure cuff housed inside a hard polyurethane sleeve. Our results showed that indeed this device worked, but its use was limited by severe epicardial hemorrhages. Our device did not
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have any active diastolic relaxation mechanism in the cup, which I think is the most important feature of your device. Did you have any endocardial hemorrhage in the last patient shown? Was there anything on autopsy to show if there were any endocardial or epicardial hemorrhages? This is a device that, I think, should be pursued clinically in many patients who may need it as an initial stage support. I congratulate Dr Lowe and associates for this interesting new device or application.
DR LOWE: I sincerely thank Dr Pennington and Dr Subramanian for their comments. I agree with Dr Pennington that this is an exciting and new way to bridge to bridge, so to speak. I think our next challenge is to perform a series of long-term experiments. We hope to have cows or sheep fibrillating for long periods of time. Obviously, these are very expensive experiments and we are going to require substantial support. I believe that with currently available biotechnology we will be able to manufacture durable cups and we will be able to support patients for extended periods of time. Eventually, this device may have applicability as a long-term biventricular support device. An interesting clinical study with a group like Dr Pennington's would be to use this device initially, in other words, instead of committing to very expensive biventricular assist devices. Current biventricular assist devices require a support team and careful anticoagulation of the patient. Direct mechanical ventricular actuation could be applied initially and clinical characteristics could be sorted out. We all know that 50% of deaths in these patients commonly occur within hours to 4 or 5 days after application. Therefore, we would not commit to very expensive technology early on, and we could use this device to select patients for more complex devices including total artificial hearts at some point in the future. We agree with Dr Subramanian. A key concept that we have realized in the last several years is the importance of appropriate timing, and I do not mean electrophysiologic timing. One of the advantages is that you do not have to time this device because the heart will actually track with the mechanical actuation of the device. We can easily keep track of compressive forces to make sure that we do not collapse the right ventricle or left ventricle prematurely into the septum. The excised hearts from both of these patients were studied extensively in the cardiovascular pathology laboratory of Dr Keith Reimer. He found no epicardial or endocardial or midmyocardial trauma. We have performed more than 200 animal experiments in the laboratory, and the only consistent site of injury that we have seen is a small area of superficial epicardial hemorrhage or contusion over the right ventricular outflow tract. I think the reason is that the heart is allowed to eject with the forces of compression, so we do not have a vector of friction along the epicardial surface of the heart. DR GERARD GUIRAUDON (London, Ont, Canada): Congratulations for a very stimulating presentation. The mechanical assist device seems to have controlled a serious mitral valve regurgitation. I presume, based on the data presented, that the device decreased the left ventricular diastolic volume and diastolic diameter, especially at the level of the papillary of muscles. Do you have any better speculation? DR LOWE: That is an excellent observation, Dr Guiraudon, and we cannot explain it. I thought in our first patient, who had serious mitral regurgitation, that the device would not be effective and that we would be giving a lot of nitroprusside for left-sided afterload to allow successful left-sided ejection. How-
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ever, this was not at all a problem during her entire 56-hour period of support. I believe that there are two possible explanations. One is that we may be altering mitral valve geometry because the device is close to the base of the heart. In addition, we are driving the right and left sides of the heart equally, and so we are getting blood through the lungs whether it wants to go through the lungs or not, and we can get it out of the left ventricle whether it wants to or not. We have not yet applied DMVA to a patient with aortic insufficiency, and we d o not know how the device will function with severe aortic insufficiency.
DR CARY W. AKINS (Boston, MA): I really enjoyed your presentation. I have three quick questions. You make the claim that this is biventricular support. All of your data in the 2 patients would seem to show that it is more left ventricular support than right ventricular support. What have you shown in the laboratory? In 1patient part of the right ventricle appeared to be outside of the cup, and I am wondering if you have evidence that the right ventricle can be also supported. The second thing is that the size of the heart changes, presumably. Does this device ride
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higher up the heart, and will it cause damage to other areas? The third question is, can you design this device such that the inflation of the inner diaphragm begins at the apex and goes up toward the outflow tract, or does it all just squeeze as one unit?
DR LOWE: Those are all very good questions. In the laboratory, we have induced global ischemic insults to both ventricles. We have extensive experimental evidence showing that this technology does indeed work as a biventricular assist device. I think we have now proven this in patients. As you recall, the second patient was fibrillating during the entire period of device support. Therefore, to achieve normal left- and right-sided pressures, clearly, we were successfully pumping both ventricles. I would answer "yes" to your last question. I believe that we could design a sequence inflator, but we do not believe it is necessary. The free walls of the left and right ventricles collapse into the septum in a physiologic fashion during device systole. The pulse pressure curves are certainly physiologic, which adds further support to the concept that DMVA results in physiologic ejection. It is very easy to achieve cardiac outputs from 80% to 130% of control, even in fibrillating hearts.
Currently available ventricular assist devices are technically difficult to implant, require continuous anticoagulation, and are associated with hemorrhagic and thromboembolic complications. Direct mechanical ventricular actuation is a biventricular assist device that can be applied in 3 to 5 minutes through a left anterior thoracotomy and has no direct blood contact or need for anticoagulation. The present study was designed to determine the effects of direct mechanical ventricular actuation in total biventricular circulatory support. Cardiogenic shack refractory to standard therapy developed in 2 patients awaiting cardiac transplantation. Direct mechanical ventricular actuation was applied and provided immediate hemodynamic stabilization in both. All inotropic agents and intraaortic balloon support were then discontinued. Fifty-six hours of circulatory support bridged the first patient to successful cardiac transplan-
tation without complication. The patient is alive and well more than 1 year later without incident of infection or rejection. The second patient suffered cardiac arrest and required closed chest cardiopulmonary resuscitation before device application. After 45 hours of support, it was determined that irreversible neurologic injury had occurred and direct mechanical ventricular actuation was discontinued. Neither patient’s native heart exhibited any histologic evidence of device-related trauma. Direct mechanical ventricular actuation has undergone limited clinical investigation since its original description 25 years ago, but in these initial trials, the device has proved effective. The concept of mechanically actuating the ventricles appears to be a valuable, yet under-utilized method of total circulatory support.
T
he concept of applying rhythmic, external mechanical compression and decompression to both ventricles of the failing heart was first described in 1965 [l].Extensive laboratory investigations have shown that direct mechanical ventricular actuation (DMVA) produces cardiac outputs of 80% to 110% of control values compared with outputs of 20% to 40% using open chest bimanual compression [l-61. Animal studies also have shown that DMVA results in minimal epicardial trauma, does not require sophisticated electrophysiologic timing, and can produce normal cardiac outputs in the failing, asystolic, and even fibrillating heart. Conceptually, this technology is simple and elegant, and offers several advantages compared with other existing ventricular assist devices as well as partial cardiopulmonary bypass. First, there is no blood contact or need for anticoagulation, which should reduce thromboembolic, hemorrhagic, and infectious complications. Second, the support cup can be rapidly applied through a left anterior thoracotomy to achieve biventricular support within 3 minutes [l-61. The anterior thoracotomy application preserves the sternal approach for subsequent cardiac operations including cardiac transplantation. Third, physiologic and pulsatile flow rates are rapidly achieved without the need for inotropic support.
Until the present study, clinical applications of DMVA were primarily limited to heroic efforts of resuscitation after prolonged periods of failed standard external cardiopulmonary resuscitation [2-61. These initial clinical applications did not result in long-term survivors but did convincingly demonstrate that previous experimental results could be duplicated in humans. The present investigation was designed to determine whether DMVA could be used to support patients with refractory cardiogenic shock who were otherwise candidates for cardiac transplantation. This particular group of patients was chosen to attempt to answer a number of important questions: can the technology provide prolonged circulatory support without systemic complications, is there serious trauma to the native heart, and finally, what are the present limitations in device design and construction that could lead to device failure? Based on extensive laboratory testing, the Institutional Review Board at Duke University Medical Center approved DMVA for use in patients with refractory cardiogenic shock or cardiac arrest including those awaiting cardiac transplantation.
Presented at the Twenty-seventh Annual Meeting of The Society of Thoracic Surgeons, San Francisco, CA, Feb 1%20, 1991.
Direct mechanical ventricular actuation employs an elliptically contoured cup which fits over both ventricles. The cup consists of an outer shell or housing and an inner flexible diaphragm. The housing can be made of either a
Address reprint requests to Dr Lowe, Duke University Medical Center, Box 3954, Durham, NC 27710.
0 1991 by The Society of Thoracic Surgeons
(Ann Tliorac Surg 1991;52:123745)
Material and Methods
0003-4975/91/$3.50
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Fig 1 . Schematic diagram of direct mechanical ventricular actuation drive system and cup. The cup is shown actuating the ventricles into both systolic (right) and diastolic (left) configurations.
hard translucent material (Pyrex) or a soft material (Dacron-reinforced Silastic) which produces a semirigid structure. The advantage of the soft shell is its ease of application through a smaller incision, while the rigid shell has the advantage of allowing visualization of the diaphragm’s action on the heart. The flexible diaphragm currently used in both the hard and soft cups is a Silastic membrane (Dow Corning Corp). The cup attaches itself to both ventricles via a continuous vacuum at the apex of the cup. Once the cup is in position, positive and negative pneumatic forces operate a diaphragm within the cup to ”actuate” the ventricles into their normal systolic and diastolic configurations. Appropriate delivery of uniform positive and negative forces to the ventricles rapidly returns the failing, asystolic, or fibrillating heart to its function as a blood pump (Fig 1). The apical vacuum source provides device attachment, but more importantly and critical to the concept, it seals the actuating diaphragm to the myocardial surface. Consequently, the device not only compresses the ventricles to create systole but also enhances cardiac filling by decompressing the ventricles into a diastolic configuration. The massaging action of DMVA is con;rolled by a pneumatic drive unit that has both pulsed pressure and sustained vacuum systems (see Fig 1). The vacuum system is responsible for device attachment and can be adjusted to the least degree of suction (approximately -70 mm Hg line pressure) that will maintain a constant diaphragm-to-epicardium seal. The pulsed pressure system consists of a positive pneumatic source for systolic
compression and a negative pneumatic source for diastolic filling. The internal diameter of each assist cup is identified by a numerical label in millimeters. An appropriate cup size is one that approximates the greatest transverse diameter of the unassisted heart. Cups varying in size from 90 to 150 mm in transverse diameter were prepared for the present study. This particular range was chosen by evaluation of chest radiographs of cardiac transplant candidates on the waiting list at Duke University Medical Center. Once a general size has been selected, the assist cup can rapidly be positioned through a small left anterior, sixth intercostal space thoracotomy. After the heart is adequately exposed, the device is positioned over the ventricular apex while set in a diastolic mode. The drive system’s continuous vacuum source causes the device to aspirate itself onto the heart. Once attached, the drive system is switched into an actuating mode which cycles positive and negative forces from the pulsed pressure source resulting in ventricular systole and diastole. The process of DMVA application takes seconds after adequate exposure. The entire procedure has been performed in less than 3 minutes for emergency resuscitation in both the clinical [3-61 and the laboratory setting [l]. After acute hemodynamic stabilization, systolic (+120 mm Hg to +130 mm Hg) a n d diastolic (-100 mm Hg to -115 mm Hg) forces and flow rates can be adjusted to maximize hemodynamics. Cycle rates are generally set between 80 per minute (large hearts) to 120 per minute (small hearts). Adequate left ventricular emptying is achieved by systolic durations set at 50% of the
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Fig 2 . Ciry apylicatiori is made hy exposing the heart through a left U I Z tcrior thoracotoiii~y;positioning the clip oiicr tl7e vciztricirlar apex rcwlts iiz self attachrirerit ( k j t ) . The chest is then closed after the d r i w lines arc broirght out through separate stah incisions (right).
DMVA actuating cycle. This is important to prevent any potential for pulmonary edema, which could result if an abbreviated systolic force effectively emptied the right ventricle but not the left. Assurance of avoiding this situation is possible by monitoring pulmonary wedge pressures. An increase in wedge pressures during support indicates the need for increased systolic durations. Other conceivable complications can be circumvented by the usual preparations for any mechanical failures. If a leak develops in the actuating diaphragm, it is easily detected by fluctuations in drive pressures and vacuum attachment pressures. Although such an event requires device replacement, initial hemodynamic stabilization can be maintained by increasing drive pressures. The possibility of a pneumothorax is prevented by placement of a chest tube at the time of initial thoracotomy. The pneumatic drive units are an unlikely source of mechanical failure but were monitored as with any other device. For these reasons, an additional drive unit and set of devices were available for emergency back-up in the present study. Institutional Review Board approval was obtained in August 1989. After informed consent, DMVA was applied to 2 patients in whom refractory cardiogenic shock developed while they were awaiting cardiac transplantation. Patients with preexisting infection and multiorgan failure were excluded from the investigation.
Patient 1 In January 1990, a 56-year-old woman, diagnosed 2 years previously with an idiopathic dilated cardiomyopathy, was seen in acute congestive failure. The patient had been previously approved as a candidate for cardiac transplantation. Cardiac catheterization revealed an ejection fraction of 0.08 with normal coronary arteries, 3+ mitral regurgitation, and a pulmonary vascular resistance of 3 Wood units. At the time of presentation to the emergency room, she was in pulmonary edema with a cardiac index
of less than 2.0 L/m2. After admission to the intensive care unit, the patient was successfully resuscitated with inotropic agents and vigorous diuresis. Shortly after being transferred to a step-down unit, the patient required readmission to the intensive care unit for hypotension and pulmonary edema. She was placed on a regimen of maximal doses of three inotropic agents yet continued to deteriorate hemodynamically; she became oliguric, and episodes of nonsustained ventricular tachycardia developed. Cardiac index dropped to 1.8 L/m2 with mean pulmonary artery pressures of more than 40 mm Hg and arterial pressures of 70140 mm Hg. After informed consent, the patient was taken on an emergency basis to the operating room for device application. During transport, cardiac index (<1.8 L/m2) and arterial pressures (60/40 mm Hg) fell further, with increases in pulmonary diastolic pressures to more than 45 mm Hg.
Patient 2 In November 1990, a 46-year-old man with no past medical history was seen at the emergency room with an acute, massive myocardial infarction. The patient was given thrombolytic therapy, which did not result in electrocardiographic evidence of reperfusion. Therefore, he was taken to the cardiac catheterization laboratory for emergency percutaneous transluminal coronary angioplasty. Catheterization revealed an ejection fraction of 0.10, severe global hypokinesis, and 100% occlusions of the proximal anterior descending and circumflex arteries with a 75% proximal right coronary occlusion. Multiple attempts to open the anterior descending artery using percutaneous transluminal coronary angioplasty techniques were unsuccessful and resulted in hernodynamic deterioration requiring placement of an intraaortic balloon pump and initiation of inotropic support. The patient’s condition stabilized over the next 24 hours, and he was placed on the active cardiac transplant list. The patient’s hemodynamic status subsequently deteriorated. Inotropic
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of larger size (125 mm) provided adequate support; however, a subsequent change to a slightly smaller size (120 mm) substantially improved hemodynamics.
Patient 1
Fig 3 . Systemic arterial and venous pressures before and during 56 hours of support in the first direct mechanical ventricular actuation recipient. The patient was weaned from all inotropic agents during the first 12 hours of support.
agents were increased to maximal doses along with continued intraaortic balloon pump support. However, the patient became oliguric with a cardiac index worsening to less than 1.8 L/m2. Systemic pressures fell to 80/60 mm Hg and pulmonary artery diastolic pressure was greater than 40 mm Hg. After informed consent, the patient was taken on an emergency basis to the operating room where he suffered cardiac arrest upon arrival. Cardiopulmonary resuscitation was begun using standard closed chest cardiac massage while the chest was prepared and draped. However, cardiac index (0.5 L/m2) and mean arterial pressures (40 mm Hg) were severely depressed for 15 minutes before device application.
Results Both patients had transesophageal echocardiography performed in the operating room immediately before device application. This allowed for determination of transverse cardiac dimensions, and an appropriate device size was estimated preoperatively. A 115-mm diameter cup was selected for the first patient based on a 115-mm transverse cardiac diameter. The device fit perfectly, and DMVA application through an anterior thoracotomy was completed in less than 3 minutes. In the second patient, a cup
Fig 4. Cardiac outputs and uenous oxygen saturations before and during 56 hours of support in the first direct mechanical ventricular actuation recipient.
After DMVA application, hemodynamics immediately improved to a cardiac output of 3.9 L/min (2.78 L/m2). Systemic arterial pressure increased to 100/60 mm Hg, and pulmonary pressure dropped to 24/8 mm Hg. Drive lines and a single chest tube exited the chest through separate intercostal incisions (Fig 2). The entire operation from skin incision to closure took 38 minutes. During the subsequent 12 hours administration of all inotropic agents was discontinued. The patient remained hemodynamically 1.0/63 -+ stable with normal systemic arterial (106 0.4 mm Hg) and venous pressures (12 k 0.3 mm Hg) (Fig 3). Cardiac outputs averaged 3.16 0.05 L/min (2.26 0.03 L/m2)during support, with adequate tissue perfusion as evidenced by normal venous saturations (Fig 4) and return of normal urine output. Pulmonary artery pressures (33 k 0.9/16 0.5 mm Hg) remained normal during the entire support period (Fig 5). All end organs demonstrated normal function during the period of DMVA support. After 56 hours, a donor heart became available and the patient was returned to the operating room where cardiopulmonary bypass was instituted through a virgin sternotomy. The device was easily removed after the patient was placed on cardiopulmonary bypass by cutting the sterile, intrathoracic portions of the drive and suction lines (Fig 6). Cardiac transplantation was then performed with a subsequent uncomplicated recovery. The patient is alive and in functional class I more than 1 year after transplantation without incidence of either infection or rejection.
*
*
*
*
Patient 2 The heart could only be briefly defibrillated before cup application and remained fibrillating during the entire period of support. Initial cardiac outputs increased to 4.7 L/min (2.14 L/m2) upon placement of DMVA. These results were dramatic in comparison with the patient’s severely depressed outputs (approximately 1 L/min) during his resuscitation for cardiac arrest. Systemic arterial pressures increased to 120/80 mm Hg, whereas pulmo-
Fig 5. Pulmonary artery pressures before and during 56 hours of support in the first direct mechanical ventricular actuation recipient.
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Fig 6. Before cardiac transplantation in patient 1, cardiopulmonary bypass was instituted using standard cannulation techniques through a virgin sternotomy (left). Device removal was performed by cutting the sterile drive lines within the chest and removing the cup through the sternotomy (right).
nary diastolic pressures decreased from 45 mm Hg to 22 mm Hg. As in the first patient, the chest was closed and the patient transferred to the intensive care unit. Hemodynamics remained stable during circulatory support with a mean cardiac output of 6.2 0.3 L/min (2.8 ? 0.1 L/m2) (Fig 7). A gradual decline in cardiac output occurred after 6 hours of support owing to a leak in a defective diaphragm. Placement of a new device resulted in initial cardiac outputs of 11 L/min. Systemic pressures (110 5 2/66 ? 1 mm Hg) and central venous pressures (9.9 ? 1.5 mm Hg) remained adequate throughout support, despite the initial cup failure (Fig 8) and refractory ventricular fibrillation. Pulmonary diastolic pressures (21.3 k 0.9 mm Hg) remained below device implant values (Fig 9). Venous saturations averaged 0.57 k 0.04 during support, which indicated improved tissue perfusion (see Fig 7). Unfortunately, the patient remained neurologically unresponsive after his cardiac arrest and was pronounced brain-dead. Therefore, the device was removed after 45 hours of circulatory support, and the patient died.
*
Histologic Examination Both patients' native hearts underwent extensive histologic examination. Despite the presence of recent un100 h
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derlying myocardial infarctions, neither heart showed any device-related trauma. In the first patient, myocardial infarction, predominantly in the right ventricle, was estimated to have occurred 3 to 4 days before device application. In the second patient, myocardial infarctions throughout both ventricles involved 60% of the myocardial mass. Approximately half of the infarcted myocardium was acute and represented two recent events that had occurred approximately 3 to 4 and 6 to 9 days before device implantation. The remaining infarctions appeared as well-defined scars that originated months to years earlier.
Complications There were no complications during the entire period of support in the first patient. However, in the second patient, defective material led to premature diaphragm fatigue and a small leak in the cup diaphragm where it was attached to the housing. Cardiac outputs gradually declined at a rate of approximately 0.5 L . min-' . h-' after onset of the leak. This slow clinical failure of the cup confirmed failures observed during prolonged experimental in vivo and in vitro studies. Because sudden, complete cup failure has not been encountered, there is adequate time for cup replacement while hemodynamic support is 150 130
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Fig 7. Cardiac outputs and venous oxygen saturations before and during 45 hours of support in the second direct mechanical ventricular actuation recipient. Use of the intraaortic balloon and all inotropic agents was discontinued immediately after direct mechanical ventricular actuation application. Arrow indicates the onset of a leak in the cup diaphragm at 6 hours of support. Replacement of a new cup at 14 hours resulted in return of normal hemodynamics.
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Fig 8. Systemic arterial and venous pressures before and during 45 hours of support in the second direct mechanical ventricular actuation recipient. Use of the intraaortic balloon and all inotropic agents was discontinued immediately after direct mechanical ventricular actuation application. Pressures remained relatively stable despite a device leak during the early support period.
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Fig 9. Pulmonary diastolic pressures before and during 45 hours of support in the second direct mechanical ventricular actuation recipient. Pulmonary systolic pressures could not be interpreted because of recording artifacts.
still adequately maintained. Furthermore, as demonstrated in the second patient, the cup can be replaced at the bedside using a standard thoracotomy tray. The initial hard-shell device was replaced in the second patient using a more pliable soft-shell device. The soft-shell device was very easy to apply through the small anterior thoracotomy.
Comment These initial clinical results show that DMVA can be successfully used in patients with biventricular failure and refractory cardiogenic shock as a means of total circulatory support while awaiting cardiac transplantation. Based on numerous experimental studies and the present clinical results, we believe that this technology deserves further human application. Direct mechanical ventricular actuation has many proven and theoretical advantages compared with current blood contacting assist devices. Because DMVA requires no anticoagulation or vascular cannulation, hemorrhagic and thromboembolic complications should theoretically be markedly reduced. In addition, implantation of DMVA does not require any vascular anastomoses. Reoperation for hemorrhage using current blood-contacting devices continues to be a major complication occurring in nearly 60% of patients [9-151. Although newer devices employ “antithrombogenic” surfaces, thromboembolism remains an often catastrophic complication. Often these thromboemboli arise at sites of anastomosis or from mechanical valves or sewing rings and not from the moving membrane used to create blood flow [16-181. In addition, DMVA application requires only a small left anterior thoracotomy, and complete biventricular support can be established in only 3 to 5 minutes. The installation of current blood-contacting univentricular and biventricular assist devices requires a major and timeconsuming operative intervention complicated at times by technical problems [9-11, 17, 191. These devices, unlike DMVA, also require an elaborate set-up and support team. Finally, as shown in the present study, DMVA can
restore physiologic, pulsatile flow rates even in the fibrillating heart, which is not possible with standard bloodcontacting ventricular assist devices. This technology does not require an elaborate set-up or support team and does not necessitate prolonged training courses. Once DMVA is applied, a number of options become available: (1) support can be provided to determine whether endorgan injury is reversible or irreversible, (2) the device can serve as a temporary circulatory support system to bridge to implantation of a total artificial heart, or ( 3 ) the device can provide a definitive bridge to cardiac transplantation. Through these options, DMVA can provide initial support and allow thorough patient assessment before committing to more elaborate and expensive devices. Such an approach may reduce early mortality and morbidity and minimize heroic and costly resuscitation efforts currently applied to patients who subsequently succumb early-on. For example, of those deaths occurring before transplantation while assist devices are being used, approximately 50% occur during the first hours to days of support [lo, 14, 181. Direct mechanical ventricular actuation may decrease early mortality by allowing rapid hemodynamic stabilization and avoidance of the complications associated with blood-contacting assist devices. In addition, if continued support is not justified secondary to end-organ failure, the unfortunate loss of the patient is not associated with tremendous expense. Direct mechanical ventricular actuation requires further evaluation to determine its potential for providing longterm circulatory support. On the other hand, its ability to serve as a valuable adjunct in this regard has been shown in the present study. There are a number of potential future applications for DMVA: Bridging to cardiac transplantation Bridging to any other cardiac assist devices Resuscitation from refractory cardiac arrest Circulatory support for cardiogenic shock Postcardiotomy circulatory support Resuscitation from profound hypothermia Noncardiac donor organ preservation after neurologic death In certain situations, the device may actually prove critical in determining a patient’s suitability for transplantation. For instance, some selection criteria for potential transplant candidates are difficult to adequately assess during acute cardiovascular collapse. Pulmonary vascular resistance is a particularly relevant example. Pulmonary vascular resistance is sometimes even more difficult to assess during conventional methods of circulatory support. This can be a major problem because substantial elevations in pulmonary vascular resistance have been found to be associated with right ventricular failure and subsequent mortality after transplantation [20]. Because DMVA creates hemodynamic conditions similar to the normal physiologic state, pulmonary vascular resistance can be calculated using standard techniques. A major drawback of DMVA is its current state of cup manufacture. Presently, all devices are hand-fabricated
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using Silastic (Dow Corning) diaphragms. Industrial fabrication with careful quality control must be accomplished before widespread application of this technology. Another potential drawback may be trauma to previously placed coronary artery bypass grafts. However, we have used DMVA after coronary artery bypass grafting in 1 patient [3] as well as in experimental animal studies. In the acute setting, there was no evidence of graft trauma or interference with graft flow after 4 hours of device application. However, further experimental work will be required to determine DMVA's effect on bypass grafts during prolonged periods of circulatory support. Finally, it is unknown whether this particular technology can be routinely applied in patients who have had previous cardiac operations. In those patients who have had previous cardiac operations, the heart would have to be totally dissected free before device application. This would require a median sternotomy instead of the preferred left anterior thoracotomy approach. In summary, we believe that our initial clinical results are most encouraging and justify further clinical application of this unique form of biventricular assistance. Although the technology was originally conceived to be applicable only to those patients who suffer acute refractory cardiac arrest, we believe that the technology can be perfected to provide a simple means for long-term circulatory support.
References 1. Anstadt GL, Blakemore WS, Baue AE. A new instrument for prolonged mechanical massage [Abstract]. Circulation 1965; 31(Suppl 2):43. 2. Anstadt MP, Anstadt GL, Lowe JE. Direct mechanical ventricular actuation: a review. Resuscitation 1991;21:7-23. 3. Anstadt MP, Bartlett RL, Malone JP, et al. Direct mechanical ventricular actuation for cardiac arrest in humans: a clinical feasibility trial. Chest 1991;100:86-92. 4. Skinner DB, Schechter E, Hood RH, Camp TF, Anstadt MP. Mechanical ventricular assistance in human beings. Ann Thorac Surg 1968;5:13140. 5. Baue AE, Tragus ET, Anstadt GL, Blakemore WS. Mechanical ventricular assistance in man. Circulation 1968;37(Suppl 2):3M.
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6 . Baue AE, Tragus ET, Anstadt GL, Blakemore WS. Resuscitation and circulatory support by mechanical cardiac massage in man. Biomed Sci Instrum 1969;5:69-74. 7. Skinner DB, Orringer MB, Williams GM. Successful kidney transplantation after 6 hours of cadaver organ preservation by mechanical ventricular assistance. J Surg Res 1987;lO: 287-90. 8. Skinner DB, Leonard LG, Cooke SAR. Resuscitation following prolonged cardiac arrest. Ann Thorac Surg 1971;11:201-9. 9. Hill JD. Bridging to cardiac transplantation. Ann Thorac Surg 1989;47167-71. 10. Gray LA Jr, Ganzel BL, Mavroudis C, Slater AD. The Pierce-Donachy ventricular assist device as a bridge to cardiac transplantation. Ann Thorac Surg 1989;48:222-7. 11. Kormos RL, Borovetz HS, Gasior T, et al. Experience with univentricular support in mortally ill cardiac transplant candidates. Ann Thorac Surg 1990;49:261-72. 12. Champsaur G, Ninet J, Vigneron M, et al. Use of the Abiomed BVS system 5000 as a bridge to cardiac transplantation. J Thorac Cardiovasc Surg 1990;100:122-8. 13. Kanter KR, McBride LR, Pennington DG, et al. Bridging to cardiac transplantation with pulsatile ventricular assist devices. Ann Thorac Surg 1988;46:13&40. 14. Brugger JP, Bonandi L, Meli M, et al. SWAT team approach to ventricular assistance. Ann Thorac Surg 1989;47:136-41. 15. Miller CA, Pae WE, Pierce WS. Combined registry for the clinical use of mechanical ventricular assist pumps and the total artificial heart in conjunction with cardiac transplantation: fourth official report. J Heart Transplant 1990;9:45W. 16. Joyce LD, Johnson KE, Toninato CJ, et al. Results of the first 100 patients who received Symbion total artificial hearts as a bridge to cardiac transplantation. Circulation 1989;8O(Suppl 3):192-201. 17. Copeland JG, Smith RG, Icenogle TB, et al. Early experience with the total artificial heart as a bridge to cardiac transplantation. Surg Clin North Am 1988;68:621-34. 18. Portner PM, Oyer PE, Pennington DG, et al. Implantable electrical left ventricular assist system: bridge to transplantation and the future. Ann Thorac Surg 1989;47:142-50. 19. Bolman RM 111, Cox JL, Marshall W, et al. Circulatory support with a centrifugal pump as a bridge to cardiac transplantation. Ann Thorac Surg 1989;47:108-12. 20. Kirklin JK, Naftel DC, Kirklin JW, et al. Pulmonary vascular resistance and the risk of heart transplantation. J Heart Transplant 1988;73314.
DISCUSSION DR DAVID B. SKINNER (New York, NY): I was delighted to
hear this report. Back in the late 1960s, beginning in 1966 on until about 1972, George Anstadt and I and others had a chance to explore this device extensively. We were able to support dogs up to 72 hours with a fibrillating heart followed by defibrillation and normal organ function throughout that time, including regional blood flow studies. We were able to study coronary circulation while the cup was in place and found that it was not diminished by the device itself, and based on that our initial hope was that it might be useful in cardiac resuscitation. There were initial clinical trials with this at the Wilford-Hall US Air Force Hospital and at Johns Hopkins Hospital in the late 1960s and early 1970s. We had patients maintained as described here with good hernodynamics
on the device but were unsuccessful in weaning anybody off the cup. We did not have the heart transplant option available at that time. So this heart transplant option is the necessary finish for this story. Other possible applications of the device that were explored included the use of the device in a patient who was brain-dead with heart failure to sustain the brain-dead cadaver, if you will, while other organs were being harvested for transplantation as the perfusion of the other organs with this device is quite good. Dr Lowe, did you consider that possibility in this second patient who, at his young age, might have been a good donor for another organ? We stopped the work in 1972 because the National Institutes of
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Health, who had been funding the work up until that time, decided not to fund this avenue of research anymore. We were at a point where there were problems with using hand-made devices that were not standardized and could not be of certain reliability. It appears that this still remains a problem. Dr Lowe, what plans are there to try to take this device beyond a handmade, experimental mode into something that can be standardized and reproducibly available for the rest of us? This is an excellent report. I am delighted to see the successful outcome after 20 years of hoping this would happen. Congratulations.
DR LOWE: Thank you very much, Dr Skinner, for your comments. Drs Skinner and Anstadt did indeed prove that this technology could be used to preserve a brain-dead patient so that a kidney could be harvested for successful transplantation. I believe bridging to cardiac transplantation has now been established as another application. Furthermore, in the immediate future, we hope to apply DMVA for resuscitation from refractory cardiac arrest. As Dr Skinner stated, however, before we can take this technology further, even within our own hospital, we must obtain appropriate industrial support. At the present time, all cups are handmade. We believe that industrial techniques including injection molding and application of new biomers will eliminate inner membrane rupture or leak. I personally believe that DMVA will become a means for long-term circulatory support. We plan to apply it for biventricular support in patients with cardiogenic shock after cardiac surgical operations. At the present time, we do not know whether or not we can apply DMVA technology in patients with recent coronary artery bypass grafts. We have done bypass grafts in animals and put the cup on for a number of hours and did not tear anastomoses or adversely affect blood flow. However, in a patient with a short or tight internal mammary artery, I would not recommend applying DMVA. DR STEVEN F. BOLLING (Ann Arbor, MI): I see Dr Pennington in the audience, who has tried virtually all of these devices at one time or another. Dr Pennington, have you had any experience with this type of device, and what do you think about its potential for long-term support? DR D . GLENN PENNINGTON (St. Louis, MO): Well, I have no experience whatsoever with this system. I suppose my own bias at this point would be to consider this as a bridge to a bridge. We have learned from our bridging experience that one of the major benefits is its great rehabilitative potential. This sort of short-term support you are reporting would not allow for that. The salvage rates now among bridged patients are almost as good as those among the nonbridged patients. And so what you would have to do is show that this device could last for weeks or months until one could have an elective transplantation under optimal circumstances. I suspect you are quite a way from that. But it is an exciting device, and I am looking forward to hearing more about it. DR VALAVANUR A. SUBRAMANIAN (New York, NY): Around the same time as Drs Skinner and Anstadt were developing the ventricular cup and trying in the laboratory for cardiogenic shock support, we at Dr C. Walton Lillehei's lab at The New York Hospital-Cornell Medical Center, developed a left ventricular direct mechanical assistance cup made from a blood pressure cuff housed inside a hard polyurethane sleeve. Our results showed that indeed this device worked, but its use was limited by severe epicardial hemorrhages. Our device did not
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have any active diastolic relaxation mechanism in the cup, which I think is the most important feature of your device. Did you have any endocardial hemorrhage in the last patient shown? Was there anything on autopsy to show if there were any endocardial or epicardial hemorrhages? This is a device that, I think, should be pursued clinically in many patients who may need it as an initial stage support. I congratulate Dr Lowe and associates for this interesting new device or application.
DR LOWE: I sincerely thank Dr Pennington and Dr Subramanian for their comments. I agree with Dr Pennington that this is an exciting and new way to bridge to bridge, so to speak. I think our next challenge is to perform a series of long-term experiments. We hope to have cows or sheep fibrillating for long periods of time. Obviously, these are very expensive experiments and we are going to require substantial support. I believe that with currently available biotechnology we will be able to manufacture durable cups and we will be able to support patients for extended periods of time. Eventually, this device may have applicability as a long-term biventricular support device. An interesting clinical study with a group like Dr Pennington's would be to use this device initially, in other words, instead of committing to very expensive biventricular assist devices. Current biventricular assist devices require a support team and careful anticoagulation of the patient. Direct mechanical ventricular actuation could be applied initially and clinical characteristics could be sorted out. We all know that 50% of deaths in these patients commonly occur within hours to 4 or 5 days after application. Therefore, we would not commit to very expensive technology early on, and we could use this device to select patients for more complex devices including total artificial hearts at some point in the future. We agree with Dr Subramanian. A key concept that we have realized in the last several years is the importance of appropriate timing, and I do not mean electrophysiologic timing. One of the advantages is that you do not have to time this device because the heart will actually track with the mechanical actuation of the device. We can easily keep track of compressive forces to make sure that we do not collapse the right ventricle or left ventricle prematurely into the septum. The excised hearts from both of these patients were studied extensively in the cardiovascular pathology laboratory of Dr Keith Reimer. He found no epicardial or endocardial or midmyocardial trauma. We have performed more than 200 animal experiments in the laboratory, and the only consistent site of injury that we have seen is a small area of superficial epicardial hemorrhage or contusion over the right ventricular outflow tract. I think the reason is that the heart is allowed to eject with the forces of compression, so we do not have a vector of friction along the epicardial surface of the heart. DR GERARD GUIRAUDON (London, Ont, Canada): Congratulations for a very stimulating presentation. The mechanical assist device seems to have controlled a serious mitral valve regurgitation. I presume, based on the data presented, that the device decreased the left ventricular diastolic volume and diastolic diameter, especially at the level of the papillary of muscles. Do you have any better speculation? DR LOWE: That is an excellent observation, Dr Guiraudon, and we cannot explain it. I thought in our first patient, who had serious mitral regurgitation, that the device would not be effective and that we would be giving a lot of nitroprusside for left-sided afterload to allow successful left-sided ejection. How-
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ever, this was not at all a problem during her entire 56-hour period of support. I believe that there are two possible explanations. One is that we may be altering mitral valve geometry because the device is close to the base of the heart. In addition, we are driving the right and left sides of the heart equally, and so we are getting blood through the lungs whether it wants to go through the lungs or not, and we can get it out of the left ventricle whether it wants to or not. We have not yet applied DMVA to a patient with aortic insufficiency, and we d o not know how the device will function with severe aortic insufficiency.
DR CARY W. AKINS (Boston, MA): I really enjoyed your presentation. I have three quick questions. You make the claim that this is biventricular support. All of your data in the 2 patients would seem to show that it is more left ventricular support than right ventricular support. What have you shown in the laboratory? In 1patient part of the right ventricle appeared to be outside of the cup, and I am wondering if you have evidence that the right ventricle can be also supported. The second thing is that the size of the heart changes, presumably. Does this device ride
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higher up the heart, and will it cause damage to other areas? The third question is, can you design this device such that the inflation of the inner diaphragm begins at the apex and goes up toward the outflow tract, or does it all just squeeze as one unit?
DR LOWE: Those are all very good questions. In the laboratory, we have induced global ischemic insults to both ventricles. We have extensive experimental evidence showing that this technology does indeed work as a biventricular assist device. I think we have now proven this in patients. As you recall, the second patient was fibrillating during the entire period of device support. Therefore, to achieve normal left- and right-sided pressures, clearly, we were successfully pumping both ventricles. I would answer "yes" to your last question. I believe that we could design a sequence inflator, but we do not believe it is necessary. The free walls of the left and right ventricles collapse into the septum in a physiologic fashion during device systole. The pulse pressure curves are certainly physiologic, which adds further support to the concept that DMVA results in physiologic ejection. It is very easy to achieve cardiac outputs from 80% to 130% of control, even in fibrillating hearts.