Future Technology for Off-Pump Coronary Artery Bypass (OPCAB) Lishan Aklog Over the past 5 years, many coronary artery surgeons have embraced technology and advanced the field of beating heart surgery to the point where off-pump coronary artery bypass (OPCAB) is becoming a mature procedure. Enabling technologies are now available for all stages of the procedure, including cardiac positioning, coronary artery stabilization, coronary artery visualization, and performance of the proximal and distal anastomoses. Despite these successes, only a minority of cardiac surgeons performs this procedure routinely. Proponents of OPCAB and the medical device industry will need to continue to develop new technologies to make OPCAB less technically challenging and more widely accepted. Progress towards routine single-vessel off-pump totally endoscopic coronary artery bypass has been slow. Translating the benefits of multivessel OPCAB to an endoscopic setting remains a formidable challenge that will require further technologic breakthroughs. © 2003 Elsevier Inc. All rights reserved. Key words: Off-pump coronary artery bypass surgery, beating heart surgery, technology, anastomotic devices.
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onventional Coronary Artery Bypass Grafting (CABG), under cardiopulmonary bypass with cardioplegic arrest using the left internal mammary artery and reversed saphenous veins, is arguably the most successful major surgical procedure in history. In 1999 it was surpassed only by caesarean sections and hysterectomies as the most common major surgical procedure in the United States and was by far the most common procedure in the elderly.1 Mortality and morbidity after CABG have declined dramatically despite an increasingly higher risk patient population.2 Late outcomes, including survival, re-intervention, and freedom from angina, remain excellent.3 This perspective of CABG as a highly successful and refined therapy for advanced coronary artery disease has been challenged by the rapid rise of catheter-based interventions over the past decade. This rise has been driven by improved results, that is, falling restenosis rates, which can be directly attributed to a constant flow of new From the Department of Cardiothoracic Surgery Mount Sinai Medical Center New York, NY. Address reprint requests to Lishan Aklog, MD, Department of Cardiothoracic Surgery Mount Sinai Medical Center 1190 Fifth Avenue New York, NY 10029. © 2003 Elsevier Inc. All rights reserved. 1043-0679/03/1501-00006-6$30.00/0 doi:10.1016/S1043-0679(03)00006-6
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technologies, most recently drug-eluting stents. CABG, in contrast, has until recently remained stagnant, perhaps a victim of its own success. The primary techniques of coronary artery surgery had been well established by the early 1970s. Besides the routine use of the internal mammary artery, the procedure has remained essentially unchanged in the past 20 years, whereas major technologic advances have occurred in other areas of cardiac surgery (valve prostheses, ventricular assist devices). Improved outcomes after CABG can be primarily attributed to safer cardiopulmonary bypass, better myocardial protection, and improved postoperative care and not to new techniques in coronary artery surgery itself. Over the past 5 years, cardiac surgeons have risen to the challenge and have sought to advance coronary artery surgery by making it more durable and less invasive. Early efforts at beating heart surgery, including single-vessel thoracotomy approaches, minimally invasive direct coronary artery bypass (MIDCAB), and multivessel full-sternotomy approaches (off-pump coronary artery bypass grafting, or OPCAB), were decidedly low-tech, using, at most, a simple stabilizer, a few pericardial sutures, and conventional anastomotic techniques. These critical early steps represented more of a philosophical advance, a paradigm shift, than a technologic breakthrough. They, however, opened the doors and stimulated
Seminars in Thoracic and Cardiovascular Surgery, Vol 15, No 1 ( January), 2003: pp 92-102
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Figure 1. Schematic of the role of enabling technologies replacing cardiopulmonary bypass (CPB) and cardioplegic (CP) arrest during OPCAB.
the imagination of surgeons and engineers to develop new enabling technologies to re-invent the way we perform coronary artery surgery.
Enabling Technologies in OPCAB OPCAB or multivessel grafting on a beating heart through a full sternotomy has reached its adolescence. It accounts for 20-25% of all CABG procedures in the United States and most cardiac surgeons have performed it. Despite its increasing popularity over the past 5 years, the majority of OPCAB procedures are performed by a small minority of surgeons, and many among the majority remain deeply skeptical of its purported benefits. There are, in my opinion, two key strategies to increasing OPCAB adoption beyond its current niche role: continue to expand the evidence base for its use through large, well-designed clinical trials and continue to develop enabling technologies to make the procedure less technically demanding and therefore more widely applicable. The fundamental goal of OPCAB is to perform an equivalent, complete revascularization without exposing the patient to the known risks of cardiopulmonary bypass. Cardiopulmonary bypass with cardioplegic arrest (in conjunction with surgical loupes) converts a 1- to 2-mm moving
target on the back of a beating heart into a magnified view of the same target in a still, bloodless field, permitting a technically precise anastomosis. To achieve equivalent technical precision and wider applicability, OPCAB must replace one enabling technology, cardiopulmonary bypass, with other enabling technologies (Fig 1). There are several key technical steps to performing a precise anastomosis on a beating heart: 1. Cardiac positioning with hemodynamic stability 2. Coronary artery stabilization 3. Coronary artery visualization 4. Proximal and distal anastomoses Enabling technologies and tools are currently available to facilitate each of these steps. New technologies are being introduced or under development.
Cardiac Positioning with Hemodynamic Stability The first, and often most challenging, step in performing a beating heart anastomosis is positioning the heart such that the coronary target is well visualized and accessible while at the same
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time maintaining hemodynamic stability. The ideal system would permit access to all targets with a normal blood pressure and cardiac output for as long as is necessary to perform a technically precise anastomosis. In an interesting study by Czerny and coworkers,4 hemodynamic compromise during cardiac positioning was the most common obstacle to achieving complete revascularization during OPCAB.
Classic Techniques The classic techniques for positioning the heart during OPCAB include one or more deep pericardial sutures. The hemodynamic compromise associated with these maneuvers was typically overcome with a variety of measures, including deep Trendelenburg positioning, volume loading, and the use of vasoconstrictors. Some surgeons adopted a policy of ‘permissive hypotension’ with neurologic monitoring whereby the systolic blood pressure was permitted to fall to the 70 to 80 range as long as the cerebral oximetry indicated acceptable cerebral perfusion. Others have found a wide right pleuropericardiotomy, with herniation of the apex into the right hemithorax, quite helpful in achieving good exposure with acceptable hemodynamics. Most of these techniques, however, merely address the symptom, hemodynamic compromise, not the underlying pathophysiologic mechanism, which is cardiac compression with impaired ventricular filling. Although they work well in routine patients requiring a handful of grafts, more complex patients can be very challenging, especially to surgeons who are at the beginning of their learning curve. These patients include those who require multiple posterolateral wall grafts and those who have cardiomegaly and left ventricular dysfunction. Many patients, including those with left main or severe proximal stenoses, advanced cerebrovascular disease, peripheral vascular disease, and marginal end-organ function (eg, renal failure) cannot safely tolerate prolonged periods of even mild hypotension or low cardiac output. Volume loading can lead to ventricular distension, which can compromise exposure, as well as hemodilution and postoperative edema. Overaggressive use of vasoconstrictors can lead to coronary vasospasm, peripheral and gastrointestinal ischemia, and increase the afterload on poor ventricles. In my opinion, providing
the average surgeon with the enabling technology to position the heart with good exposure and rock-solid hemodynamics is perhaps the most critical step in expanding OPCAB adoption.
Apical Suction Devices Although a variety of slings and pads have been used as alternatives to pericardial sutures for cardiac positioning during OPCAB, the first true enabling technology for cardiac positioning were the apical suction devices. The first such device was the Xpose™ device introduced by Guidant Corporation in 2000. This device consists of a silicone suction cup with an inner cushion, which is attached to the retractor with a locking link-arm mechanism. The suction cup attaches securely to the heart, typically on the apex, when connected to 250 mm Hg of suction. A ball joint and spring at the apex of the cup preserves long axis shortening and apical twisting. The Starfish™ device, introduced more recently by Medtronic Corporation uses a similar principle but, instead of a single cup, uses four suction feet. By lifting the heart out of the chest, these devices can provide better exposure than traditional pericardial sutures, especially to posterolateral wall targets near the atrioventricular groove. With these devices, the heart is relatively fixed at two points. This provides two additional advantages. The apex does not ‘flop’ around in and out of the surgical field and cardiac positioning is decoupled from stabilization, that is, the stabilizer foot does not have to compress or retract quite so hard because it no longer needs to contribute much to exposure. The most dramatic benefit of apical suction devices, however, is their ability to provide exposure with much less hemodynamic compromise than the classical maneuvers described above. In a recent animal study, Sepic and coworkers showed that an apical suction device provided superior hemodynamics during cardiac positioning compared with pericardial sutures. Deep pericardial sutures led to buckling and compression of the right atrium and ventricle, impairing right ventricular filling. This dramatically decreased left ventricular preload and resulted in a 20-40% decrease in cardiac output, mean arterial pressure and stroke work. By lifting the heart out of the chest, the apical suction device ‘unbuckled’
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Figure 2. Proposed mechanism by which apical suction devices provide superior exposure and hemodynamics and deep pericardial sutures. The apical suction device lifts the heart out of the chest, which prevents compression of the right heart.
the right ventricle and minimized the compressive effect of positioning on the right heart resulting in near normal hemodynamic parameters (Fig 2).
Other Cardiac Positioning Enabling Devices Two new technologies, miniature right heart support and perfusion-assisted direct coronary artery bypass (PADCAB), along with traditional intraaortic balloon counterpulsation (IABP), although not cardiac positioning devices, per se, seek to enable OPCAB by ameliorating some the hemodynamic consequences of cardiac manipulation. Right heart support devices, such as the PARAFlow™ system by A-Med Systems, Inc., are typically miniature, low-prime centrifugal systems that pump blood from the right atrium to the pulmonary artery. They seek to overcome the deleterious effects of cardiac manipulation on right heart function while avoiding the major negative inflammatory, hematologic, and embolic consequences of full cardiopulmonary bypass. The primary challenge with these devices is titrating flows to maintain left heart preload and cardiac output without causing left ventricular distension. Proponents have documented significant hemodynamic benefits in a small series of patients and claim superior visualization of the posterolateral wall with decompression of the right heart.5 Others have argued that, particu-
larly since the advent of apical suction devices, nearly all patients can undergo complete revascularization off-pump without the need to reintroduce extracorporeal circulation. The PADCAB system, developed by the Emory group, uses a small pump system to provide direct perfusion to the heart through constructed vein grafts.6 The perfusate can be enhanced with pharmacologic agents (eg, coronary vasodilators) or metabolic substrates. Its proponents argue that hemodynamic instability during cardiac manipulation is often a result of a vicious cycle whereby decreased systemic pressure leads to decreased coronary perfusion and myocardial ischemia, which leads to impaired contractile function and further decreases in systemic pressure. By maintaining coronary perfusion in the face of decreased systemic pressures during cardiac manipulation, PADCAB can prevent this vicious cycle and maintain stable hemodynamics. Others argue that the left internal mammary artery to left anterior descending anastomosis, which is typically performed first and requires very little cardiac manipulation, augments coronary perfusion enough to enable exposure of the posterior wall with good hemodynamics. Simply performing proximal anastomoses first can also progressively improve coronary perfusion during OPCAB. Although the IABP is obviously not a new technology, its enabling role in OPCAB is only recently being appreciated. By increasing coronary
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perfusion and unloading the left ventricle, it can help maintain stable hemodynamics during cardiac manipulation. It can be particular useful in those patients in whom coronary perfusion is most tenuous (left main or severe proximal coronary artery disease, left ventricular hypertrophy) and those with cardiomegaly and left ventricular dysfunction. In the latter group, the unloading effect of the IABP can decrease ventricular dimensions, improving exposure to the posterolateral wall.
Coronary Artery Stabilization The development of modern coronary artery stabilizers was probably the most important development of beating heart coronary surgery. Good stabilization is critical to achieving a technically precise anastomosis. Patency rates of anastomoses performed on a beating heart did not reach on-pump rates until the advent of modern stabilizers.7 Coronary artery stabilizers are a fairly mature technology today. Among experienced OPCAB surgeons, coronary artery stabilization is rarely a significant challenge once adequate exposure with good hemodynamics has been achieved. A variety of suction-type and compression-type stabilizers are available from several manufacturers, and the choice of stabilizer has become a matter of personal preference. The suction stabilizers tend to provide a somewhat more stable field with less compression of the myocardium than compression stabilizers but tend to be somewhat bulkier which can compromise exposure. Advances in this technology have focused on incremental changes to streamline the stabilizer’s profile and improve its performance (rigidity, grip, and so on).
Coronary Artery Visualization Coronary Occlusion Achieving the traditional ‘still bloodless field’ in beating heart surgery can often be a challenge. Good visualization of the edges of the arteriotomy, however, is critical to achieving a technically precise anastomosis. The conventional technique for achieving coronary artery hemostasis during OPCAB has been coronary artery occlusion (proximal only or proximal and distal) using
some type of vascular snare (silicone loop, polypropylene suture, etc.) often supplemented with a CO2 blower-mister to displace any residual blood emanating from the distal coronary or nearby side branches. Coronary occlusion is widely used, is simple to apply, and usually provides good hemostasis without direct intraluminal trauma. Disadvantages, however, include the potential for external trauma to the coronary artery and regional ischemia. New stenoses thought to be related to snare injuries have been documented in the literature,8,9 and most surgeons try to avoid snaring the distal coronary artery. Although transient coronary occlusion is usually well tolerated, the resulting regional ischemia can result in decreased regional contractility and hemodynamic compromise during cardiac manipulation, especially in patients with extensive proximal coronary artery disease (decreased coronary flow reserve) and those with compromised left ventricular function (decreased contractility reserve).
Intracoronary Shunts Intracoronary shunts attempt to maintain distal coronary perfusion during performance of the anastomosis. The early models were fairly crude---they were difficult to insert and remove, tended to buckle, did not have very good flow characteristics, and were not available in smaller sizes. The latest generation models are very pliable with atraumatic tips, have improved flow dynamics and are available in sizes down to 1 mm. Some surgeons use shunts routinely10 whereas others are more selective,11 focusing their use on high-risk situations, such as grafting a collateralizing proximal or midleft anterior descending artery or a large right coronary artery as well as when occlusion causes clear-cut ischemic or hemodynamic changes. Proponents argue that minimizing ischemic time improves hemodynamic stability during OPCAB and eliminates the ‘ticking clock,’ which can compromise technical precision during performance of the anastomosis. Although it does require some experience to get comfortable suturing around a shunt, advocates maintain that the shunt can actually improve technical precision by ‘presenting’ the artery for suturing and protecting against back-walling the artery. The string on the shunt can be very help-
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Figure 3. Proximal anastomotic devices. (a) Novare Enclose™; (b) St. Jude Symmetry™ Aortic Connector; and (c) Ethicon Cardiovations Corlink™.
ful in manipulating the artery to expose the edge of the arteriotomy during suturing. With a shunt in place, the mister-blower can be used sparingly and when it is used, the shunt protects most of the endothelium from it. Some have questioned whether shunts provide significant nutritive flow, particularly in small arteries. Although this has not been established definitively in humans, a recent animal study in normal pigs showed that a 1.5-mm shunt in the LAD maintained normal regional blood flow and contractility, in contrast with coronary occlusion, which decreased both by 50%. Several human studies have also documented hemodynamic benefits to shunting.12-15 The effect of shunting on the endothelium remains a subject of great debate. Some studies suggest significant trauma and others find minimal effects.16-18
Anastomoses Proximal Anastomotic Devices The proximal anastomoses for saphenous vein grafts during OPCAB have traditionally been performed using a side-biting clamp on the aorta. Some have suggested that this has been the Achilles’ heel of OPCAB. As the typical CABG patient has gotten older, with more comorbidity, the incidence of atherosclerotic disease of the ascending aorta has increased significantly. This incidence is even greater in OPCAB patients because many surgeon reserve OPCAB specifically for older, sicker patients. Although alternative techniques, including multiple pedicled conduits and composite (Y- or T-grafts), are available to avoid aortic manipulation during OPCAB, these techniques have
not been widely adopted and may not be most appropriate for typical OPCAB patients. Because one of the primary proposed benefits of OPCAB is decreased neurocognitive dysfunction, minimizing aortic manipulation and the potential for cerebral emboli is very important in this procedure.19 One study of cerebral embolic activity during on-pump CABG found that approximately 10% of the activity occurred during placement and removal of the side-biting clamp.20 Another potential drawback of placing a side-biting clamp on a pressurized, pulsatile aorta is the potential for aortic dissection. One recent study has suggested that the incidence of this rare but catastrophic complication is somewhat higher during OPCAB.21 The desire to further minimize manipulation of the aorta during CABG has led to the development of devices to permit construction of a proximal anastomosis to the aorta without the need to clamp it (Fig 3). Relatively low-tech proximal assist devices have been developed, which allow a portion of the aortic wall to be excluded from the circulation. Once deployed, a standard aortotomy and sutured anastomosis can be performed at this portion of the aorta. The first such device to receive Food and Drug Administration (FDA) approval and to be available on the US market was the Enclose™ device by Novare Surgical Systems, Inc. The sealing membrane is introduced through a separate needle hole in the aorta and deployed against an external fork-like arm to achieve a seal. Although no published data exist, the early anecdotal experience with this device appears to be good. Other recently introduced proximal anastomosis devices include the
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HeartString™ device by Guidart, Inc., and the IPAD™ device by Coalescent Surgical, Inc. A more high-tech approach to the problem of the side-biting clamp is the use of proximal anastomotic devices. These devices automatically create an anastomosis between a conduit and the aorta. Although many companies are developing proximal anastomotic devices, only two have been used clinically in published reports. The St. Jude Symmetry Aortic Connector, approved by the FDA and marketed in the United States, has been implanted approximately 30,000 times according to the company. It is a self-expanding nitinol-based device that is loaded onto the proximal end of a saphenous vein. It is deployed in a two-step process. An aortotomy is first created using a precise aortic cutter and the device is then rapidly deployed through the aortotomy creating the anastomosis. The early published experience with the device is good, but long-term data are not yet available.22-26 A large registry and a randomized trial are currently underway. The Ethicon Cardiovations Corlink™ device has been approved by the FDA but has not yet been marketed in the United States. The device is also self-expanding and nitinol-based. The published experience to date is small.27 Purported advantages include the ability to perform distal anastomoses first, the fact that the vein is not cannulated and the presence of less intraluminal foreign material. Although still in their infancy, devices to facilitate proximal anastomoses will likely play a significant role in the future of OPCAB. Although documenting a clinical benefit to eliminating the side-biting clamp will require care clinical studies, the theoretical advantages of minimal aortic manipulation are too attractive to ignore. To provide the maximal benefit during OPCAB, the ideal proximal anastomotic device would have the following characteristics: 1. Applicable to the full size range of venous and arterial conduits 2. Easy to load on the conduit 3. Can be deployed before or after completion of the distal anastomosis 4. Perfectly reproducible deployment (preferably one-shot) across a range of aortic wall thicknesses and locations 5. Perpendicular or angled trajectory off the aorta to minimize the risk of kinking
6. Minimal or no intraluminal foreign material to assure excellent long-term patency 7. Cost effective Although the early success of the St. Jude device has established that proximal anastomotic devices can be widely used with good results, future generation devices will need to incorporate these characteristics before their use becomes commonplace.
Distal Anastomotic Devices Although as much, if not more, resources have been devoted to the development of semiautomatic or automatic devices to perform distal coronary anastomoses, these devices have a long road ahead of them. The engineering challenge of joining two 1- to 3-mm biologic structures, creating a water-tight nonthrombogenic channel that remains widely patent during the healing process is formidable. The theoretical advantage of proximal anastomotic devices in full-sternotomy OPCAB is fairly clear---reduced aortic manipulation. Although distal anastomotic devices will likely be important enabling devices in endoscopic coronary artery surgery, their potential advantages in a typical OPCAB setting are less obvious. Deployment of such a device should theoretically be faster than suturing. However, even if deployment times were reduced to a minute or two per anastomosis, the cumulative time-savings on a typical four-vessel OPCAB would be no more than 30 or 40 minutes with debatable benefit to the patient. Another potential benefit would be that such a device should be theoretically be easier to deploy than suturing to targets where exposure and stabilization are not ideal. However, even the slickest, fully automated device will require adequate exposure and stabilization to dissect and open the coronary artery. These challenges and questions notwithstanding, at least 20 companies worldwide are trying to develop distal anastomotic devices. Each device falls somewhere on the spectrum between sutures and fully automated devices (Fig 4). Only one device, the U-Clip from Coalescent Surgical, is clinically available and approved by the FDA for use in coronary anastomoses. The U-Clip is a nitinol device that is loaded on a needle in the shape of a “U” and, when deployed, automatically closes to a predetermined diameter and force in
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Figure 4. Spectrum of potential distal anastomotic devices. (MICS - minimally invasive cardiac surgery).
the shape of a pig-tail. It permits an interrupted anastomosis to be performed without the need for countertraction, suture following, or knot-tying. According to the company, approximately 50,000 anastomoses have been performed to date using this device. Laboratory28 and early clinical data29 suggest the compliant, interrupted U-Clip anastomoses may in fact be superior to a running sutured anastomosis. In terms of its role in OPCAB, surgeons experienced with this device have found that it can facilitate off-pump grafting by decreasing the demands on the assistants when exposure is difficult. Three other devices have been using in small clinical series in Europe but are not yet approved by the FDA for use in the United States. The Magnetic Vascular Positioning™ device from Ventrica, Inc., uses magnetic coupling to create a side-to-side anastomosis. Two pairs of elliptical magnets are deployed, one pair on the conduit and the other on the coronary artery. The anastomosis is created by simply bringing the conduit and coronary artery docking ports in close proximity to each other. The magnets instantly selfalign and create a hemostatic seal. The primary advantage is the rapidity of deployment whereas the primary disadvantage is the presence of foreign material in the lumen. The early laboratory
and clinical experience is encouraging with good short-term patency.30 The company recently received regulatory approval in Europe. The St. Jude Distal Connector is a stainlesssteel stent-like device that is deployed balloon inflation creating a side-to-side anastomosis between the conduit and coronary. The Jomed GraftConnector™ is a PTFE-covered nitinol stent that is deployed into the coronary artery and connected to a conduit. Laboratory results appear promising.31-33 The clinical experience with these two devices is fairly limited.22 Although early efforts with coupling devices have been met with some success, they have generally been deployed in relatively large ([mt]2 mm) vessels free of significant disease. Whether the underlying principles behind these devices can be ultimately be applied to the full spectrum of coronary arteries presenting for grafting remains to be seen.
Endoscopic OPCAB Although significant progress has been made in applying enabling technologies to facilitate the performance full-sternotomy OPCAB, the future of endoscopic multivessel OPCAB remains uncertain. Advances in robotic technology, particularly
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Figure 5. Distal anastomotic devices. (a) Coalescent Surgical U-Clip™; (b) Ventrica Magnetic Vascular Positioner™; (c) St. Jude Distal Connector; and (d) Jomed GraftConnector™.
the da Vinci™ Surgical System by Intuitive Surgical, Inc., have made single-vessel off-pump totally endoscopic coronary artery bypass (OPTECAB) a reality.34-36 Despite several years of research and development, this procedure has been performed in only a few dozen patients worldwide. It remains a formidable procedure, with a high conversion rate, even among surgeons with heavy experience in robotic-assisted mammary artery harvest and on-pump TECAB. Although it likely that with improvements in endoscopic instruments and stabilizers, single-vessel OP-TECAB will eventually become a viable procedure, the theoretical barriers to multivessel OP-TECAB may be insurmountable. Even if sophisticated positioning devices, stabilizers and anastomotic devices are developed, the primary obstacle will always be the limited working space in the chest with a full beating heart. Patients with multivessel disease who desire an endoscopic CABG will, in my opinion, have to choose
between some type of hybrid revascularization (single-vessel OP-TECAB to the LAD plus percutaneous intervention to the other systems) or perhaps multivessel TECAB with some type of circulatory support short of full cardiopulmonary bypass.
Conclusions Over the past 5 years, many coronary artery surgeons have embraced technology and dramatically advanced the field of OPCAB. Enabling technologies are now available for all aspects of OPCAB. Proponents of OPCAB and the medical device industry will need to continue to develop new technologies to make OPCAB less technically challenging and more widely accepted. Translating the benefits of multivessel OPCAB to an endoscopic setting remains a formidable challenge.
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35. Falk V, Diegeler A, Walther T, et al: Endoscopic coronary artery bypass grafting on the beating heart using a computer enhanced telemanipulation system. Heart Surg Forum 2:199-205, 1999 36. Falk V, Diegeler A, Walther T, et al: Total endoscopic off-pump coronary artery bypass grafting. Heart Surg Forum 3:29-31, 2000 37. Falk V, Fann JI, Grunenfelder J, et al: Endoscopic computer-enhanced beating heart coronary artery bypass grafting. Ann Thorac Surg 70:2029-2033, 2000