Is it time to adopt beating-heart coronary artery bypass grafting? A review of literature

Artigo recebido em 27 de maio de 2010 Artigo aprovado em 21 de junho de 2010 Resumo Evitar a morbidade da circulação extracorpórea (CEC) deveria, teoricamente, reduzir a incidência de disfunção de órgãos e levar a melhora no estado dos pacientes. Recentemente, técnicas de estabilização mecânica cardíaca foram desenvolvidas, facilitando a cirurgia de revascularização do miocárdio com CEC. O uso da CEC pode influenciar o resultado econômico, mantendo a qualidade do atendimento e satisfação do paciente. As bases de dados MEDLINE, EMBASE, Cochrane Controlled Trials Register (CCTR), Banco de Dados Cochrane de Revisões Sistemáticas (CDSR), banco de dados de resumos de revisões dos Efeitos (DARE), Science Citation Index (SCI), Current


INTRODUCTION
Coronary artery bypass grafting was first performed without the use of cardiopulmonary bypass (CPB) in the late 1960s [1], but this technique was largely abandoned after the use of CPB and cardioplegic arrest became routine [2]. CPB is known to induce inflammatory response that has been documented in the lungs, heart, central nervous system, kidneys, and gastrointestinal tract. Stroke is a well known complication related to CPB, cannulation, or surgical manipulation, cross-clamping of the ascending aorta. Interventional cardiologists have applied percutaneous myocardial revascularization to an increasing proportion of the population with coronary artery disease, leaving surgeons with an increasingly complex group of patients for surgical revascularization.
Cardiopulmonary bypass may be less well tolerated in these elderly patients who present with significant comorbidities [3]. Off-pump coronary bypass emerged as a new refined technique that is thought to provide a safer form of surgical revascularization by avoiding the unwanted complications of cardiopulmonary bypass, particularly in the increasingly complex patients being referred for operation [3]. Hemodynamic instability during OPCAB may prevent grafting of the posterior wall, thus compromising the basic principle of complete revascularization [4]. The Octopus as cardiac stabilization techniques is one of the devices that can immobilize andpresent all sides of the beating heart [5]. This allows off-pump coronary artery bypass grafting (CABG) in patients with 3-vessel disease [3]. Nevertheless, it has to be stated that the rate of incomplete revascularization in the early series of CABG without CPB is higher, and compromises the basic principle of complete revascularization [4]. There has been a lot concern regarding a decrement in graft patency rate in patients undergoing OPCAB.
The major determinant of costs in conventional coronary artery surgery still remain the variable and fixed direct costs in terms of materials used for routine operations, postoperative care, and the management of postoperative complications [6,7]. Therefore, further savings could be obtained by using a surgical technique able to decrease the fixed direct cost while maintaining clinical quality of care [8].

MEDLINE, EMBASE, Cochrane Controlled Trials
Register (CCTR), Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE), Science Citation Index (SCI), Current Contents, NHS Economic Evaluation Database (NEED), and International Network of Agencies for Health Technology substantially when re-exploration for bleeding is necessary [16]. Many recent studies documented the beneficiary effect of off-pump in reducing the rate of post operative bleeding and blood transfusion. In a prospective non-randomized cohort study, Casati et al. [13] demonstrated significantly higher antithrombin and plasminogen concentrations and reduced D-dimer formation (fibrinolysis) in patients undergoing off-compared to on-pump CABG. Randomized trials, matched cohort and retrospective studies [16][17][18][19] consistently demonstrate reduced blood loss, re-operation for bleeding and requirements for allogenic blood products in OPCAB than in on-pump patients. Ascione et al. [8], in their study shows that transfusion requirements were higher in the on-pump group, and this reflected the significantly higher mean transfusion costs, re-entry for bleeding occurred infrequently in the OPCAB group.
Puskas et al. [11], in a prospective randomized study, included 51 off-pump patients who were seen from November 1996 through December 1997 and underwent offpump CABG by a single surgeon at Crawford Long Hospital, Emory University. The control group included 245 patients, for a total sample of 296 patients. More than half of the patients in the control group required transfusion of one blood product or more during hospitalization, whereas less than a quarter of the off-pump group received any blood products. Puskas et al. [20] in retrospective study included 200 undergoing OPCAB by a single surgeon at Emory University. A statistically significant difference was found in favor of off pump group as compared to on pump group in regards of requirement of perioperative transfusion.
Cleveland et al. [21] using the Society of Thoracic Surgeons (STS) National Adult Cardiac Surgery Database, procedural outcomes were compared for conventional and off-pump CABG procedures from January 1, 1998, through December 31, 1999. A total of 126 experienced centers performed 118,140 total CABG procedures. The number of off-pump CABG cases was 11,717 cases (9.9% of total cases). Importantly there data suggest that an off-pump strategy reduces the likelihood of reoperation for bleeding. There conclusion agrees with others [22,23] who have documented less perioperative bloodloss with off-pump CABG. The need for transfusion was significantly less in the beating heart group.

Cerebral injury
Permanent neurologic dysfunction (stroke or coma) after conventional CABG is a devastating complication. Cerebral injury is considered to be the most significant and disabling complication of CABG. Stroke occurs in roughly 3% of patients after CABG, although up to two thirds of patients show a cognitive decline of variable duration [24]. Although the pathogenesis of cerebral injury and cognitive dysfunction after cardiac surgery is multifactorial, there is increasing evidence that multiple microemboli arising from the ascending aorta, the heart chambers, or the bypass circuit are the primary pathophysiologic mechanisms producing diffuse ischemic cerebral injury [25]. Theoretically procedures that do not use CPB are likely to prevent these unwanted effects. In fact, cerebral microembolization is markedly reduced when CPB is avoided [26,27]. However, reducing cerebral microembolization by avoiding CPB has not resulted in a statistically significant reduction in the incidence of stroke and postoperative neurocognitive dysfunction [28].
The comparable incidence of postoperative stroke after OPCAB may be attributable to aortic manipulation related to the use of a side-biting clamp that is applied during the construction of the proximal anastomoses [29]. Available evidence from the randomized controlled trials does not unequivocally show that OPCAB is better than conventional CABG with respect to occurrence of stroke and postoperative neurocognitive dysfunction [17,18,30]. The adoption of the aortic "no touch" technique, which avoids intraoperative atheromatous embolization from the atherosclerotic aorta into the cerebral circulation, may improve neurologic outcomes after OPCAB [31].
Cleveland et al. [21] suggest that off-pump CABG may protect against cerebrovascular accidents (CVA).The observed-to-expected ratio from the multivariate analysis for off-pump CABG and stroke is 0.62. Furthermore, analyzing the subgroup with preoperative cerebrovascular disease (CVD) suggests that off-pump CABG reduces the rate of postoperative CVA compared to conventional CABG. Again, the absolute risk of stroke was reduced from 4.6% to 2.5%, a difference of 2.1%. Clearly, previous reports have identified preoperative CVD as a robust predictor of postoperative adverse neurological events [32], and interventions to reduce this risk are necessary.
Bowles et al. [33], in a series comparing the occurrence of microemboli in patients undergoing coronary revascularization with and without CPB, have demonstrated a significant reduction in the cerebral embolic burden with the elimination of the extracorporeal bypass circuit. Although manipulation does account for some of the emboli during CABG, the vast majority (84%) occurred while the patient was receiving CPB with no specific surgical manipulation identified. In contrast, the relatively sparse emboli count recorded during OPCAB was more often related to surgical manipulation, especially lifting the heart for distal anastomoses and placing and releasing the partial occlusion aortic clamp. The results are interesting, they have demonstrated a significant reduction in the number of microemboli detected by transcranial Doppler ultrasonography, as well as a trend toward a reduction in the stroke rate in patients undergoing OPCAB compared with CABG. The true clinical significance of this dramatic reduction in cerebral microemboli, however, remains to be determined.

Gastrointestinal dysfunction
Gastrointestinal dysfunction following cardiac surgery, occur in about 2.5% of patients but with a disproportionate mortality (about 33%) [34]. CPB is associated with significant physiologic alterations in mucosal perfusion, epithelial permeability, edema formation, and blood flow regulation. Inhibition of C5a limits neutrophil-mediated impairment of ileal microvascular regulation after bypass, but does not improve extravascular mesenteric dysfunction after CPB [35].
Severe intestinal mucosal ischemia can occur during CPB even when the indices of global perfusion remain normal. Factors released during CPB, such as vasopressin, catecholamines, and thromboxane A 2 and B 2 , lead to redistribution of blood flow away from the mucosa because of regional vasoconstriction, and may contribute to mucosal ischemia [35]. Velissaris et al. [36] recruited low-risk patients for a randomized controlled trial (RCT) evaluating global oxygen flux and gastric mucosal oxygenation during CABG with and without CPB. Their findings suggested that despite superior global oxygen flux associated with beatingheart revascularization, gastric mucosal hypoxia occurred to similar extents in both groups with worsening trends for the OPCAB patients postoperatively. The splanchnic pathophysiology during beating-heart revascularization should be further explored.
A prospective, randomised study done by Raja et al. [37] was designed to define the role of cardiopulmonary bypass (CPB) and cardioplegic arrest in the pathogenesis of gastrointestinal complications following coronary artery surgery. This prospective, randomised study was designed to define the role of cardiopulmonary bypass (CPB) and cardioplegic arrest in the pathogenesis of gastrointestinal complications following coronary artery surgery. They concluded that cardiopulmonary bypass, inclusive of cardioplegic arrest, is the main independent predictor of post-operative gastrointestinal complications in patients undergoing coronary revascularization.

Acute renal failure
The etiology of renal dysfunction after cardiac surgery is multi-factorial [38] and in patients with co-morbid conditions that are associated with post-operative renal dysfunction (elderly, diabetics, renal impairment), CPB is associated with an increased risk of dialysis dependant renal failure [39,40]. However, renal hypoperfusion and inflammatory damage resulting from CPB are widely regarded as the most important causes of acute renal failure [41,42]. Beating Heart versus Cardioplegic Arrest Studies (BHACAS-1 study) [43], as well as a non-randomized prospective study [44], demonstrated a significant reduction in glomerular (creatinine clearance) and tubular function (fractional excretion of sodium and free water clearance) in on-pump compared to off-pump surgery [44]. In a prospective randomized trial, Ascione et al. [43] used biochemical evaluation to show that off-pump reduced the frequency of renal impairment. Loef et al. [44] recruited 22 low-risk patients (10 of whom underwent OPCAB and 12, conventional CABG) to a randomized controlled trials (RCT) studying the progress and extent of renal damage after bypass surgery. The results showed that OPCAB induced significantly fewer changes in microalbuminuria (P <0.01), free sodium clearance (P <0.05), free water clearance (P <0.01), N-acetyl glucosaminidase activity (P <0.01), and free hemoglobin (P <0.01) than did bypass procedures using CPB.
In addition, the retrospective study by Magee et al. [45] demonstrated a reduction in the frequency of renal failure after Off-pump (2.1% vs. 3.3%, respectively), despite significantly worse preoperative renal function in this group. These findings were consistent with results from other retrospective studies.

Myocardial injury
During CPB, before and after cardioplegia or fibrillatory arrest, the heart, like all other organs and tissues, is subject to microemboli, protease and chemical cytotoxins, activated neutrophils and monocytes, and regional hypoperfusion [46]. Both myocardial edema and distention of the flaccid cardioplegic heart during aortic cross-clamping reduce myocardial contractility [47]. Furthermore, if myocardial contractility is weak, excessive preloading or high after loading during weaning from CPB increases ventricular enddiastolic volume, myocardial wall stress, and oxygen consumption [46]. Off-pump should therefore reduce myocardial injury, since it allows continuous perfusion of the beating heart [48]. In the randomized trial conducted by Angelini et al. [17] the frequency of myocardial infarction was reduced in the off-pump group (2%), relative to the onpump group (4%), at 2 years of follow-up. More recently, cardiovascular MRI has provided evidence in support of reduced myocardial injury with off-pump [48].
Several randomized controlled trials (RCTs) [28] have found that the incidence of postoperative myocardial infarction is comparable after OPCAB and CABG with CPB but that OPCAB is associated with a more rapid recovery of myocardial oxidative metabolism, better myocardial function, and a lower requirement for inotropic agents. Puskas et al. [11] in a prospective randomized study reported no incidence of myocardial infarction with significant reduction in postoperative intraaortic balloon pump use in the off-pump group and a strong trend toward a reduction in requirement of inotropic support. In a randomized trial of 60 patients, Selvanayagam et al. [49] reported significantly better postoperative left ventricular function in the Off-pump group. Vedin et al. [50] have found that immediately after surgery (OPCAB), there was better cardiovascular performance and less release of markers of myocardial damage after OPCAB. Sahlman et al. [51] reported less CK-MB release and better myocardial preservation in OPCAB patients.

Atrial fibrillation
Atrial fibrillation (AF), the most common complication of CABG, occurs in 20% to 40% of patients [52]. By avoiding the atrial myocyte alterations that result from aortic crossclamping and avoiding the systemic inflammatory response to CPB, OPCAB should decrease the incidence of postoperative AF [28]. There is a general consensus from randomized trials [18,53,54] and prospective nonrandomized cohort studies [55,56] that CABG performed using CPB and cardioplegic arrest is associated with a significantly greater degree of myocardial injury than OPCAB. Puskas et al. [11] founds no difference in the incidence of atrial fibrillation between groups, despite the absence of atrial sutures, cannulation, and CPB in the offpump group. Both groups received a similar postoperative regimen of tapering beta-blockade as prophylaxis against atrial fibrillation.
A retrospective analysis of 72 patients undergoing myocardial revascularization was performed by Scherer et al. [57], concluded that avoiding cardiopulmonary bypass and minimizing surgical trauma did not reduce the incidence of postoperative AF in this patient collective. It remains an attractive hypothesis that postoperative AF is reduced by off-pump myocardial revascularization and minimizing surgical trauma but more robust data are required. Two metaanalyses have been performed to evaluate the impact of OPCAB on the incidence of atrial fibrillation [58,59], and all found that the incidence of postoperative AF is substantially lower after OPCAB. Angelini et al. [17] performed a pooled analysis of the Beating Heart Against Cardioplegic Arrest Studies (BHACAS 1 and 2) and found that the incidence of AF decreased from 37% to 13% with OPCAB, which was a highly significant finding.

Pulmonary dysfunction
Pulmonary functions deteriorate significantly for at least 3.5 months after cardiac surgery. Preoperative cardiac ischaemic and failure symptoms are inversely related to perioperative pulmonary function tests (PFTs) [60]. Compared to CABG with CPB, OPCAB was associated with a greater reduction in postoperative respiratory compliance associated with increased fluid administration and rotation of the heart into the right chest to perform posterolateral grafts. OPCAB yielded better gas exchange and earlier extubation but no difference in chest radiographs, spirometry, or rates of death, pneumonia, pleural effusion, or pulmonary edema [61].
Avoiding full heparinization allows safe use of a thoracic epidural catheter. Apart from thoracic sympatholysis, this may lead to improved postoperative pain relief and reduced mechanical ventilation time [62]. Most randomized controlled trials (RCTs) that have recruited low-risk patients have shown that OPCAB definitely reduces the duration of ventilation and allows earlier extubation of OPCAB patients, yet its effects on respiratory mechanics, oxygenation, and effort of breathing are similar to those in patients undergoing CABG with CPB [28]. The benefits of OPCAB are more pronounced in patients with preexisting pulmonary disease. In these patients, adverse effects on the alveolar stability by activation of the complement cascade, sequestration of the neutrophil in the pulmonary microvascular bed, release of oxygen-derived free radicals, and changes in the composition of alveolar surfactant are not seen, because CPB is avoided [63,64].

Length of hospital stay, mortality rates and cost savings
The length of hospital stay and the incidence of death after CABG is a function of multiple variables primarily related to a patients premorbid condition and the morbidity associated with the procedure [28]. Three large metaanalyses [59,65,66] have reported that the mortality rate after OPCAB is comparable with that seen after CABG and CPB but that the duration of hospital stay is substantially reduced in patients who undergo OPCAB. Two of these meta-analyses [65,66] pooled the results of randomized controlled trial (RCTs) only. Similar results were later found by several RCTs [30,67]. By reducing the morbidity rates associated with the procedure and decreasing the incidence of complications, the use of OPCAB has decreased the length of hospital stay [28]. Cleveland et al. [21] showed that the risk-adjusted mortality in the conventional CABG group was 2.93%, where as the mortality in the off-pump CABG group was 2.31%, which was significantly lower (P< 0.0001). The absolute reductionin mortality was 0.61%.
Hart et al. [3] review the entire experience of the Medtronic Octopus System (Medtronic, Minneapolis, MN) for beating heart bypass from 7 surgeons. A total of 1,582 patients underwent attempted Octopus OPCAB. Inhospital or 30-day mortality was also low at 1.0% (range 0% to 3.7%). Postoperative length of stay averaged 5.8 days (range 4.9 to 7.6 days). The gratifyingly low rates of morbidity and mortality demonstrated in this large group of OPCAB patients compare favorably with the early outcomes described in recent reports of CPB-supported CABG [68]. Three RCTs have compared the economic outcomes of Off-pump with those of On-pump [8,67,68], and founds that OPCAB is less expensive than conventional CABG because of lower complication rates, shorter intubation times and shorter stays in the ICU and hospital for Off-pump patients.
Graft patency and quality of anastomosis Many authors [2,69] have reported series of OPCAB. Although they have presented excellent mortality rates, concern has been rased over a decrement in graft patency rates [70]. One of the main concerns about OPCAB is that performing vascular anastomoses on the small arteries of a beating heart compromises graft patency and results in incomplete myocardial revascularization [71]. The two larger randomized controlled trials (RCTS) [67,72] showed no significant differences in patency at various time points. More recently, however, the results of BHACAS trials 1 and 2 showed no difference (at a mean follow-up of 29 months and 16 months, respectively) between OPCAB and CABG with bypass groups in terms of late mortality, cardiac events, and the need for further coronary revascularization procedures [17]. This evidence is supported by angiographic studies of Off-pump procedures, which have demonstrated graft patency rates at least equivalent to those of On-pump procedures [23]. Khan et al. [73] reported patency rates of 88% and 98%, respectively, in OPCAB and CABG with bypass surgery. However, a closer analysis of this study [73] shows that the limited experience of the surgeons, coupled with the intraoperative administration of a relatively low dose of heparin, the absence of aggressive postoperative antiplatelet therapy with clopidogrel, and the failure to use new suction devices to optimize exposure, may have confounded the analyses of graft patency among patients who underwent off-pump procedures [74].
Kim et al. [75] done a study including 402 patients who underwent off-pump coronary artery bypass surgery. Morphologic changes of grafts were traced by the Fitz Gibbon grading system. They proved that midterm angiographic follow-up demonstrated acceptable patency rates of grafts after off-pump coronary artery bypass surgery. Approximately half of the Fitz Gibbon grade B arterial grafts in the early angiograms became grade A at 5 years after surgery, but the proportion of grade B saphenous vein grafts gradually increased over the 5 postoperative years. Muneretto et al. [76] prospectively enrolled 176 patients undergoing total arterial myocardial revascularization and assigned them at random to one of two groups: group 1 was composed of 88 patients undergoing coronary surgery with cardiopulmonary bypass (CPB); group 2 consisted of 88 patients receiving the OPCAB procedure. They concluded that Off-pump coronary artery surgery could be successfully used for total arterial grafting without compromising the completeness of revascularization.
El-Hamamsy et al. [77] in there series, showed that complete coronary revascularization was accomplished in 95% of cases (average 3.2 grafts/patient). Although completeness of revascularization was a major concern in the early era of beating heart surgery, most recent series have shown the absence of any such disparity between OPCAB and conventional on-pump CABG [18]. However, with the advent of newer stabilizers and low-profile apical suction devices, this problem has been all but solved [18]. All the vessels of the heart are now approached with the .improvement of biomedical technology and suction stabilizer. The compression device (Speroni) is more associated with changes than the suction device (Octopus) [78]. Milani et al. [79], in a prospective study, suggested that the operation for myocardial revascularization is safe and efficient and can be applied to all patients who need coronary surgery, with low rates of complication and mortality. In a prospective study Pinto e Silva et al. [80] showed that the in-hospital outcome of elderly patients aged 70 years and older who underwent off-pump coronary artery bypass graft surgery with an intraluminal shunt in urgent, emergent, and elective coronary revascularizations associated with low rates of postoperative complications and mortality in relation to the studied population. They concluded that in same group patients (over 70 years-old), elective and non-elective off-pump coronary artery bypass grafting with intracoronary shunt showed to be safe and effective.

Future developments
Introduction of recent improved mechanical stabilizing devices facilitated multivessel OPCAB. Eliminating the need for aortic manipulation and CPB, aortic "no touch" technique and total arterial grafting offering the advantages of longevity of arterial grafts in a younger population, avoids intraoperative atheromatous embolization from the atherosclerotic aorta into the cerebral circulation, and reduce the risk of neurological complications in the elderly after OPCAB. Improving of sutureless anastomotic devices eliminates the need for side-biting aortic clamps avoiding dislodgment of atheromatous material and improving the neurologic outcome. The further development of distal coronary anastomotic devices may technical improving the distal coronary anastomoses especially with OPCAB surgery. The reproducibility and the feasibility of teaching the new surgical technique will reflect on its widespread adoption among the next generation of surgeons. Stepwise introduction of OPCAB can lead to improved overall total coronary artery revascularization surgical outcomes.

CONCLUSION
Off-pump coronary artery bypass grafting is safe, reduces hospital cost, postoperative length of stay, decreased mortality and morbidity compared with CABG on cardiopulmonary bypass. OPCAB surgery associated with excellent graft patency, significantly fewer cerebral microemboli. The present review demonstrates the safety and efficacy of OPCAB surgery in nonselected patients on long-term outcomes. Therefore, with increasing follow-up periods, OPCAB surgery remains a viable and widely applicable surgical option for patients with coronary insufficiency.