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Ann Thorac Surg 2001;72:S2260-S2265
© 2001 The Society of Thoracic Surgeons
a Department of Cardiovascular Surgery, Hôpital Bichat, Paris, France
* Address reprint requests to Dr Menasché, Department of Cardiovascular Surgery, Hôpital Bichat, 46, rue Henri Huchard, 75018 Paris, France
e-mail: ccv-bloc.sec3{at}bch.ap-hop-paris.fr
Presented at Monitoring and Improving Patient Safety During and Following Cardiac Surgery, San Diego, CA, May 5, 2001.
Abstract
There is compelling evidence that off-pump coronary artery bypass operations are associated with reduced circulating levels of inflammatory mediators. Whereas complement activation and release of acute-phase reactants such as interleukin-6 are still expected to occur as consequences of a nonbypass-related general surgical trauma, a major feature of off-pump surgery seems to be a decreased production of interleukin-8, which may have important practical implications because of the participation of this cytokine in neutrophil trafficking and myocardial injury. The scarcity of carefully controlled, randomized trials precludes firm conclusions regarding the extent to which these biological changes translate into meaningful improvements in clinical outcomes. The problem is further complicated by the fact that the adverse effects of cardiopulmonary bypass largely depend on a genetically controlled balance between proinflammatory and antiinflammatory mediators. Currently, it is still impossible to predict, in a given patient, the side toward which this balance will be shifted. Nevertheless, accumulating experience identifies patient subgroups who may greatly benefit from avoiding extracorporeal circulation. These subsets include patients with severe extracardiac comorbidities (in particular, renal failure) and, possibly, patients with advanced left ventricular dysfunction, who may poorly tolerate superimposed, bypass-related, inflammatory tissue injuries.
Apart from financial incentives (expected reduction of the length of hospital stay and the attendant costs), the two major reasons that account for the increasingly strong interest in off-pump coronary artery bypass grafting (CABG) operations are a limitation of myocardial ischemic injury that is otherwise associated with aortic cross-clamping and cardioplegia, and the elimination of the systemic inflammatory response known to be elicited by cardiopulmonary bypass (CPB). A critical and, hopefully, balanced review of the available literature shows that whereas limitation of ischemic injury is a consistent finding in off-pump surgical series, that of the bypass-induced inflammatory response remains a much more questionable issue. The lack of an unequivocal answer to this question is primarily due to methodologic concerns, which include the scarcity of randomized trials (the majority of comparisons being made with historical or case-matched controls); the usual inclusion in these few randomized studies of small numbers of low-risk patients with surrogate end points as primary outcome measurements and the lack of control for several potentially confounding factors like protocols of heparin/protamine administration, prevalence of diabetes, blood transfusions and aprotinin use. Furthermore, in the setting of off-pump operations, an additional bias is occasionally introduced by the comparison of thoracotomy (ie, minimally invasive direct coronary artery bypass [MIDCAB]) versus median sternotomy (ie, off-pump coronary artery bypass [OPCAB]) approaches.
Limitation of myocardial ischemic injury
A dramatic reduction in postoperative concentrations of cardiac enzymes (the MB ioenzyme of creatine kinase and troponins T and I), as compared with conventional on-pump CABG, is a strikingly consistent observation after uncomplicated off-pump myocardial revascularization procedures [1, 2]. Although transient occlusion of the target vessel on the beating non–cross-clamped heart does cause some ischemia as reflected by an increased release of lactate in the coronary sinus at the time of reperfusion, at least in the absence of an endocoronary shunt [3], this ischemia is unlikely to be severe enough to cause substantial myocardial damage, as undetectable postoperative levels of cardiac-specific enzymatic markers are almost undetectable. Interestingly, however, this biological observation of reduced cardiac enzymes does not translate into a decreased incidence of clinically relevant Q-wave myocardial infarcts [2] and a reduction in inotropic requirements, as compared with conventional CABG, and is not consistently reported after off-pump operations. It is sound, however, to hypothesize that if the unavoidable (and usually limited) loss of myocardial cells inherent in aortic cross-clamping and cardioplegia is probably inconsequential in low-risk or even medium-risk patients, it may become a concern in those with severe impairment of left ventricular function who are thus expected to tolerate poorly additional loss from an already reduced cardiomyocyte pool. Furthermore, patients with advanced left ventricular dysfunction are reported to release more cytokines, which are potentially injurious to the heart after CABG surgery [4]. This may represent an additional argument for operating without the pump. This off-pump approach is supported by some reports of improved outcomes in patients with poor ventricles [5], but others have failed to reach similar conclusions [6]. It is also fair to acknowledge that these patients often have dilated hearts that, in spite of all the available maneuvers, may produce hemodynamic compromise if posterior coronary arteries are exposed for grafting. A short pump run may then be preferable to circulatory instability or increased requirements of vasoactive drugs. The same dilemma occurs in patients who urgently need CABG for acute coronary events. It is not clear whether it is better, in that case, to protect against superimposed CPB-induced inflammatory damage or, conversely, to "rest" the ischemic heart during a transient period of blood cardioplegic arrest.
Limitation of the inflammatory response
Biological effects
Before analyzing how elimination of CPB may affect the systemic inflammatory response, it is appropriate to briefly review major events of this response.
One of the major effects of CPB is to activate the complement cascade (both the alternative and classic pathways). This, in turn, causes neutrophil activation and cytokine production. Whereas an important feature of activated neutrophils is upregulation of adhesion molecules (integrins), cytokines also cause increased expression of endothelial receptors (in particular, the intercellular adhesion molecule [ICAM]–1), which serve as ligands for neutrophil integrins. This interaction firmly anchors neutrophils to the endothelial wall, a process that triggers release of cytotoxic compounds such as proteolytic enzymes or oxygen-derived free radicals [7, 8]. Adherent neutrophils also migrate through the endothelial barrier and come closer to parenchymal cells (ICAM-1, for example, is expressed on the surface of cardiomyocytes), which then become more vulnerable to neutrophil-derived byproducts [9]. Interleukin (IL)–8 is the cytokine that is thought to play a major role in the control of this neutrophil trafficking [10]. It is important, however, to point out that the proinflammatory effects of the above-mentioned events are normally counteracted, at least to some extent, by antiinflammatory compounds that are also released during CPB, of which IL-10 is of particular importance [11]. The finding that the kinetics of tumor necrosis factor–a/IL-8 and IL-10 feature opposite patterns of release [12, 13] strongly suggests that it is the genetically controlled balance between these proinflammatory and antiinflammatory cytokines that determines the ultimate severity of the clinical response to CPB, and also accounts for its variable magnitude among patients. This view is supported by a recent study showing that the postbypass production of IL-8 is increased in patients carrying the E4 allele of apolipoprotein E, as compared with the noncarriers [14].
This scheme provides a convenient framework for analyzing the effects of off-pump operations. Two randomized studies report reduced complement activation, as reflected by lower postoperative values of C3a, after off-pump CABG [15, 16]. One of these studies, however, is biased by the fact that on-pump surgery performed through a conventional median sternotomy was compared with an off-pump group undergoing a small left lateral thoracotomy (MIDCAB) [15]. Surgical tissue injury is a major source of complement activation, as shown by the greater release of C3a and C5b9 (the terminal component of the cascade also known as the membrane attack complex) after sternotomy as compared with thoracotomy [17, 18]. Thus, it is important not to attribute to CPB patterns of complement activation that are actually related to the surgical approach. Therefore, we are left with a single study that shows that among patients operated on through a median sternotomy, patients randomized to the off-pump group release less C3a postoperatively [16]. Another randomized study reports an exactly opposite result, ie, the lack of any significant difference in C3a (and C5a) levels between on-pump and off-pump patients [19]. The reason for this discrepancy cannot be conclusively established, but a major difference between these two trials is threefold higher doses of heparin in the former study, which is consistent with previous observations that heparin inhibits complement activation in a dose-dependent fashion [20-22]. Notwithstanding the real cause of these divergent results, the controversy suggests that it is probably naive to expect elimination of complement activation from an off-pump operation, particularly if the operation is performed through a median sternotomy (which is increasingly the case for the sake of complete revascularization), or if the dose of heparin is not strictly controlled. Moreover, if heparin is neutralized at the end of the procedure, the classic pathway for complement is activated by heparin-protamine complexes [23].
The effect of surgical trauma on complement activation also pertains to IL-6. This cytokine is one of the acute-phase reactants released in response to tissue injury, which probably accounts for its greater release after sternotomy, as compared with thoracotomy in off-pump patients [18]. The consistent observation that postoperative IL-6 levels are similar in on-pump and off-pump patients [2, 24-26] further supports the view that the effects of surgical injury on IL-6 release (including the exposure and stabilization maneuvers inherent in off-pump procedures) are likely to outweigh the reduction in IL-6 that might result from elimination of CPB.
Although IL-6 production appears to be a nonspecific consequence of major surgical procedures and a marker rather than an inducer of tissue injury, release of IL-8 may be more directly related to CPB. This is evidenced by consistently lower postoperative levels of this cytokine after off-pump CABG operations as compared with the standard on-pump technique [16, 19, 24, 26]. Those findings may have important practical implications in that IL-8 not only is involved in the regulation of neutrophil trafficking [10] but also seems to participate in myocardial ischemic injury; indeed, a monoclonal antibody directed against IL-8 reduces myocardial ischemia-reperefusion injury [27]. Interleukin-8 is generated by ischemic-reperfused myocardium [28] and its release may be reduced after short, and occasionally protected, periods of local ischemia during completion of distal coronary anastomoses on the beating heart during off-pump procedures. This reduced IL-8 release correlates with lower postoperative troponin I levels [24]. It must be acknowledged, however, that on-pump operations are also associated with increased release of IL-10 [2, 24, 26], which not only suppresses production of proinflammatory cytokines [13] but also protects ischemic-reperfused myocardium by limiting neutrophil recruitment [11]. Thus it becomes extremely difficult to determine whether a reduced cytokine response during off-pump operations or a properly regulated cytokine response during on-pump procedures makes any difference with respect to postoperative events. As previously suggested, absolute postbypass values of cytokines are probably less important for the ultimate clinical outcome than is the balance between proinflammatory and antiinflammatory cytokines, which are controlled by individual variations in gene expression. Fortunately, in most patients, this endogenous regulatory balance seems to function appropriately, and it accounts for the daily observation that the inflammatory response to CPB is generally well tolerated and does not translate into clinically meangingful adverse events. In the future, prospective identification of patients in whom the balance may be genetically shifted toward a pro-inflammatory reaction and subsequent development of the "postpump syndrome" provides a good reason to perform off-pump CABG. In the meantime, observations of a greater proinflammatory cytokine response in elderly patients [29] and in patients with preoperative left ventricular dysfunction [4] associated with more severely impaired postoperative hemodynamics provide a rationale for considering off-pump CABG in these selected, high-risk subgroups.
A few studies have looked at downstream effectors of the inflammatory response. One study, in which 15 patients were randomly allocated to on-pump or off-pump groups, failed to detect any significant difference in postoperative levels of endothelial adhesion molecules such as P-selectin (which mediates the initial "rolling" of circulating neutrophils along the vascular wall) or ICAM-1 [2]. Although heparin inhibits binding of the neutrophil integrin MAC-1 to its ligands (including ICAM-1) and reduces neutrophil-endothelial cell adhesive interactions [30], on-pump surgery produces consistently greater neutrophil activation, as reflected by increased postoperative elastase [16, 19, 31] and markers of oxidative stress [16]. The membrane-damaging effects of these cytotoxins may explain the observation that off-pump CABG is associated with fewer fluid shifts [16, 19] and more favorable postoperative pulmonary function. Similarly, reduced activation of coagulation/fibrinolysis cascades and elimination of hemodilution from the pump prime probably accounts for the reduced postoperative blood losses and related transfusion requirements of off-pump surgery [6, 16, 19, 32, 33].
Clinical events
Pulmonary function
We are aware of a single prospective, randomized study that compared the effects of on-pump versus off-pump surgery on postoperative pulmonary function in patients with good preoperative left ventricular function and no pulmonary disease [34]. These authors failed to document any significant difference in arterial–alveolar oxygen gradient between the two groups, at any of the tested levels of FIO2. A similar conclusion was reached by another nonrandomized trial [31]. Based on the capability of the Drew-Anderson technique, which consists of bypassing both ventricles with two separate pumps without using an oxygenator, to reduce release of pro-inflammatory cytokines and to improve postoperative pulmonary gas exchange [35, 36], one can hypothesize that eliminating extracorporeal perfusion should reduce intraoperative, inflammatory pulmonary damage. However, this expected benefit of off-pump surgery is obfuscated by several confounding factors including surgical trauma, atelectasis, pleural opening, and restriction of deep breathing and coughing by pain, which impair postoperative pulmonary function. In the clinical setting, the purported advantage of the off-pump bypass with respect to earlier extubation, particularly in patients with chronic obstructive pulmonary disease [6], is difficult to interpret because the between-group difference in time to extubation is often magnified by prolonged times in "control" on-pump patients that are longer than commonly seen with current fast-track protocols [37]. A recent study by Diegeler and colleagues [26] actually failed to show any difference in ventilation time, blood loss, and length of stay between on-pump and off-pump operations (whether performed through a median sternotomy or a limited thoracotomy) despite consistently higher levels of multiple inflammatory markers (C5a, C3d, TNF-a receptors, IL-6, and IL-8) in the on-pump group.
Renal function
As for the lung, there are few studies that have been designed to prospectively compare on- versus off-pump operations with regard to postoperative renal function. Indeed, the only trial we are aware of is that of Ascione et al. [38] who have randomized 50 patients into two equal groups and used the urinary levels of the microalbumin-to-creatinine ratio and N-acetyl-ß-glucosaminidase as markers of glomerular and tubular damage, respectively. Their results provide clear evidence for a greater degree of impairment of renal function in the on-pump group, a conclusion supported by the findings of Yokohama et al. [6] that off-pump surgery decreases the incidence of further renal deterioration in patients with preoperative renal insufficiency. Because of the poor prognosis associated with severe preoperative renal failure [39], these data taken together, provide a sound rationale for considering this comorbidity as an elective indication for the off-pump strategy.
Neuropsychologic function
Postbypass brain injury, whether manifest as a stroke or as an alteration of cognitive functions, results from the interplay of several factors, including reduction in cerebral blood flow, microemboli and macroemboli (either gaseous or atheromatous debris originating from the ascending aorta), and the systemic inflammatory response. This conclusion is suggested by brain swelling documented by magnetic resonance imaging in the early post-CPB period [40]. Theoretically, one would expect that elimination of CPB would drastically reduce the incidence of these events if exposure of posterior target vessels did not cause hemodynamic instability and if aortic manipulations were avoided. However, analysis of off-pump data reveals, once again, a more complex reality.
Using blood levels of the S100 protein as a marker of damage to astroglial cells and the blood–brain barrier, several authors report markedly lower values after off-pump surgery [41-43]. In keeping with these data, embolic episodes, as assessed by high-intensity transient signals recorded by transcranial Doppler ultrasound, are less frequent in off-pump patients [43]. These observations, however, sharply contrast with the failure of most series to document significant differences in neurologic outcome or cognitive functions between on-pump and off-pump patients [32, 44, 45]. As with the lung, confounding variables may obscure the reduced brain injury and improved neuropsychologic function expected from eliminating CPB. These variables include side-biting of aortic clamping, anesthesia, or sleep deprivation. It is noteworthy that 5% of patients undergoing surgery for total knee replacement are reported to experience a long-term, clinically significant deterioration of cognitive function [46]. A recent survey [47], based on a pooled analysis of comparable studies, yielded a 22.5% incidence of patients still demonstrating a cognitive deficit 2 months after their coronary surgery, and it certainly provides a useful benchmark for comparative assessment of the putative benefits of off-pump CABG.
Because elderly patients are more vulnerable to CPB-induced brain damage, one would intuitively expect them to benefit most from an off-pump operation. The lack of an unequivocal answer to this question is well illustrated by divergent results of two large, retrospective, nonrandomized studies that were recently conducted. In one study, the benefits of off-pump CABG were claimed on the basis of a 0% incidence of postoperative stroke in 97 octogenarians, as compared with an unusually high incidence of 9.3% in the control on-pump group of 172 patients of the same age [48]. However, another study that also included patients whose mean age was 79 years reported a 2.3% incidence of post-CPB stroke, which is much closer to the usual incidence [49]. In that report, the off-pump technique failed to yield any reduction in the occurrence of postoperative stroke (2.2%). Notwithstanding the limitations of these studies due to nonrandomization and difficulties in detecting subtle cognitive changes in cardiac surgical patients, clinical observations suggest that elderly patients tend to experience less postoperative mental confusion after off-pump operations. Therefore, these patients probably represent good candidates for off-pump operations whenever feasible under technically adequate conditions. Regardless of age, the massively calcified aorta is an absolute indication for off-pump CABG, either using arterial grafts exclusively or attaching saphenous vein conduits to the innominate trunk or to one of the subclavian arteries. It would actually be unfair to blame CPB for inducing neurologic damage that is directly related to hazardous aortic manipulations.
Conclusion
The available data provide reasonable evidence that off-pump surgery reduces biological markers of the inflammatory response that occurs, to some degree, after any major surgical procedure. The limited number of carefully controlled, comparative trials prevents conclusive proof, however, of improved clinical outcomes due to the attenuated inflammatory response. One postulates that maximal benefit should be observed in elderly patients, those with severe impairment of left ventricular function, and those with major extracardiac comorbidity. The preoperative status of these patients could make them more vulnerable to a superimposed inflammatory injury. To some extent, this hypothesis is supported by a recent study showing that improved patient outcomes after off-pump CABG are seen only in high-risk subgroups, as defined by the predicted risk model provided by the Society of Thoracic Surgeons National Cardiac Surgery Database [50]. Diabetes may represent another elective indication for off-pump surgery, as CPB seems to be associated with increased neutrophil–endothelial cell adhesion in these patients [51]. However, definite validation of these strategies requires long-term follow-up studies to ensure that purported early benefits of off-pump operations are not offset by increased delayed coronary events due to incomplete revascularization or technically inadequate anastomoses.
It should be emphasized that an important spin-off of off-pump surgery is the continuous effort to make CPB less invasive. Device-based techniques (heparin-coated circuits, leukocyte filters, modified ultrafiltration) mitigate biological inflammatory markers generated by CPB; but the absence of clinically meaningful improvements in patient outcomes preclude wide acceptance of these techniques in daily practice. This skepticism, however, may change with the use of new coatings that are still in the developmental stage, or with "miniaturized" circuits that feature a dramatic reduction in pump prime and elimination of cardiotomy suction. Promising results may also be anticipated from pharmacology-based interventions. For example, aprotinin, in addition to its efficacy in reducing bleeding, has potent antiinflammatory properties [52-54], and it is likely that this protective effect outweighs the theoretical risk of increased graft occlusion, which remains uncertain. There is also compelling evidence that a short perioperative pulse of corticosteroids blunts the inflammatory response to CPB, possibly by inhibiting nuclear transcription factor NF-
B, which controls expression of a myriad of genes encoding major pro-inflammatory proteins [55]. It is my belief that these drugs are probably underused, or are used according to inappropriate dose/timing of administration regimens, in clinical practice. Finally, it has recently been reported that a single-chain antibody specific for human C5 not only reduces formation of the membrane attack complex and leukocyte integrin expression, but also attenuates enzymatic markers of myocardial injury, cognitive deficits, and blood loss [56]. This finding raises hope that appropriately targeted interventions may effectively blunt some of the key events of CPB-triggered inflammatory pathways and may further improve the safety of on-pump operations.
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