PRO: Attenuating the Stress Response Associated with Cardiac Surgery is Beneficial

John G. Laffey, MD, BSc, FFARSCI
Consultant in Anaesthesia and Intensive Care
University College Hospital Galway
Clinical Lecturer in Anaesthesia and Intensive Care Medicine
National University of Ireland
Galway, Ireland

Introduction
Four issues are of central importance when considering the therapeutic potential of strategies to attenuate the stress response to cardiac surgery, and I wish to focus on each in turn. First, I will consider what constitutes the stress response to cardiac surgery. Second, the potential for the stress response to have beneficial effects in patients undergoing Cardiac Surgery will be examined. Third, the deleterious consequences of the stress response in Cardiac Surgical patients are discussed. Finally, the potential for strategies that aim to limit or control the stress response to cardiac surgery to exert beneficial effects will be considered. In considering these issues, I will focus primarily on the inflammatory, rather than the stress hormonal, component of the stress response.

The Stress Response to Cardiac Surgery
Cardiac surgery, with or without cardiopulmonary bypass [CPB], elicits a potent stress response. This stress response has two key components, activation of the inflammatory response and the release of stress hormones, including Epinephrine, norepinephrine, cortisol, and adrenocortical hormone. Nonspecific activators of the stress response include surgical trauma, blood loss and/or transfusion, and hypothermia. CPB may directly activate the inflammatory response via at least three distinct mechanisms. One mechanism involves direct 'contact activation' of the immune system following exposure of blood to the foreign surfaces of the CPB circuit. A second mechanism involves ischemia-reperfusion injury to vital organs as a result of aortic cross clamping. Restoration of perfusion on release of the aortic cross clamp is associated with activation of key indices of the inflammatory response. In addition, systemic endotoxemia, resulting from gut translocation of endotoxin across a damaged mucosal barrier compromised following splanchnic hypoperfusion, may indirectly activate the inflammatory cascade.

The inflammatory component of the stress response to cardiac surgery is increasingly well characterized. Scientific knowledge in this field is continually expanding and this area constitutes a major interface of clinical and basic scientific research. Inflammation constitutes generalized, non-specific response to tissue injury, of whatever etiology, and is a rapid, highly amplified, controlled humoral and cellular response. There are several key components of the inflammatory response to cardiac surgery. The complement cascade is activated upon contact of the blood with the foreign surfaces of extracorporeal circuit, reperfusion of ischemic tissues, and heparin neutralization with protamine. Proinflammatory cytokines such as tumor necrosis factor-a [TNFa], Interleukin-1b [IL-1b], IL-6 and IL-8 play a pivotal role in stimulating and coordinating the inflammatory process. The role of the coagulation/fibrinolytic cascades and its interaction with the inflammatory response is increasingly recognized. The cellular immune response, in particular the process of neutrophil-endothelial adhesion, may lead to widespread endothelial damage and dysfunction. The inflammatory response may result in widespread endothelial activation and diffuse endothelial injury, which is considered a key event leading widespread organ injury and dysfunction.

The clinical consequences of the stress response constitute a pathophysiologic continuum, from a mild generalized transient response, termed the 'systemic inflammatory response syndrome' [SIRS], to life threatening organ dysfunction. While SIRS is well tolerated by most patients, and may have important beneficial effects, a significant minority of patients progress to the development of single or multiple organ dysfunction, termed multiple organ dysfunction syndrome [MODS]. The factors that influence the incidence, severity and clinical outcome of the inflammatory response, and in particular the reasons why certain patients develop life-threatening perioperative complications, are currently not well understood.

Beneficial effects of the Stress Response
The stress response is highly conserved across species and serves important functions. In the context of cardiac surgery, the stress response may have important beneficial effects such as immune system priming, which may aid in preventing perioperative infection and promoting wound healing. The priming of neutrophils in response to CPB may be beneficial in preparing the host to mount a robust response to the physiologic stresses of the perioperative period. Furthermore, TNFa and IL-1b are necessary for wound healing. A controlled, self-limiting stress response, comprising a coordinated stress hormone and inflammatory response, is a key component of the body's defense against the physiologic insult imposed by cardiac surgery and extracorporeal circulation.

Role of the Stress Response in the pathogenesis of Adverse Events
While direct cause and effect relationships have not been clearly demonstrated, there is increasing evidence linking the stress response, particularly if abnormal [exacerbated and/or prolonged], with adverse outcome following cardiac surgery. Several key points underline the potential for the inflammatory response to contribute to the pathogenesis of acute organ dysfunction following cardiac surgery.

First, the degree of activation of the components of the complement cascade have been demonstrated to correlate with indices of pulmonary (1), renal (2), and hemostatic (2) dysfunction, and the incidence of postoperative arrhythmia (3,4) following CABG. Strategies which reduce indices of complement activation, such as improvements in CPB circuit biocompatibility (5,6), or specific anti-complement strategies (7) reduce the morbidity in patients undergoing cardiac surgery. Second, systemic spillover of pro-inflammatory cytokines, such as TNFa, IL-1b and IL-6 appear to contribute to the pathogenesis of post-CPB myocardial stunning, ischemia and dysfunction (8,9). TNFa released during CPB may contribute to the pathogenesis of postoperative hepatic (10) and renal (11) dysfunction. Strategies to remove pro-inflammatory mediators, such as mechanical removal of cytokines by hemofiltration, limit these adverse effects (12).

Third, neutrophils which become sequestered in the pulmonary circulation and primed for enhanced free radical generation (13,14) during CPB, are central to the pathogenesis of pulmonary vascular endothelial damage. The primed neutrophils release cytotoxic proteases, such as elastase and myeloperoxidase, and reactive oxygen species (13,14), resulting in damage to the vascular endothelium and surrounding tissues. The degree of neutrophil lysosomal degranulation correlates with the extent of lung injury post CPB (13,15). Furthermore, alterations in pulmonary vascular permeability following CPB correlate strongly with indices of injury induced by neutrophil release of oxygen-radicals (16). Strategies such as depletion of leukocyte during CPB (17), or blockade of neutrophil adhesion (18,19), limit these adverse effects. Finally, low preoperative levels of IgM Endotoxin Core antibody predicted an increased incidence and severity of post-op cognitive dysfunction, especially among older patients, in a recent large scale study (20). This highlights the contribution of endotoxemia to the pathogenesis of adverse neurologic outcome.

Are Strategies that inhibit the Stress Response to Cardiac Surgery beneficial?
The potential for therapeutic strategies to control the stress response to cardiac surgery is clear. This potential is supported by increasing evidence for a diverse range of therapeutic strategies, ranging from preoperative prediction and stratification of risk, novel cardiac surgical techniques, minimization or avoidance of cardiopulmonary bypass, modification of the anesthetic regimen, to specific drug therapies designed to inhibit aspects of the inflammatory response and minimize endothelial injury. Three large scale studies, which clearly demonstrate the therapeutic potential of diverse therapeutic strategies, will now be examined.

One strategy to reduce activation of the immune system on contact with the extracorporeal circuit involves modifications of the surface of the circuit by coating with heparin. The therapeutic potential of heparin coated circuits [HCC's] has been clearly demonstrated in a recent large scale study. Ranucci et al enrolled 886 in high risk patients in a multi-center, prospective, randomized trial (5). Patients were randomized to CPB with either Duraflo II HCCs [n = 442] or conventional circuits [n = 444]. The use of HCC's decreased the duration of ICU and hospital stay, and reduced the incidence of poor outcome [defined as prolonged ICU or death]. Subgroup analysis demonstrated less renal dysfunction in diabetic patients, and less lung dysfunction in patients with COPD or post mitral valve procedure.

The use of corticosteroids in the context of CPB continues to be controversial, largely as a result of past negative experience, particularly with the use of steroids in septic shock. The therapeutic potential of steroids in patients undergoing cardiac surgery has been clearly demonstrated in a recent large scale study. Kilger et al enrolled 91 patients at high risk for severe SIRS undergoing cardiac surgery with CPB to participate in a prospective controlled non-blinded randomised clinical trial (21). Patients were randomized to receive either stress doses of Hydrocortisone at induction and for 7 postoperative days [n = 43] or standard therapy [n = 48]. Hydrocortisone decreased indices of inflammation and mean scores for severity of the postoperative illness. There was a reduction in the severity of cardiovascular [decreased inotrope and vasopressor support], respiratory [reduced duration of mechanical ventilation, increased PaO2/FiO2 ratio] and hemostatic [increased Antithrombin III levels, decreased blood loss and blood transfusion requirement] dysfunction. Patients randomised to Hydrocortisone had a decreased ICU and Hospital stay. While this study was not designed to detect overall differences in mortality, the therapeutic potential of Hydrocortisone in patients at high risk for severe SIRS post CPB is clearly demonstrated (21).

The contribution of leukocytes in transfused blood products to the pathogenesis of adverse outcome following cardiac surgery, and the advantages of leukodelpetion, have also been demonstrated. Van de Watering et al enrolled over 900 adult patients undergoing CABG/Heart valve or combined operations. Patients were randomised to receive either Freshly leukocyte depleted [n = 305] vs. stored leukocyte depleted [n = 303] vs. non leukocyte depleted [n = 306] transfused blood in adult patients for CABG/Heart valve or combined operations (22). Leukodepletion significantly reduced the overall 60 day mortality, with a dramatic reduction in death from MODS, and a reduced postoperative infection rate in patients who received more than 3 units of blood (22).

Conclusions
The therapeutic potential of strategies to control the stress response, particularly the inflammatory component of the response, is clear. However the optimal therapeutic strategy [or strategies], and the optimal target subgroup of cardiac surgical patients, remain to be fully elucidated. Our goal must be to attenuate deleterious effects of the stress response while preserving the ability of the patient to mount an appropriate defense to the physiologic trespasses of the perioperative period. Modulation of the stress response, rather than simple inhibition, is likely to confer substantial benefit. Furthermore, therapeutic strategies should be focused on the subset of cardiac surgical patients most likely to suffer deleterious consequences, and hence most likely to experience benefit. This subgroup of high risk patients is increasingly well characterized. Large scale clinical trials of the more promising therapeutic strategies, restricted to the patient group at significant risk of perioperative morbidity, are urgently needed.

In conclusion, the beneficial effects of attenuating the stress response to cardiac surgery are clear. Many aspects of a patient's risk of serious perioperative complications are perceived as being relatively fixed [genotype, preoperative health status, surgical difficulty etc.], and the degree to which these may be is not known. Conversely, the contribution of the stress response to adverse patient outcome is potentially remediable and therefore deserves attention. The further development of existing and novel strategies to control the stress response, particularly the inflammatory component of this response, offers us the best opportunity to reduce morbidity and mortality in patients presenting for cardiac surgery.

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