Inflammatory response and cardioprotection during open-heart surgery: the importance of anaesthetics

Systemic inflammatory response

Open-heart surgery with CPB is associated with an acute inflammatory response, which has implications for postoperative recovery and myocardial function (^{Freyholdt et al., 2003}). Despite significant changes and improvements in surgical techniques, inflammation remains a significant problem. Therefore, the development of strategies to control the inflammatory response continues to be the focus of extensive experimental research and clinical studies (^{Raja and Dreyfus, 2005}). In addition to CPB, reperfusion injury of the myocardium and the lungs, and surgical trauma are also important triggers of the inflammatory response (^{Wan et al., 2004}; ^{Franke et al., 2005}; ^{Prondzinsky et al., 2005}). However, other factors such as temperature, anaesthesia, oxidative stress and genetic predisposal may also contribute. Recent and interesting evidence suggests that the inflammatory response during open-heart surgery is at least in part related to the genetic background of the individual (^{Lehmann et al., 2006}).

Myocardial ischaemia and reperfusion

Myocardial ischaemia describes a condition of reduced coronary blood flow resulting in a decrease in the supply of oxygen and nutrients to the heart (reviewed in ^{Suleiman et al., 2001}). This in turn provokes a fall in energy production by the mitochondria, which is quickly followed by abnormal accumulation and depletion of several intracellular metabolites (for example, a fall in ATP and a rise in lactate). These metabolic changes lead to a decrease in intracellular pH and an increase in the intracellular concentrations of Na⁺ and Ca²⁺, which further consumes ATP. Several membrane ionic pumps and channels are disrupted, leading to membrane depolarization and loss of excitability. If coronary flow is restored quickly, then metabolic and ionic homeostasis are re-established, the plasma membrane repolarizes and recovery occurs. However, reperfusion following prolonged ischaemia can result in irreversible damage (death by necrosis or apoptosis). The main causes of reperfusion injury are cytosolic Ca²⁺ loading and generation of ROS, both of which exacerbate mitochondrial dysfunction and can result in opening of the mitochondrial permeability transition pore. Consequences of reperfusion injury include ventricular fibrillation, myocardial stunning and loss of intracellular proteins. Furthermore, cardiac generation of ROS and their release to the extracellular space can further compromise the cardiac function by, amongst other things, promoting an inflammatory response.

In view of the fact that a reduction in myocardial infarct size improves myocardial function and reduces infarct-related acute mortality (^{Miller et al., 1998}), the translation of diverse experimental cardioprotective interventions into clinical settings has been limited (^{Bolli et al., 2004}; ^{Cannon, 2005}). Reasons like availability of relevant models and species-related differences may be responsible for this.

Cardiac cytokines and oxidative stress during ischaemia and reperfusion

The controversial views regarding the role of CPB in triggering an inflammatory and oxidative response during open-heart surgery have significantly shifted the focus away from the potential role of myocardial reperfusion injury as a source of inflammatory mediators.

Whether oxidative stress is a cause or an effect of myocardial injury during open-heart surgery is not known, but has been implicated in postoperative complications (^{Christen et al., 2005}). The primary source of ROS during open-heart surgery on CPB is thought to be the neutrophils (^{Vinten-Johansen, 2004}), which also release several proteolytic enzymes. Neutrophils are activated by agents derived from the systemic circulation, coronary vasculature and myocytes. Cytokines stimulate the upregulation of adhesion molecules on cardiomyocytes that allow neutrophils to adhere and release ROS and proteolytic enzymes (^{Ren et al., 2003}). Neutrophils accumulate in the ischaemically damaged and/or reperfused area of the myocardium.

In addition to CPB, the myocardium generates inflammatory mediators and ROS during ischaemia–reperfusion, which would contribute to cardiac functional depression and apoptosis (^{Wang et al., 2005}). In a variety of experimental models, cardiac myocytes, when exposed to ischaemia (hypoxia)-reperfusion have been shown to produce interleukin (IL)-6 (^{Sawa et al., 1998}; ^{Chandrasekar et al., 1999}). This cytokine is also produced by the myocardium arrested using cold crystalloid cardioplegia in an experimental model of CPB (^{Dreyer et al., 2000}), and in the coronary bed of patients undergoing coronary artery bypass graft (CABG) surgery (^{Zahler et al., 1999}). Other inflammatory cytokines can be produced locally in the heart, including IL-8 that is released in the ischaemic myocardium, which would stimulate the upregulation of adhesion molecules on different cell types (^{Ren et al., 2003}). This in turn allows neutrophils to adhere to the myocytes and release ROS and proteolytic enzymes. Other proinflammatory cytokines produced by the heart during cardiac insults include IL-18 and IL-1β (^{Matsumori et al., 1999}; ^{Pomerantz et al., 2001}; ^{Deten et al., 2003}). In addition, heart cells produce IL-10, which is a potent anti-inflammatory cytokine (^{Jones et al., 2001}). It is evident therefore that the myocardium is a source of cytokines particularly during ischaemia and reperfusion. What is not known, however, is whether the cytokines synthesized in heart cells are released and therefore could be involved in modulating the inflammatory response. More interestingly would be to know whether cytokines and their action on membrane receptors would alter the myocyte response to cardiac insults.

The cardiac actions of cytokines

It is evident from the above discussion that cytokines, depending on their type, can contribute to either myocardial injury or protection. This effect could be direct on the myocardium or via altering the levels of mediators of cardiac injury. In this respect, proinflammatory cytokines would influence the heart differently from anti-inflammatory ones. IL-6 production has been associated with negative inotropic effects (^{Finkel et al., 1992}) and myocardial stunning (^{Zahler et al., 1999}). It has been suggested that the acute cardiodepressant (negative inotropic) effect of cytokines is related to enhanced production of nitric oxide (NO) (^{Stangl et al., 2002}). NO increases intracellular cyclic guanosine monophosphate, which activates cyclic guanosine monophosphate-dependent protein kinase that inhibits L-type Ca²⁺ channels inducing negative inotropic effects (^{Kojda et al., 1999}). In addition, IL-6 has been implicated in reperfusion injury, where its levels correlated with the extent of left ventricular dysfunction and poor clinical outcome in patients undergoing thrombolysis after myocardial infarction (^{Bennermo et al., 2004}; ^{Ikonomidis et al., 2005}). An effect on neutrophil infiltration may underlie the action of IL-6 as mice deficient in IL-6 showed a reduced neutrophil infiltration in intestine (^{Cuzzocrea et al., 1999}). IL-6 has also been shown to inhibit cardiac myocyte apoptosis (^{Dreyer et al., 2000}). However this antiapoptotic effect was not confirmed by infusing IL-6 into rat heart but was seen upon infusing an IL-6/soluble IL-6 receptor complex (^{Matsushita et al., 2005}). This complex stimulates several cell types not stimulated by IL-6 alone, a process called trans-signalling (^{Jones et al., 2005}). Thus, based on currently available data, the role of IL-6 in reperfusion injury has to remain open, but several lines of evidence suggest that high IL-6 plasma levels positively correlate with myocardial damage following reperfusion. Contrary to all this is a proposal (^{Deten et al., 2003}) suggesting that proinflammatory cytokines produced by the ischaemic myocytes may be involved in the initiation of wound healing of the necrotic area.

In addition to IL-6, other inflammatory cytokines that originate locally or from the systemic circulation, particularly IL-8, that would also exacerbate cardiac injury by enhancing leukocyte activation and accumulation. In fact, postoperative levels of cardiac troponin-I have been shown to correlate with IL-8 levels in patients undergoing CABG surgery (^{Wan and Yim, 1999}). Another cytokine, IL-18 has been shown to activate proapoptotic signalling pathways and induces endothelial cell death (^{Chandrasekar et al., 2004}). In addition to the effects of proinflammatory cytokines, the heart is also influenced by anti-inflammatory ones. For example IL-10 deficiency augments reperfusion injury possibly by enhancing the infiltration of neutrophils into the myocardium (^{Jones et al., 2001}).

The anti-inflammatory approach

Several anti-inflammatory techniques and pharmacological agents (largely aimed at coping with CPB) have been used in recent years in cardiac surgery. These include leukocyte filtration, corticosteroids, aprotinin, heparin and NO donor compounds (^{Harig et al., 2001}; ^{Paparella et al., 2002}; ^{Asimakopoulos and Gourlay, 2003}; ^{Goudeau et al., 2007}). Despite the relatively small number of studies investigating the effects of reducing the inflammatory response on myocardial reperfusion injury, majority of these studies have shown evidence of myocardial protection. For example, aprotinin (serine protease inhibitor) pretreatment has been shown to reduce reperfusion injury in patients undergoing cardiac surgery (CABG and valvular) on CPB (^{Goudeau et al., 2007}). The administration of sodium nitroprusside (NO donor compound) at a non-vasodilatory dosage in patients undergoing CABG on CPB reduces the myocardial inflammatory response and improves postoperative cardiac pump function (^{Freyholdt et al., 2003}). Reducing the inflammatory response by leukocyte filtration has also been shown to improve clinical and biochemical indices of myocardial reperfusion injury after elective coronary revascularization with CPB (^{Matheis et al., 2001}; ^{Palatianos et al., 2004}). Heparin-coated circuits were found to reduce inflammatory responses to CPB and myocardial injury in patients undergoing heart or heart–lung transplantation (^{Wan et al., 1999}), and in patients undergoing elective CABG with CPB (^{Harig et al., 1999}). More recently, this technique was found to reduce reperfusion injury in patients undergoing cardiac surgery on CPB (^{Goudeau et al., 2007}). Corticosteroids are used during cardiac surgery to reduce CPB-induced systemic inflammatory response (for example, ^{Harig et al., 2001}). in children undergoing open-heart surgery on CPB and pretreated with dexamethasone, this anti-inflammatory response has been associated with a reduction in cardiac reperfusion injury (^{Checchia et al., 2003}). Although major reviews of clinical studies have indicated that such intervention has little clinical benefit (^{Chaney, 2002}; ^{Asimakopoulos and Gourlay, 2003}), a recent randomized, multicentre trial demonstrated that intravenous hydrocortisone significantly reduces atrial fibrillation after cardiac surgery (^{Halonen et al., 2007}).

Whether the cardiac actions of these techniques and pharmacological agents are directly due to a reduction in inflammatory response remains to be determined, as this issue is complicated by the fact that there are several myocardial factors (changes) that could influence reperfusion injury following on-pump cardiac surgery. For example there are haemodynamic and osmotic changes that can result in oedema in the heart (^{Simonardottir et al., 2006}).

Off-pump coronary artery bypass surgery

It has been proposed for many years that excluding CBP circuit and avoiding cardioplegic ischaemic arrest would significantly reduce the stress response associated with open-heart surgery. It is now widely accepted that beating heart surgery performed without the aid of CPB significantly attenuates cytokine and stress response (^{Ganapathy et al., 2001}; ^{Raja, 2004}; ^{Yamaguchi et al., 2005}; ^{Lehmann et al., 2006}). The reduced inflammatory response has been associated with improvement in organ function (^{Ascione et al., 2000}, ²⁰⁰¹, ^2002a, ^2002b; ^{Caputo et al., 2002b}) and postoperative bleeding (^{Raja and Dreyfus, 2006}). However, as the inflammatory response is only reduced and not prevented, it is likely to continue to influence cardiac function and clinical outcome (^{Quaniers et al., 2006}). The main source is likely to be surgical trauma, which will continue to trigger a stress response mediated by the release of various cytokines and stress hormones. Therefore, not employing CPB and cardioplegic arrest does not necessarily mean the absence of inflammatory response.

Although the relationship between inflammation and clinical outcome after off-pump coronary artery bypass (OPCAB) has been addressed (^{Aljassim et al., 2006}; ^{Raja and Dreyfus, 2006}), little work has investigating the relationship between inflammatory response and cardiac function been done. The use of a miniature bypass system (beating-heart surgery) was not effective in improving haemodynamic performance or reducing myocardial injury compared to on-pump surgery (^{Rex et al., 2006}). However, an early study investigating the safety of OPCAB revascularization demonstrated that this procedure also reduced myocardial injury (^{Ascione et al., 1999}).

A block of cardiac sympathetic activity is an interesting route to reduce inflammation and myocardial injury during OPCAB surgery (^{Ganapathy et al., 2001}). In fact it has been suggested that differences in the changes in plasma catecholamines may explain why outcome during an inflammatory response is different. Catecholamines increase intracellular cyclic adenosine monophosphate (cAMP), which in rat cardiac myocytes induces IL-6 production (^{Briest et al., 2003}). In humans, adrenaline infusions have been shown to stimulate plasma IL-6 production both in healthy adult volunteers and in HIV-infected patients (^{Sondergaard et al., 2000}; ^{Keller et al., 2004}).

Cardioplegic solutions

Major advances have been made in the preservation of myocardial function during open-heart surgery since the introduction of cardioplegic arrest (^{Melrose et al., 1955}). However, despite variation in the composition of cardioplegia, myocardial protection has been based primarily on high-potassium cold cardioplegic solution. Although cardioplegia does confer protection, human hearts still suffer damage. This is because under these conditions the heart is rendered ischaemic and therefore susceptible to reperfusion injury. More recent strategies for myocardial protection include one or more combinations of warm- versus cold-blood cardioplegia, antegrade versus retrograde delivery, intermittent versus continuous perfusion, and the inclusion of various additives that aim at reducing Ca²⁺ overload, provide energy substrates and remove harmful ROS (^{Demmy et al., 1994}; ^{Buckberg, 1995}; ^{Caputo et al., 1998a}, ^1998b, ^2002a; ^{Liebold et al., 1999}; ^{Thourani et al., 1999}; ^{Matsuda et al., 2000}; ^{Imura et al., 2001}; ^{Ascione et al., 2002}; ^{Lotto et al., 2003}; ^{Ji et al., 2006}; ^{Kacila et al., 2006}; ^{Pouard et al., 2006}; ^{Susumu et al., 2006}).

Ischaemic conditioning (pre- and post-conditioning)

Hearts can be protected from reperfusion injury by subjecting them to brief ischaemia/reperfusion cycles before (preconditioning) or after (post conditioning) starting the prolonged period of ischaemia (see recent reviews, ^{Bolli, 2007}; ^{Hausenloy and Yellon, 2007}). The mechanisms responsible for this protection are not fully understood, but several processes have been implicated (^{Tsang et al., 2004}, ²⁰⁰⁵; ^{Hausenloy et al., 2005}; ^{Vinten-Johansen et al., 2005}; ^{Yellon and Hausenloy, 2005}; ^{Hausenloy and Yellon, 2006}, ²⁰⁰⁷; ^{Yellon and Opie, 2006}; ^{Bolli, 2007}). The signal transduction pathways underlying classical preconditioning involve ‘triggers’ that activate ‘mediators’ (for example, protein kinases), which in turn activate effectors. In addition, heart cells appear to have a memory so that several days later the protection is still detectable. This delayed preconditioning involves the stimulation of transcription of distal mediators and effectors. More recently, the concept of conditioning has been extended to post-conditioning, which describes the cardioprotection resulting from brief ischaemia/reperfusion cycles during reperfusion (^{Hausenloy and Yellon, 2007}). Conditioning (pre and post) are potentially useful in cardiological and cardiac surgical settings (^{Hausenloy and Yellon, 2007}). In addition to ischaemia-related protective conditioning, other conditioning-type interventions (for example, pharmacological, temperature) before or after prolonged ischaemia have also been reported (^{Bolli, 2007}; ^{Khaliulin et al., 2007}).

Ischaemic conditioning has strong clinical implications both in cardiology and during cardiac surgery. The human myocardium can be preconditioned (reviewed in ^{Yellon and Downey, 2003}) as shown in vitro (for example, muscle preparations) and in vivo (for example, angioplasty and surgical studies). There is also evidence that the human myocardium can undergo remote and post-conditioning (^{Hausenloy and Yellon, 2007}). However, despite the potential benefits of these phenomena and an array of conditioning agents, clinical applications and use remains controversial.

Cardioprotection with inhalation anaesthetics

Volatile anaesthetics to various degrees have been shown to decrease myocardial contractility and myocardial oxygen demand, a property that has been suggested to explain cardioprotection against ischaemia and reperfusion (^{Coetzee et al., 1993}; ^{Mattheussen et al., 1993}; ^{Schlack et al., 1998}). However, these anaesthetics were also found to induce cardioprotection via mechanisms that are similar to pathways involved in ischaemic preconditioning (^{Cope et al., 1997}). It is, however, a combination of alteration in contractility and metabolism, as well as a preconditioning-like effect, that appears to be responsible for the protective properties against ischaemia and reperfusion damage (reviewed in ^{De Hert, 2006}).

Cardioprotection with intravenous anaesthetics

Examples of injected drugs that are used during anaesthesia are barbiturates, propofol, ketamine and etomidate, as well as larger doses of opioids (for example, fentanyl) and benzodiazepines. In contrast to inhalation anaesthetics, some of theses anaesthtics (for example, pentobarbital, ketamine–xylazine or propofol) are not as effective at protecting the heart against reperfusion injury, and their action is not related to ischaemic preconditioning. Etomidate (carboxylated imidazole) is a popular choice for the induction of anaesthesia in cardiac compromised patients, as it does not alter cardiovascular activity (^{Bovill, 2006}).

Anaesthetics, the inflammatory response and cardioprotection

As already discussed, several anaesthetics appear to alter the systemic inflammatory response. This is likely to be a direct effect on the inflammatory mediators or indirectly by reducing myocardial reperfusion injury and associated inflammatory response or both. Unfortunately this issue is likely to remain controversial for the time being, as clinical studies investigating different anaesthetic regimen on systemic inflammatory response and myocardial injury during CPB cardiac surgery are few. In one study comparing sevoflurane and propofol in patients undergoing CABG surgery, ^{Kawamura et al. (2006)} showed that sevoflurane was associated with less production of cytokines and reduced myocardial injury. The beneficial effects of sevoflurane are also seen when the drug is added to the cardioplegia, where it decreases the inflammatory response and improves myocardial function after CPB in CABG patients (^{Nader et al., 2004}, ²⁰⁰⁶). On the other hand, propofol controlled infusion (compared with saline) immediately before aortic cross-clamp release and during reperfusion in patients undergoing CABG was found to reduce systemic inflammatory response without attenuating myocardial injury (^{Corcoran et al., 2006}).

An earlier study investigating the effect of anaesthesia on inflammatory response during CABG surgery has shown no difference in cytokine production using high-dose fentanyl or low-dose opioid anaesthesia (^{Brix-Christensen et al., 1998}). More recently, the administration of morphine, but not fentanyl, as part of standardized opioid–isoflurane anaesthetic technique suppressed the inflammatory response to CABG surgery and CPB (^{Murphy et al., 2007})

The effects of volatile anaesthetics have also been associated with preventing the neutrophil-induced coronary endothelial dysfunction. This relationship has been demonstrated in a series of experimental studies by Crystal and co-workers (^{Hu et al., 2003}, ²⁰⁰⁴, ^2005a, ^2005b). More recently, a clinical study on patients undergoing CABG surgery on CPB has shown that the addition of sevofluarne to cardioplegia reduces neutrophils activity (^{Nader et al., 2006}). The finding that desflurane induces greater systemic proinflammatory response than sevoflurane during anaesthesia for ear surgery (^{Koksal et al., 2005}), suggests that the latter would be a better choice in clinical settings like OPCAB surgery.