Myocardial protection in cardiac surgery

Abstracts

JUSTIFICATIVA E OBJETIVOS: A proteção miocárdica define o conjunto de estratégias que objetivam atenuar a intensidade da lesão de isquemia-reperfusão miocárdica durante a cirurgia cardíaca e suas conseqüências sobre a função miocárdica. Um melhor entendimento dos fenômenos fisiopatológicos relacionados à isquemia-reperfusão miocárdica e da cardioproteção promovida por determinados fármacos e técnicas anestésicas tem dado ao anestesiologista papel importante na proteção miocárdica durante o procedimento cirúrgico. O objetivo desta revisão foi abordar os mecanismos de lesão miocárdica e as modalidades de proteção miocárdica com enfoque para a técnica anestésica. CONTEÚDO: São abordados os mecanismos de lesão miocárdica durante os eventos de isquemia-reperfusão e suas conseqüências clínicas assim como às técnicas de proteção realizadas durante a cirurgia cardíaca. Ênfase especial é dada aos fármacos e técnicas anestésicas, como anestésicos halogenados, opióides e fármacos adjuvantes, pois estes têm mostrado efeitos cardioprotetores em cirurgia cardíaca. CONCLUSÕES: A associação de técnica anestésica adequada com agentes anestésicos cardioprotetores às técnicas habituais de proteção miocárdica realizadas pelo cirurgião pode contribuir para prevenção de disfunção miocárdica e promover melhor recuperação no período pós-operatório.

ANALGÉSICOS; ANESTÉSICOS; CIRURGIA; COMPLICAÇÕES; COMPLICAÇÕES

REVIEW ARTICLE

Myocardial protection in cardiac surgery^*

Protección miocárdica en cirugía cardiaca

Luiz Marcelo Sá Malbouisson, TSA, M.D.^I; Luciana Moraes dos Santos, M.D.^II; José Otávio Costa Auler Jr, TSA, M.D.^III; Maria José Carvalho Carmona, TSA, M.D.^IV

^IDoutor em Ciências pela Universidade de São Paulo. Especialista em Terapia Intensiva, AMIB. Médico Assistente do Serviço de Anestesiologia e Terapia Intensiva Cirúrgica do Instituto do Coração (InCor), HCFMUSP

^IIPós-Graduanda da Disciplina de Anestesiologia da FMUSP. Médica Assistente do Serviço de Anestesiologia e Terapia Intensiva Cirúrgica do Instituto do Coração (InCor), HCFMUSP

^IIIProfessor Titular da Disciplina de Anestesiologia da Faculdade de Medicina da Universidade de São Paulo. Especialista em Terapia Intensiva, AMIB. Diretor do Serviço de Anestesiologia e Terapia Intensiva Cirúrgica do Instituto do Coração (InCor), HCFMUSP

^IVProfessora Associada da Disciplina de Anestesiologia da Faculdade de Medicina da Universidade de São Paulo. Especialista em Terapia Intensiva, AMIB. Médica Supervisora do Serviço de Anestesiologia e Terapia Intensiva Cirúrgica do Instituto do Coração (InCor), HCFMUSP

^{Correspondence to}

SUMMARY

BACKGROUND AND OBJECTIVES: Myocardial protection defines the set of strategies aiming at attenuating the intensity of myocardial ischemia-reperfusion injury during heart surgery and its harmful consequences on myocardial function. A better understanding of pathophysiological phenomena related to ischemia-reperfusion events and of the anesthetic-induced heart protection has given to the anesthesiologist a major role in intraoperative myocardial protection. The objective of this update was to review the mechanisms of ischemia-reperfusion-induced myocardial injury and myocardial protection modalities focusing on anesthetic techniques.

CONTENTS: Ischemia-reperfusion-induced myocardial injury mechanisms and their clinical consequences on heart as well as myocardial protection techniques used during heart surgery are addressed in this review. Special emphasis is given to the role of anesthetic drugs and techniques such as inhaled halogenate anesthetics, opioids and adjuvant anesthetic drugs, since they have been shown to have heart protecting effects during cardiac surgery.

CONCLUSIONS: The association of adequate anesthetic technique using heart protecting agents to usual myocardial protection modalities performed by the surgeon may contribute to the prevention of cardiac surgery-induced myocardial dysfunction and improve postoperative outcome.

Key Words: ANALGESICS, Opioid; ANESTHETICS, Volatile; COMPLICATIONS, Cardiovascular: ischemia-reperfusion; SURGERY, Cardiac

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: La protección miocárdica define el conjunto de estrategias que tienen por objetivo atenuar la intensidad de la lesión de isquemia-reperfusión miocárdica durante la cirugía cardiaca y sus consecuencias sobre la función miocárdica. Un mejor entendimiento de los fenómenos fisiopatológicos relacionados a la isquemia-reperfusión miocárdica y de la cardioprotección promovida por determinados fármacos y técnicas anestésicas ha dado al anestesiologista papel importante en la protección miocárdica durante el procedimiento quirúrgico. El objetivo de esta revisión fue abordar los mecanismos de la lesión miocárdica y las modalidades de protección miocárdica con enfoque para la técnica anestésica.

CONTENIDO: Son abordados los mecanismos de lesión miocárdica durante los eventos de isquemia-reperfusión y sus consecuencias clínicas así como las técnicas de protección realizadas durante la cirugía cardiaca. Énfasis especial fue dada a los fármacos y técnicas anestésicas, como anestésicos halogenados, opioides y fármacos adyuvantes, pues éstos han mostrado efectos cardioprotectores en cirugía cardiaca.

CONCLUSIONES: La asociación de la técnica anestésica adecuada con agentes anestésicos cardioprotectores a las técnicas habituales de protección miocárdica realizadas por el cirujano puede aportar para la prevención de disfunción miocárdica y promover mejor recuperación en el período pos-operatorio.

INTRODUCTION

Myocardial protection during cardiac surgery is defined as the set of strategies aiming at decreasing myocardial oxygen consumption adapting it to the momentary tissue supply and/or at making cardiac cells more resistant to ischemic episodes. The goal is to attenuate the magnitude of ischemia-reperfusion-induced injuries and their noxious early and late consequences, such as acute myocardial infarction (AMI), arrhythmias, ventricular dysfunction, cardiogenic shock and increased perioperative mortality.

The importance of limiting ischemia-reperfusion injuries has been discussed for more than three decades. Maroko et al., in 1971, have proposed that the extension and severity of tissue injury alter coronary occlusion were not determined at ischemia onset, but rather they could be changed by therapeutic manipulations during ischemia ¹. Since then, a large number of experimental studies have investigated ischemic mechanisms and myocardial protection modalities. However, few therapeutic interventions have shown to be clinically effective.

Notwithstanding progresses in understanding what determines coronary blood flow, of the relationships between oxygen supply and demand and of cell mechanisms triggered by ischemia, there is still a high incidence of perioperative AMI, which varies from 3% to 30%, depending on the study ².

Among myocardial protection modalities used during cardiac surgeries, drugs and anesthetic techniques improving tolerance to ischemia and contributing to protect myocardial function are becoming increasingly important for the clinical practice and may influence better postoperative outcomes.

The objective of this review was to address injury mechanisms and myocardial protection modalities with special emphasis to anesthetic techniques able to promote heart protection.

ISCHEMIA AND REPERFUSION INJURY

Myocardial ischemia triggers a series of cell events which start mildly and become progressive noxious with time. Although reperfusion is the final stage of the ischemic process and is essential to restore normal functions and cell survival, this may paradoxically amplify the damage secondary to ischemia. Clinically, it is impossible to separate one process from the other and since ischemia is often followed by reperfusion, cell injuries are indistinctly called ischemia-reperfusion injuries.

During ischemia, regional oxygen supply is beneath metabolic needs, resulting in depletion of adenosine triphosphate (ATP) cell reserves. There is decreased efficiency of ATP-dependent sodium (Na⁺) and potassium (K⁺) pumps with increased levels of intracellular sodium. Intracellular ionic hydrogen (H⁺) is built up as result of decreased excretion of metabolic residues, NADH₂ mitochondrial oxidation inhibition and ATP break down. Intracellular H⁺ build up promotes increased H⁺ for Na⁺ exchange in an attempt to maintain cell pH, increasing intracellular Na⁺ levels and promoting increased intracellular calcium (Ca²⁺) levels due to the exchange of Na⁺ for calcium ^3,4.

Using intracellular calcium measurement techniques, Marban et al. have found increased intracellular calcium concentrations during ischemia and early reperfusion ⁵. High intracellular Ca²⁺ levels activate protein kinases with degradation of proteins and phospholipids ^3,6 and decreased maximum calcium-dependent microfilament strength ⁷. The production of neutrophils and mitochondria-derived free radicals also contributes for proteins and phospholipids degradation ⁶, which are major constituents of cells and enzymes structure after ischemia is installed.

The post-ischemia injury seems to be amplified when coronary vessels are damaged. Edematous endothelial cells decrease gas exchange efficacy. Vascular smooth and endothelial muscles cells with abnormal function are unable to promote vasodilation and to match regional blood flow to momentary needs. Neutrophils play a central role in spreading cell injury. These cells are attracted by dysfunctional endothelial cells and migrate to the extravascular space releasing free radicals, cytokines and pro-inflammatory substances, with worsening of the endothelial, smooth muscles and myocytes injury ⁸. There is also neutrophils and platelets aggregation with microvascular obstruction, contributing to supply/demand relationship mismatching ⁶. One way to activate and scavenger neutrophils is their interaction with ICAM-1, L-selectine and CD11b/CD18 adhesion molecules, the expression of which is induced by ischemia-reperfusion injury ⁸.

During reperfusion, H⁺ is rapidly decreased reaching normal levels, and intracellular Na⁺ is exchanged for extracellular Ca²⁺ to balance transmembrane electrochemical potentials, increasing intracellular calcium overload ^3,4. Recent evidences suggest that intracellular calcium overload may activate selective proteolytic enzymes, the calpains, resulting in selective myofibrils proteolysis, and the time needed for damaged proteins synthesis would explain the time needed for myocardial function recovery after ischemia-reperfusion ^9,10. In association with high intracellular calcium levels, there is major increase in oxygen free radicals due to reperfusion with oxygenated blood. Free radicals such as superoxide (O₂), hydroxyl (OH^-) and hydrogen peroxide (H₂O₂) are extremely reactive and indistinctly damage all cell components, increasing ischemia-induced cell injuries. Clinical consequences may go from reversible myocardial dysfunction persisting after reperfusion and known as myocardial stunning, to myocardial infarction ^3,11,12.

ISCHEMIA-REPERFUSION INJURY AND PERIOPERATIVE MYOCARDIAL COMPLICATIONS

Since the 1960s, the development of perioperative micro-infarctions related to cardiac surgery is admitted as a problem, which may lead to low cardiac, output syndrome and death ¹³. Some risk factors identified in patients submitted to coronary artery bypass (CAB) procedures, such as coronary disease severity, presence of collateral circulation, previous CAB, recent AMI, emergency procedure, aortic clamping beyond 100 minutes and inadequate myocardial protection, were directly related to perioperative AMI ^2,14.

Perioperative AMI may be due to increased oxygen consumption at anesthetic induction or during postoperative recovery ¹⁵. However, myocardial ischemia is more likely to develop during the surgical procedure itself. Ischemia during CPB is not solely related to coronary failure severity, but also to the type of myocardial protection, the cardioplegic solution infusion interval and the presence of myocardial hypertrophy. In patients submitted to valve procedures with no evidences of coronary failure, there may be significant CKMB increase in up to 40% of cases without significant manipulation of myocardial muscles ¹⁶.

In spite of current perioperative myocardial protection techniques, up to 50% of patients submitted to CAB may release enzymes ¹⁷, and mortality is related to the intensity of enzyme release ¹⁸. Attempting to prevent undesirable CPB effects, CAB without CPB has been adopted as a feasible alternative to traditional surgery. During CAB without CPB, due to temporary coronary flow occlusion during anastomosis, ischemic preconditioning is the myocardial protection technique of choice.

However, even if the surgery is performed with a beating heart, perioperative AMI may develop in the grafted territory due to poor myocardial tolerance to ischemia, or in non-grafted regions. Although elderly patients submitted to coronary artery bypass, especially in re-operations, and with poor ventricular function, are major candidates to perioperative myocardial ischemia, this may be observed in all age brackets and different types of cardiac procedures.

MYOCARDIAL PROTECTION TECHNIQUES

Cardioplegia

Most widely used myocardial protection technique during coronary artery bypass is the infusion of hypothermic cardioplegic blood or crystalloid solution, being used in 84.3% of procedures with CPB, according to Karthik et al. ¹⁹. Early reports on cardioplegia date from the 1950s, describing electrochemical cardiac arrest in diastole induced by potassium citrate solutions ²⁰, allowing cardiac surgery on standstill and flaccid heart.

However, this solution was associated to high incidence of myocardial necrosis ²¹. Cardioplegic solutions rich in potassium were abandoned in the mid 1970s, when it has been detected that myocardial necrosis was related to its high concentration and hypertonicity ²². Until the 1980s, hypothermal cardioplegic crystalloid solutions were the major myocardial protection technique during cardiac surgeries. As from the 1980s, studies have shown that cardioplegic blood solutions with potassium would promote more effective myocardial protection as compared to crystalloid solutions, fact observed by decrease in CK-MB release and in the incidence of perioperative infarction ²³. Since then, blood cardioplegia has been the milestone of myocardial protection with defined role in intraoperative heart protection ²⁴.

Most widely used cardioplegia administration technique is the intermittent anterograde infusion in the aorta, proximally to the heart, after aortic clamping, or direct infusion in coronary arteries sinus, especially in the presence of associated aortic valve disease. It has been recently proposed the infusion of retrograde cardioplegia in the coronary sinus ostium. This technique assumes the possibility of maintaining uninterrupted infusion and the distribution of cardioplegia to regions irrigated by stenotic coronary vessels, improving sub-endocardial protection ²⁵. The CABG Patch Trial multicentric study has shown that the combination of intermittent anterograde and continuous retrograde cardioplegia would decrease the rate of postoperative cardiac complications as compared to both methods used alone in coronary patients with high surgical risk ²⁶.

The optimal cardioplegic solution temperature is still controversial. Solutions below 15 ºC seem to be more effective in decreasing myocardial oxygen consumption, production of lactates and cell hypoxia markers, as compared to solutions at room temperature. However, solutions around 27 ºC seem to be related to better left ventricular function recovery in the immediate postoperative period ²⁷, in addition to lower incidence of arrhythmias, lower need for defibrillation and less bleeding ²⁸. Another controversial issue is the time interval between cardioplegic infusions, being 20 to 25 minutes the mean period adopted by surgeons. There is also no consensus on the optimal cardioplegic dose, as well as on the addition of substrates, such as I-arginine, anti-arrhythmics or beta-adrenergic antagonists ^29,30.

Hypothermia

Therapeutic hypothermia is a different strategy to decrease myocardial injury secondary to ischemia during cardiac surgery with cardiopulmonary bypass. The mechanism of this myocardial protection is still not totally explained. Classic explanation is decreased oxygen consumption induced by decreased metabolic cell activity and enzyme reactions, which could limit ischemic zones in risky myocardial regions. In humans cooled to 32 ºC, total oxygen consumption is decreased in 45% and is unrelated to changes in arterial oxygen saturation ³¹. The increased affinity of oxygen by hemoglobin is compensated by increased blood solubility, maintaining coupled oxygen supply and demand. As temperature decreases, myocardial oxygen consumption also decreases, being below 1% at 12 ºC ³². This heart protective effect is independent of hypothermia-induced bradycardia because it persists after heart rate normalization with a pacemaker ^33-35.

Decreased metabolic activity, however, does not seem to be the sole mechanism related to hypothermia-induced heart protection. Decreased lipidic peroxidase and free radicals production were described in a hypothermia model. Globus et al. have shown that post-ischemic and post-traumatic hypothermia decreases extracellular levels of 2,3-dihydrobenzoic acid, which is an indicator of free radicals production ³⁶. In ischemia models after neuro-trauma, mild hypothermia has induced major increase in anti-apoptotic Bsl 2 protein, which may attenuate the onset of cell apoptosis ³⁷. In animal models and in isolated hearts it has been shown that hypothermia preserves cell ATP reserves during ischemia. It has also been shown in acute myocardial infarction animal models that heart protective effects of hypothermia included decrease in infarction size, preservation of microvascular flow and maintenance of cardiac output ^38,39.

Hypothermia intensity and duration are determined according to the surgical procedure. Notwithstanding beneficial hypothermia effects on organs protection, increased hypothermia time seems to have paradoxical effects, worsening myocardial injury induced by ischemia-reperfusion. Deep hypothermia for very long periods may exacerbate intracellular calcium overload and induce the formation of peroxides and oxygen reactive species ^40,41. Other undesirable hypothermia side effects in patients submitted to heart surgery are electrolytic disorders, increased systemic vascular resistance, tachycardia, decreased metabolism and drugs clearance, coagulation disorders and immune suppression ^42-44.

Ischemic Preconditioning

Ischemic preconditioning is an endogenous adaptative and protective response against prolonged myocardial ischemia. This concept was proposed as from early observations by Murry et al., who have observed up to 75% decrease in infarction size after 40-minute occlusion of the left circumflex artery in animal model, when previous minor 5-minute occlusions of this same artery were performed ^45,46. This fact was also observed in a series of models, going from isolated cardiomyocytes to in situ hearts, in different animal species ^47-49. Although being initially used to decrease infarction incidence and size, it has been observed that this myocardial protection modality could also decrease the incidence of post-ischemic reversible myocardial dysfunction ⁵⁰ and coronary circulation dysfunction ⁴⁷.

Different membrane receptors seem to be involved in the ischemic preconditioning phenomenon, including b receptors, opioid and adenosine receptors ^51-54. The mechanisms by which ischemic preconditioning triggers the sequence of intracellular events which promotes myocardial protection against repeated ischemic injuries are still subject to massive investigation and are discussed under the section ''preconditioning induced by halogenate inhalational anesthetics''.

Ischemic preconditioning assumes temporary blood flow arrest, may be protective in the presence of several ischemic injuries and play a beneficial role during cardiac procedures. Ghosh and Galinanes have investigated the effects of ischemic preconditioning during procedures with and without CPB. Ischemic preconditioning was achieved by aortic clamping for five minutes followed by 5 minutes reperfusion before the procedure. In patients submitted to CAB without CPB, ischemic preconditioning has promoted less postoperative troponin release ⁵⁵. This heart protective technique may be used in CAB without CPB and in CAB with CPB ¹⁹.

Preconditioning Induced by Halogenate Inhalational Anesthetics

Studies during the 1970s have shown strong evidences that volatile inhalational anesthetics protect myocardium against reversible and irreversible ischemic injuries. Bland et al. have shown that halothane decreased ST segment elevation in a canine model of short-duration occlusion of coronary arteries ⁵⁶. This same group has also observed decreased infarction size in dogs when halothane was administered before coronary occlusion ⁵⁷.

Warltier et al. have observed that dogs previously treated with 2% halothane or isoflurane would totally recover myocardial contractile function within 3 to 5 hours after myocardial ischemia, while there was only 50% contractility recovery 5 hours later in the control group ⁵⁸. The same results were observed in different animal species ^59,60. Heart protection has also been observed during cardioplegia-induced cardiac arrest and reperfusion in animal models under inhalational anesthetics ^61,62. Mechanisms by which these drugs promote heart protection are not totally known and are issues under massive investigation, however they seem to mimic heart protection by ischemic preconditioning, being defined as anesthetic-induced preconditioning.

Halogenate agents decrease blood pressure, depress myocardial contractility, produce coronary vasodilation, delay electric stimulation conduction and attenuate sympathetic nervous system activity, which contributes to decreased myocardial oxygen consumption. However, other mechanisms different from matching oxygen supply and demand seem to be related to heart protection promoted by halogenate agents. Preservation of high-energy phosphates is one suggested hypothesis.

Freedman et al. have observed higher creatinine-phosphate and ATP concentrations in isolated heart model treated with enflurane before ischemia-reperfusion, as compared to control group ⁶³. Similar results were observed with halothane and other halogenates agents ⁶⁴. A different mechanism suggested to explain heart protection induced by halogenate agents is the modulation of cell calcium inflow. Some investigators have experimentally shown that halothane, isoflurane and enflurane decreased total cell calcium flow in rats ⁶⁵ and Guinea pigs ^66,67, and canine ventricular myocytes ⁶⁸.

Eskinder et al. has observed that inhalational anesthetics promote decrease in peak electric potentials induced by calcium inflow through calcium channels type L and T in Purkinje fibers in isolated canine cells ⁶⁹. The same authors have suggested that these calcium channels located in the sarcoplasmic reticulum, are the major action sites for these anesthetics to modulate calcium inflow. Other proposed mechanisms to decrease cell calcium inflow induced by inhalational anesthetics are the inhibition of sodium-calcium pump ⁷⁰ and increase in calcium channels expression in the membrane induced by ischemia-reperfusion ⁶¹.

The opening of ATP-dependent potassium channels, decreasing action potential duration and attenuating membrane depolarization, could result in lower intracellular calcium levels during ischemic preconditioning and acute myocardial infarction ⁷¹ and seems to be involved in heart protection induced by halogenate agents. ATP-dependent potassium channels inhibition by glibenclamide, specific blocker of these channels, was able to eliminate ATP conservation induced by isoflurane in dogs ⁷². It has also been observed that the maintenance of myocardial contractility after ischemia in dogs inhaling isoflurane was partially inhibited by glibenclamide ⁷³.

There is no consensus on which halogenate agent or inhaled concentration should be used to promote heart protection during cardiac procedures. Some authors have suggested that concentrations close to 1 MAC of different halogenate agents produce similar effects in terms of magnitude of myocardial protection ⁷⁴. However, some studies have reported significant differences in myocardial protection intensity and in the action mechanisms of different halogenate agents ^75-78. To date, halogenate agents have shown consistent myocardial protection effects in animal models of ischemia-reperfusion, however there is no consensus on the agent and dose to be used during cardiac procedures.

Opioids Analgesics

Experimental animal studies have shown protection against ischemia-reperfusion by opioid receptors. The contribution of endogenous opioids to body adaptation to hypoxia was firstly reported by Mayfield et al., who have observed that D-Pen2-D-Pen5-Encephaline, sigma receptors agonist, would increase tolerance and survival in mice submitted to severe hypoxia ^79,80. It has also been observed that sigma receptor agonist D-Ala2-D-Leu5-Encephaline, trigger for the hibernation of large animals, would induce protective effects in multiple preparations of organs, including isolated hearts for transplant ⁸¹.

Schultz et al., in 1996, have show that 300 µg.kg^-1 morphine 30 minutes before anterior interventricular artery occlusion would decrease infarction zone from 54% to 12% in rats ⁸². This morphine-induced decrease was also observed in isolated heart models, in situ hearts and cardiomyocytes ^83-85. Improved ventricular contractility after ischemia has also been observed with morphine and fentanyl ⁸⁶.

The involvement of opioid receptors in ischemic preconditioning, especially sigma receptors, has been observed in several animal species and in humans ^{51,74,84,85,87}. Schultz et al., in 1995, have shown that naloxone would block opioid heart protective effects in rats submitted to ischemic preconditioning, however with no effect in animals not submitted to preconditioning ⁸⁸. In addition to participating in the triggering of the cascade of ischemic events, opioids seem also to mediate its memory phase in some animal species ⁸⁹.

Heart protection induced by opioids seems to be modulated by the activation of cardiac receptors, regardless of the action of these drugs on central nervous system. Chien et al. have observed that a naloxone-derived quaternary opioid receptor antagonist, which does not cross blood-brain barrier, was able to totally block protective effects of ischemic preconditioning in isolated heart of rabbits ⁹⁰. The mechanism by which opioids promote myocardial protection is still under investigation. It has been proposed that opioid-induced heart protection would be result of the activation of ATP-dependent potassium channels, possibly in the mitochondrial membrane ^85-87,91. However, intracellular pathways which transduce sigma receptors stimulation effects to final effectors responsible for myocardial protection are not clear. Other opioid-induced intracellular heart protection pathways seem to be related to the activation of inhibitory G ⁹² protein and C1 proteinokinase ^84,91,93.

Other Anesthetic Agents

Some studies have suggested that propofol might attenuate mechanical myocardial dysfunction after ischemia, infarction size and histological changes ^94-97. Due to its chemical structure similar to free radical kelating phenolic derived, such as vitamin E, propofol decreases free radicals concentration and their noxious effects ⁹⁸. Other authors have described that propofol decreases cell ionic calcium inflow and attenuate neutrophils activity, intervening during critical phases of myocardial reperfusion ^99,100.

It seems that propofol provides some level of myocardial protection when given during reperfusion in experimental models of isolated heart of rats ¹⁰¹. However, propofol protective effect seems to be momentary, not being considered preconditioning or myocardial protection induced. The administration of blockers of intracellular transduction pathway related to ischemic preconditioning, such as glibenclamide, does not inhibit momentary propofol protective effects ¹⁰¹. De Hert et al. have compared contractile myocardial function and myocardial injury markers in patients submitted to coronary artery bypass with CPB and anesthetized with propofol or sevoflurane and have observed that sevoflurane, but not propofol, was able to preserve postoperative myocardial function, with evidences of decreased myocardial injury after coronary artery bypass surgery ¹⁰².

Xenon, an inhalational anesthetic drug experimentally used, has been implied in reversible myocardial dysfunction recovery in ischemia-reperfusion animal model. Animals treated with xenon have evolved with total recovery of ventricular wall thickening fraction, which is a myocardial contractility index, in up to 12 hours after surgery, as compared to the control group where thickening fraction was only back to pre-ischemic levels 48 hours after. Still in the group treated with xenon, there has been attenuation of post-ischemic catecholamine release as compared to control group, which could have contributed to decrease post-ischemia oxygen consumption ¹⁰³. However, there are no evidences of the clinical use of xenon for myocardial protection in humans.

Notwithstanding the well established role of ketamine as anesthetic agent for congenital heart surgery in patients evolving with circulatory shock, this drug seems to block ischemic preconditioning ^104,105 and to intensify myocardial injury. Ketamine decreases 1, 4, 5 triphosphate inositol production ¹⁰⁶ and inhibits ATP-dependent potassium channels in the sarcoplasmic membrane ¹⁰⁷. Barbiturates have also been classified as possible inhibitors of myocardial protection induced by ischemic preconditioning ¹⁰⁸.

Adjuvant Drugs

Different drugs have been investigated for direct administration in cardioplegic solution or for systemic administration before CPB. Beta-adrenergic antagonists are among drugs knowingly decreasing AMI injury, by decreasing myocardial oxygen consumption and sympathetic tone, and by stabilizing cell membranes ¹⁰⁹. Beta-adrenergic antagonists in the early hours after AMI were clearly beneficial in decreasing mortality and AMI-related complications. Hours preceding surgery, the anesthetic-surgical procedure per se and CPB trigger massive adrenergic stimulation ¹¹⁰. Since myocardial infarction during cardiac surgery may be related to perioperative tachycardia and ischemia, beta-adrenergic antagonists are particularly interesting ¹¹¹, and may be used preventively before intervention or therapeutically during surgery ¹¹².

The maintenance of beta-adrenergic antagonists until the day of the coronary artery bypass surgery was controversial ^113,114 and clinical research has brought arguments favoring this practice as of 1979. Similarly to non-cardiac surgeries, beta-adrenergic antagonists should be maintained until the day of the surgery ¹¹⁵. Ponten et al. ¹¹⁶ have shown in a randomized study that metroprolol withdrawal 60 hours before surgery was followed by preoperative AMI and perioperative tachycardia and ischemia. Similar results were observed by Chung et al. ¹¹⁷. Studies by du Cailar et al. ¹¹⁸ and Rao et al. ¹¹⁹ have shown that preoperative propranolol has significantly lowered creatinophosphokinase MB fraction increase.

Oral 80 mg sotalol every 12 hours starting two hours before surgery has promoted 43% decrease in the incidence of postoperative supraventricular arrhythmias ¹²⁰. Podesser et al. have shown that continuous intraoperative nifedipine infusion associated to 12 µg.kg^-1.h^-1 metroprolol, after CPB for 24 hours, has decreased the incidence of ischemia and supraventricular tachycardia ¹²¹.

Slogoff et al. ¹²² have compared, in a prospective non-randomized study, the incidence of ischemia in patients submitted to coronary artery bypass. Individuals treated with beta-adrenergic antagonists until the intervention presented less tachycardia or myocardial ischemia as compared to those receiving diltiazem or nifedipine. For the latter, the number of ischemic episodes was similar to patients not receiving beta-adrenergic antagonists or calcium channel blockers. The reason for the difference between beta-adrenergic antagonists and calcium channel blockers is still unknown ¹¹².

However Kyosola et al. ¹²³ have described a network of intra-axonal catecholamines in the right atrium of 16 out of 65 patients during cardiac surgery, and have shown that its presence is related to severe complications, such as arrhythmias lasting up to 2 weeks after surgery, myocardial infarction and death. According to Piriou et al., continuing the treatment with beta-adrenergic antagonists could have prevented these complications ¹¹².

Although beta-adrenergic antagonists were effective in decreasing perioperative events in high-risk patients submitted to non cardiac surgery and to vascular surgery, no randomized study has yet evaluated whether this therapy is beneficial when used in the preoperative period of coronary artery bypass procedures ¹²⁴. A therapeutic trial involving 60 patients submitted to CAB with CPB has shown that esmolol, beta-adrenergic antagonist with ultra-short action, used to decrease myocardial contractility during continuous normothermal coronary perfusion promotes myocardial protection comparable to blood or crystalloid cardioplegia ¹²⁵.

As to a₂ receptor agonists, perioperative clonidine is effective in decreasing morbidity/mortality in patients submitted to non-cardiac surgeries ¹²⁶. There are no evidences of heart protecting effects of a₂-adrenergic agonists and further studies are needed to define the precise indication of such drugs for patients submitted to cardiac surgery. Loick et al. have observed that clonidine was less effective than high thoracic epidural anesthesia in decreasing perioperative stress via sympatholysis and troponin release in patients submitted to coronary artery bypass ¹²⁷.

Experimental studies and small clinical trials have shown encouraging results of myocardial performance improvement in patients submitted to cardiac surgery with the infusion of glucose-insulin-potassium (GIK) solution ^128-130. The mechanism by which GIK solution promotes heart protection seems to be related to ATP-dependent potassium channel activity recovery since glucose decreases the activity of such channels ¹²⁹.

Zhang et al. have observed that insulin infusion decreases apoptosis induced by ischemia and reperfusion ¹³¹. However, notwithstanding the beneficial effect experimentally observed in small series, one study was unable to show the benefits of GIK in high-risk patients submitted to coronary artery bypass with CPB ¹³². The same result was observed in patients submitted to CAB without CPB ¹³⁰. On the other hand, strict control of perioperative glycemia both in diabetes and non-diabetes patients, may play a critical role in decreasing morbidity and mortality during this period ¹³³.

Some authors have shown in experimental models that adenosine activates proteinokinase C metabolic pathway, supposedly involved with myocardial protection induced by ischemic preconditioning. However, clinical trials with adenosine have not shown the expected benefits as compared to results obtained by experimental studies ^29,134.

Thoracic Epidural Anesthesia

Thoracic epidural anesthesia with local anesthetics has been used to promote perioperative analgesia and decrease myocardial oxygen consumption by blocking T₁ to T₅ thoracic sympathetic fiber roots, which supply sympathetic innervation to the heart. Heart protection provided by thoracic epidural anesthesia is related to improved myocardial oxygen balance induced by sympathetic block, which decreases myocardial oxygen consumption secondary to bradycardia, decreases cardiac output and systemic vascular resistance, and improves regional perfusion with dilatation of post stenotic segments of partially obstructed arteries.

Studies have shown that thoracic epidural anesthesia may attenuate endocrine-metabolic response secondary to surgery, with decrease in catecholamine release and serum levels, which contributes to decrease oxygen consumption ¹³⁵. This improvement in myocardial oxygen balance is clinically observed by improved angina in coronary artery disease patients ¹³⁶. Due to the efficiency of thoracic epidural analgesia, it is possible to decrease the doses of systemic opioids thus decreasing tracheal intubation time and pulmonary diseases in the postoperative period of cardiac surgeries ^137-139.

However, in spite of beneficial effects of thoracic epidural anesthesia on myocardial oxygen balance, no direct myocardial mechanism to increase tolerance to ischemia and reperfusion has been described. In a recent meta analysis with 15 trials and 1178 patients, thoracic epidural anesthesia for coronary artery bypass was not effective in decreasing mortality (0.7% versus 0.3% general anesthesia) or the incidence of myocardial infarction (2.3% versus 3.4% general anesthesia). On the other hand, there has been significant decrease in arrhythmias (OR 0.52), pulmonary complications (OR 0.41) and tracheal intubation time (4.5 hours). Spinal analgesia with opioids has had no effects on mortality, incidence of infarction, arrhythmias, mortality and tracheal intubation time as compared to general anesthesia ¹⁴⁰.

CONCLUSIONS

To date, most widely used heart protection modalities during cardiac surgery with CPB are cardioplegic solutions infusion in their different modalities, and regional and systemic hypothermia, which effectively decrease myocardial oxygen consumption and preserve myocardial contractility. In patients submitted to CAB without CPB, ischemic preconditioning has a well-established role, being even used in patients submitted to cardiac surgery with CPB. Some substances, such as systemic or regional beta-adrenergic antagonists have shown to protect myocardial function sometimes similarly to the protection given by cardioplegic solutions. Regional anesthetic techniques, considered protective, play no confirmed role on heart protection. On the other hand, inhalational anesthetics and opioids play important roles in heart protection. The association of myocardial protection techniques implemented by surgical and anesthetic teams may have synergistic effects, contributing to better myocardial function preservation and postoperative evolution in cardiac surgery.

REFERENCES

Submitted for publication January 6, 2005

Accepted for publication May 24, 2005

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^*

Received from Serviço de Anestesiologia e Terapia Intensiva Cirúrgica Instituto do Coração (InCor) HCFMUSP, São Paulo, SP

Publication Dates

• Publication in this collection
  13 Feb 2006
• Date of issue
  Oct 2005

History

• Accepted
  24 May 2005
• Received
  06 Jan 2005