Adenosine and high-energy phosphates in cardiac anesthesiology

Transcription

1 261 Adenosine and high-energy phosphates in cardiac anesthesiology Laboratory of Hemodynamics, Institute for Biomedical Research, Kaunas University of Medicine, Clinic of Cardiac surgery, Kaunas Medical University Hospital, Lithuania Key words: adenosine, phosphocreatine, high energy phosphates, cardioprotection, myocardial preservation, cardiac anesthesiology. Summary. Usage of adenosine and high-energy phosphates in cardiac anesthesiology is widely discussed. Implementation of above substances can be achieved via three possible ways: during the preparation of patients for cardiac surgery, during surgery and after the surgery during intensive postoperative care. Optimum methods for cardiac protection, which could guarantee safe, lasting heart function preservation after the surgery are investigated till now. Advantages and disadvantages of adenosine application during preoperative and postoperative periods as well as in cardiac surgery are presented. Posibilities to use phosphocreatine for cardioprotection will be discussed as well. Introduction Appropriate preparation of patients for cardiac surgery, myocardial protection during the surgery and intensive postoperative care is inseparable part of recent studies in cardiac surgery and anesthesiology. Preoperative preparation of the patients and choice of postoperative tactics is one of the most important factors for improvement of patient prognosis. Postoperative improvement of myocardial function is very important task as well. All these methods influence reduction of postoperative morbidity and mortality. Application of adenosine (ADO) and high-energy phosphates (HEP) in cardiac anesthesiology will be discussed. ADO (nucleoside) is a precursor of HEP (adenosine monophosphate (AMP), diphosphate (ADP) and triphosphate (ATP)). Due to this reason application of ADO will be discussed together with application of HEP (phosphocreatine). A great number of ADO effects are conditioned by its interaction with specific receptors. This is very important in perioperative myocardial protection. This problem will be discussed thoroughly in the article. Problem of ADO and HEP application in cardiac anesthesiology will be discussed in three different aspects: 1. Application of ADO and HEP for diagnostic purposes and in order to prepare patients for surgery, 2. Myocardial protection achieved by application of ADO and HEP during cardiac surgery (not for cardioplegia), 3. Usage of ADO and HEP in postoperative treatment. Theoretical preconditions for adenosine and high-energy phosphates application It is important to mention that importance of ADO and HEP application in cardiac anesthesiology is conditioned by two main mechanisms of action of above substances: a) Preservation of energy resources, b) Effects conditioned by ADO interaction with specific receptors. ADO and phosphocreatine are two main substances could be used for energetic aspect. As it was mentioned above, ADO is a precursor of AMP, ADP and ATP, at the same time phosphocreatine is a buffer of ATP, in the cells where creatine kinase is found [26]. Exogenous ADO is metabolized via three ways: 1. By adenosine kinase synthesis of AMP, 2. By adenosine deaminase formation of inosine, 3. Formation of adenine. Exogenous ADO can be excreted through kidneys [19]. Main way of ADO metabolism is AMP formation. Formation of inosine is initiated, if great amount of ADO is administered (due to therapeutic reasons). Further inosine is transformed by nucleosidphosphorylase to hypoxanthine, which is transformed to AMP by phosphorylase [19]. It is proven that ADO, inosine, hypoxanthine, adenine are important in preservation of post ischemic ATP and myocardial function [26]. Application of ADO for synthesis of HEP is one of the possible mechanisms of ADO action. Second, specific way of action, is conditioned by adenosine Correspondence to E.Širvinskas, Laboratory of Hemodynamics Institute for Biomedical Research, Kaunas University of Medicine, Eivenių 4, 3007 Kaunas, Lithuania

2 262 interaction with specific receptors (A 1, A 2α, A 2β, A 3 ) [19]. A 1 type receptors, are located on cardiomyocytes. ADO interaction with these receptors reduces formation of cyclic AMP (camp), this conditions negative chronotropic and dromotropic effects. As a result this reduces consumption and demand of oxygen. This is important during surgery as well as in postoperative period [10,15,16]. A 1 type receptors are responsible for anaerobic glycolysis activation [1,27]. A 2 type receptors are present on coronary vascular smooth muscle and endothelial cells. Interaction of ADO with the A 2 receptors leads to as stimulation of adenylate cyclase activity and subsequent increase in intracellular camp levels. It is reported that ADO interaction with A 2 receptors is associated with reduction of local damage through inhibition of neutrophil endothelial adherence and plugging, reduction of toxic free radical formation by neutrophils or ischemic cells. Recent studies indicate that A 2 receptors are also expressed in adult cardiac tissue, is coupled to phosphoinositide metabolism and mediates positive inotropic action [10,19,21]. Q.Y. Zhou et al. in 1992 identified A 3 type receptors (called new A 3 receptors), what expected to condition decrease of systemic blood pressure (proven in experimental models) [19]. Important effects for myocardial protection are conditioned by ADO interaction with receptors: 1. Negative chronotropic and dromotropic effects, 2. Positive inotropic action, 3. Anaerobic glycolysis and gluconeogenesis, 4. Dilatation of coronary arteries, 5. Inhibition of thrombocyte aggregation, 6. Hypotension All above effects can be used in preoperative preparation of patients and during postoperative intensive care. Effects of ADO action are indicated in Fig. 1, 2. Precursor of ADO acadesine and inhibitors of ADO transport are explored in order to prolong action of ADO [19]. Decreased energy supply Increased energy demand Adenosine Increased AMP A 1 A 2 Working tissue Decreased energy demand Vascular tissue Increased energy supply Increased energy charge 1 Fig. The role of adenosine in the energy supply-demand balance (according to Mubagwa K., 1996)

3 Adenosine and high-energy phosphates in cardiac anesthesiology 263 Sinus rate Ventricular escape rate AV node conduction Adenosine Coronary blood flow Reperfusion damage Antiadrenergic action Antiarrhythmic effect Negative inotropic effect IMP Oxygen demand Oxygen supply 2 Fig. Schematic outline of the cardiac effects of adenosine (according to Mubagwa K, 1996) Application of adenosine and high energy phosphates during preoperative period ADO has wide spectrum of indications for application during preoperative period in comparison with other substances reviewed in the article. ADO can be administered either for therapeutic or diagnostic purposes [19]. Recent indications for ADO application are limited only for diagnostic and treatment purposes of supraventricular tachycardias [19]. Other indications for ADO administration during perioperative period are discussed as well: 1. Correction of hypertension, 2. Correction of pulmonary hypertension, 3. Increment of cardiac output, 4. Correction of arrhythmias, 5. Reduction of reperfusion injury (myocardial protection), 6. Reduction of myocardial infarction zone [19]. Reduction of ischemic zone by administration of ADO is not finally proved. Some authors indicate that such effect can be achieved if treatment with ADO is started within first three hours after the onset [16,19]. ADO can be successfully applied for pulmonary hypertension treatment. This was undoubtedly proven: pressure in pulmonary artery is reduced up to 40%, at the same time cardiac output is increased up to 50% [19]. This indication of ADO application is very important during preoperative and postoperative improvement of cardiac function. Indications for ADO application in diagnostic purposes are: 1. Diagnostic procedures for ischemic heart disease evaluation combined with scintigraphy and ectoscopy. 2. Diagnosis and differentiation of arrhythmias (tachycardias and preexcitation) [19]. Application of HEP (phosphocreatine) during preoperative period in order to prepare patients for cardiac surgery has been widely discussed [14,22]. In 1984 V. Pedone et al. indicated antiarrhythmic action of phosphocreatine for patients undergoing cardiac surgery due to ischemic heart disease [14,20]. M. Cisowski et al. presented a study, where phosphocreatine was administered in order to prepare pa-

4 264 tients for cardiac surgery (CAGB). Phosphocreatine was applied for three days before surgery (cardioplegic solution was enriched with phosphocreatine as well). Statistically significant decrease in requirement of inotropic drugs, reduction of incidence of ventricular arrhythmias was observed; damages of sarcolemma were less expressed during postoperative period [6]. In 1995 Weber P et al. presented research study, where phosphocreatine treatment was applied for patients with acute myocardial infarction. Reduced incidence of angina pectoris, ventricular arrhythmias, decreased ratio of heart failure was observed. Improved psychosomatic status of the patients in comparison with control group was observed as well [29]. Application of adenosine and high-energy phosphates during intraoperative and postoperative periods H. V. Thourani et al. in 1999 presented experimental model, where possibility to apply ADO was explored in case of severe regional ischemia. Left anterior descending coronary artery was loosely encircled. This produced regional myocardial ischemia. Adenosine was administered in two study groups (third control one): in first group ADO was added to cardioplegic solution, in second group continuous intravenous infusion of ADO was given together with ADO enrichment of cardioplegic solution. Authors observed reduced zone of myocardial infarction. It was proved that application of ADO guarantees protection of ischemic myocardium [25]. This may condition improved prognosis. Decreased levels of creatine kinase and myeloperoxidase were observed in the group where ADO was administered intravenously in comparison with control group. Authors observed statistically significant difference by comparing zone of myocardial edema in the group, where ADO was applied intravenously with other two groups. This zone was significantly reduced in the group where ADO was used intravenously [25]. Reduced activity of neutrophil adhesion in left anterior descending coronary artery at the time of reperfusion was observed in the second group as well [25]. Enhance of energetic resources is important during postoperative period. Application of HEP is one of possible solutions. Reduction of duration of postoperative intensive care treatment and mortality is main the task of usage of these substances. Such effects were observed, if phosphocreatine was applied during the operation. Other effects such as reduced requirement of inotropic substances, improved contractile function of myocardium was observed as well [2,4,6]. Correction of systemic hypertension is a proven effect of ADO. Continuous infusion of ADO reduces blood pressure down to expected level within 1-3 minutes. Discontinuation of ADO continuous infusion provides restoration of blood pressure level within 1-5 minutes. Due to those specific characteristics of blood pressure correction, ADO can be successfully applied for controlled hypotension during operation, but according to recent studies this effect is handy to achieve postoperative correction of hypertension [30]. Further clinical studies are needed to base indications of ADO administration for correction of blood pressure. Unfortunately, there is lack of studies to prove advantages and disadvantages of ADO and HEP administration in postoperative period [4]. Discussion Problem of ADO and HEP application has not been solved yet. Different results of research studies were presented. Some authors observed positive effects of ADO and phosphocreatine application, improving and preserving inotropic function of the heart during whole perioperative period (improved response, reduced requirement of inotropic substances) [14,15]. Application of phosphocreatine reduced occurrence of arrhythmias, number of DC-shocks at the end of operations, decreased requirement of inotropic drugs in postoperative period [2,6]. Alternative opinion supports position that application of ADO in preoperative period doesn t give any reliable effect [13]. This is based on short stability and rapid disintegration of phosphates in the body. This disadvantage might be improved by administration of continuous infusions, searching specific transport inhibitors of ADO, reducing absorption to the cells. Conclusions: 1. Positive effects of ADO and HEP application in cardiac anesthesiology for preoperative and postoperative treatment are conditioned by improved preservation of myocardial function during postoperative period. 2. Application of phosphocreatine before the operation can significantly reduce incidence of arrhythmias and requirement of inotropic drugs during postoperative intensive care. 3. Research studies for ADO and HEP application are needed for further usage of these substances during postoperative period.

5 Adenosine and high-energy phosphates in cardiac anesthesiology 265 Adenozino ir didelės energinės vertės fosfatų vartojimas kardioanesteziologijai Kauno medicinos universiteto Biomedicininių tyrimų instituto Hemodinamikos laboratorija, Kauno medicinos universiteto klinikų Kardiochirurgijos klinika Raktažodžiai: adenozinas, kreatinfosfatas, didelės energijos fosfatai, miokardo apsauga, kardioanesteziologija. Santrauka. Dėl adenozino ir didelės energinės vertės fosfatų vartojimo kardioanesteziologijai plačiai diskutuojama. Šiuos preparatus vartoti galima trejopai: ruošiant ligonius širdies operacijoms, operacijų metu bei pooperaciniu laikotarpiu. Iki šiol ieškoma optimalių miokardo apsaugos metodų, kurie užtikrintų ilgalaikę kardioprotekciją širdies operacijų metu, gerintų širdies funkciją pooperaciniu laikotarpiu. Straipsnyje apžvelgiami adenozino ir kreatinfosfato vartojimo privalumai bei trūkumai ruošiant ligonius širdies operacijoms, jų metu bei pooperaciniu laikotarpiu. Adresas susirašinėjimui: E.Širvinskas, KMU Biomedicininių tyrimų instituto Hemodinamikos laboratorija, Eivenių 4, 3007 Kaunas References 1. Belardinelli L, Linden J, Berne RM. The cardiac effects of adenosine. Prog Cardiovasc Dis 1989;32: Chauhan S, Wasir HS, Bhan A, et al. Adenosine for cardioplegic induction a comparison with St Thomas solution. J Cardiothorac Vasc Anesth 2000;14(1): Chambers DJ. Creatine phospate added to St Thomas cardioplegia. Creatinine and creatinine phosphate: scientific and clinical perspectives. London p Chambers DJ, Haire K, Morley N, et al. St Thomas Hospital cardioplegia: enhanced protection with exogenous creatine phosphate. Ann thorac surg 1996;61(1): Chien S, Zhang F, Niu W. Fructose-1,6-diphosphate and a glucose-free solution enhances functional recovery in hypothermic heart preservation. J Heart Lung Transplant 2000;19(3): Cisowski M, Bochenek A, Kucewicz E, et al. The use of exogenous creatine phosphate for myocardial protection in patients undergoing coronary artery bypass surgery. J Cardiovasc Surg 1996;37(6 Suppl 1): Fogelson BG, Nawas SI, Law WR. Mechanisms of myocardial protection by adenosine supplemented cardioplegic solution: myofilament and metabolic responses. J Thorac Cardiovasc Surg 2000;119(3): Habazelt H, Palmisano BW, Graf BM, et al. Improvement in functional recovery of the isolated guinea pig heart after hypercalemic reperfusion with adenosine. Transplant Proc 1996;28(1): Haverich A, Karck M, Exogenous adenosine in cardioplegia. Z Kardiol 1996;85(suppl 6): Henry P, Demolombe S, Puceat M, et al. Adenosine A1 stimulation activates δ-protein kinase C in rat ventricular myocytes. Circ Res 1996;75: Jovanovic A, Lopez JR, Alekseev AE, et al. Adenosine prevents K+ induced Ca 2+ loading: insight into cardioprotection during cardioplegia. Ann Thorac Surg 1998; 65(2): Jovanovic A, Lopez JR, Alekseev AE, et al. Adenosine prevents hyperkalemia calcium loading in cardiac cells: relevance for cardioplegia. Ann Thorac Surg 1997;65(2): Jaywant AM, Damiano RJ. The superiority of pinacidil over adenosine cardioplegia in blood-perfused isolated hearts. Ann Thorac Surg 1998;66(4): Kalsi KK, Smolenski RT, Pritchard RD, et al. Energetics and function of the failing human heart with dilated or hypertrophic cardiomyophaty. Eur J Clin Invest 1999;29(6): Lasley RD, Rhee JW, Wan Wylen DGL, et al. Adenosine A1 receptor mediated protection of the globally ischemic isolated rat heart. J Mol Cell Cardiol 1990;22: Liu GS, Thornton J, Van Winkle DM, et al. Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart. Circulation 1991;84: Maddali MM, Reddy JD, Krishnaswami S. Adenosine as an adjunct to inducing rapid asystole during cardioplegic arrest. Indian Heart J 2000;52(2): Mentzer RM, Rahko PS, Molina-Viamonte V, et al. Safety, tolerance, and efficacy of adenosine as an additive to blood cardioplegia in humans during coronary artery bypass surgery. Am J Cardiol 1997;79(12): Mubagwa K, Mullane K, Flameng W. Role of adenosine in the heart and circulation. Cardiovascular research 1996;32: Pedone V, Frondini C, Bellotti, et al. An assessment of the activity of creatine phosphate on premature ventricular beats by continuous ECG monitoring in patients with coronary cardiac disease. Clin Trails J 1984;93: Roberts PA, Newby AC, Hallett MB, et al. Inhibition by adenosine of active oxygen metabolite production by human polymorphonuclear leucocytes. Biochem J 1985;227: Samaja M, Allibardi S, De Jonge R, et al. High enegy phosphates metabolism and recovery in reperfused hearts. Eur J Clin Invest 1998;28(12): Sunamori M, Miyamoto H, Yoshida T, Suzuki A. Successful cardiac preservation for 12 hours using nondepolarizing cold cardioplegia. A canine model. Transpl Int 1994;7(suppl 1):485-8.

6 Širvinskas E, Kinduris Š, Railienė L. Anestezija, dirbtinė kraujo apytaka ir miokardo apsauga kardiochirurginių operacijų metu (Anesthesia, cardiopulmonary bypass and myocardial protection during cardiac surgery). Kaunas: Kauno medicinos universiteto spaudos ir leidybos centro leidykla; 2001.p Thourani VH, Ronson RS, Van Wylen DGL, et al. Adenosine supplemented blood cardioplegia attenuates postischemic dysfunction after severe regional ischemia. Circulation 1999;100(supplII): Voet D, Voet JG. Thermodynamics of phosphate compounds. In: Biochemistry 1 st ed. New York: John Wiley and sons.; p Wayatt DA, Edmunds MC, Rubio R, et al. Adenosine stimulates glycolytic flux in isolated perfuded rat hearts by A1 adenosine receptors. Am J Physiol 1989;257: Wayatt DA, Ely SW, Lasley RD, et al. Rurine-enriched asanguineous cardioplegia retards adenosine triphosphate degradation during ischemia and improves postischemic ventricular function. J Thorac Cardiovasc Surg 1989; 98: 97: Weber P, Vlasicova Y, Labrova R, et al. Use of creatine phosphate in treatment of cardiocerebral syndrome associated with acute myocardial infarct in te aged. Cas Lek Cesk 1995;134(2): Zall S, Miloco I, Rickesten S-E. Effects on renal function and central hemodynamics after coronary artery bypass surgery. Anesth Analg 1993;76: Received 5 February 2002, accepted 28 February 2002