Journal of
Cardiothoracic and Vascular Anesthesia VOL 6, NO 5
OCTOBER 1992
EDITORIAL Glucose/Insulin/Potassium Therapy: A Reevaluation of Myocardial During Cardiopulmonary Bypass
1
SCHEMIA IS known to trigger a sequence of metabolic and biochemical changes ending in irreversible injury and cel1 death, if prolonged. During coronary artery bypass grafting (CABG), the heart is subjected to prolonged periods of ischemia, very likely accompanied by varying degrees of postischemic reperfusion injury. Despite the established protective procedures during cardiopulmonary bypass (CPB), such as tissue-cooling and potassium cardioplegic arrest of the heart, the extent of reperfusion injury stil1 remains a major determinant of myocardial damage. From the currently available information, it is obvious that the potential of refractory contractile dysfunction following ischemia has continued to carry a consistently high risk of mortality. A series of laboratory and clinical experiments have been done proposing strategies of substrate manipulation that aim to maximize the goals of prevention, avoidance, and reversal of myocardial ischemia/reperfusion injury. These strategies have been of clinical interest in the setting of myocardial infarction (MI), thrombolytic therapy, and percutaneous transluminal coronary angioplasty (PTCA), as wel1 as cardiac surgery. One available therapeutic option that has been suggested to preserve the ischemic myocardium, as wel1 as improve postischemic contractile dysfunction, is to provide the heart with glucose-insulin-potassium (GIK) as a substrate. Considerable insight has been gained into the cardiac effects of this modality since its introduction in 1965.’ Further, the mechanism responsible for the benefit of glucose in the ischemicireperfused heart has been developed over the past 30 years since glucose-containing priming solutions were introduced for extracorporeal circuits during cardiac surgery. Moreover, data of several investigations have indicated that glucose supplement in cardioplegic solutions is a rational constituent that should be provided to the heart to preserve continued anaerobic and/or aerobic energy production. The enhanced energy supply is assumed to be beneficial even if cold cardioplegia (4” to SC) is used to lower the metabolic rate in the arrested heart. In this issue of the Joumal, Wistbacka et al report the effects of prebypass GIK infusion (glucose 0.6 g/kg/h, insulin 0.12 U/kg/h, and potassium 0.12 mMol/kg/h) in elective nondiabetic CABG patients, as compared to Ringer’s acetate.* The solutions were administered for 1 to 2 Journalofcardioihoracic
Benefits
hours between the onset of anesthesia and crossclamping of the aorta. The investigation was performed in a total of 32 patients with New York Heart Association (NYHA) class 11-IV symptoms, and a left ventricular ejection fraction (EF) of at least 50%. None of the studied subjects was older than 66 years, and had fasted preoperatively for 12 hours. Cardiac protection during surgery was initiated with a warm hyperkalemic/oxygenated blood solution (ratio of 1:4), and was maintained by a cold moderately hyperkalemic 3.5% glucose/oxygenated blood solution (ratio of 1:l). In both groups, an infusion containing glucose (0.05 g/kg/h), as wel1 as NaCl, potassium, phosphate, and MgC12,was started before coming off CPB, and was continued until the first postoperative morning. They concluded that prebypass GIK infusion entailed no clinical benefit as compared to Ringer’s acetate when attention was focused on postoperative myocardial injury (ie, CK-MB enzyme fraction), ECG and hemodynamic changes, as wel1 as the need for inotropic support, arrhythmia frequency, or duration of the intensive care unit (ICU) stay. The conclusion, based on related literature and the results of their investigation, deserves reflection. At present, the utility of therapeutic glucose as GIK remains controversial, and there are conflicting data that have discouraged the widespread use of this metabolic support for cardiac treatment. In interpreting the results of numerous animal and human studies of GIK, the following issues must be clarified: (1) the amount and duration of GIK administration; (2) the unique metabolic characteristics of cardiac ischemic arrest; and (3) the differences between in vivo and in vitro studies. AMOUNT
AND DURATION
EMPHASIS
OF GIK SUPPLY WITH SPECIAL
ON MYOCARDIAL
GLYCOGEN
CONTENT
purposes of preoperative GIK are primarily intended to (1) elevate the glycogen content in the heart; (2) trigger the enzyme system of the glycolytic pathway; (3) esterify intracellular free fatty acids (FFA) by enhancing the supply of a-glycerophosphate; and (4) prevent systemic ketosis. The cardiac glycogen content is thought to be a The
Key words: glucose, insulin, potassium, cardiac surgery, cardiopulmonary bypass
and VascularAnesthesia, Vol 6, NO 5 (October), 1992: pp 517-520
517
WIESE AND ASKAtiM
518
potential sourcc of energy rescrvcd for hypoxic emergencies. Experimentally in animals. it was demonstrated that an elevation in cardiac glycogen content improves resistancc to hypoxia by enhancing aerobic and anaerobic adenosine triphosphate (ATP) production.’ Further, a preoperative clevation of myocardial glycogen levels has been proposed to be of value in preserving the human heart during elective CABG.4 This stratcgy is most useful when cardiac ischemic arrest is initiated by a warm cardioplegic solution, which is accompanied by an enhanced rate of fuel and oxygen utilization, especially in energy-depletcd hearts of cardiac patients.’ However, it is worth keeping in mind that cardiac glycogen stores may be affected not only by preoperative infusion of GIK, but also by fasting.h In this statc, increased plasma levels of FFAs can inhibit glycolysis.’ and promote a variable increase in cardiac glycogen content despite a lack of insulin. Biochemical measurements of myocardial enzyme activities have shown that even during lowered plasma insulin concentrations glycogen synthesis stil1 proceeds because of the high levels of glucose-ó-phosphate in the heart. This impact of fasting should be considered when the effects of prebypass GIK versus Ringer’s acetate are compared. Theoretically. the already substantial cardiac glycogen stores in both groups of fasted patients might have diminished the proposed benefit of prebypass GIK infusion. Another point worthy of emphasis is the limited duration of the GIK infusion (1.5 to 2 hours before aortic clamping), along with the high glucose concentration, used by Wistbacks et al.? In a study of Oldfield et aIx the almost identical GIK solution was more effective in myocardial protection when it was administered at a lower rate over a longer preoperative period, ie, 12 hours. It has been assumed that GIK infusion at rates smaller than 12.5 g of glucose per hour would keep blood glucose levels below 200 mg/dL.” Likewise, the decreased insulin concentration that would be required in the GIK solution would diminish the danger of late hypoglycemia. Regular insulin injected intravenously has a plasma half-life of less than 9 minutes, but it can exert a duration of action of several hours.i(i The high glucose amounts administered in the study of Wistbacks et al” could be accompanied by an increase in thc respiratory quotient (RQ), and thus in the carbon dioxide production,” which may lead to an undesired elevation of the afterload in cardiac patients. Moreover, there is a body of convincing data indicating a potential risk of hyperglycemia predisposing to cerebrovascular accidents. Elevated blood glucose levels have been found to contribute to a worsened neurologie outcome from both global and focal cerebral ischemia, the types of ischemia most relevant during CPB.‘? UNIQUE METABOLIC
CHARACTERISTICS
OF CARDIAC
ISCHEMIC ARREST
Oxygen deficiency due to both hypoxia/anoxia and ischemia leads to a rapid burst of anaerobic glycolysis. Further, the conversion of phosphorylasc b to a, as wel1 as the
ischemia-induccd local catecholaminc release and the gen cration of cyclic AMP. are al1 known to contribute to 111~ promotion of rapid glycogcnolysis. Additional activation cii scveral cnzymatic stcps accclcratcs anacrobic glycolvsi\ with the onsct of both ischemia and hypoxia. Howcver. 111 scvcrc ischcmia. the glycolytic ATP gcneration aftcr thc initial burst is slowcd. nevcr kecping pace with the highenergy phosphate utilization, and accompanied by an accumulation of protons and lactate, as wel1 as by incrcasing contractile failure. In contrast. thc continuous coronary perfusion during hypoxiaianoxia may sustain acceleratcd anaerobic glycolysis. most iikely dut to thc washout of the acid glycolytic end products (ie. lactic acid due to lactate and H+). Thus, the slower ATP depletion is associated with a longer maintenancc of contractile function.” A variety of approaches have been taken toward cvaluating the unique metabolic consequences of cardiac ischemic arrest. The assumption that the mctabolic alterations during cardioplegia are intcrmediatc between myocardial ischemia and hypoxia appears to be consistent with the current knowlcdge of cardioplegia. The intermittent reinfusion of oxygenated cardioplegic solution that is buffered and alkaline may correct thc local tissuc acidosis, and may wash out the acid glycolytic end products gcnerated during the advanced ischemic interval.‘? Ii Therefore, it has been suggcsted that intermittent cardioplegic reinfusion altera the ischemic arrest during cardiac surgery into several ischemic intcrvals of shortcr duration. which are each possibly accompanied by an accelerated aerobicianaerobic glycolysis. In ischemia. therc is little information available providing evidencc of the amount of glucose required to serve as the major fuel. It is assumed that the heart adapts to ischemia by downregulating energy requirements.ih,i7 This assumption is consistent with data suggesting that only a smal1 amount of glycolytic ATP is required to delay or even prevent ischemic myocardial contracture,ix possibly through prescrving internal calcium homeostasis.” In mechanica1 cardiac arrest. the energy demands of myocardial cells have been calculated to be about 40 nmol ATP/min/mg of protein.Z” which is about 10 times less than in the regularly beating heart. Reducing the environmental temperature of the heart is known to additionally diminish the energy requircments. Simultaneously, there is a reduction of oxygen demand, which is assumed to be a further protectivc adaptation of the ischcmic myocardium maintaining its ccll viability during reduced oxygen supply.” Estimations have demonstrated that thc oxygen demand of an arrested heart at 20°C is as low as 0.3 mL/ 100 gm/min, and is reduced to 0.15 mL/lOO gmimin at lo”C,‘- whereas it is up to IO-fold higher in the beating myocardium at similar temperatures. To date, it seems apparent that the extent of reperfusion and reoxygenation damage is not only dependent on the metabolic status bcfore ischemia, but is also influenced by the status at the time of reintroduction of the coronary blood flo~.~” From the onset of cardiac arrest, all patients in the study of Wistbacka et alL rcceived the same amount of glucose in the cold cardioplegic solution and in the postop-
519
GIK INFUSION
erative period. The question as to whether the substrate administration in the cardioplegic solution, as wel1 as in the postoperative period, influenced the results is an open one. DIFFERENCES BETWEEN IN VIVO AND IN VITRO STUDIES
Experimentally, in dog hearts, it has been suggested that total ischemia in vitro (ie, in the papillary muscle) can be used as a model of severe ischemia in vivo (ie, ligation of the circumflex artery in the intact animal) to evaluate the relationship among the metabolic, functional, and structural consequences of ischemic injury. However, more striking differences are apparent when metabolic effects of a specific substrate as the only external fuel in an isolated heart preparation are compared with the substrate impact on myocardial metabolism in a whole-body study. The normal heart consumes what it is supplied; thus, a sole fuel (eg, glucose) can account for almost al1 the oxygen uptake of an isolated heart. On the other hand, the relative contribution of different substrates, such as FFAs, lactate, and glucose in a whole-body study is complex, and influenced by several mechanisms, including the hormonal impact. The characteristic hormonal response during surgery interferes with the assessment of the efficacy of prebypass GIK administration. The decrease in the action of insulin, along with elevated levels of catecholamines, glucagon, cortisol, and growth hormone, provoke depressed periphera1 glucose uptake with a subsequent rise in blood glucose levels. Hyperglycemia can be diminished with hypothermie perfusion during CPB, however, reflecting the thermal sensitivity of hepatic glucose production. The depressed total body perfusion associated with hypothermia can contribute to decreased glucose utilization during CPB, as wel1 as to the persistently elevated postoperative stress hormone levels. After cardiac surgery, the action of insulin slowly returns towards preoperative values, which supports the view that large doses of insulin are required immediately after coming off CPB if GIK is used.26 More striking effects of GIK have been suggested when it was supplied postoperatively to a reperfused, failing myocardium after hypothermie ischemic arrest.27 This beneficial
impact of GIK on contractile dysfunction might be explained by the assumption that the previously ischemic myocardium adapts to reperfusion by upregulating its energy and oxygen demands. However, reperfusion of stil1 viable myocytes is accompanied by a cascade of events, such as abnormal calcium flux, production of oxygen-derived free radicals, abnormalities of the coronary microvasculature, as we11as an accumulation of white bloed cells in the ischemic tissue. These alterations in the postischemic and reperfused myocardium are believed to cause a state of contractile dysfunction that is termed myocardial “stunning.” Recent evidente suggests that an abnormal energy transduction or utilization, and not the lack of energy, contributes to this complex postischemic myocardia1 stunning. The characteristic abnormalities observed in both high-energy phosphate metabolism and contractile dysfunction are prolonged, but transient, lasting hours to daysz8 Therefore, it seems doubtful that large amounts of GIK supplied during myocardial stunning wil1 be of major benefit. Many unresolved issues remain that may affect understanding of glucose/insulin metabolism during cardiac surgery. Considering the potential side effects of GIK, it may be wise to administer glucose with moderation to patients undergoing CPB. At present, there seems to be no clear necessity for perioperative glucose administration when glucose requirements are provided by the appropriate cardioplegic solution, especially when a warm induction is used that accelerates the metabolic rate in energy-depleted hearts of cardiac patients. The best therapeutic approach with GIK is to administer the solution over the period of preoperative fasting (ie, 12 hours) with a modest glucose concentration. Further clinical trials are needed to more precisely define whether preoperative substrate supply is a real factor in postoperative morbidity. Stefan Wiese, MD
Albert Einstein School of Medicine Jefiey Askanazi, MD
Mount Sinai School of Medicine New York, NY
REFERENCES 1. Sodi-Palares D, Testelli MD, Fisleder BL, et al: Effects of an intravenous infusion of a potassium-glucose-insulin solution on the electrocardiographic signs of myocardial infarction. Am J Cardiol 9:165,1965 2. Wistbacka JM, Kankoranta PK, Nuutinen LS: Prebypass glucose-insulin-potassium infusion to elective nondiabetic CABG surgery patients: J Cardiothorac Vast Anesth 6:521-527, 1992 3. Scheuer J, Stezoski SW: Protective role of increased myocardia1 glycogen stores in cardiac anoxia in the rat. Circ Res 27:835, 1970 4. Lolley DM, Ray JF 111, Myers WO, et al: Importante of preoperative myocardial glycogen levels in human cardiac preservation. Preliminary report. J Thorac Cardiovasc Surg 78:678,1979 5. Buckberg GD: Strategies and logie of cardioplegic delivery to prevent, avoid, and reverse ischemic and reperfusion damage. J Thorac Cardiovasc Surg 93:127,1987
6. Schneider A, Taegtmeyer H: Fasting in vivo delays myocardial cell damage after brief periods of ischemia in the isolated working rat heart. Circ Res 681045, 1991 7. Issad T, Penicaud L, Ferre P, et al: Effects of fasting on tissue glucose utilization in conscious resting rats. Biochem J 246:241, 1987 8. Oldfield GS, Commerford PJ, Opie LH: Effects of preoperative glucose-insulin-potassium on myocardial glycogen levels and on complications of mitral valve replacement. J Thorac Cardiovasc Surg 91:874,1986 9. Sieber FE, Smith DS, Traystman RJ, Wollman H: Glucose: A reevaluation of its intraoperative use. Anesthesiology 67:72, 1987 10. Larner J: Insulin and oral hypoglycemie drugs; Glucagon, in Goodman LS, Gilman AG (eds): The Pharmacological Basis of Therapeutics, (ed 7). New York NY, Macmillan, 1985, pp 14901516
520
WIESE AND ASKANAI:
ll. Rogers WJ, Russell RO, McDaniel HG, Rackley CE: Acute effects of glucose-insulin-potassium on myocardial substrates, coronary blood flow and oxygen consumption in man. Am J Cardiol 40:421. 1977 12. Slogoff S, Girgis KZ, Keats AS: Etiologic factors psychiatrie complications associated with cardiopulmonary Anesth Analg 61:165, 1982
in neurobypass.
13. Neely JR, Rovetto MJ, Whitmer JT, Morgan H: Effects of ischemia on function and metabolism of the isolated working rat heart. Am J Physiol225:H651, 1973 14. Buckberg GD: A proposed “solution” to the cardioplegia controversy. J Thorac Cardiovasc Surg 77:803, 1979 15. Wechsler AS: Overview of myocardial thorac Anesth 4:2, 1990 (suppl5)
protection.
J Cardio-
16. Arai AE, Pantely GA, Anselone CG, et al: Active downregulation of myocardial energy requirements during prolonged moderate ischemia in swine. Circ Res 69:1458, 1991 17. Rahimtoola SH: A perspective of the three large multicenter randomized clinical trials of coronary bypass surgery for chronic stable angina. Circulation 72:V 123, 1985 (suppl5) 18. Owen P. Dennis S, Opie LH: Glucose flux regulates the onset of ischemic contracture in globally underperfused rat hearts. Circ Res 66:344, 1990 19. McDonald TF, Hunter EG, MacLeod DP: ATP partition in cardiac muscle with respect to transmembrane electrical activity. Pfluegers Arch 322:95. 1971 20. Probst
1, Spahr
R, Piper HM: Carbohydrate
and fatty acid
metabolism of adult cardiac myocytes maintained in shoi t-terni culture. Am J Physiol 25O:H853. 1986 21. Kloner RA, Przyklenk K, Patel B: Altered myocardial states. The stunned and hibernating myocardium. Am J Med 8614. 1989 (suppl IA) 22. Buckberg GD. Dyson CW. Emerson RC: Techniques fol administering clinical cardioplegia: Blood cardioplegia, In Levitaky S. Engelman RM (eds): A Textbook of Clinical Cardioplegia. Mt Kisco, NY, Futura, 1982 23. Opie LH: Reperfusion injury and its pharmacologic modification. Circulation 80:1049, 1989 24. Jennings RB, Reimer KA, Hill ML, Mayer SE: Total ischemia in dog hearts. in vitro. 1. Comparison of high-energy phosphate production. utilization, and depletion, and of adenine nucleotide catabolism in total ischemia in vitro vs. severe ischemia in vivo. Circ Res 49:X92, 1981 25. Kuntschen FR. Galetti M, Hahn C: Glucose-insulin interactions during cardiopulmonary bypass. Hypothermia versus normothermia. J Thorac Cardiovasc Surg 91:451, 1986 26. Svedjeholm R. Hallhagen S, Ekroth R, et al: Dopamine and high-dose insulin infusion (glucose-insulin-potassium) after a cardiac operation: Effects on myocardial metabolism. Ann Thorac Surg51:262. 1991 27. Gradinac S, Coleman CM. Taegtmeyer H, et al: Improved cardiac function with glucose-insulin-potassium after aortocoronary bypass grafting. Ann Thorac Surg 48:484, 1989 28. Braunwald E, Kloner RA: The stunned myocardium: Prolonged, postischemic ventricular dysfunction. Circulation 66:1146, 1982
Cardiothoracic and Vascular Anesthesia VOL 6, NO 5
OCTOBER 1992
EDITORIAL Glucose/Insulin/Potassium Therapy: A Reevaluation of Myocardial During Cardiopulmonary Bypass
1
SCHEMIA IS known to trigger a sequence of metabolic and biochemical changes ending in irreversible injury and cel1 death, if prolonged. During coronary artery bypass grafting (CABG), the heart is subjected to prolonged periods of ischemia, very likely accompanied by varying degrees of postischemic reperfusion injury. Despite the established protective procedures during cardiopulmonary bypass (CPB), such as tissue-cooling and potassium cardioplegic arrest of the heart, the extent of reperfusion injury stil1 remains a major determinant of myocardial damage. From the currently available information, it is obvious that the potential of refractory contractile dysfunction following ischemia has continued to carry a consistently high risk of mortality. A series of laboratory and clinical experiments have been done proposing strategies of substrate manipulation that aim to maximize the goals of prevention, avoidance, and reversal of myocardial ischemia/reperfusion injury. These strategies have been of clinical interest in the setting of myocardial infarction (MI), thrombolytic therapy, and percutaneous transluminal coronary angioplasty (PTCA), as wel1 as cardiac surgery. One available therapeutic option that has been suggested to preserve the ischemic myocardium, as wel1 as improve postischemic contractile dysfunction, is to provide the heart with glucose-insulin-potassium (GIK) as a substrate. Considerable insight has been gained into the cardiac effects of this modality since its introduction in 1965.’ Further, the mechanism responsible for the benefit of glucose in the ischemicireperfused heart has been developed over the past 30 years since glucose-containing priming solutions were introduced for extracorporeal circuits during cardiac surgery. Moreover, data of several investigations have indicated that glucose supplement in cardioplegic solutions is a rational constituent that should be provided to the heart to preserve continued anaerobic and/or aerobic energy production. The enhanced energy supply is assumed to be beneficial even if cold cardioplegia (4” to SC) is used to lower the metabolic rate in the arrested heart. In this issue of the Joumal, Wistbacka et al report the effects of prebypass GIK infusion (glucose 0.6 g/kg/h, insulin 0.12 U/kg/h, and potassium 0.12 mMol/kg/h) in elective nondiabetic CABG patients, as compared to Ringer’s acetate.* The solutions were administered for 1 to 2 Journalofcardioihoracic
Benefits
hours between the onset of anesthesia and crossclamping of the aorta. The investigation was performed in a total of 32 patients with New York Heart Association (NYHA) class 11-IV symptoms, and a left ventricular ejection fraction (EF) of at least 50%. None of the studied subjects was older than 66 years, and had fasted preoperatively for 12 hours. Cardiac protection during surgery was initiated with a warm hyperkalemic/oxygenated blood solution (ratio of 1:4), and was maintained by a cold moderately hyperkalemic 3.5% glucose/oxygenated blood solution (ratio of 1:l). In both groups, an infusion containing glucose (0.05 g/kg/h), as wel1 as NaCl, potassium, phosphate, and MgC12,was started before coming off CPB, and was continued until the first postoperative morning. They concluded that prebypass GIK infusion entailed no clinical benefit as compared to Ringer’s acetate when attention was focused on postoperative myocardial injury (ie, CK-MB enzyme fraction), ECG and hemodynamic changes, as wel1 as the need for inotropic support, arrhythmia frequency, or duration of the intensive care unit (ICU) stay. The conclusion, based on related literature and the results of their investigation, deserves reflection. At present, the utility of therapeutic glucose as GIK remains controversial, and there are conflicting data that have discouraged the widespread use of this metabolic support for cardiac treatment. In interpreting the results of numerous animal and human studies of GIK, the following issues must be clarified: (1) the amount and duration of GIK administration; (2) the unique metabolic characteristics of cardiac ischemic arrest; and (3) the differences between in vivo and in vitro studies. AMOUNT
AND DURATION
EMPHASIS
OF GIK SUPPLY WITH SPECIAL
ON MYOCARDIAL
GLYCOGEN
CONTENT
purposes of preoperative GIK are primarily intended to (1) elevate the glycogen content in the heart; (2) trigger the enzyme system of the glycolytic pathway; (3) esterify intracellular free fatty acids (FFA) by enhancing the supply of a-glycerophosphate; and (4) prevent systemic ketosis. The cardiac glycogen content is thought to be a The
Key words: glucose, insulin, potassium, cardiac surgery, cardiopulmonary bypass
and VascularAnesthesia, Vol 6, NO 5 (October), 1992: pp 517-520
517
WIESE AND ASKAtiM
518
potential sourcc of energy rescrvcd for hypoxic emergencies. Experimentally in animals. it was demonstrated that an elevation in cardiac glycogen content improves resistancc to hypoxia by enhancing aerobic and anaerobic adenosine triphosphate (ATP) production.’ Further, a preoperative clevation of myocardial glycogen levels has been proposed to be of value in preserving the human heart during elective CABG.4 This stratcgy is most useful when cardiac ischemic arrest is initiated by a warm cardioplegic solution, which is accompanied by an enhanced rate of fuel and oxygen utilization, especially in energy-depletcd hearts of cardiac patients.’ However, it is worth keeping in mind that cardiac glycogen stores may be affected not only by preoperative infusion of GIK, but also by fasting.h In this statc, increased plasma levels of FFAs can inhibit glycolysis.’ and promote a variable increase in cardiac glycogen content despite a lack of insulin. Biochemical measurements of myocardial enzyme activities have shown that even during lowered plasma insulin concentrations glycogen synthesis stil1 proceeds because of the high levels of glucose-ó-phosphate in the heart. This impact of fasting should be considered when the effects of prebypass GIK versus Ringer’s acetate are compared. Theoretically. the already substantial cardiac glycogen stores in both groups of fasted patients might have diminished the proposed benefit of prebypass GIK infusion. Another point worthy of emphasis is the limited duration of the GIK infusion (1.5 to 2 hours before aortic clamping), along with the high glucose concentration, used by Wistbacks et al.? In a study of Oldfield et aIx the almost identical GIK solution was more effective in myocardial protection when it was administered at a lower rate over a longer preoperative period, ie, 12 hours. It has been assumed that GIK infusion at rates smaller than 12.5 g of glucose per hour would keep blood glucose levels below 200 mg/dL.” Likewise, the decreased insulin concentration that would be required in the GIK solution would diminish the danger of late hypoglycemia. Regular insulin injected intravenously has a plasma half-life of less than 9 minutes, but it can exert a duration of action of several hours.i(i The high glucose amounts administered in the study of Wistbacks et al” could be accompanied by an increase in thc respiratory quotient (RQ), and thus in the carbon dioxide production,” which may lead to an undesired elevation of the afterload in cardiac patients. Moreover, there is a body of convincing data indicating a potential risk of hyperglycemia predisposing to cerebrovascular accidents. Elevated blood glucose levels have been found to contribute to a worsened neurologie outcome from both global and focal cerebral ischemia, the types of ischemia most relevant during CPB.‘? UNIQUE METABOLIC
CHARACTERISTICS
OF CARDIAC
ISCHEMIC ARREST
Oxygen deficiency due to both hypoxia/anoxia and ischemia leads to a rapid burst of anaerobic glycolysis. Further, the conversion of phosphorylasc b to a, as wel1 as the
ischemia-induccd local catecholaminc release and the gen cration of cyclic AMP. are al1 known to contribute to 111~ promotion of rapid glycogcnolysis. Additional activation cii scveral cnzymatic stcps accclcratcs anacrobic glycolvsi\ with the onsct of both ischemia and hypoxia. Howcver. 111 scvcrc ischcmia. the glycolytic ATP gcneration aftcr thc initial burst is slowcd. nevcr kecping pace with the highenergy phosphate utilization, and accompanied by an accumulation of protons and lactate, as wel1 as by incrcasing contractile failure. In contrast. thc continuous coronary perfusion during hypoxiaianoxia may sustain acceleratcd anaerobic glycolysis. most iikely dut to thc washout of the acid glycolytic end products (ie. lactic acid due to lactate and H+). Thus, the slower ATP depletion is associated with a longer maintenancc of contractile function.” A variety of approaches have been taken toward cvaluating the unique metabolic consequences of cardiac ischemic arrest. The assumption that the mctabolic alterations during cardioplegia are intcrmediatc between myocardial ischemia and hypoxia appears to be consistent with the current knowlcdge of cardioplegia. The intermittent reinfusion of oxygenated cardioplegic solution that is buffered and alkaline may correct thc local tissuc acidosis, and may wash out the acid glycolytic end products gcnerated during the advanced ischemic interval.‘? Ii Therefore, it has been suggcsted that intermittent cardioplegic reinfusion altera the ischemic arrest during cardiac surgery into several ischemic intcrvals of shortcr duration. which are each possibly accompanied by an accelerated aerobicianaerobic glycolysis. In ischemia. therc is little information available providing evidencc of the amount of glucose required to serve as the major fuel. It is assumed that the heart adapts to ischemia by downregulating energy requirements.ih,i7 This assumption is consistent with data suggesting that only a smal1 amount of glycolytic ATP is required to delay or even prevent ischemic myocardial contracture,ix possibly through prescrving internal calcium homeostasis.” In mechanica1 cardiac arrest. the energy demands of myocardial cells have been calculated to be about 40 nmol ATP/min/mg of protein.Z” which is about 10 times less than in the regularly beating heart. Reducing the environmental temperature of the heart is known to additionally diminish the energy requircments. Simultaneously, there is a reduction of oxygen demand, which is assumed to be a further protectivc adaptation of the ischcmic myocardium maintaining its ccll viability during reduced oxygen supply.” Estimations have demonstrated that thc oxygen demand of an arrested heart at 20°C is as low as 0.3 mL/ 100 gm/min, and is reduced to 0.15 mL/lOO gmimin at lo”C,‘- whereas it is up to IO-fold higher in the beating myocardium at similar temperatures. To date, it seems apparent that the extent of reperfusion and reoxygenation damage is not only dependent on the metabolic status bcfore ischemia, but is also influenced by the status at the time of reintroduction of the coronary blood flo~.~” From the onset of cardiac arrest, all patients in the study of Wistbacka et alL rcceived the same amount of glucose in the cold cardioplegic solution and in the postop-
519
GIK INFUSION
erative period. The question as to whether the substrate administration in the cardioplegic solution, as wel1 as in the postoperative period, influenced the results is an open one. DIFFERENCES BETWEEN IN VIVO AND IN VITRO STUDIES
Experimentally, in dog hearts, it has been suggested that total ischemia in vitro (ie, in the papillary muscle) can be used as a model of severe ischemia in vivo (ie, ligation of the circumflex artery in the intact animal) to evaluate the relationship among the metabolic, functional, and structural consequences of ischemic injury. However, more striking differences are apparent when metabolic effects of a specific substrate as the only external fuel in an isolated heart preparation are compared with the substrate impact on myocardial metabolism in a whole-body study. The normal heart consumes what it is supplied; thus, a sole fuel (eg, glucose) can account for almost al1 the oxygen uptake of an isolated heart. On the other hand, the relative contribution of different substrates, such as FFAs, lactate, and glucose in a whole-body study is complex, and influenced by several mechanisms, including the hormonal impact. The characteristic hormonal response during surgery interferes with the assessment of the efficacy of prebypass GIK administration. The decrease in the action of insulin, along with elevated levels of catecholamines, glucagon, cortisol, and growth hormone, provoke depressed periphera1 glucose uptake with a subsequent rise in blood glucose levels. Hyperglycemia can be diminished with hypothermie perfusion during CPB, however, reflecting the thermal sensitivity of hepatic glucose production. The depressed total body perfusion associated with hypothermia can contribute to decreased glucose utilization during CPB, as wel1 as to the persistently elevated postoperative stress hormone levels. After cardiac surgery, the action of insulin slowly returns towards preoperative values, which supports the view that large doses of insulin are required immediately after coming off CPB if GIK is used.26 More striking effects of GIK have been suggested when it was supplied postoperatively to a reperfused, failing myocardium after hypothermie ischemic arrest.27 This beneficial
impact of GIK on contractile dysfunction might be explained by the assumption that the previously ischemic myocardium adapts to reperfusion by upregulating its energy and oxygen demands. However, reperfusion of stil1 viable myocytes is accompanied by a cascade of events, such as abnormal calcium flux, production of oxygen-derived free radicals, abnormalities of the coronary microvasculature, as we11as an accumulation of white bloed cells in the ischemic tissue. These alterations in the postischemic and reperfused myocardium are believed to cause a state of contractile dysfunction that is termed myocardial “stunning.” Recent evidente suggests that an abnormal energy transduction or utilization, and not the lack of energy, contributes to this complex postischemic myocardia1 stunning. The characteristic abnormalities observed in both high-energy phosphate metabolism and contractile dysfunction are prolonged, but transient, lasting hours to daysz8 Therefore, it seems doubtful that large amounts of GIK supplied during myocardial stunning wil1 be of major benefit. Many unresolved issues remain that may affect understanding of glucose/insulin metabolism during cardiac surgery. Considering the potential side effects of GIK, it may be wise to administer glucose with moderation to patients undergoing CPB. At present, there seems to be no clear necessity for perioperative glucose administration when glucose requirements are provided by the appropriate cardioplegic solution, especially when a warm induction is used that accelerates the metabolic rate in energy-depleted hearts of cardiac patients. The best therapeutic approach with GIK is to administer the solution over the period of preoperative fasting (ie, 12 hours) with a modest glucose concentration. Further clinical trials are needed to more precisely define whether preoperative substrate supply is a real factor in postoperative morbidity. Stefan Wiese, MD
Albert Einstein School of Medicine Jefiey Askanazi, MD
Mount Sinai School of Medicine New York, NY
REFERENCES 1. Sodi-Palares D, Testelli MD, Fisleder BL, et al: Effects of an intravenous infusion of a potassium-glucose-insulin solution on the electrocardiographic signs of myocardial infarction. Am J Cardiol 9:165,1965 2. Wistbacka JM, Kankoranta PK, Nuutinen LS: Prebypass glucose-insulin-potassium infusion to elective nondiabetic CABG surgery patients: J Cardiothorac Vast Anesth 6:521-527, 1992 3. Scheuer J, Stezoski SW: Protective role of increased myocardia1 glycogen stores in cardiac anoxia in the rat. Circ Res 27:835, 1970 4. Lolley DM, Ray JF 111, Myers WO, et al: Importante of preoperative myocardial glycogen levels in human cardiac preservation. Preliminary report. J Thorac Cardiovasc Surg 78:678,1979 5. Buckberg GD: Strategies and logie of cardioplegic delivery to prevent, avoid, and reverse ischemic and reperfusion damage. J Thorac Cardiovasc Surg 93:127,1987
6. Schneider A, Taegtmeyer H: Fasting in vivo delays myocardial cell damage after brief periods of ischemia in the isolated working rat heart. Circ Res 681045, 1991 7. Issad T, Penicaud L, Ferre P, et al: Effects of fasting on tissue glucose utilization in conscious resting rats. Biochem J 246:241, 1987 8. Oldfield GS, Commerford PJ, Opie LH: Effects of preoperative glucose-insulin-potassium on myocardial glycogen levels and on complications of mitral valve replacement. J Thorac Cardiovasc Surg 91:874,1986 9. Sieber FE, Smith DS, Traystman RJ, Wollman H: Glucose: A reevaluation of its intraoperative use. Anesthesiology 67:72, 1987 10. Larner J: Insulin and oral hypoglycemie drugs; Glucagon, in Goodman LS, Gilman AG (eds): The Pharmacological Basis of Therapeutics, (ed 7). New York NY, Macmillan, 1985, pp 14901516
520
WIESE AND ASKANAI:
ll. Rogers WJ, Russell RO, McDaniel HG, Rackley CE: Acute effects of glucose-insulin-potassium on myocardial substrates, coronary blood flow and oxygen consumption in man. Am J Cardiol 40:421. 1977 12. Slogoff S, Girgis KZ, Keats AS: Etiologic factors psychiatrie complications associated with cardiopulmonary Anesth Analg 61:165, 1982
in neurobypass.
13. Neely JR, Rovetto MJ, Whitmer JT, Morgan H: Effects of ischemia on function and metabolism of the isolated working rat heart. Am J Physiol225:H651, 1973 14. Buckberg GD: A proposed “solution” to the cardioplegia controversy. J Thorac Cardiovasc Surg 77:803, 1979 15. Wechsler AS: Overview of myocardial thorac Anesth 4:2, 1990 (suppl5)
protection.
J Cardio-
16. Arai AE, Pantely GA, Anselone CG, et al: Active downregulation of myocardial energy requirements during prolonged moderate ischemia in swine. Circ Res 69:1458, 1991 17. Rahimtoola SH: A perspective of the three large multicenter randomized clinical trials of coronary bypass surgery for chronic stable angina. Circulation 72:V 123, 1985 (suppl5) 18. Owen P. Dennis S, Opie LH: Glucose flux regulates the onset of ischemic contracture in globally underperfused rat hearts. Circ Res 66:344, 1990 19. McDonald TF, Hunter EG, MacLeod DP: ATP partition in cardiac muscle with respect to transmembrane electrical activity. Pfluegers Arch 322:95. 1971 20. Probst
1, Spahr
R, Piper HM: Carbohydrate
and fatty acid
metabolism of adult cardiac myocytes maintained in shoi t-terni culture. Am J Physiol 25O:H853. 1986 21. Kloner RA, Przyklenk K, Patel B: Altered myocardial states. The stunned and hibernating myocardium. Am J Med 8614. 1989 (suppl IA) 22. Buckberg GD. Dyson CW. Emerson RC: Techniques fol administering clinical cardioplegia: Blood cardioplegia, In Levitaky S. Engelman RM (eds): A Textbook of Clinical Cardioplegia. Mt Kisco, NY, Futura, 1982 23. Opie LH: Reperfusion injury and its pharmacologic modification. Circulation 80:1049, 1989 24. Jennings RB, Reimer KA, Hill ML, Mayer SE: Total ischemia in dog hearts. in vitro. 1. Comparison of high-energy phosphate production. utilization, and depletion, and of adenine nucleotide catabolism in total ischemia in vitro vs. severe ischemia in vivo. Circ Res 49:X92, 1981 25. Kuntschen FR. Galetti M, Hahn C: Glucose-insulin interactions during cardiopulmonary bypass. Hypothermia versus normothermia. J Thorac Cardiovasc Surg 91:451, 1986 26. Svedjeholm R. Hallhagen S, Ekroth R, et al: Dopamine and high-dose insulin infusion (glucose-insulin-potassium) after a cardiac operation: Effects on myocardial metabolism. Ann Thorac Surg51:262. 1991 27. Gradinac S, Coleman CM. Taegtmeyer H, et al: Improved cardiac function with glucose-insulin-potassium after aortocoronary bypass grafting. Ann Thorac Surg 48:484, 1989 28. Braunwald E, Kloner RA: The stunned myocardium: Prolonged, postischemic ventricular dysfunction. Circulation 66:1146, 1982
