Glucose insulin Mixture as a Cardioprotective Agent in Cardiology and Cardiac Surgery ( Review )

В обзоре литературы представлен анализ публикаций, посвященных использованию инсулино%глюкоз% ной смеси в качестве кардиопротектора при остром инфаркте миокарда и при кардиохирургических опе% рациях с искусственным кровообращением (ИК). Кратко изложены исторические аспекты внедрения ин% сулино%глюкозной терапии в кардиологии и кардиохирургии. Проанализированы возможные механизмы действия глюкозо%инсулин%калиевой смеси при острой ишемии и инфаркте миокарда (нормализация эле% ктрических процессов на мембране кардиомиоцитов, пополнение метаболический субстратов и увеличе% ние гликолитической продукции аденозинтрифосфорной кислоты, снижение интенсивности окисления неэстерефицированных жирных кислот, уменьшение апоптоза и др.). Рассмотрены результаты клиничес% ких исследований по назначению смеси при остром инфаркте миокарда, включая данные мета%анализов. Продемонстрировано, что роль и клиническая эффективность рассматриваемой лечебно%профилактичес% кой меры при остром инфаркте миокарда остаются предметом дискуссии и требует дальнейших исследо% ваний. Также проанализированы современные концепции, объясняющие кардиопротекторные эффекты глюкозы и инсулина при операциях с ИК (уменьшение инсулинорезистентности, активизация анаплеро% зиса, стимуляция внутриклеточных сигнальных путей, обеспечивающих сохранение жизнеспособности клеток, снижение выраженности системной воспалительной реакции, иммуномодулирующее действие, и др.). Представлены результаты клинических исследований, включая данные рандомизированных клини% ческих исследований и мета%анализов, выполненных за последние 5 лет и продемонстрировавших оттсут% ствие влияния глюкозо%инсулиновой терапии на госпитальную летальность. Вместе с тем, в ряде работ вы% явлены и обсуждаются ее положительные эффекты: снижение частоты периоперационных инфарктов миокарда, уменьшение интенсивности инотропной поддержки, лучшие значения послеоперационного сер% дечного индекса и укорочение длительности послеоперационной искусствкнной вентиляции легких, пре% бывания в отделении интенсивной терапии и др. Сделано заключение, что в последние годы отмечается возрат интереса к лечебно%профилактическому использованию глюкозо%инсулиновой смеси как в экстрен% ной кардиологии, так и в кардиохирургии.


Ключевые слова: глюкозо инсулин калиевая смесь; адъювантная кардиопотекция; инсулин; глюкоза; уг леводный метаболизма при остром инфаркте миокарда; гипергликемия в кардиохирургии
The literature review presents an analysis of publications describing the use of a glucose insulin mixture as a cardioprotective agent in acute myocardial infarction and in cardiac surgeries with extracorporeal circulation (ECC).It summarizes historical aspects of implementation of the glucose insulin therapy in cardiology and car diac surgery.Possible mechanisms of action of the glucose insulin potassium mixture in acute ischemia and myocardial infarction were analyzed (normalization of electrical processes on the cardiomyocyte membrane, replenishment of metabolic substrates and increased production rate of adenosine triphosphoric acid due to gly

Глюкозо инсулиновая смесь как кардиопротектор в кардиологии и кардиохирургии (обзор) Introduction
The glucose insulin cardiotropic therapy is apparently one of the oldest therapeutic options that have preserved their relevance to the present day and continue to attract the attention of researchers.More than 100 years ago, in the British Medical Journal, A.Goulston described an experience of the successful use of large quantities of sugarcane for the treatment of dilated cardiomyopathy, valvular heart defects and other etiological variants of chronic cir culatory failure [1].In the introduction, the author stated that data on a significant role of glycogen in muscles functioning became a precondition for the treatment of heart dysfunctions.In 1927, M.B.Visscher and E.A.Muller [2] demonstrated that insulin increased the contractile function of an iso lated mammal's heart without any direct effect on the intensity of oxidative processes in the myocardi um.In 1933, the experiment of C.L.Evans et al. demonstrated that the consumption of glucose increased in the ischemic myocardium.
In the earliest period of the development of cardiac surgery with extracorporeal circulation (ECC), researchers' interest in the possibility of metabolic protection of the myocardium from harm ful effects of ischemia reperfusion using a natural bioenergetic substrate, glucose, and an anabolic hor mone, insulin, which regulates the carbohydrate metabolism, revived.A preventive infusion of glu cose and insulin to increase intramyocardial stocks of glycogen was supposed to support heart's bioen ergetics during the aortic cross clamping due to anaerobic glycolysis.In 1959, H.L.Conn et al. [4] demonstrated the cardioprotective effect of glyco gen stocks augmented due to administration of glu cose and insulin had a limited duration without spe cific protective measures for the mycardium.Lactate accumulation and acidosis quickly become the main factors affecting cardiomyocytes.colysis, decreased intensity of non esterified fatty acid oxidation, decreased apoptosis, etc.).It discusses results of clinical studies evaluating prescription of the mixture for acute myocardial infarction, including data from meta analyses.It demonstrated that the role and the clinical efficacy of the preventive and therapeutic measure under consideration in acute myocardial infarction are still the subject of discussion and require further research.It also analyzed modern concepts explaining the cardioprotective effects of insulin and glucose during surgeries with ECC (decreased insulin resistance, activation of anaplerosis, stimulation of intracellular signaling pathways main taining the viability of cells, reduction of the severity of systemic inflammatory response, immunomodulating effect, etc.).Review discusses results of clinical studies including data from randomized clinical trials and meta analyses performed over the last 5 years that demonstrated the absence of the effect of the glucose insulin therapy on the hospital mortality.Various studies demonstrated its positive effects including decreased incidence of peri operative myocardial infarctions and intensity of inotropic support, increased values of postoperative cardiac index, decreased duration of postoperative mechanical ventilation and ICU stay, etc. Review concludes that the interest to the therapeutic and preventive use of the glucose insulin mixture in both emergency cardiology and cardiac surgery has been revived recently.В начале 1960 х годов Sodi Pallares D. и со авт.в серии работ предприняли попытку обосно вать назначение глюкозы, инсулина и калия на те рапевтической модели ишемии реперфузииостром инфаркте миокарда (ОИМ) [5][6][7][8][9][10].Ин фузия глюкозо инсулин калиевой смеси (ГИКС), которую авторы называли «поляризующей», должна была, прежде всего, обеспечить электриче скую стабильность миокарда, насыщая кардиоми оциты K + и нормализуя мембранный потенциал действия, а также предоставить сердцу дополни тельный метаболический субстрат, который тре бует меньшего количества кислорода при ишемии.Инсулин в этой ситуации служил, по мнению ав торов, в основном, «мессенджером» для K + и глю козы.Исследователи продемонстрировали, что ГИКС уменьшает электрокардиографические признаки ОИМ и снижает частоту аритмий [5,7].
When the works of Sodi Pallares D. and col legues were published, the GIPM was applied by two principal ways, the intensive AMI treatment and adjuvant cardioprotection in cardiac surgery.

Glucose and Insulin in AMI
The mechanism of action.Several effects of GIPM in acute myocardial infarction have been dis cussed [11,12].Its antiarrhythmic properties were attributed to cardiomyocyte membrane stabilization.Its favorable effect on the metabolism of ischemic myocardium was also considered relevant.The metabolism of non esterified fatty acids (NEFA) in ischemia is known to take place with the formation of toxic metabolites and free radicals impairing the contractility and causing ventricular arrhythmias.In addition, NEFA may damage membranes by increas ing the acylcarnitine level [13].Increased glycolytic ATP production due to administration of exogenous glucose should reduce the intensity of the NEFA oxi dation.In addition, insulin reduces the blood levels of these compounds by inhibiting lipolysis.The potential effects of the GIPM (such as the reduction of ischemic myocardial contracture, protective effects on smooth muscles of coronary arteries, angiospasm prevention, increased spontaneous fibri nolysis, reduction of reperfusion damage, and pre vention of the no reflow phenomenon after myocar dial revascularization, etc.) have been discussed [11,14].Reduction of cardiomyocyte apoptosis which is activated after the ischemic reperfusion damage may represent the another possible cardioprotective effect of GIPM.Significant reduction in apoptosis mediators in blood of AMI patients underwent coro nary angioplasty and GIPM injections was also described [15].
A meta analysis including data on 1932 patients summarized clinical trials carried out over the period from 1965 till 1987 [11].The authors con cluded that the GIPM contributed to a 28% reduc tion in AMI related hospital mortality.In early 2000s, a detailed clinical study (GIPS I) was per formed.It demonstrated that a 8-12 hour GIPM infusion affected the 30 day mortality in patients with no signs of chronic circulatory failure, who underwent coronary angioplasty for AMI; however, it had no significant effect on this parameter in the general population and in patients with heart failure [12].It then demonstrated that a 24 hour GIPM infusion to patients with STEMI contributed to the decrease in the left ventricle remodeling 6 months after the angioplasty [14].
However, despite a large number of publica tions describing a favorable clinical effect of the GIPM, it could not be recommended as a standard therapeutic option for AMI from a position of the evidence based medicine.In 2010, a meta analysis summarizing treatment outcomes of 28,374 patients over 40 years was carried out [18].The authors demonstrated similar 30 day mortality rates in patient groups receiving and not receiving the GIPM during their hospital stay.They concluded that prescription of the GIPM did not affect clinical outcomes when modern AMI treatment protocols including fibrinolysis and primary coronary angio plasty were applied.Moreover, the studies demon strated no effect of the GIPM in the subgroup of patients, in which myocardial reperfusion was not achieved.Therefore, the appropriateness of the GIPM prescription in the hospital AMI treatment is considered unproven.However, no final conclusion on the prescription of GIPM in the clinical situation under consideration has been drawn.

Glucose and Insulin in Cardiac Surgery
The problem of using the GIPM in cardiac surgery is even more complicated and disputable than its prescription in AMI.In 1969, M. V. Braimbridge et al. [21] published a report on successful tricuspid valve replacement surgeries that included an effective post operative prescription of GIPM (50 U of insulin, 50% glucose solution and 50 meq of K + ) for treatment of ventrical arrhythmias and low cardiac output irre sponsive to inotropic agents.
After that, several studies demonstrated the use of GIPM in cardiosurgical patients.In addition to a «classic» variant of the GIPM, many clinicians have reported on prescription of glucose insulin mixture (GIM) using a potassium chloride solution for correction of the potassemia level, when indicat ed.Therefore, hereinafter the mixture will be referred to as GIM.
In early 1980s, W.Haider et al. carried out a series of studies.[22][23][24][25][26][27].The authors described a successful use of the GIM with increased doses of insulin to improve cardioprotection during aortic cross clamping, as well as a part of combined treat ment of acute heart failure.According to their data, the improved myocardial bioenergetics due to GIM administration allowed to reduce the doses of car diotonic agents significantly; at that, the cardiac out put increased and clinical outcomes improved.
National studies during the same period have also demonstrated favorable effects of the GIM and elevated doses of insulin on myocardial function and severity of perioperative hyperglycemia [28][29][30][31].One experimental studydemonstrated that an insulin infusion increased the pumping ability of the heart and velocity characteristics of contractility [29].Hypothesis was suggested that autoimmune factors contributed to genesis of perioperative hyperglycemia, and possible prevention of the latter with GIM was due to a lower titer of autoantibodies against insulin [30,31].In addition, the authors demonstrated that ultrahigh doses of insulin could provide the recovery of myocardial sensitivity to sympathomimetic drugs in case of persistent acute heart failure and inability to discontinue the car diopulmonary bypass [28].
Membrane stabilizing and antiarrhythmic effects of the GIM (GIPM) were discussed at the ini tial stage of clinical implementation of the proce dure.It was assumed (similarly for cardiac surgery) that an increased inflow of potassium to cardiomy ocytes facilitated the restoration of the sinus rhythm and reduced the risk of postoperative ventricular arrhythmias and atrial fibrillation [22,32,33].In later studies, the role of this protector mechanism was challenged [36].
Improved glucose utilization in the myocardi um during GIM administration takes place due to the effect of insulin on transmembrane glucose trans porters (GLUT).GLUT 4 typical for myocardium is insulin dependent; under the effect of the hormone, its expression can be increased several times; as a result, the activity of Na K ATPases increases and the myocardial contractility improves [16,22,28].Data demonstrated that the glucose utilization in the myocardium increased by more than 50% during reperfusion after warm blood cardioplegia under the effect of GIM [37].
Decreased blood NEFA level due to GIM administration is an important effect because the surgical stress inevitably leads to hypercate cholaminemia resulting in lipolysis.Adverse effects of the NEFA metabolism in ischemic myocardium have been discussed above.Systemic insulin admin istration is believed to reduce lipolysis due to direct inhibition of hormone sensitive lipases in fat tissue, as well as due to activation of mitochondrial acetyl CoA carboxylase directly inhibiting the NEFA oxi dation [16].In an experimental model of cardiac surgery, it has been demonstrated that reperfusion with GIM after cardioplegia reduces utilization of NEFA in the myocardium by more than 1.5 fold [37].
However, some fears were expressed that administration of the GIM could worsen the periop erative hyperglycemia [16].At present, there is no doubt that hyperglycemia «triggers» numerous pathological processes and worsens them.Hyperglycemia enhances the apoptosis of cardiomy ocytes and endothelial cells of coronary arteries via a variety of mechanisms, particularly, via increased secretion of tumor necrosis factor (TNF α) and the expression of its receptor, or affecting the metabolism of nitric oxide, etc. [41][42][43][44].In case of hyper glycemia, pharmacological preconditioning and post conditioning of myocardium is deployed through inhalation anesthetics and levosimendan.This effect is based on inhibition of the activity of ATP depen dent potassium channels in cardiomyocyte mitochon dria [45][46][47].Hyperglycemia induces impairment of immunity by increasing the secretion of TNF α and other proinflammatory cytokines including inter leukin 18 due to increased expression of pro inflam matory transcription factors [48]; it also impairs hemostasis system predisposing the patient to hyper coagulation [49], affects the endothelium dependent vasodilation and worsens the oxidative stress [42,50].In the liver, heart, and kidney cells, the excess of glucose causes toxic effects due to impairment of mitochondria and reduces autophagy, a process intended to eliminate damaged organelles and toxic protein disintegration products [42,51].Finally, high blood concentrations of glucose can provoke osmotic diuresis causing hypovolemia and reduced cardiac output [52].Hyperosmolarity can also predispose to cerebral complications [16].
Currently, the need for correction of hyper glycemia in cardiosurgical patients is undisputed [53].Experts believe that introduction of insulin, which provides «rigid» control of hyperglycemia in the postoperative period, significantly reduces the mortality in this patient population.There are data demonstrating that the achievement of normo glycemia using insulin provides an effective cardio protection [54].During an elective myocardial revas cularization, the infusion of insulin and glucose in modes that support normoglycemia reduces the post cardioplegic increase in blood troponin I and inhibits the AMP activated protein kinase, indicating a decrease in cellular consequences of ischemia [55].
Кроме того, в эксперименте доказано, что ин сулин повышает толерантность кардиомиоцитов к cussed.It is assumed that the GIM activates anaplerosis, intermediate enzymatic reactions ensur ing the restoration of a sufficient pool of substrates for the functioning of the Krebs cycle and increases the availability of amino acids needed for protein synthesis in cardiomyocytes [56][57].It has been established that the intra operative introduction of the GIM stimulates the synthesis of hormones and growth factors after an elective myocardial revascu larization [58].Several studies demonstrated an increase in cardiac output as a result of the GIM introduction to decreased afterload due to reduced peripheral vascular resistance [59][60].
In addition, an experiment demonstrated that insulin increased cardiomyocytes' tolerance to ischemia by direct activation of specific intracellular signaling pathways ensuring preservation of the cell viability under the effect of different adverse factors [61][62].The influence of the GIM on intracellular signaling pathways, in particular, on those regulating the functions of mitochondria associated proteins has been also demonstrated in clinical trials over recent years [63].At that, the direct insulin stimula tion of intracellular signaling system regulated by the O linked β N acetylglucosamine (O GlcNAc) [63] was emphasized; the latter is an integral compo nent of the system which provides a cellular response to physiological and pathophysiological stimuli, in particular, protection against the oxidative stress.In addition, the ability of O GlcNAc to regulate the GLUT system by supporting the transportation of glucose and providing cellular effects of insulin was considered.
Relief of the severity of a systemic inflammato ry reaction is an important aspect of organ protec tive (in general) and cardioprotective (in particular) effects of insulin, which is confirmed by a decrease in blood levels of proinflammatory cytokines [54,64].Finally, insulin enhances the phagocytic activity of neutrophils, thus reducing the risk of infectious com plications [65].
Results of clinical studies.A meta analysis pub lished in 2004 and covering data on 468 patients was the first study with the highest level of evidence evaluating the GIM effectiveness in cardiosurgical patients [66].It demonstrated that the use of the GIM provides a higher post perfusion growth of the cardiac output and a 1.8 fold decrease in the inci dence of postoperative ciliary arrhythmia.The authors noted that only 11 of 35 works dedicated to the problem carried out in 1970-2002 were suitable for the analysis.J.D. Schipke et al. [16] explained the small num ber of studies with a high level of evidence dedicated to the GIM clinical effectiveness in cardiac surgery despite the 40 year experience of its use using a num ber of reasons.First of all, in most studies, clinicians did not perform a proper randomization to study Важным аспектом органопротекторных, в целом, и кардиопротекторных, в частности, эф фектов инсулина является снижение выраженно сти системной воспалительной реакции, что под тверждено уменьшением уровня в крови провоспалительных цитокинов [54,64].Наконец, инсулин повышает фагоцитарную активность нейтрофилов, что снижает риск инфекционных осложнений [65].
After that, randomized clinical studies demon strated contradictory results.For example, it was shown that in elective myocardial revascularization with ECC, an intra operative GIM introduction provided the cardioprotective effect in the form of improved pumping ability of the heart and oxygen transport optimization after ECC [67].At that, the effect was pronounced when high (2 IU/kg per 1 L of 30% glucose solution) and low (32 IU/L of 10% glu cose solution) insulin doses were used.
In another study, it was demonstrated that the intraoperative GIM infusion of (80 IU of insulin in 500 ml of 5% glucose solution) improved the systolic func tion of the left ventricle and had no cardioprotective effect during the elective myocardial revascularization with ECC in patients with type 2 diabetes [68].
Similarly to the clinical studies, the conclusions of the meta analyses performed in 2010-2011 are contradictory.One of them analyzed data from 20 studies over the period 1978-2006 (2943 patients who underwent revascularization of the myocardium with ECC) and showed that the GIM did not affect the hospital mortality and the incidence of postoper ative ciliary arrhythmia.It was concluded that the GIM should not be prescribed as a standard medical measure because it produced no positive effect and no evidence of its safety were obtained [69].The fea ture of this study was the analysis of the endpoints in the general observation group, which included patients with and without diabetes, as well as patients receiving insulin only during cardioplegia.Of 1498 observations in the GIPM group, 857 patients were treated in 4 studies where insulin at a dose of 10 IU/L was included in the cardioplegic solution used during emergency revascularization of the myocardium.Results of these studies did not show any benefits of insulin containing cardioplegia.It is unlikely that the latter can be characterized as a full fledged therapy using GIM.Another meta analysis examined data from 2113 patients published in 33 studies carried out over the period from 1977 till 2008.[70].Patients with and without diabetes who underwent surgeries with ECC for the coronary heart disease and valve defects were enrolled in the studies.The analysis was performed in both general population and subgroups (with and without diabetes, before and after 2000, etc.).The authors identified a number of positive effects of the GIM: decreased incidence of periopera tive myocardial infarctions, decreased intensity of the inotropic support, better values of postoperative cardiac index and decreased duration of postopera tive mechanical ventilation, and decreased ICU stay.Favorable effects of the GIM administration were observed in various subgroups; at that, in patients with diabetes, they were registered only when a care ful control of glycemia was provided.
Another meta analysis published in 2012 con firmed that the GIM reduced the incidence of peri operative myocardial infarctions and reduced the need for inotropic support in patients who under went revascularization of the myocardium.At the same time, postoperative ciliary arrhythmia occured more frequently in the GIM group [71].
Well designed clinical studies performed over recent years demonstrated clear clinical advantages of the GIM in different categories of cardiosurgical patients, including those at high risk.GIPM infu sions (40 IU of insulin, 500 mL of 10% glucose and 40 meq of KCl at an infusion rate of 1 mL/kg/h) started 10 hours before the surgery and continued until removal of the aortic clamp during revascular ization of the myocardium in patients with a low left ventricular ejection fraction provided almost a two fold decrease in the postoperative growth of natri uretic B type peptide and a significant reduction of the postoperative mechanical ventilation [72].During elective myocardial revascularization of the myocardium in diabetic patients, the intraoperative GIM infusion provided a greater of postoperative stability of the cardiac output, lower incidence of cil iary arrhythmia and a better control of glycemia with less insulin requirements as compared to the refer ence group [40].Satisfactory results were obtained with GIM in emergency revascularization of the myocardium without AC.The GIM infusion (325 IU of insulin, 500 mL of 50% glucose and 80 meq of potassium at an infusion rate of 0.3 mL/kg/h) in the intraoperative and early postoperative period after a multivessel coronary artery bypass graft surgery pro vided a significant relief of biochemical signs of myocardial damage: decreased blood level of MB CPK and troponin T [73].Recently published data confirming the essential role of hyperglycemia cor rection during prescription of the GIM to AMI patients undergoing coronary bypass surgery attracted much attention [74].Based on the Еще один мета анализ, опубликованный в 2012 г., подтвердил, что ГИС снижает частоту пе риоперационных инфарктов миокарда и умень шает потребность в инотропной поддержке у больных, которым выполняют реваскуляризацию миокарда.Вместе с тем, в «группе ГИС» чаще ре гистрировали послеоперационную мерцательную аритмию [71].
Adjuvant cardioprotection in the surgical treatment of patients with severe myocardial hyper trophy is an individual aspect of the GIM application in cardiac surgery.In 2011, results of a randomized clinical trial of clinical and metabolic effects of the perioperative GIM introduction in the surgical treatment of aortic stenosis were published [63].After examination of 217 patients randomized in 2 groups the authors found that the GIPM reduces the incidence of low cardiac output episodes after aortic valve replacement by more than 3 fold; it also signif icantly reduces the need for inotropic medications.This study confirmed the assumption about the potential effectiveness of the GIPM in the surgical treatment of aortic stenosis published in early 1980s.Then it was shown that increased sensitivity to insulin and high glucose utilization regressing after aortic valve replacement was typical for patients with myocardial hypertrophy [75][76].The authors interpreted the obtained data as manifestations of metabolic heart adaptation which created a basis for prescription of the GIPM in the perioperative peri od.Modern researchers [63] suggest the involve ment of the cardioprotection mechanism provided by O GlcNAc.The latter affects the function of the mitochondria associated proteins that increase car diomyocyte resistance to ischemia reperfusion, stim ulates the transport of glucose through the GLUT system, etc. [77,78].
1 60 w w w .r e a n i m a t o l o g y .c o m DOI:10.15360/18139779 2017 1 57 72 Обзор w w w .r e a n i m a t o l o g y .c o m DOI:10.15360/18139779 2017 1 57 72 . r e a n i m a t o l o g y .c o m DOI:10.15360/18139779 2017 1 57 72 Review Обзор w w w .r e a n i m a t o l o g y .c o m DOI:10.15360/18139779 2017 1 57 72