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Asian Cardiovasc Thorac Ann 1998;6:273-278
© 1998 Asia Publishing EXchange Pte Ltd

ORIGINAL CONTRIBUTION

Benefits of Glucose-Insulin-Potassium Before Mitral Valve Replacement

Bülent Tünerir, MD, Recep Aslan, MD, Serap Isiksoy, MD1, Ömer Çolak, MD2, Yavuz Besogul, MD, Tugrul Kural, MD

Department of Thoracic and Cardiovascular Surgery
1 Department of Pathology
2 Department of Biochemistry Osmangazi University Medical School and Research Hospital Eskisehir, Turkey
For reprint information contact: Bülent Tünerir, MD Hasan Polatkan Bulvari No. 122 D. 19 Eskisehir 26120, Turkey Tel:90 222 225 0606 Fax:90 222 230 6215 Email:utuneri1{at}akbank.com.tr

   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Of 30 consecutive patients undergoing mitral valve replacement, 15 were randomly assigned to receive pretreatment with glucose-insulin-potassium, while the other 15 received the same volume of normal saline. The characteristics of both groups were similar and all patients were in New York Heart Association functional class III or IV. Papillary muscle samples were obtained at the time of surgery and analyzed for glycogen both biochemically and histochemically. The clinical course was monitored closely during the first 24 hours after surgery. The treated patients had significantly higher glycogen levels (mean, 43 ± 13.54 µmol·g–1) in their heart muscle samples compared to the controls (mean, 22 ± 10.39 µmol·g–1). The treated patients required less pharmacological inotropic support and they had fewer ventricular arrhythmias and more favorable cardiac output and systemic vascular resistance. However, there was no difference in postoperative pulmonary capillary wedge pressure or mortality between the 2 groups. It was concluded that pretreatment with glucose-insulin-potassium had a significant myocardial protective effect in patients in advanced functional class undergoing mitral valve replacement.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Extensive research has been carried out on the preservation of ischemic myocardium, including during periods of ischemia on cardiopulmonary bypass (CPB). Sodi-Pallares and colleagues1 were the first to use a solution of glucose, insulin, and potassium (GIK) to protect the heart during evolving acute myocardial infarction. GIK prolongs myocardial ischemic tolerance by increasing glycogen levels and preserving high-energy phosphates in cardiac muscle cells.2–4 GIK solution became popular for the treatment of acute myocardial infarction in the early 1970s.5–8 Subsequently, it has been used for protection of the myocardium during ischemic periods on CPB.9–11 This study was designed to assess the potential benefits of GIK in patients undergoing mitral valve replacement.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The study was carried out on 30 consecutive patients undergoing mitral valve replacement because of rheumatic mitral valvular disease. Approval was granted by the Committee for the Protection of Human Subjects and informed consent of the patients was obtained. There were 7 males and 23 females and their mean age was 38 years (range, 21 to 63 years). All of them were in New York Heart Association functional class III or IV. Fifteen patients were randomly assigned to receive 1000 mL of GIK solution (glucose 200 g, potassium chloride 45 mmol, and soluble insulin 10 IU) containing 2000 IU of heparin, 12 hours before the operation. The other 15 patients received the same volume of normal saline containing 2000 IU heparin. The preoperative clinical and hemodynamic characteristics of both groups were similar (Table 1Go).


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  		Table 1. Characteristics of 30 Patients Undergoing Mitral Valve Replacement
 
All operations were performed under the fentanyl anesthesia. After sternotomy, all patients were routinely given heparin 3 mg·kg–1. Cardiopulmonary bypass was performed using a membrane oxygenator (Ultrox; Avecor Cardiovascular Inc., Plymouth, MN, USA) and a centrifugal pump (Biopump; Bio-Medicus, Minneapolis, MN, USA). St. Thomas' Hospital no. 2 solution was used intermittently for cold cardioplegic arrest. The temperature of the myocardium was monitored and maintained at 10°C to 12°C.

During resection of the mitral valve apparatus, biopsy samples (0.5 to 1 g) of papillary muscle were obtained and stored in liquid nitrogen. The glycogen content of these samples was measured biochemically.12 In addition, sections of the biopsies were fixed in alcohol and stained with periodic acid Schiff (PAS) solution to evaluate the glycogen histochemically.13 The glycogen content was scored in the PAS-stained areas on a scale of 0 to 4+ (no glycogen 0; trace 1+; slight 2+; moderate 3+; and 4+ rich in glycogen).

The clinical course of all patients was monitored closely during the first 24 hours after surgery. Central venous pressure, pulmonary capillary wedge pressure, mean cardiac index, and systemic vascular resistance were recorded at 0, 12, and 24 hours postoperatively by a thermodilution catheter system (Hemopro 1 Hemodynamic Profile Computer; Spectramed, Inc., Oxnard, CA, USA).14 Central venous pressure was maintained between 14 and 16 cm H2O during and after surgery. The mean arterial pressure values were recorded continuously and postoperative inotropic requirements were noted. Inotropic support was required when the mean arterial pressure was less than 80 mm Hg, urine output less than 30 mL per hour, and clinical signs of cardiac failure were detected. Inotropic support in the intensive care unit was decided by a surgeon who was not informed of the use of GIK. The inotropic requirement of each patient was scored by the method of Gradinac and colleagues10 during the first and second 12-hour periods after surgery. Patients requiring no inotropic support were given a score of 0. The score was 1 if dopamine (at a dose greater than 5 µg·kg·min–1), dobutamine, or amrinone was used alone. The score was 2 if both dopamine and dobutamine or a similar combination of two agents were used. When either epinephrine of norepinephrine was used in combination with pharmacologic doses of two other agents (dopamine, dobutamine, or amrinone), a score of 3 was assigned. A score of 4 was given when four or more agents were used in combination. No patients required mechanical support. Postoperative arrhythmias within 72 hours were recorded.

All data presented were analyzed statistically. Mean values, standard deviations, and standard errors were calculated. The two-tailed paired Student t test and two-dimensional variant analysis were used.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Operative and postoperative findings are listed in Table 2Go. Mean cardiac index in the GIK-treated patients was higher than in the controls at 12 and 24 hours after the operation (p < 0.025, p < 0.005 for 12 and 24 hours respectively) as shown in Figure 1Go. Systemic vascular resistance was markedly lower in GIK-treated patients 12 hours after surgery compared to the controls. However, there was no statistically significant difference in the postoperative pulmonary capillary wedge pressure measurements of the two groups. The requirement for inotropic support was significantly less in the GIK-treated patients at 0 to 12 hours and 12 to 24 hours postoperatively (p < 0.001). GIK-treated patients also had notably fewer ventricular arrhythmias than the controls.


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  		Table 2. Postoperative Findings in 30 Patients After Mitral Valve Replacement
 


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  		Figure 1. Comparison of postoperative mean cardiac index. *p < 0.025. **p < 0.005.

 
The mean papillary muscle glycogen content determined biochemically (Table 3Go) was higher in the patients who received GIK than in the control patients (p < 0.001). Glycogen stores evaluated histochemically by the Wittels-Reiner scoring method (Table 3Go) showed that in the GIK-treated group, the number of patients (n = 14) who had 2+, 3+, and 4+ PAS-stained biopsy samples was greater than that of the control group (n = 3). Examples of degrees of PAS-staining are shown in Figure 2Go.


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  		Table 3. Cardiac Muscle Glycogen
 


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  		Figure 2. Myocardial glycogen quantified according to degree of staining with periodic acid Schiff: (A) 1+, trace; (B) 2+, slight; (C) 3+, moderate; and (D) 4+, rich. Samples were counterstained with hematoxylin and eosin (original magnification x 200).

 
There was one late mortality in each group. One death was due to postoperative renal failure and the other was due to septic shock. These were probably unrelated to the study.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Left ventricular function is one of the major determinants of the prognosis in patients undergoing valve replacement. If the myocardium cannot be preserved adequately during CPB, structural cell damage and functional failure will occur. Generally, following this type of surgery, the heart requires pharmacological or mechanical support in the early postoperative period.15

Cardiac glycogen is an important source of substrate for glycolysis and generation of adenosine triphosphate during cardiac anoxia. Elevated glycogen levels have been shown to increase cardiac tolerance to anoxic stress.2,16 Lolley and colleagues17 reported that GIK increased myocardial glycogen levels in patients undergoing coronary artery bypass grafting. In this study, we showed that glycogen levels could be increased during the anoxic period of CPB in patients undergoing mitral valve replacement by preoperatively infused GIK solution. Glycogen levels are closely related to myocardial function after CPB.16,18–22

Gradinac and colleagues10 gave GIK solution postoperatively to patients requiring balloon pump support. They observed that the mean cardiac index increased and the requirement for mechanical and pharmacological support decreased. We obtained similar hemodynamic results in this study on patients undergoing mitral valve replacement who were treated preoperatively with GIK. These patients had a higher postoperative mean cardiac index and a lower mean systemic vascular resistance than controls. In addition, they required less pharmacological inotropic support.

Anaerobic glycolytic adenosine triphosphate production can provide most of the energy required for maintenance of cell viability in a cold arrested nonworking heart via the Embden-Meyerhof metabolic cycle and the rate of glycolysis correlates directly with the pre-anoxic glycogen level.23 Enhanced glycogen stores may be of benefit not only during the anoxic arrest period but also in the reperfusion period and especially during the early postoperative course. Our results support this biochemical hypothesis.

Although the mechanism is not fully defined, infusion of GIK decreases arrhythmias after open-heart surgery.6,24,25 It was suggested that the effect of glucose and insulin in reducing lipid accumulation in hypoxic myocardial cells might be a factor in addition to the provision of potassium in preventing cardiac arrhythmias.22,24,26,27 It has been reported in many studies that GIK reduces both atrial and ventricular arrhythmias.12,13 However, in this study, we found a reduction in ventricular arrhythmias only. CPB decreases the excretion of insulin, which has a positive inotropic effect on the myocardium.28–34

Wittels and Reiner13 demonstrated glycogen by PAS-staining in postmortem samples of myocardium in the 1950s. We applied their system of scoring for glycogen content in the biopsy samples obtained during the period of anoxic arrest for mitral valve replacement. The histochemical study confirmed our biochemical findings of higher glycogen stores in the cardiac muscle cells of GIK-treated patients.

Hachida and colleagues35 demonstrated that GIK as well as histidine-tryptophan-potassium solution was beneficial in prolonging myocardial preservation in patients with severely dilated hearts. In this study, we also found postoperative hemodynamic improvement in GIK-treated patients who underwent mitral valve replacement in an advanced New York Heart Association functional class. These data confirm the protective effect of glucose-insulin-potassium pretreatment during periods of ischemia for open-heart surgery.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Sodi-Pallares D, Testelli MR, Fishleder BL, Bisteni A, Medrano GA, Friedland C, et al. Effects of an intravenous infusion of potassium-glucose-insulin solution on the electrocardiographic signs of myocardial infarction. Am J Cardiol 1962;9:166–81.[Medline]

  2. Whitlow PL, Rogers WJ, Smith LR, McDaniel HG, Papapietro SE, Mantle JA, et al. Enhancement of ventri-cular function by glucose-insulin-potassium infusion in acute myocardial infarction.Am J Cardiol 1982;49:811–20.[Medline]

  3. Levites R, Anderson G. Electrophysiological effects of glucose-insulin-potassium in canine myocardial ischemia.Circulation 1977;55(Suppl III):III–11–81.

  4. Calva E, Mujica A, Nuñez R, Aoki K, Bisteni A, Sodi-Pallares D. Mitochondrial biochemical changes and glucose-KCl-insulin solution in cardiac infarct. Am J Physiol 1966;211:71–6.

  5. Opie LH, Bruyneel K, Owen P. Effects of glucose, insulin and potassium infusion on tissue metabolic changeswithin first hour of myocardial infarction in the baboon.Circulation 1975;52:49–57.[Abstract/Free Full Text]

  6. Hewitt LR, Lolley DM, Adrouny GA. Protective effect of myocardial glycogen on cardiac function during anoxia. Surgery 1973;73:444–53.[Medline]

  7. Lolley DM, Hewitt LH. Protective effect of glycogen and glucose on the anoxic arrested heart during cardiopulmo-nary bypass.Surg Forum 1972;23:145–7.[Medline]

  8. Rogers WJ, Segall PH, McDaniel HG, Mantle JA, Russell RO, Rackley CE. Prospective randomized trial of glucose-insulin-potassium in acute myocardial infarction: effects on myocardial hemodynamics, substrates and rhythm. Am J Cardiol 1979;43:801–9.[Medline]

  9. 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 Cardivasc Surg 1986;91:874–8.[Abstract]

  10. Gradinac S, Coleman GM, Taegtmeyer H, Sweeney MS, Frazier OH. Improved cardiac function with glucose- insulin-potassium after aortocoronary bypass grafting. Ann Thorac Surg 1989;48:484–9.[Abstract]

  11. Kappelman MD, Hewitt LR. Protection of the ischemic heart with energy substrate and potassium during cardio-pulmonary bypass.Surg Forum 1974;25:153–5.[Medline]

  12. Good CA, Kramer H, Somogy M. The determination of glycogen. J Biol Chem 1933;100:485–96.[Free Full Text]

  13. Wittels B, Reiner L. Histochemical observations on glycogen in the human myocardium. Am J Pathol 1960; 36:55–75.

  14. Ganz W, Tamura K, Marcus HS, Donoso R, Yoshida S, Swan HJC. Measurement of coronary sinus blood flow by continuous thermodilution in man.Circulation 1971; XLIV:181–95.

  15. Kirklin JW, Barratt-Boyes BC. Myocardial protection during cardiac surgery with cardiopulmonary bypass. In: Kirklin JW, Barratt-Boyes BC, editors. Cardiac Surgery. New York: Wiley, 1986;83–101.

  16. Scheuer J, Stezoski W. Protective role of increased myo-cardial glycogen stores in cardiac anoxia in the rat.Circ Res 1970;XXVII:835–49.

  17. Lolley DM, Jefferson FR, Myers WO, Sautter RD, Tewksbury DA. Importance of preoperative myocardial glycogen levels in human cardiac preservation. J Thorac Cardiovasc Surg 1979;78:678–87.[Abstract]

  18. Opie LH. Myocardial energy metabolism. Adv Cardiol 1974;12:70–83.[Medline]

  19. Hewitt RL, Lolley DM, Adrouny GA, Drapanas T. Protective effect of glycogen and glucose on the anoxic arrested heart. Surgery 1974;74:1–10.

  20. Doherty NE, Turocy JF, Geffin GA, O'Keefe DD, Titus JS, Daggott WM. Benefits of glucose and oxygen in multidose cold cardioplegia. J Thorac Cardiovasc Surg 1992;103:219–29.[Abstract]

  21. Dhalla NS, Singh JN, Fedelesova M, Balasubramanian V, McNamara DB. Biochemical basis of heart function XII. Sodium-potassium stimulated adenosine triphosphatase activity in the perfused rat heart made to fail by substrate- lack. Cardiovasc Res 1974;8:227–36.[Medline]

  22. Aslan R, Tünerir B, Dernek S, Kural T, Sevin B, Kaklikkaya I, et al. The factors effecting complement activation in open heart surgery. J Cardiovasc Surg 1992;33:754–60.[Medline]

  23. Nuutinen LS, Mononen P, Kairaluoma M, Tunonen S. Effects of open-heart surgery on carbohydrate and lipid metabolism. J Thorac Cardiovasc Surg 1977;73:680–3.[Abstract]

  24. Moffitt EA, Molnar GD, Pluth JR, White RD, McGoon DC. Effects on metabolism and cardiac output of glucose- potassium solution, with and without insulin. Ann Thorac Surg 1973;15:1–15.[Medline]

  25. Obeid AI, Verrier RL, Lown B. Influence of glucose, insulin and potassium on vulnerability to ventricular fibrillation in the canine heart. Circ Res 1978;43:601–8.[Free Full Text]

  26. Rogers WJ, Russel RO, McDaniel HG, Rackley CE. Acute effects of glucose-insulin-potassium infusion on myocardial substrates, coronary blood flow and oxygen consumption in man. Am J Cardiol 1977;40:421–8.[Medline]

  27. Svedjeholm R, Hallkagen S, Ekrothh R, Joachimsson PO, Ronquist G. Dopamine and high-dose insulin infusion (glucose-insulin-potassium) after a cardiac operation: effects on myocardial metabolism. Ann Thorac Surg 1991; 51:262–70.[Abstract]

  28. Crass MF III, Sterrett PR. Distribution of glycogen and lipids in the ischemic canine left ventricle: biochemical and light and electron microscopic correlates. In: Roy PE, Rona G, editors. Recent advances in studies on cardiac structure and metabolism. Baltimore: University Park Press, 1975:251–63.

  29. Sybers HD, Maroko PR, Ashraf M, Libby P, Braunwald E. The effect of glucose-insulin-potassium on cardiac ultra-structure following acute experimental coronary occlusion.Am J Pathol 1973;70:401–20.[Medline]

  30. Allison SP. Changes in insulin secretion during open heart surgery. Br J Anaesth 1971;43:138–43.[Abstract/Free Full Text]

  31. Moffitt EA, Rosevear JW, Molnar GD, McGoon DC, Minn R. Myocardial metabolism in open-heart surgery. J Thorac Cardiovasc Surg 1970;59:691–706.[Medline]

  32. Hewitt RL, Woo RD, Ryan JR, Drapanas T. Plasma insulin and glucose relationship during cardiopulmonary bypass. Surgery 1972;71:905–12.[Medline]

  33. Baum D, Dillard DH, Porte D. Inhibition of insulin release in infants undergoing deep hypothermic cardiovascular surgery. N Engl J Med 1968;279:1309–14.

  34. Chiu RCJ, McArdle HA. Levels of plasma cyclic AMP and insulin in cardiac surgery. J Thorac Cardiovasc Surg 1978;75:286–9.[Abstract]

  35. Hachida M, Nonoyama M, Bankohara Y. Clinical assess-ment of prolonged myocardial preservation for patients with a severely dilated heart.Ann Thorac Surg 1997;64:59–63.[Abstract/Free Full Text]





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