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Ann Thorac Surg 1996;62:1825-1829
© 1996 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Glucose Level and Myocardial Recovery After Warm Arrest

Section of Thoracic Surgery, University of Michigan Medical Center, Ann Arbor, Michigan

Accepted for publication August 7, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. During induced cold ischemia for cardiac operations, increasing glucose concentration is not thought to enhance myocardial protection and may detrimentally affect recovery. However, during "warm aerobic" arrest, increased glucose availability as substrate could enhance postischemic metabolic and functional recovery, as during and after ischemia, myocytes shift preference for substrate from fatty acids to glucose. Unfortunately, hyperglycemia may also increase patient susceptibility to neurologic injury.

Methods. This experiment was designed to study the optimal dose of glucose and its effect on function during warm arrest. Isolated, retrograde-perfused rabbit hearts received multidose cardioplegia containing increasing concentrations of glucose, from 0 to 88 mmol/L, and underwent 120 minutes of "warm" 34°C global ischemia. Osmolarities were adjusted equivalently.

Results. After 34°C ischemia, hearts treated with 5 to 88 mmol/L glucose showed significantly better functional recovery than those treated with 0 to 1 mmol/L glucose. However, the addition of 22 mmol/L glucose demonstrated optimal recovery with no further incremental enhancement with more glucose. Additional hearts receiving 0 or 22 mmol/L glucose had high-energy phosphates, lactate, CO₂, and pH measured. The 22 mmol/L glucose hearts demonstrated active metabolism and significantly better recovery of high-energy phosphate levels than controls.

Conclusions. Increasing glucose level modestly during warm arrest enhanced recovery, but profound hyperglycemia did not incrementally improve this effect, mandating a cautious use of glucose.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Cardiac surgery is safe and effective with current myocardial protection techniques. However, difficult, repeat, longer operations increase demands on myocardial protection. Recently, "warm" cardioplegia has been introduced, maintaining the heart in electromechanical arrest by providing oxygenated warm blood cardioplegia [1, 2], and could theoretically provide superior myocardial protection [3]. During warm cardioplegia, supplying substrate to arrested hearts could potentially enhance myocardial metabolism and therefore myocardial protection, as during and after ischemia myocytes shift preference for substrate from fatty acids to glucose [4, 5].

Many previous reports have shown that glucose added to cardioplegic solutions can improve cardiac functional recovery during reperfusion [6–10]. Conversely, other studies have demonstrated no beneficial effect of glucose in cardioplegia or even a detriment upon recovery of function [11–13]. This divergence has been in part postulated to relate to differences in specific glucose dose, temperature, or accumulation of metabolic byproducts [14–16]. Furthermore, a recent prospective, randomized clinical study compared cold cardioplegia with warm blood cardioplegia containing supranormal glucose levels [17]. Unfortunately, although function was well preserved, significantly more adverse neurologic events were seen in warm blood cardioplegia patients (5% versus 1.4%), which was attributed to the increased susceptibility of the brain to injury during extreme hyperglycemia [18]. Therefore, in this study, to investigate an optimal glucose level, we examined myocardial metabolic and functional recovery after global ischemia and reperfusion using warm cardioplegia with increasing glucose concentrations. Results were correlated in terms of functional recovery, as well as myocardial adenosine triphosphate (ATP) concentration, pH, lactate, and CO₂ production in a simple model of warm global ischemia.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Preparation of Isolated Heart
All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research. Rabbits (male or female, 2.2 to 2.7 kg body weight) were anesthetized with sodium pentobarbital (45 mg/kg intravenously) and heparinized (700 U/kg intravenously). The heart was rapidly excised and immersed in ice-cold physiologic salt solution, pH 7.4, containing 118.0 mmol/L NaCl, 4.0 mmol/L KCl, 22.3 mmol/L NaHCO₃, 11.1 mmol/L glucose, 0.66 mmol/L KH₂PO₄, 1.23 mmol/L MgCl₂, and 2.38 mmol/L CaCl₂. The aorta was cannulated in the Langendorff mode and the heart was perfused with physiologic salt solution that had been equilibrated with 95% O₂–5% CO₂ at 37°C and passed twice through filters with a pore size of 3.0 µm. Perfusion pressure was maintained at 90 mm Hg. An incision was made in the left atrium, and a fluid-filled latex balloon was passed through the mitral orifice and placed in the left ventricle. The balloon was connected to a pressure transducer for continuous measurement of left ventricular pressure and its first derivative. The caudal vena cava, the left and right cranial vena cava, and the azygos vein were ligated. The pulmonary artery was cannulated to enable timed collection measurements of coronary flow, and the cannula was connected to an oxygen meter (Diamond Electro-Tech, Inc, Ann Arbor, MI) for continuous measurement of the oxygen partial pressure.

The analog signals were continuously recorded on a pressurized ink chart recorder (model 2600S; Gould, Inc, Cleveland, OH) and digitized to an on-line computer (AST Premium/386; AST Research Inc, Irvine, CA). To characterize cardiac function, developed pressure was defined as peak systolic pressure minus end-diastolic pressure. Myocardial oxygen consumption was calculated as CF x [(PaO₂ - PvO₂) x (c/760)], where CF is coronary flow (mL•min^-1•g^-1), (PaO₂ - PvO₂) is the difference in the partial pressure of oxygen (mm Hg) between perfusate and coronary effluent flow, and c is the Bunsen solubility coefficient of O₂ in perfusate at 37°C (22.7 µL O₂•atm^-1•mL^-1 perfusate). The partial pressure of oxygen of the perfusate was 665 mm Hg. Coronary flow was measured by performing timed collections of the pulmonary effluent flow with a graduated cylinder. Oxygen extraction was calculated as myocardial oxygen consumption/oxygen content in the perfusate. Wet weight of the heart was determined at the conclusion of each experiment after trimming the great vessels and fat and blot drying with nine-layer cotton gauze. The left ventricular wall was weighed, desiccated for 48 hours at 65°C, and reweighed. Water content was determined using the formula (1-dry weight/wet weight)100%.

Lactate, pH, and CO₂ Measurement
The first 1.5 mL of coronary effluent was collected with each cardioplegic flush and at baseline and during reflow. Lactate content was measured with a lactate analyzer (Yellows Springs Instrument Co, Yellows Springs, OH). Concentrations of O₂ and CO₂ were measured with a Radiometer (ABL 2, Copenhagen, Denmark). A Khuri Regional Tissue pH Monitor intramural pH electrode (Vascular Technology, Chelmsford, MA) was placed in the left ventricular free wall.

Measurement of High-Energy Phosphates
To observe changes in tissue nucleotides (ATP, adenosine monophosphate, adenosine diphosphate, inosine monophosphate) and nucleosides (adenosine, inosine, hypoxanthine, and xanthine), heart biopsy specimens were rapidly frozen in liquid N₂ at baseline or at 15 minutes of reperfusion and then lyophilized (n = 4, each group). Tissue was processed as previously described by our laboratory [5]. High-performance liquid chromatography was performed with a Waters µBondapak C18 column. The spectrophotometric detector was set at 254 nm for determination of nucleotides and nucleosides and at 210 nm for plasma creatinine. Samples of coronary effluent were also assayed for adenosine, inosine, hypoxanthine, and xanthine. Analysis was performed with Waters Maxima 820 software and NEC Power Mate 1.

Experimental Protocols
PHASE I.
After instrumentation was completed and calibrations were performed, left ventricular balloon volumes were varied over a range of values to construct modified left ventricular function curves. In this manner, it is possible to define a specific balloon volume that is associated with a developed pressure from 100 to 140 mm Hg. This volume was maintained the same during baseline and reperfusion conditions. The intraventricular balloon volumes were not adjusted to produce specific end-diastolic pressures (rather, we defined a level of systolic pressure development), but end-diastolic pressures at baseline greater than 10 mm Hg were not considered acceptable. Hearts characterized by developed pressures less than 100 mm Hg or greater than 140 mm Hg were not used. Baseline data were obtained after an equilibration period of 30 minutes. The same procedures were followed in each experiment. During the baseline period, data were obtained with hearts maintained at 37°C by a water-jacketed organ bath.

During ischemia, the organ bath temperature was reduced to 34°C. The physiologic salt solution infusion was stopped and 60 mL of cardioplegic solution at 34°C was injected into the aorta at a rate of 1 mL/s to begin the 2-hour ischemia. Fifteen milliliters of cardioplegia (34°C) was injected every 30 minutes thereafter, as reported previously [5]. The cardioplegia contained 109.0 mmol/L NaCl, 25.0 mmol/L KCl, 21.9 mmol/L NaHCO₃, 16.0 mmol/L MgCl₂, and 0.8 mmol/L CaCl₂. The partial pressure of oxygen of the cardioplegia is 665 mm Hg. When the 2-hour ischemic period was ended, the hearts were reperfused with oxygenated physiologic salt solution at 37°C and the water bath temperature was increased to 37°C. Hemodynamic data were recorded every 15 minutes for 45 minutes to compare with baseline data and to determine the degree of functional recovery. In the first phase of the study concentrations of 0, 1.4, 5.5, 11, 22, 44, and 88 mmol/L glucose were randomly added into cardioplegic solution. Osmolarity was adjusted to be equivalent in all groups.

PHASE II.
In the second phase of the study, further hearts receiving 0 (22 mmol/L of mannitol added to cardioplegia as osmolarity control) or 22 mmol/L glucose (best recovery group) in cardioplegia had functional recovery, high-energy phosphates, lactate, CO₂, and pH measured during and for 15 minutes after ischemia.

Statistical Analysis
Values reported in the text and table are means ± standard deviation. The Statview 5.01 Program (Abacus Concepts, Inc, Berkeley, CA) was used for statistical analysis. Data were evaluated with analysis of variance (Scheffé's test). Differences were considered significant when p was less than 0.05.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
There were no significant differences in developed pressure, positive or negative maximum first derivative of left ventricular pressure, coronary flow, and myocardial oxygen consumption among groups during baseline conditions during either phase. We assumed baseline values as 100% to compare the changes in the percentage recovery between the groups during reperfusion.

Phase I: Glucose Level and Functional Recovery After 34°C Ischemia
There were no significant differences in heart weight and water content between groups in the postischemic period. There was also no difference in any functional index during the preischemic period between groups. Table 1 summarizes the 45-minute postischemic metabolic and functional recovery results. Adding 5.5 mmol/L to 88 mmol/L glucose showed significantly better functional recovery than the 0 mmol/L glucose-treated group (p < 0.05); however, there were no significant statistical incremental improvement or differences among the 5.5 mmol/L to 88 mmol/L glucose-treated groups. Recovery appeared to peak at the 22 mmol/L glucose dose, which was also significantly improved against 1.4 mmol/L glucose.

LACTATE.
During preischemia, lactate level in coronary effluent was zero in both groups. During ischemia, lactate accumulation occurred at 30 and 60 minutes in both the glucose-treated group (1.20 ± 0.22 mmol/L, 2.20 ± 0.37 mmol/L) and controls (1.20 ± 0.44 mmol/L, 1.90 ± 0.33 mmol/L). However, lactate concentration increased continuously in glucose-treated hearts throughout ischemia and was significantly greater at 90 and 120 minutes of ischemia (3.10 ± 0.59 and 4.60 ± 0.75 mmol/L) versus controls (1.90 ± 0.42 and 2.10 ± 0.34 mmol/L). At 5 and 15 minutes of reperfusion there was no difference in lactate level in the glucose-treated group (0.27 ± 0.01 and 0.01 ± 0.01 mmol/L) and the controls (0.20 ± 0.09 and 0.10 ± 0.04 mmol/L).

CO₂.
The partial pressure of CO₂ in the coronary effluent was not significantly different between groups (38.4 ± 4.9 versus 40.2 ± 7.2 mm hg) during the preischemic period. during ischemia, the partial pressure of co₂ increased at 30 and 60 minutes of ischemia in both control (51.1 ± 9.5 and 53.4 ± 8.2 mm hg) and glucose-treated hearts (53.7 ± 115.8 and 60.8 ± 15.2 mm hg). again the partial pressure of co₂ increased continuously throughout ischemia only with glucose and was significantly greater at 90 and 120 minutes of ischemia in the glucose-treated group (70.0 ± 21.4 and 92.3 ± 30.2 mm hg) than in the controls (46.0 ± 9.3 and 47.9 ± 5.0 mm hg). by 5 and 15 minutes of reperfusion the partial pressure of co₂ returned to the preischemic level in both groups.

PH.
During the preischemic period, myocardial pH was not significantly different between control (7.05 ± 0.10) and glucose hearts (7.06 ± 0.04). During ischemia, the maximal decrease of pH was reached at 60 minutes in controls; however, pH continued to decrease until end-ischemia with glucose and was significantly less at 60, 90, and 120 minutes of ischemia (6.32 ± 0.25, 6.18 ± 0.24, and 6.14 ± 0.26) than in controls (6.56 ± 0.26, 6.64 ± 0.23, and 6.77 ± 0.24). At 5 and 15 minutes of reperfusion, there was no significant pH difference between the glucose-treated group (6.78 ± 0.19 and 6.96 ± 0.14) and the controls (6.96 ± 0.15 and 7.08 ± 0.12).

ENERGY STATUS.
Total nucleotides (ATP, adenosine diphosphate, adenosine monophosphate, inosine monophosphate) and nucleosides (adenosine, inosine, hypoxanthine, xanthine) were measured by high-performance liquid chromatography (µmol/g wet tissue). Preischemic values were equal; however, by the end of ischemia, the myocardial ATP concentration decreased in the glucose group to 12 ± 2, less than preischemic values (19 ± 1) but significantly greater than controls (2 ± 1). Furthermore, 15 minutes after reflow the ATP level was 8 ± 1 versus 15 ± 2, total nucleotides were 23 ± 3 versus 50 ± 4 and total nucleotides were 8 ± 2 versus 15 ± 2 in controls versus glucose, respectively. All of these postischemic high-energy phosphate levels were significantly enhanced with glucose. Finally, the postischemic adenylate energy charge was 0.82 ± 0.03 in glucose-treated hearts, which was significantly greater than in controls (0.51 ± 0.12) and not significantly different from the preischemic value (0.91 ± 0.01).

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Although myocardial protection using cold cardioplegia yields excellent outcome, poor functional recovery is occasionally encountered, as injury to contractile proteins from hypothermia and a finite time the heart can safely remain cold limit this technique. The myocardium still requires energy to maintain basic cellular metabolism, ionic equilibrium, and membrane integrity [19]. Unfortunately, cold cardioplegia may be inadequate to meet even the much-reduced metabolic demands of the cold arrested heart, as hypothermia impairs glycolysis and energy utilization. One proposed solution is warm cardioplegia, which theoretically obviates the need for hypothermia and delivers adequate oxygen and substrate to the myocardium. The primary substrate for normal myocardium is free fatty acids; however, glucose appears to be a superior myocardial substrate during periods of myocardial ischemia and has been shown to decrease infarct size, increase ATP and creatinine phosphate levels, and improve ventricular function in many studies [6–10].

Unfortunately, reports of glucose supplementation during ischemia have been contradictory as to the best glucose level. In cellular preparations, Fremes and associates [20] observed that cultured human ventricular myocytes stored at 0°C for 12 hours with 30 mmol/L glucose had improved adenine nucleotide and protein preservation versus controls [8]. Orita and colleagues [21] reported that rat cardiac myocytes incubated at 4°C for 24 hours with medium containing 4 mmol/L glucose showed a protective effect. In normothermic whole organ systems, a beneficial effect has been reported with 5 mmol/L glucose administration in isolated guinea pig hearts during 38°C ischemia and with 11 mmol/L glucose in rat hearts during 37°C ischemia; a beneficial effect was also observed in dog hearts in vivo with 22 mmol/L glucose administration [6–10, 19]. This beneficial effect may extend to hypothermia, as Doherty and associates [6] observed a beneficial effect with 28 mmol/L glucose in rat hearts after 2 hours' ischemia at 8°C, and Kao and Magovern [22] reported that 28 mmol/L glucose showed a beneficial effect on postischemic function at both 8° and 28°C.

However, more glucose may not always be better, as Owen and associates [23] reported an optimal glucose concentration of 11 mmol/L in rat hearts during 3 hours of ischemia at 10°C and that 20 and 50 mmol/L glucose was harmful. Hearse and colleagues [12] also observed a deleterious effect of greater than 11 mmol/L glucose in rat hearts at 28°C and 70 minutes of ischemia. In addition, Yang and Hearse [24] have reported a U-shaped response to glucose dosage in rat hearts for 60 minutes of ischemia. They observed a deleterious effect with 10, 20, and 40 mmol/L glucose. Our study shows that at near-normothermic conditions, there exists a large range of optimal glucose concentrations, which may peak at 22 mmol/L.

At near-normothermia (34°C cardioplegic ischemia), both aerobic and anaerobic glycolysis may be important for energy production in the ischemic myocardium, because even with warm cardioplegia oxygen supply may be limited. One molecule of glucose is broken down to two molecules of lactate under anaerobic conditions and yields two moles of net ATP, but under aerobic conditions, one molecule of glucose is broken down to six molecules of CO₂ and can yield 36 moles of net ATP. As shown in the present study, at 34°C conditions, the addition of glucose to warm cardioplegia resulted in a continued increase in the level of not only lactate with a decrease in pH, but also CO₂ throughout ischemia, suggesting that both aerobic and anaerobic metabolism were enhanced. At the end of ischemia, this greater CO₂ and lactate production was accompanied by greater levels of ATP in the glucose-treated hearts, suggesting that metabolic status was better than in control hearts, despite accumulation of metabolic "end products." The improved metabolic status is consistent with the better recovery of myocardial energetics by the glucose-treated hearts versus control hearts with moderate levels of glucose added to cardioplegia at 34°C ischemia.

In a recent clinical study, better recovery of myocardial energetics, as reflected by contractility, was noted after cardiopulmonary bypass in patients given glucose, but contractility decreased significantly in controls, while diastolic properties were unchanged in both groups [25]. Importantly, the arterial glucose concentration increased markedly in the glucose-treated group (7.3 to 18.5 mmol/L) and minimally (6.4 to 8.2 mmol/L) in controls. However, again more glucose is not always better, as extreme hyperglycemia noted in a clinical study of more than 1,000 patients was associated with significantly more adverse neurologic events than in control patients, which was attributed to the increased susceptibility of the brain to injury during extreme hyperglycemia.

In conclusion, maintaining optimal anaerobic and aerobic metabolism in 34°C ischemic myocardium with glucose administration leads to increased energy level and consequently enhanced functional recovery. The accumulation of lactate and CO₂ and lowered pH are not associated with reflow dysfunction under optimal metabolic conditions attained with glucose addition. Finally, in this simple model, exploring the dose/effect relationship of glucose under these set conditions, we found that increasing glucose modestly during warm arrest enhanced recovery, but profound hyperglycemia did not incrementally improve this effect. Although the limits of this model do not allow direct transferance to clinical practice, these findings mandate a cautious use of glucose, in light of other possible deleterious effects of extreme hyperglycemia.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This work was supported in part by grant G41934 from the American Heart Association of Michigan.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Bolling, Section of Thoracic Surgery, The University of Michigan Hospitals, 1500 E. Medical Center Dr, 2120D Taubman Center, Box 0344, Ann Arbor, MI 48109.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Steven F. Bolling Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ning, X.-H. Articles by Bolling, S. F. Search for Related Content PubMed PubMed Citation Articles by Ning, X.-H. Articles by Bolling, S. F.