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a Division of Cardiothoracic Surgery, Department of Surgery, McGill University Health Center, McGill University, Montreal, Quebec, Canada
b Department of Anaesthesia, McGill University Health Center, McGill University, Montreal, Quebec, Canada
Accepted for publication July 2, 2007.
* Address correspondence to Dr Lachapelle, McGill University, Royal Victoria Hospital, 687 Pine Ave W, Ste S8.30, Montreal, Quebec, H3A 1A1, Canada (Email: kevin.lachapelle{at}muhc.mcgill.ca).
Presented at the Forty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 29–31, 2007.
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Abstract |
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Methods: A total of 44 patients undergoing elective CABG were randomized to receive intraoperative titrated intravenous insulin infusion (n = 22) or a fixed high-dose systemic insulin infusion at 5 mU/kg/min (n = 22). Blood samples were collected simultaneously from the radial artery and the coronary sinus before starting CPB and at 5 and 10 minutes after the release of the aortic cross-clamp to determine lactate, oxygen saturation, and hemoglobin concentration. Lactate extraction/excretion and myocardial oxygen extraction were calculated and compared between the two groups. The change in cardiac indices was determined immediately postoperatively as a measure of functional recovery, and the troponin I level was measured 4 hours postoperatively as an indicator of myocardial protection.
Results: Operative characteristics, including CPB and aortic cross-clamp time, were similar between the two groups. Arterial oxygen content was similar in both groups. The high-dose insulin therapy group had early extraction of lactate and higher oxygen extraction immediately postoperatively compared with the standard group. In addition, the high-dose insulin group had a lower troponin I level 4 hours postoperatively, with greater improvement in cardiac indices.
Conclusions: High-dose insulin therapy promotes early metabolic recovery of the heart during elective CABG, leading to better myocardial protection and functional recovery.
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Introduction |
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Metabolic preconditioning of the ischemic myocardium by using glucose-insulin-potassium has demonstrated inconsistent beneficial results. That may be due to the controversy in the relative concentration of insulin and glucose required, the degree of blood glucose control achievable, the optimum timing of administration, and delivery techniques [2]. It is also known that cardiac surgery done with CPB induces a marked insulin resistance, often leading to elevated blood glucose levels that could be detrimental [3]. These elevated blood glucose levels may be difficult to control using insulin protocols that titrate insulin to the glucose level.
The favorable outcome of patients with "tight glucose control" stimulated our group to use a technique that titrates glucose to a preset, fixed, high dose of insulin [4]. We therefore hypothesized that the fixed high-dose insulin therapy used for serum glucose control would also have an important cellular metabolic effect that would enhance the protective effects of standard cardioplegic solutions and enhance early metabolic recovery of the arrested heart during coronary revascularization.
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Material and Methods |
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Treatment Protocols
The study included diabetic and nondiabetic patients. In diabetic patients taking oral hypoglycemics, administration of oral hypoglycemic agents was discontinued 24 hours before the operation and administration of subcutaneous insulin on a sliding scale was started according to the protocol specified in Table 1. For diabetic patients taking insulin, their daily dose was held the evening before surgery and an intravenous insulin infusion was titrated to maintain blood glucose below the level of 10 mmol/L.
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Surgical Procedure
All patients had CABG by the same surgeon with the use of CPB, which was conducted with a roller pump and a membrane oxygenator primed with a solution consisting of 1 L of Ringer’s lactate, 5000 IU of heparin, 750 mL of Pentaspan (DuPont Pharmaceuticals Co, Newark, DE), and 44 mEq of bicarbonate. During CPB, pump flow was set at 2.4 times the body surface area, and mean arterial pressure maintained between 50 and 60 mm Hg. The temperature was allowed to drift with active rewarming at the end of CPB. Cardioplegia solution (Plegisol, Hospira, Inc, Lake Forest, IL), which was used at the discretion of the cardiac surgeon, was free of glucose and consisted of high-dose (100 mEq/L) and low-dose (40 mEq/L) potassium.
A single-clamp technique was used, and cardioplegia was given in an anterograde fashion with blood in a ratio of 1:4. Blood cardioplegia was also administered with each successive distal vein graft anastomosis. In all patients, the left internal mammary artery harvested and anastomosed to the left anterior descending artery. The rest of the grafts were constructed using the great saphenous vein.
After rewarming and suturing of all anastomoses but before the removal of the aortic cross-clamp, "a hot shot" of 1 L of warm cardioplegia was administered. After total release of the aortic cross-clamp, epicardial atrial or ventricular pacing wires, or both, were placed. Aortic and venous cannulas were removed after an appropriate test dose of protamine, and the surgery proceeded with closure of the pericardium and sternum.
Lactic Acid Balance and Myocardial Oxygen Extraction
A retrograde perfusion cannula was used to collect simultaneous blood samples from arterial blood and the coronary sinus just before commencing CPB and at 5 and 10 minutes after the release of the aortic cross-clamp. These samples were used to determine lactate concentration, hemoglobin (Hb) concentration, and oxygen saturation (O2 Sat). Lactate balance was calculated as: Lactate balance = arterial – coronary sinus lactate concentration. A negative value indicates lactate excretion, and a positive value indicates lactate uptake. These values were expressed as a ratio of lactate balance to the arterial lactate concentration at the same time point. Oxygen content in both arterial and coronary sinus blood was calculated using the formula: Oxygen content = 1.38 x Hb x O2 Sat. Arterial – coronary sinus oxygen content difference was calculated and its ratio to arterial oxygen content represented oxygen extraction.
Functional Recovery and Postoperative Troponin I Level
The cardiac index was calculated before and immediately postoperatively to determine the percentage change in the cardiac index as an indicator of functional recovery. Central venous pressure and pulmonary capillary wedge pressure measurements were compared at the same time points to ensure similar preload filling status. Troponin I concentrations (normal reference range, 0.00 to 0.06 ng/L) were measured by using the Access Immunoassay System (AccuTNI reagent, DXI 800 System, Beckman Coulter Canada, Mississauga, Ontario, Canada) preoperatively, immediately postoperatively, and 4 hours later as an indicator of myocardial protection.
Statistical Analysis
Statistical analysis was performed using NCSS 2004 statistical software (NCSS, Kaysville, Utah). Continuous variables were presented as mean ± standard error of the mean or as median values with 95% confidence limits (CL) and compared by using the two-sample t test or the Wilcoxon rank sum test, as appropriate by the distribution of data. Categoric variables were compared using 
2 test or the Fisher exact test, depending on the number of items in each group. The statistical analysis was done using the "per protocol" method, and statistical significance was set at a value of p < 0.05.
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Results |
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Lactic Acid Balance and Myocardial Oxygen Extraction
The myocardial lactate balance started to change from excretion to uptake in group II after 5 minutes of aortic cross-clamp removal and reperfusion, with 0% balance at 5 minutes and 3% at 10 minutes, whereas in group I, the myocardium continued to excrete lactate for more than 10 minutes, as indicated in Figure 1. More patients in the high-dose insulin group had lactate uptake both before ischemia (18 [82%] versus 11 [50%], p = 0.001) and 5 minutes after reperfusion (7 [32%] versus 1 [5%], p = 0.01).
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Comment |
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Similar results were shown by Haider and colleagues [5] in patients who underwent mitral valve replacement in which the preventive application of high doses of insulin led to an augmented myocardial adenosine triphosphate provision and a better preservation of cellular energy charge during coronary ischemia. As a result, ischemic tolerance was enhanced and myocardial protection was improved.
Rationale for the Use of High-Dose Insulin Therapy in Cardiac Procedures
Glucose-insulin-potassium has been applied in several studies suggesting similar effects, that is, a reduction in mortality and improvement of postoperative recovery [6–10]. However, this technique is still a matter of controversy after 40 years of its use, despite a plethora of theoretical and clinical studies, owing to the extreme heterogeneity in insulin doses that results from titrating the insulin-to-glucose level and the time of administration in these studies, which can only be compared with difficulty. In patients with diabetes mellitus type 2, insulin sensitivity is impaired to varying degrees [11]; therefore, infusion of insulin may require adjustments in the protocol or may not even be effective at all. It is conceivable that the changes in insulin sensitivity observed in the entire organism are also present in the heart, which opens the question of whether the insulin dosage requires adjustment.
Nondiabetic patients undergoing cardiac operations, especially the growing cohort of elderly cardiac surgical patients who have a history of severe chronic coronary artery disease (CAD), chronic heart failure, and reduced contractile reserve preoperatively, frequently require inotropic support with exogenous catecholamines, which will result in insulin resistance and a reduction in myocardial glucose uptake and utilization [8, 12]. Such insulin resistance may explain why protocols supplying low doses of insulin (0.5 to 2.0 U/h) have failed to demonstrate significant beneficial effects [13]. It is no secret that large amounts of insulin can be safely administered after cardiac procedures [14], and the beneficial effects of insulin were most prevalent when glucose and insulin were given in high dosages (10 to 70 U/h). In addition, the use of glucose-insulin-potassium in a titrated manner may cause severe disturbances in glucose homeostasis, oscillating between hyperglycemia and hypoglycemia.
The use of fixed high-dose insulin therapy to maintain glucose homeostasis may therefore be a convincing concept. High-dose insulin therapy given early during anesthetic induction may have the beneficial effect of treating impaired insulin sensitivity in patients with diabetes mellitus type 2 and insulin resistance in nondiabetic patients due to endogenous and exogenous catecholamines.
Lazar and associates [15] demonstrated that a perioperative continuous insulin infusion resulted in survival advantage during a 2-year period, decreased recurrent ischemia, and decreased the rate of wound infection compared with intermittent subcutaneous insulin injections. However, their target euglycemic levels were higher than the current standards of glycemic control. The Portland group demonstrated similar results, but they advocated this therapy to be continued for 3 days to achieve their clinical end points [16]. Although prolonged administration of insulin may reduce morbidity and mortality in patients requiring longer ICU stays [17, 18], it may interfere with patient transfer in those recovering uneventfully. In contrast with these two studies, our study illustrates from a mechanistic point of view that the beneficial effects of insulin therapy, when used continuously and in fixed high doses, could be achieved immediately when used intraoperatively at anesthetic induction, which may exert a metabolic preconditioning effect.
Rao and associates [19], in their initial data from the Insulin-Cardioplegia trial, showed some subtle metabolic changes in lactic acid and oxygen extraction. However, they were unable to demonstrate a reduction in postoperative low output syndrome or mortality after completion of their study [20]. In light of our results, we think that their insulin infusion was lower than the one used in our protocol, was administered for shorter time, and excluded the beneficial effects of systemic insulin infusion that we used in our study.
Ischemia, as observed in patients during cardiac surgical procedures, results in metabolic disturbance and consequently myocardial injury that contributes to the observed decrease in cardiac function. Furthermore, significant evidence shows that preserving or enhancing aerobic metabolism, or both, is a key in maintaining cardiac function after ischemia [21]. The findings from trials comparing different cardioplegia strategies indicated that early lactate uptake is consistent with a more rapid recovery of aerobic metabolism. Moreover, the higher lactate release during reperfusion could be an expression of a more elevated glycolytic activity and anaerobic production of adenosine triphosphate [22]. Therefore, myocardial lactate release was advocated as an alternative end point in clinical trials evaluating perioperative myocardial protection [23]. Although it has been shown that mortality could be significantly lowered by achieving normoglycemia, elevated insulin levels and prevention of hyperglycemia are required concomitantly to increase myocardial systolic function [24].
Intraoperative net troponin release has a functional significance because it is closely related to ischemic time and reflects delayed recovery of left ventricular function and oxidative metabolism; therefore, its measurement can be used as an indicator of myocardial injury sustained during CABG [25]. In a meta-analysis conducted by Bothe and colleagues [2], despite the theoretical protective effects of glucose-insulin-potassium, no cardioprotective effect was observed when the troponin I level was used as a marker of myocardial protection [2]. That supports our hypothesis that high-dose insulin therapy is essential for myocardial protection.
In our study, the high-dose insulin therapy was started as soon as the patient was brought to the operating room, which resulted in higher lactate uptake in group II even before onset of ischemia and consequently led to earlier recovery after ischemia and reperfusion. This agrees with the previous clinical and experimental studies that suggested that interventions aimed at decreasing ischemic damage before cardioplegic arrest and reperfusion will result in the best recovery of myocardial function. It was also shown that substrate enhancement before cardioplegic arrest in acutely ischemic myocardium may limit myocardial necrosis [15]. Although theoretically—and based on strong experimental evidence—glucose-insulin-potassium was advocated to be given early to the ischemic myocardium before reperfusion, glucose or insulin, or both, when present before induction of ischemia, gave better protection from regional ischemia in the isolated rat heart [12].
Study Limitations
One study limitation relates to the use of concentration differences between arterial and coronary sinus blood to evaluate myocardial metabolism. When this measure is positive, it reflects myocardial uptake, and when it is negative, it indicates a release from the myocardium. However, the actual uptake or release is also determined by blood flow. This study did not measure coronary blood flow. Great caution should therefore be used in the interpretation of our data.
Thes results have to be taken with caution because we studied patients who were generally fit, with preserveed ventricular function.
Although we did not demonstrate any differences in morbidity and mortality after the application of this high-dose insulin treatment, our goal was to evaluate the metabolic alterations, and as such, our study was not powered to determine the differences in clinical outcome.
Conclusion
Fixed high-dose insulin therapy administered at anesthetic induction promotes early metabolic recovery of the heart during elective CABG and leads to better myocardial protection and functional recovery. For this therapy to exert its beneficial cardioprotective effects, it has to be administered systematically, in high doses, and before the onset of ischemic insult. This was a metabolic study, and a large-scale clinical outcome study is warranted to investigate the effect of this therapy on perioperative morbidity and mortality.
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Discussion |
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DR ALBACKER: Thank you, Dr. Ruel. This is a very important question.
As I indicated in my conclusion, for this therapy to be effective, it has to be a high dose, given systemically, and it has to be given early. In the randomized study conducted by the Toronto group: they gave the insulin with cardioplegia solution. So the insulin was given for only a short period and only after starting the ischemic time. In our protocol, we gave insulin 2 hours before the induction of ischemia and it was given for the whole operative time. We also used higher doses of insulin, and we administered it in the systemic circulation. We think that if we give the insulin only in the cardioplegia solution, then we exclude all the systemic effects of insulin that includes the reduction of free fatty acid, the reduction of inflammatory markers, and many of the other beneficial systemic effects of insulin.
DR ALFRED S. CASALE (Danville, PA): First of all, thank you for sharing this very interesting information. I just have a couple of practical questions.
Am I to understand that you measured glucose levels every 5 minutes during the period of infusion? And if so, from a practical standpoint, how did you go about doing that? It would seem that in our operating room that would almost take an additional FTE of a person to stand there and continually run the specimens. I know that some online glucose measuring devices will soon be available, but to my knowledge none are currently available to use in the operating room.
The second question is, what happens to potassium during all of this? How much extra potassium did you need to use? Do you think that made a difference?
And then the last question is how long did you continue the infusion in the perioperative period? Most of us have recognized that controlling glucose levels carefully for up to 48 hours, and sometimes even 48 hours or longer, impacts infection rates and sometimes even mortality. Have you continued the same level of tight glucose control into the ICU and thereafter?
DR ALBACKER: These are very important questions, and I really thank you very much for asking them.
The first question regarding how did we go about measuring the glucose level every 5 minutes, I really think this is not practical. We have in our lab, in which we conducted a pilot study on some patients, a machine that measures the blood glucose continuously from the blood immediately. And then it analyzes the data and then gives the specific amount of insulin to maintain a normoglycemic level that you program in the machine. We didn’t feel comfortable using it with our patients in this clinical study; but, as you mentioned, it will become soon available for use in clinical practice. We wanted to show a point of principle and we will let the technology help us to resolve the practical issues.
The second question regarding the potassium, in our study, we give 20 mEq/L of potassium in each bag of insulin infusion (1 L). We gave additional potassium infusions as needed. We didn’t find any differences in potassium level between the two groups, and we didn’t have any hypo- or hyperkalemia.
The third question regarding continuing the insulin infusion postoperatively, that was difficult to do in the intensive care unit because of the close monitoring required for this protocol. So our aim was only to investigate the effect of insulin intraoperatively. And if you ask me what would I prefer, I would prefer to start this infusion even preoperatively on the floor and continue it for 24 to 48 hours postoperatively, but we know that is difficult to do in the surgical ward with a nurse taking care of 4 or 5 patients at a time.
DR MICHAEL E. JESSEN (Dallas, TX): What was your form of myocardial protection? Specifically, did you use blood cardioplegia in these studies?
DR ALBACKER: We used blood cardioplegia in all of our patients, and the protocol that we used in both groups was similar.
DR JESSEN: So the blood component in the cardioplegia that you are giving is subject to the insulin and/or glucose infusions as well. So does that soften your stance on the lack of importance of what happens in the intraoperative phase, or during the cross-clamp interval, when this therapy may be having important effects in the heart?
DR ALBACKER: Well, that’s true. But as I mentioned, we gave the same protocol in both groups, and we saw a difference in myocardial protection and functionality. So if this a softened effect, then maybe the effect of our protocol is even greater than what we found. This also brings the attention to the importance of the systemic administration of this therapy, which will not be affected by the dilutional effect of cardioplegia.
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Acknowledgments |
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TopAbstractIntroductionMaterial and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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References |
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TopAbstractIntroductionMaterial and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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ski L, Budaj A, Czepiel A, et al. Low-dose glucose-insulin-potassium is ineffective in acute myocardial infarction: results of a randomized multicenter Pol-GIK trial Cardiovasc Drug Ther 1999;13:191-200.[Medline]This article has been cited by other articles:
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  S. Wan Invited commentary. Ann. Thorac. Surg., July 1, 2008; 86(1): 27 - 28. [Full Text] [PDF]
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