ORIGINAL ARTICLE

Refractory hyperglycaemia induced by glucose-insulin-potassium infusion in acute

myocardial infarction M. Vogelzang, T. Svilaas, I.C.C. van der Horst, M.W.N. Nijsten, F. Zijlstra

Background. Recent randomised dinical trials have not confirmed the beneficial effects of glucoseinsulin-potassium (GIK) infusion observed in experimental models of myocardial ischaemia and infarction. Methods. We investigated glucose levels and insulin dose in 107 patients treated with reperfusion therapy and GIK for acute myocardial infarction. Results. Despite high insulin infusion rates, persistent hyperglycaemia occurred in 37% of the patients. These patients had significantly larger infarctions, as measured by enzyme release (p=0.006). In a multivariate model predicting high troponin levels, refractory hyperglycaemia remained a significant parameter (p=0.02). Conclusion. These findings suggest that refractory hyperglycaemia caused by high-dose glucose infusion may, at least in part, explain the discrepancy between the experimental and clinical data. (Netb HeartJ2006;14:46-8.)

Keywords: myocardial infarction, glucose, hyperglycaemia, insulin

M. Vogeizang T. Svilaas I.C.C. van der Horst F. ZlJlstra Department of Cardiology, Thoraxcentre, University Medical Centre, University of Groningen, Groningen, the Netherlands M.W.N. NlJsten Surgical Intensive Care Unit, Department of Surgery, University Medical Centre, University of Groningen, Groningen, the Netherlands

Correspondence to: M. Vogeizang Department of Cardiology, Thoraxcentre, University Medical Centre, University of Groningen, P0 Box 30001, 9700 RB Groningen, the Netherlands E-mail: [email protected]

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A lthough mechanical reperfusion therapy has significantly improved outcome after acute STsegment elevation myocardial infarction (STEMI), heart failure due to impaired pump function remains an important problem. Metabolic intervention has been suggested as the next step to improve outcome by protecting ischaemic myocardial cells. In animal experiments, glucose-insulin-potassium (GIK) infusion has been shown to improve outcome after myocardial infarction." 2 Recently, however, several randomised controlled trials did not demonstrate any significant benefit for GIKinfusion.34 The reasons for these failures remain unclear. One of the potential explanations could be that hyperglycaemia induced by GIK may have offset intrinsic benefits of GIK in these clinical trials. We analysed the magnitude of hyperglycaemia and its relation with enzymatic infarct size in GIKtreated patients in the GIPS-II trial.

Patients and methods The GIPS-II trial was a randomised controlled trial comparing GIK infusion with conventional treatment in STEMI patients.' Primary percutaneous coronary intervention was aimed for in all patients. We examined the glucose levels and insulin doses of the subgroup treated with GIKat our centre. Patients received an infusion of 2.0 ml/kg/hour of 20% glucose (equivalent to 400 mg/kg/hour) with 80 mmol/l potassium for 12 hours. Insulin was administered at a variable rate through a perfusor. Blood glucose was checked hourly and the insulin pump rate was adjusted according to a previously published algorithm.' Maximum pump rate was set to 38 IU/hour. Ischaemic time was defined as time from onset of symptoms to first balloon inflation. Infarct size was measured as the area under the linearly interpolated curve ofserial measurements oflactate dehydrogenase (LDH), troponin I, creatine phosphokinase (CK), and the myocardial band of CK (CK-MB) for the first 48 hours after admission. Patients were considered as suffering from 'refractory hyperglycaemia' if they had a period of at least three consecutive hours with a glucose level above 10 mmol/l despite insulin infusion of more than 10 units per hour. To compare groups, we used student's t test, Ne4lerlands Heart journal, Volume 14, Number 2, February 2006

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Refractory hyperglycaemia induced by glucose-insulin-potassium infusion in acute myocardial infarction

Table 1. Comparison of patients with and without refractory hyperglycaemia.

No refractory hyperglycaemia

Refractory hyperglycaemia

67 (63%) 58±12 51 (76%) 25.7±2.9 186±76 0 (0%) 23 (34%) 7.0±1.9 9.9±2.5 9.0 (6.5-12.0) 57 (35-89) 227 (160-331) 100 (50-178) 18 (11-30) 195 (114-342)

40 (37%) 63±12 29 (73%) 27.7±3.5 234±124 4 (10%) 23 (58%) 8.7±2.0 14.7±3.5 28 (21.8-37.0) 223 (159-278) 303 (198-441) 180 (81-283) 27 (14-37) 330 (162-584)

N Age Male sex Body mass index Ischaemic time (minutes) History of diabetes Anterior infarction Admission glucose (mmol/l) Glucose after 2h of GIK infusion (mmol/l) Maximum insulin rate (IU/h)* Total units of insulin administered (IU)* AUC 48 h LDH* AUC 48 h troponin T* AUC 48 h CK-MB* AUC 48 h CK*

P value

0.03 0.85 0.003 0.03 0.02 0.03 27.5

Univarlate odds ratio (95% Cl) 3.19 (1.38-7.36) 1.45 (1.02-2.06) 6.36 (0.64-63.5) 1.17 (0.96-1.43) 1.89 (0.84-4.27) 1.27 (0.88-1.84) 0.66 (0.27-1.63) 0.76 (0.32-1.80)

P value

0.007 0.04 0.12 0.12 0.13 0.20 0.37 0.53

Cl=confidence interval.

In our study group, three patients died within 30 days of admission, two of whom suffered from refractory hyperglycaemia and one did not. In logistic regression analysis, presence of refractory hyperglycaemia and age were significantly associated with the troponin I area under the curve being within the highest tertile (table 2). In a bivariate model including these two parameters, refractory hyperglycaemia remained significantly associated with high enzyme release (odds ratio (95% CI) 2.80 (1.19 to 6.6), p=0.02).

Discussion Our findings demonstrate that high-dose glucose infusion can lead to hyperglycaemia that is barely responsive to high doses of insulin. In our study group, more than one third of the patients suffered from refractory hyperglycaemia. Furthermore, hyperglycaemia was associated with increased infarct sizes as measured by enzyme release. However, as this is an observational study, we cannot distinguish whether GIK-induced hyperglycaemia is a marker or a mediator of myocardial ischaemia and cell death. Hyperglycaemia was associated with a number of possibly unfavourable parameters such as old age, presence of diabetes, anterior infarction site, and longer ischaemic time, which may account for part of the association with enzyme release. Furthermore, myocardial damage induces a stress reaction that can lead to insulin resistance. The observation that hyperglycaemia is a marker of disease in myocardial infarction has been thoroughly studied before.6 However, a large body of evidence supports the detrimental effects of hyperglycaemia accompanying acute myocardial infarction, and its mediating role in acutely ill patients.7 We therefore hypothesise that part of the relation we found between glucose levels and enzymatic infarct size may

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be explained by hyperglycaemia playing an active role by either causing additional myocardial cell injury or by impairing repair mechanisms during reperfusion. It is conceivable that the refractory hyperglycaemia offset any positive effects of GIK, and this might in part explain why recent trials have not confirmed the positive results observed in experimental studies. Conclusion Our results show that high doses of insulin failed to adequately reduce hyperglycaemia induced by GIK, and we therefore suggest that future studies investigating GIK should use lower doses of glucose to avoid hyperglycaemia. c References 1 2 3

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Oliver MF, Opie LH. Effects of glucose and fatty acids on myocardial ischaemia and arrhythmias. Lancet 1994;343:155-8. Apstein CS, Opie LH. A challenge to the metabolic approach to myocardial ischaemia. EurHeartJ2005;26:956-9. Van der Horst IC, Zijlstra F, van 't HofAW, Doggen CJ, de Boer MJ, Suryapranata H, et al. Glucose-insulin-potassium infusion in patients treated with primary angioplasty for acute myocardial infarction - The glucose-insulin-potassium study: A Randomized trial. JAm Coll Cardiol 2003;42:784-91. Mehta SR, Yusuf S, Diaz R, Zhu J, Pais P, Xavier D, et al. Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction: the CREATEECLA randomized controlled trial. JAAL 2005;293:437-46. Van der Horst IC, Timmer JR, Ottervanger JP, Bilo HJ, Gans RO, de Boer MJ, et al. Glucose-insulin-potassium and reperfusion in acute myocardial infarction: Rationale and design of the glucose insulin-potassium study-2 (GIPS-2). Am HeartJ2005;149:58591. Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview. Lancet 2000;355:773-8. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in critically ill patients. NEngllJMed 2001;345:1359-67.

Netherlands Heart Journal, Volume 14, Number 2, February 2006

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Refractory hyperglycaemia induced by glucose-insulin-potassium infusion in acute myocardial infarction.

Recent randomised clinical trials have not confirmed the beneficial effects of glucose-insulin-potassium (GIK) infusion observed in experimental model...
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