EDITORIAL
Future perspective:
getting GRIP
on
intensive insulin therapy in acute myocardial infarction M. Vogelzang, I.C.C. van der Horst
The association between hyperglycaemia at admission and adverse outcome has been shown to exist in patients admitted to hospital for acute myocardial infarction (AMI).1 However, no interventional studies are available that give an answer to the question whether hyperglycaemia is a marker or mediator in AMI. For critically ill patients, only one randomised controlled trial showed benefit of insulin therapy. In the 'Leuven study', intensive insulin therapy reduced mortality by almost 50% in intensive care patients, the majority admitted for elective cardiac surgery.2 Since the publication of this study, intensive insulin therapy is regarded by many as one of the principal advances of critical care in the last decade. Even though much is still unknown about the processes leading to the benefit of intensive insulin therapy, a number of mechanisms leading to these impressive results have been elucidated.3 In theory, many ofthese mechanisms are as applicable to patients with AMI as to critically ill patients. The 'common pathway' to the beneficial effects of insulin therapy is prevention of glucose toxicity, a process in which hyperglycaemia leads to high intracellular levels of glucose that interfere with a wide array of intracellular processes.4 Furthermore, insulin itselfmight exhibit intrinsic benefits to injured myocardium,5 but to overcome insulin resistance it needs to be infused in such amounts that blood glucose is reduced to normal levels. Indeed, a post-hoc study of the Leuven trial suggests that glycaemic control is more important than the amount of infused insulin per se.6 Two analyses from the GIPS I and GIPS II have shed some light on postinfarct hyperglycaemia.7'8 The M. Vogeizang I.C.C. van der Horst Department of Cardiology, Thoraxcentre, University Medical Centre Groningen, Groningen, the Netherlands
Correspondence to: M. Vogeizang Department of Cardiology, Thoraxcentre, University Medical Centre Groningen, PO Box 30001, 9700 RB Groningen, the Netherlands E-mail: [email protected]
qC
Netherlands Heart Journal, Volume 14, Number 5, May 2006
GIPS I and II studies were prospective, randomised trials investigating the value of high-dose glucoseinsulin-potassium (GIK) infusion after ST-segment elevation myocardial infarction.9 In the GIPS I study, a significant positive effect of GIK was shown in the subgroup of patients with Killip class I at admission (no clinical signs ofheart failure). However, this result could not be confirmed in the GIPS II trial. Although many investigators have reported on the relation between baseline glucose levels and outcome, persistent hyperglycaemia after admission has received very little attention. This is somewhat surprising, as persistent hyperglycaemia is the entity to be treated by intensive insulin therapy. We analysed derangements in glucose and potassium levels caused by GIK infusion in the first two days after AMI and found that GIK induced significant changes in glucose and potassium levels, and that these modifications correlate with adverse outcome. This is another observation compatible with the hypothesis that keeping patients with AMI normoglycaemic is beneficial. We also analysed the active treatment group of the GIPS II study, initiated as a follow-up study of the GIPS I. In GIPS II, patients were treated with a continuous glucose-potassium infusion, with a variable insulin infusion rate titrated according to an aggressive protocol striving for near-normoglycaemia (7 to 10 mmol/l). Nevertheless, it was observed that a significant proportion of patients treated with GIK became hyperglycaemic. Even more striking is the finding that the insulin infusion regimen, with doses up to 38 units of insulin per hour, was not able to adequately reduce GIK-induced hyperglycaemia. This observation underscores the profound insulin resistance ofthese acutely ill patients, and consequently we think there is no place for high-dose glucose infusion in patients with AMI. The observed insulin resistance of patients with AMI, the relation between persistent hyperglycaemia and unfavourable outcome, and the impressive results of intensive insulin therapy in critically ill patients call for a thorough evaluation of tight glycaemic control in patients with AMI. To date, the most important studies evaluating glycaemic control in this group of 163
EDITORIAL
patients are the DIGAMI 1 and 2 studies performed by Malmberg and colleagues.'0"' In the negative DIGAMI 2 study glucose levels at admission averaged 12.7 mmol/l and fell to 9.1 mmol/l in the intensive treatment group compared with 10.0 mmol/l after standard treatment. The drop in glucose level of 3.4 mmol/l obtained in DIGAMI 2 was thereby smaller than that in the DIGAMI 1 trial (5.8 mmol/l), which showed a benefit of insulin treatment during and after hospital admission. Therefore, no conclusion with regard to tight glycaemic control can be drawn from the DIGAMI 2, as normoglycaemia was never reached. Another study investigating tight glycaemic control is the HI-5 (Hyperglycaemia: Intensive Insulin Infusion In Infarction), mentioned in a preliminary substudy.12 Unfortunately, the main results of the HI-5 trial are not yet public, and we anxiously await the findings with regard to the achievement of glucose targets and major clinical outcome measures. Why is tight glycaemic control in AMI patients so difficult to achieve? After publication of the Leuven study, many intensive care units have tried to achieve normoglycaemia in their patients. Many have discovered, by trial and occasionally far-reaching errors, that tight glycaemic control requires a tremendous amount of effort to perform safely (i.e., without high incidence of hypoglycaemia). The publication of the Leuven study was followed by a number of reports describing nurse-driven protocols to perform glycaemic control. Generally, these reports show that these protocols with a few simple rules converting the most recent glucose level into a new insulin pump rate do perform better than ad-hoc doctors' decisions.'3 In our centre, we have also chosen a nurse-driven strategy, except that the actions are not dictated by rules on a piece of paper, but by a dedicated computer programme, 'GRIP' (Glucose Regulation for Intensive care Patients). In this way, the rules defining the protocol allow complex calculations, the protocol can integrate information from the past and information from all laboratory measurements, and may ultimately lead to better control. The initial results on our surgical intensive care unit are promising, and the number of glucose measurements that need to be taken is lower than with most published paper protocols.'4 Hypoglycaemia (glucose
Future perspective:
getting GRIP
on
intensive insulin therapy in acute myocardial infarction M. Vogelzang, I.C.C. van der Horst
The association between hyperglycaemia at admission and adverse outcome has been shown to exist in patients admitted to hospital for acute myocardial infarction (AMI).1 However, no interventional studies are available that give an answer to the question whether hyperglycaemia is a marker or mediator in AMI. For critically ill patients, only one randomised controlled trial showed benefit of insulin therapy. In the 'Leuven study', intensive insulin therapy reduced mortality by almost 50% in intensive care patients, the majority admitted for elective cardiac surgery.2 Since the publication of this study, intensive insulin therapy is regarded by many as one of the principal advances of critical care in the last decade. Even though much is still unknown about the processes leading to the benefit of intensive insulin therapy, a number of mechanisms leading to these impressive results have been elucidated.3 In theory, many ofthese mechanisms are as applicable to patients with AMI as to critically ill patients. The 'common pathway' to the beneficial effects of insulin therapy is prevention of glucose toxicity, a process in which hyperglycaemia leads to high intracellular levels of glucose that interfere with a wide array of intracellular processes.4 Furthermore, insulin itselfmight exhibit intrinsic benefits to injured myocardium,5 but to overcome insulin resistance it needs to be infused in such amounts that blood glucose is reduced to normal levels. Indeed, a post-hoc study of the Leuven trial suggests that glycaemic control is more important than the amount of infused insulin per se.6 Two analyses from the GIPS I and GIPS II have shed some light on postinfarct hyperglycaemia.7'8 The M. Vogeizang I.C.C. van der Horst Department of Cardiology, Thoraxcentre, University Medical Centre Groningen, Groningen, the Netherlands
Correspondence to: M. Vogeizang Department of Cardiology, Thoraxcentre, University Medical Centre Groningen, PO Box 30001, 9700 RB Groningen, the Netherlands E-mail: [email protected]
qC
Netherlands Heart Journal, Volume 14, Number 5, May 2006
GIPS I and II studies were prospective, randomised trials investigating the value of high-dose glucoseinsulin-potassium (GIK) infusion after ST-segment elevation myocardial infarction.9 In the GIPS I study, a significant positive effect of GIK was shown in the subgroup of patients with Killip class I at admission (no clinical signs ofheart failure). However, this result could not be confirmed in the GIPS II trial. Although many investigators have reported on the relation between baseline glucose levels and outcome, persistent hyperglycaemia after admission has received very little attention. This is somewhat surprising, as persistent hyperglycaemia is the entity to be treated by intensive insulin therapy. We analysed derangements in glucose and potassium levels caused by GIK infusion in the first two days after AMI and found that GIK induced significant changes in glucose and potassium levels, and that these modifications correlate with adverse outcome. This is another observation compatible with the hypothesis that keeping patients with AMI normoglycaemic is beneficial. We also analysed the active treatment group of the GIPS II study, initiated as a follow-up study of the GIPS I. In GIPS II, patients were treated with a continuous glucose-potassium infusion, with a variable insulin infusion rate titrated according to an aggressive protocol striving for near-normoglycaemia (7 to 10 mmol/l). Nevertheless, it was observed that a significant proportion of patients treated with GIK became hyperglycaemic. Even more striking is the finding that the insulin infusion regimen, with doses up to 38 units of insulin per hour, was not able to adequately reduce GIK-induced hyperglycaemia. This observation underscores the profound insulin resistance ofthese acutely ill patients, and consequently we think there is no place for high-dose glucose infusion in patients with AMI. The observed insulin resistance of patients with AMI, the relation between persistent hyperglycaemia and unfavourable outcome, and the impressive results of intensive insulin therapy in critically ill patients call for a thorough evaluation of tight glycaemic control in patients with AMI. To date, the most important studies evaluating glycaemic control in this group of 163
EDITORIAL
patients are the DIGAMI 1 and 2 studies performed by Malmberg and colleagues.'0"' In the negative DIGAMI 2 study glucose levels at admission averaged 12.7 mmol/l and fell to 9.1 mmol/l in the intensive treatment group compared with 10.0 mmol/l after standard treatment. The drop in glucose level of 3.4 mmol/l obtained in DIGAMI 2 was thereby smaller than that in the DIGAMI 1 trial (5.8 mmol/l), which showed a benefit of insulin treatment during and after hospital admission. Therefore, no conclusion with regard to tight glycaemic control can be drawn from the DIGAMI 2, as normoglycaemia was never reached. Another study investigating tight glycaemic control is the HI-5 (Hyperglycaemia: Intensive Insulin Infusion In Infarction), mentioned in a preliminary substudy.12 Unfortunately, the main results of the HI-5 trial are not yet public, and we anxiously await the findings with regard to the achievement of glucose targets and major clinical outcome measures. Why is tight glycaemic control in AMI patients so difficult to achieve? After publication of the Leuven study, many intensive care units have tried to achieve normoglycaemia in their patients. Many have discovered, by trial and occasionally far-reaching errors, that tight glycaemic control requires a tremendous amount of effort to perform safely (i.e., without high incidence of hypoglycaemia). The publication of the Leuven study was followed by a number of reports describing nurse-driven protocols to perform glycaemic control. Generally, these reports show that these protocols with a few simple rules converting the most recent glucose level into a new insulin pump rate do perform better than ad-hoc doctors' decisions.'3 In our centre, we have also chosen a nurse-driven strategy, except that the actions are not dictated by rules on a piece of paper, but by a dedicated computer programme, 'GRIP' (Glucose Regulation for Intensive care Patients). In this way, the rules defining the protocol allow complex calculations, the protocol can integrate information from the past and information from all laboratory measurements, and may ultimately lead to better control. The initial results on our surgical intensive care unit are promising, and the number of glucose measurements that need to be taken is lower than with most published paper protocols.'4 Hypoglycaemia (glucose
