Download Optimal Dosage of Insulin and Glucose in Glucose

Optimal Dosage of Insulin and Glucose in
Glucose-Insulin-Potassium Treatment of Acute
Myocardial Infarction Remains to Be Established
Response
Downloaded from http://circ.ahajournals.org/ by guest on August 3, 2017
In their letter, Dr Svedjeholm and colleagues provide a concise
summary of the topic of glucose-insulin-potassium (GIK) therapy. Their comments reflect the current understanding of the
metabolic benefit of GIK therapy in acute myocardial infarction
(AMI). The spirit of their letter is that dose-finding studies
should be performed before a large-scale follow-up trial with
GIK is done, with the implication that higher doses of insulin
may prove more beneficial.
Should we consider a dose-finding study before the performance of a large-scale clinical trial?
Svedjeholm et al attribute the benefit of GIK in AMI to a
metabolic mechanism. However, conceptually limiting the benefit of GIK therapy to its impact on anaerobic myocardial
metabolism is a somewhat limited perspective. This assumption
fails to consider a number of other potentially beneficial effects
of GIK therapy, including a favorable effect on potassium flux,
lipid metabolism, hyperglycemia/osmolarity, and plasma volume/hemodynamics. In addition, the extrametabolic effects of
acute insulin administration likely contribute to the efficacy of
this therapy, including favorable effects on vascular tone, coagulation, arrhythmogenesis, and apoptosis.1
Although a dose-finding study could assess safety and feasibility of different regimens, it would be impractical to power
such a study for efficacy assessment. Such a study would have to
rely on surrogate markers of efficacy, such as suppression of
plasma free fatty acids, as implied by Svedjeholm et al. Although
physiologically sound, these measures have never been validated
against clinical outcomes and suffer all the limitations of reliance
on the “structure-function” relationship outlined in the previous
paragraph. One could also make a similar argument that studies
to define the optimal duration of therapy and studies of the
patient selection parameters would be required. However, we
feel that these studies are impractical, if not altogether impossible, due to the financial constraints of studying nonproprietary
pharmacotherapy.
Higher insulin doses would potentially come at the expense of
safety and tolerability. Higher insulin dosing would likely result
in more hypoglycemia. The amount of glucose infused to counter
this would incrementally increase the net volume load. Any
increase in tonicity of the glucose infusion would likely increase
the incidence of local intolerance and phlebitis during peripheral
infusion, requiring the placement of a central venous catheter.
Thirty-seven years have elapsed since Sodi-Pallares and colleagues2 introduced GIK therapy as a treatment for AMI in 1962,
yet the definitive study has not been done. Given the promising
results of our pilot study3 and the consistent results of previous
studies using a similar dosing regimen,4 we conclude beyond a
reasonable doubt that “the time has come for a large, prospective
trial” with GIK in AMI.5 To that end, we have already begun
enrollment in the follow-up GIK II trial. If GIK therapy is as
efficacious as our pilot study suggests, we feel that any delay of
confirmation would only serve to postpone the clinical application of this simple, cheap, widely available, life-saving therapy.
To the Editor:
The dosage of insulin and glucose plays an important role for
the efficacy of GIK (glucose-insulin-potassium) treatment. Until
the ECLA study, only 4 trials in acute myocardial infarction
(AMI) had used the GIK therapy required to achieve adequate
suppression of plasma free fatty acids (FFAs).1 Pooled data from
these trials demonstrated a 48% reduction in mortality. In the
ECLA study, a significant survival advantage relative to the
control group was only found in the “high-dose GIK group.”2 In
spite of these encouraging results, we do not yet know the
optimal dosage of insulin and glucose in AMI.
To establish appropriate metabolic interventions, these should
preferably be evaluated in the relevant clinical settings. Surprisingly little is known about the metabolic consequences of
myocardial infarction in humans or the impact of metabolic
interventions in this setting. In stable coronary artery disease, an
infusion of 30 g of glucose, 50 IU of regular insulin, and
80 mmol of KCl per liter at 1.5 mL/kg body weight reduced
myocardial FFA uptake and myocardial oxygen demand,
whereas the uptake of glucose and lactate increased.3 In AMI, it
was demonstrated that this regimen reduced the level of plasma
FFAs substantially.4 However, its impact on myocardial metabolism in this setting remains obscure. The neuroendocrine stress
response, for instance, may be expected to influence myocardial
metabolism and attenuate the effect of GIK due to insulin
resistance. In coronary surgery, where systematic studies on GIK
and its effects on systemic and myocardial metabolism have been
done by Dr Rolf Ekroth and colleagues at Sahlgrenska University
Hospital in Göteborg, Sweden, it has been shown that insulin
resistance can be severe early after the operation. Furthermore,
substantially higher doses of insulin are required to achieve full
metabolic effects than to achieve suppression of plasma FFAs.5
Hence, before large-scale prospective, randomized studies on
GIK in AMI are undertaken, further studies of myocardial
metabolism in AMI and the impact of different GIK regimens
may be advisable.
Rolf Svedjeholm, MD, PhD
Erik Håkanson, MD, PhD
Zoltan Szabo, MD
Departments of Cardiothoracic Surgery and
Cardiothoracic Anesthesia
Linköping Heart Center
University Hospital
Linköping, Sweden
1. Fath-Ordoubadi F, Beatt KJ. Glucose-insulin-potassium therapy for
treatment of acute myocardial infarction: an overview of randomized
placebo-controlled trials. Circulation. 1997;96:1152–1156.
2. Diaz R, Paolasso EA, Piegas LS, Tajer CD, Moreno MG, Corvalán R,
Isea JE, Romero G, on behalf of the ECLA (Estudios Cardiológicos
Latinoamérica) Collaborative Group. Metabolic modulation of acute
myocardial infarction: the ECLA Glucose-Insulin-Potassium Pilot Trial.
Circulation. 1998;98:2227–2234.
3. Rogers WJ, Russell RO Jr, 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– 428.
4. Rogers WJ, Stanley AW Jr, Breinig JB, Prather JW, McDaniel HG,
Moraski RE, Mantle JA, Russell RO Jr, Rackley CE. Reduction of
hospital mortality rate of acute myocardial infarction with glucoseinsulin-potassium infusion. Am Heart J. 1976;92:441– 454.
5. Svedjeholm R, Håkanson E, Vanhanen I. Rationale for metabolic support
with amino acids and glucose-insulin-potassium (GIK) in cardiac surgery.
Ann Thorac Surg. 1995;59:S15–S22.
Rafael Dı́az, MD
Director of ECLA
Estudios Cardiológicos Latinoamérica
Director, Cardiovascular Department
Instituto Cardiovascular de Rosario
Rosario, Argentina
Darren K. McGuire, MD
Duke Clinical Research Institute
Duke University Medical Center
Durham, NC
1
2
Correspondence
1. Opie LH. Metabolism of free fatty acids, glucose and catecholamines in
acute myocardial infarction: relation to myocardial ischemia and infarct
size. Am J Cardiol. 1975;36:938 –953.
2. Sodi-Pallares D, Testelli MR, Fischleder BL. Effects of an intravenous
infusion of a potassium-glucose-insulin solution on the electrocardiographic signs of myocardial infarction. Am J Cardiol. 1962;9:
166 –181.
3. Diaz R, Paolasso EA, Piegas LS, Tajer CD, Moreno MG, Corvalán R,
Isea JE, Romero G, on behalf of the ECLA (Estudios Cardiológicos
Latinoamérica) Collaborative Group. Metabolic modulation of acute
myocardial infarction: the ECLA Glucose-Insulin-Potassium Pilot Trial.
Circulation. 1998;98:2227–2234.
4. Fath-Ordoubadi F, Beatt KJ. Glucose-insulin-potassium therapy for
treatment of acute myocardial infarction: an overview of randomized
placebo-controlled trials. Circulation. 1997;96:1152–1156.
5. Apstein CS, Taegtmeyer H. Glucose-insulin-potassium in acute myocardial infarction. the time has come for a large, prospective trial. Circulation. 1997;96:1074 –1077.
Downloaded from http://circ.ahajournals.org/ by guest on August 3, 2017
Optimal Dosage of Insulin and Glucose in Glucose-Insulin-Potassium Treatment of Acute
Myocardial Infarction Remains to Be Established
Rolf Svedjeholm, Erik Håkanson and Zoltan Szabo
Downloaded from http://circ.ahajournals.org/ by guest on August 3, 2017
Circulation. 1999;100:e106
doi: 10.1161/01.CIR.100.22.e106
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1999 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/100/22/e106
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/