Correspondence
Intensive Insulin Therapy in Critically Ill Patients
N Engl J Med 2002; 346:1586-1588May 16, 2002
- Article
To the Editor:
Van den Berghe and colleagues (Nov. 8 issue)1 report that intensive insulin therapy reduces mortality and morbidity among patients admitted to the surgical intensive care unit. Both the authors and Evans,2 in the accompanying editorial, suggest that strict control of glycemia is the principal factor contributing to the improved outcomes reported. However, insulin might have had a role independent of its effect on glycemia.
Severely ill patients in intensive care units have a “cytokine storm” with release of tumor necrosis factor α (TNF-α) and macrophage inhibitory factor.3 TNF-α is also released in acute myocardial infarction; it causes endothelial dysfunction and triggers procoagulant activity and fibrin deposition. Macrophage inhibitory factor is released with both gram-negative and gram-positive sepsis, and neutralization of this factor may protect against endotoxemia and toxic shock.
Insulin has been shown to inhibit TNF-α 4; it is also likely that the infusion of glucose and insulin inhibits macrophage inhibitory factor.3 The improved outcomes observed in the group receiving intensive insulin therapy may have resulted primarily from the action of insulin on these cytokines, rather than from the relatively mild hyperglycemia in the conventional-treatment group. This effect of insulin could also contribute to the well-documented benefits of treating hyperglycemia in order to reduce infection. Given the practical difficulty involved in maintaining normoglycemia in critically ill patients in community hospitals and the potential dangers associated with attempts to maintain normoglycemia, it is important not to assume that these results are wholly attributable to the normalization of blood glucose levels.
4 ReferencesIrl B. Hirsch, M.D.
Andrea Coviello, M.D.
University of Washington, Seattle, WA 98195
ihirsch@u.washington. edu 1
van den Berghe G ,Wouters P ,Weekers F , et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359-1367
Full Text | Web of Science | Medline2
Evans TW . Hemodynamic and metabolic therapy in critically ill patients. N Engl J Med 2001;345:1417-1418
Full Text | Web of Science | Medline3
Das UN . Is insulin an antiinflammatory molecule? Nutrition 2001;17:409-413
CrossRef | Web of Science | Medline4
Satomi N ,Sakurai A ,Haranaka K . Relationship of hypoglycemia to tumor necrosis factor production and antitumor activity: role of glucose, insulin, and macrophages. J Natl Cancer Inst 1985;74:1255-1260
Web of Science | Medline
To the Editor:
Van den Berghe et al. note that all patients began to receive nutritional support the day after admission to the intensive care unit, but they do not indicate how many patients were treated with parenteral nutrition. Klein et al.1 found that the routine use of postoperative parenteral nutrition was actually associated with greater harm than benefit. The failure of parenteral nutrition to improve outcomes in patients after surgery may be partially attributable to iatrogenic hyperglycemia. It is possible that van den Berghe et al. observed benefits with intensive insulin therapy because it prevented hyperglycemic complications related to parenteral nutrition. We wonder whether the intensive insulin regimen was beneficial in patients who did not receive parenteral nutrition. An equivalent benefit in all patients, regardless of the type of nutritional support they received, would strengthen the conclusion that intensive insulin therapy is warranted for all critically ill patients in whom hyperglycemia develops after they have undergone surgery. If the benefit is limited to patients who receive total parenteral nutrition, such therapy would be unnecessary for most other patients.
1 ReferencesJohn E. Mazuski, M.D., Ph.D.
Jeffrey A. Bailey, M.D.
Marc J. Shapiro, M.D.
Saint Louis University School of Medicine, St. Louis, MO 63110-0250
mazuskim@slu.edu 1
Klein S ,Kinney J ,Jeejeebhoy K , et al. Nutrition support in clinical practice: review of published data and recommendations for future research directions: summary of a conference sponsored by the National Institutes of Health, American Society for Parenteral and Enteral Nutrition, and American Society for Clinical Nutrition. Am J Clin Nutr 1997;66:683-706
Web of Science | Medline
To the Editor:
There is another potential explanation for the fascinating results of the trial comparing “tight” glycemic control with “usual” glycemic control in a population composed primarily of patients who had undergone cardiac surgery. Glucose–insulin–potassium infusion1 reduces morbidity and mortality after myocardial infarction2 and coronary bypass.3 Virtually all the patients in the trial conducted by van den Berghe et al. who were randomly assigned to normoglycemia were given continuous infusions of insulin and continuous nutritional support. Administering the insulin doses used in the intensive-treatment group of the study, combined with nutrition containing more than 20 kcal per kilogram of body weight per day, is likely to produce improvements in myocardial glucose utilization and inotropic performance similar to those achieved with glucose–insulin–potassium, as well as reducing the occurrence of arrhythmias. The effect of glucose–insulin–potassium on multisystem organ failure is unclear, but better cardiac function is associated with a lower risk of death from septic shock.4 If a “glucose–insulin–potassium” effect was largely responsible for the benefit observed with intensive insulin therapy, then it might be less important to lower glucose levels into the normal range than to lower them below a particular threshold. Was there evidence of a threshold below which the glucose level was no longer associated with an increased risk of death?
4 ReferencesKaren C. McCowen, M.D.
Justin A. Maykel, M.D.
Bruce R. Bistrian, M.D., Ph.D.
Beth Israel Deaconess Medical Center, Boston, MA 02215
kmccowen@caregroup.harvard. edu 1
Sodi-Pollaris D ,Testelli MR ,Fishleder BL . Effects of an intravenous infusion of a potassium-glucose-insulin solution on the electrocardiographic signs of myocardial infarction: a preliminary clinical report. Am J Cardiol 1962;9:166-181
CrossRef | Web of Science | Medline2
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
Web of Science | Medline3
Lazar HL ,Philippides G ,Fitzgerald C ,Lancaster D ,Shemin RJ ,Apstein C . Glucose-insulin-potassium solutions enhance recovery after urgent coronary artery bypass grafting. J Thorac Cardiovasc Surg 1997;113:354-360
CrossRef | Web of Science | Medline4
Rivers E ,Nguyen B ,Havstad S , et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-1377
Full Text | Web of Science | Medline
To the Editor:
Patients assigned to either group in the study by van den Berghe et al. appropriately received active therapy (albeit of different degrees of intensity) to control their blood sugar.1,2 It seems problematic, however, that consent was “obtained from the closest family member” rather than from the research subject. The use of consent from a surrogate apparently reflected the fact that patients were enrolled only when they entered the intensive care unit after surgery.
Most of the subjects had undergone cardiac surgery and presumably could have given informed consent themselves if they had been approached before the surgery, perhaps at the same time that they consented to the surgery. This method would have enabled them to exercise choice directly rather than through a surrogate.
2 ReferencesNeil J. Nusbaum, J.D., M.D.
Veterans Affairs Capitol Health Care Network, Fort Howard, MD 21052
nusbn@aol.com 1
Huston P ,Peterson R . Withholding proven treatment in clinical research. N Engl J Med 2001;345:912-914
Full Text | Web of Science | Medline2
Emanuel EJ ,Miller FG . The ethics of placebo-controlled trials -- a middle ground. N Engl J Med 2001;345:915-919
Full Text | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Hirsch and Coviello note that we cannot differentiate between the direct effects of infused insulin and the effects of preventing hyperglycemia, since both occurred concomitantly in our study. Besides the antiinflammatory effects evoked directly by insulin through the suppression of cytokine production or signaling,1 favorable effects on coagulation and fibrinolysis2 and on macrophage function,3 partially mediated by the prevention of hyperglycemia, may also have occurred. Multivariate logistic-regression analysis revealed, however, that the daily dose of insulin and the mean blood glucose level were independent positive predictors of the risk of death. In other words, a high dose of insulin was associated with a worse outcome, and a lower blood glucose level was associated with a better outcome, suggesting that the latter had a crucial role.
Gradual transition from intravenous nutritional support to enteral nutrition resulted in the administration of similar numbers of calories and similar amounts of glucose, protein, and lipids in the patients in both treatment groups at all times. Of all patients who remained in the intensive care unit for more than five days — the group in which intensive insulin therapy was associated with reduced mortality — 60 percent received combined parenteral–enteral feeding, with up to 68 percent of nutrition administered enterally. Intensive insulin therapy reduced mortality from 18.8 percent to 10.2 percent (P<0.05) in the group receiving combined parenteral–enteral feeding and from 22.3 percent to 11.1 percent (P<0.05) in the group receiving exclusively parenteral feeding. Effects of intensive insulin therapy on morbidity were also seen regardless of the feeding regimen. Because patients receiving exclusively parenteral feeding required a higher dose of insulin in order to maintain normoglycemia than did those receiving enteral nutrition (P=0.007), we agree with Mazuski et al. that our findings have implications for the controversy surrounding early enteral feeding and underscore the potential risks of parenteral nutrition without concomitant strict control of blood glucose levels.
Our strategy of maintaining normoglycemia with insulin (0.04 U per kilogram of body weight per hour) during normal intake of glucose (9 g per hour) and calories (19 kcal per kilogram per day) differs from the administration of glucose–insulin–potassium solutions for improvement of cardiac performance during myocardial injury.4,5 The goal of using glucose–insulin–potassium solutions is to stimulate myocardial metabolization of glucose instead of fatty acids when oxygen supply is compromised. These solutions contain much greater amounts of both insulin (0.1 to 1.0 U per kilogram per hour) and glucose (30 to 80 g per hour) than we provided and are infused without targeting normoglycemia. As mentioned, our results suggest that lowering the blood glucose level, rather than administering a high dose of insulin, resulted in lower rates of complications and death. We found no identifiable threshold glucose level below which no further risk reduction occurred.
We agree with Nusbaum that obtaining informed consent from the patient is preferable to obtaining it from a surrogate whenever this is possible. Since, in our study, only a subgroup of patients would have been capable of providing informed consent before their eventual admission to the intensive care unit, we decided after extensive discussion with the institutional ethics review board to adopt the same strategy for all patients of obtaining consent from the next of kin on admission to the intensive care unit.
Finally, because we have received many requests for more information about our protocol for intensive insulin therapy, we have prepared a more detailed summary (Supplementary Appendix 1).
5 ReferencesGreet van den Berghe, M.D., Ph.D.
Roger Bouillon, M.D., Ph.D.
Peter Lauwers, M.D.
Catholic University of Leuven, B-3000 Leuven, Belgium
greta.vandenberghe@med. kuleuven. ac. be 1
Dandona P ,Aljada A ,Mohanty P , et al. Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab 2001;86:3257-3265
CrossRef | Web of Science | Medline2
Carr ME . Diabetes mellitus: a hypercoagulable state. J Diabetes Complications 2001;15:44-54
CrossRef | Web of Science | Medline3
Kwoun MO ,Ling PR ,Lydon E , et al. Immunologic effects of acute hyperglycemia in nondiabetic rats. JPEN J Parenter Enteral Nutr 1997;21:91-95
CrossRef | Web of Science | Medline4
Svensson S ,Svedjeholm R ,Ekroth R , et al. Trauma metabolism and the heart: uptake of substrates and effects of insulin early after cardiac operations. J Thorac Cardiovasc Surg 1990;99:1063-1073
Web of Science | Medline5
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
Web of Science | Medline
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MARVIS L. CUSTER. (2010) Outcomes of Clinical Nurse Specialist-Initiated System-Level Standardized Glucose Management. Clinical Nurse Specialist 24:3, 132-139
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Maxim S. Petrov, Vladimir E. Zagainov. (2007) Influence of enteral versus parenteral nutrition on blood glucose control in acute pancreatitis: A systematic review. Clinical Nutrition 26:5, 514-523
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Penny Parsons, Peter Watkinson. (2007) Blood glucose control in critical care patients ? a review of the literature. Nursing in Critical Care 12:4, 202-210
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Ian Jenkins. (2006) Evidence-based sepsis therapy: A hospitalist perspective. Journal of Hospital Medicine 1:5, 285-295
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Clarence Chant, Gail Wilson, Jan O. Friedrich. (2005) Validation of an Insulin Infusion Nomogram for Intensive Glucose Control in Critically Ill Patients. Pharmacotherapy 25:3, 352-359
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Michael Gertner, Thomas Krummel. 2004. Micro- and Nanoelectromechanical Systems in Medicine and Surgery. .
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George Carvalho, Anne Moore, Baqir Qizilbash, Kevin Lachapelle, Thomas Schricker. (2004) Maintenance of Normoglycemia During Cardiac Surgery. Anesthesia & Analgesia319-324
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Lindsay E. Robinson, Mary H. van Soeren. (2004) Insulin Resistance and Hyperglycemia in Critical Illness. AACN Clinical Issues: Advanced Practice in Acute and Critical Care 15:1, 45-62
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