To the Editor:

In the Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study (ClinicalTrials.gov number, NCT00220987 [ClinicalTrials.gov] ), reported by Finfer et al. (March 26 issue),¹ intensive glucose control increased mortality.

These findings are clearly at variance with the decreased mortality that we reported from our center in Leuven, Belgium.^2,3,4 Finfer et al. do not address several possible explanations for this discrepancy.

First, normoglycemia (blood glucose level, <110 mg per deciliter [6.1 mmol per liter]) was compared with distinct blood glucose control with target ranges of 140 to 180 mg per deciliter (7.8 to 10.0 mmol per liter) in the NICE-SUGAR study and 180 to 215 mg per deciliter (10.0 to 11.9 mmol per liter) in the Leuven studies, making the studies fundamentally different.

Second, safe adjustment of the insulin dose to target normoglycemia requires standardized and accurate techniques for glucose measurement and monitoring of the potassium level.

Otherwise, the degree of treatment compliance (the targets reached and acceptable fluctuations in glucose levels) is enigmatic.

In the NICE-SUGAR study, it is surprising that a variety of glucometers, most of which were unsuitable for this purpose,⁵ were allowed;

thus, undetected hypoglycemia, large fluctuations in glucose levels, and possibly hypokalemia were tolerated or even induced.

Such errors may have contributed to excess "cardiovascular" deaths, in the absence of differences in organ failure.

Third, in the NICE-SUGAR study, patients received enteral nutrition exclusively, whereas in the Leuven studies, parenteral nutrition supplemented insufficient enteral feeding.

The administration of insulin during hypocaloric feeding in the NICE-SUGAR study may have been deleterious.

Finally, an unexplained policy of early withdrawal of care in the NICE-SUGAR study (after a median duration of study treatment of 6 days), which was not balanced between the two treatment groups of this nonblinded study, may have introduced a bias that could explain the excess mortality.

Greet Van den Berghe, M.D., Ph.D.
Roger Bouillon, M.D., Ph.D.
Dieter Mesotten, M.D., Ph.D.

Catholic University of Leuven, B-3000 Leuven, Belgium
greet.vandenberghe@med.kuleuven.be

References

• The NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009;360:1283-1297. [Free Full Text]
• 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. [Free Full Text]
• Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449-461. [Free Full Text]
• Vlasselaers D, Milants I, Desmet L, et al. Intensive insulin therapy in paediatric intensive care unit patients: a prospective, randomised controlled study. Lancet 2009;373:547-556. [CrossRef][ISI][Medline]
• Scott MG, Bruns DE, Boyd JC, Sacks DB. Tight glucose control in the intensive care unit: are glucose meters up to the task? Clin Chem 2009;55:18-20. [Free Full Text]

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  To the Editor:
• The NICE-SUGAR study investigators randomly assigned patients not to target blood glucose values but rather to alternative strategies for the administration of insulin.
• The difference in mortality between the study groups should not be attributed to the stated targets but rather to treatment, which was shown to be less safe in the intensively treated group.
• Among critically ill patients treated under a policy of strict control, it is difficult to prove the consequences of severe hypoglycemic episodes.
• Potentially harmful effects of counterregulation may occur even when severe hypoglycemic episodes are not documented.
• In the Leuven study, involving patients in a surgical intensive care unit (ICU), hypoglycemia might have had unproven adverse consequences that were outweighed in the statistical analysis by benefits of strict control.¹
• Carefully engineered insulin-treatment algorithms can reduce severe hypoglycemia.²
• Variability in glucose levels must be managed and reported, potentially with the use of different rules according to whether the blood glucose level is above or below the true target.

The NICE-SUGAR results should prompt renewed enthusiasm for the development of techniques that will reduce the confounding factor of iatrogenic hypoglycemia and thus enable future investigators to determine optimal blood glucose targets in given populations.

Susan S. Braithwaite, M.D. Saint Francis Hospital Evanston, IL 60202 braith@uic.edu

NEJM: Volume 361:89-92 July 2, 2009 Number 1

http://content.nejm.org/cgi/content/full/361/1/89

http://www.e-medicum.com/noticiasDelDia/verNoticia.php?noticia=82885