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ARTICLES: Kalia Patricia Ulate, Germano Correia Lima Falcao, Mark Richard Bielefeld, John Mark Morales, and Alexandre Tellechea Rotta Strict Glycemic Targets Need Not Be So Strict: A More Permissive Glycemic Range for Critically Ill Children Pediatrics 2008; 122: e898-e904 [Abstract] [Full text] [PDF]

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Blood glucose "targets" in pediatric glycemic control: Actual goals or retrospective definitions?

Catherine Preissig, Mark R. Rigby, MD, PhD, Emory University   (26 January 2009)

Re: Blood glucose "targets" in pediatric glycemic control: Actual goals or retrospective definitions?

Kalia P. Ulate, MD, Alexandre T. Rotta, MD, FAAP, FCCM, Associate Professor of Clinical Pediatrics,Indiana University and Riley Hospital for Children, Indianapolis, IN   (12 August 2009)

Blood glucose "targets" in pediatric glycemic control: Actual goals or retrospective definitions? 26 January 2009
Catherine Preissig, MD Emory University, Mark R. Rigby, MD, PhD, Emory University Send letter to journal: Re: Blood glucose "targets" in pediatric glycemic control: Actual goals or retrospective definitions? catherine.preissig{at}choa.org Catherine Preissig, et al.	To the Editor: In their article “Strict glycemic targets need not be so strict: A more permissive glycemic range for critically ill children” Ulate et al[1] report the relationship between postoperative blood glucose (BG) levels and outcomes in children status-post cardiac surgery. They stratified patients into 4 groups according to BG levels during their postoperative course, and found that those with “mild” hyperglycemia have comparable outcome as the “euglycemia” group, with lower hypoglycemic events. Based on these findings the authors conclude that a more permissive glycemic "target" is associated with lower incidence of hypoglycemia but not increased mortality rates. Although the authors should be commended for their contribution to the field of glucose dysregulation in pediatric critical care, we are concerned that the way their study is described may lead to misinterpretation by readers. Throughout the article, starting with the title, the authors use the term “targets” to describe glucose ranges in their study cohorts. In strict terminology, “target” refers to a “goal to be achieved”. In this retrospective study, there was no a priori attempt to maintain BGs in any predefined range by any means (i.e. calorie restriction or insulin infusion). In the current scientific vernacular, glycemic “target” refers to situations where physicians are actively attempting to maintain BG in predetermined ranges[2,3]. Therefore the authors’ statements that indicate that glycemic “targets” were evaluated may very much be a misnomer and confuse readers. Further, the lower level of “euglycemia (60mg/dL) is based directly on and borders on this group’s definition of “hypoglycemia” (<60mg/dL). For unknown reasons this group used this cutoff, whereas most frequently euglycemia has been defined as >80mg/dL and hypoglycemia <60 or <40mg/dL[2,3]. Therefore, given these glycemic categories, it is not surprising that those in the euglycemic group had the highest rates of hypoglycemia. This study adds to the well-established observation that poorer outcomes are associated with higher BG levels in critically ill children. The authors correctly caution that studies such as theirs do not imply causation between hyperglycemia and poor outcome, yet the wording in their article (including their title) may appear contradictory to this statement and confuse readers. To date there have been no prospective outcome studies published in pediatric critical care examining the impact of truly “targeting” BG into select ranges. We should encourage prospective investigations in this field, which will assist in definitively addressing whether or not pediatric practitioners should regularly practice glycemic control. References 1. Ulate KP, Falcao G, Bielefeld MR, Morales M and Rotta A. Strict glycemic targets need not be so strict: A more permissive glycemic range for critically ill children. Pediatrics, 2008; 122(4): e989-904. 2. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinand P, Lauwers P, Bouillon R. Intensive insulin therapy in the critically ill patients. The New England journal of medicine 2001; 345:1359-67. 3. Krinsley JS. Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clinic proceedings 2004;79:992-1000. Conflict of Interest: None declared
Re: Blood glucose "targets" in pediatric glycemic control: Actual goals or retrospective definitions? 12 August 2009
Kalia P. Ulate, MD, PCCM Fellow Seattle Children's Hospital, University of Washington School of Medicine, Alexandre T. Rotta, MD, FAAP, FCCM, Associate Professor of Clinical Pediatrics,Indiana University and Riley Hospital for Children, Indianapolis, IN Send letter to journal: Re: Re: Blood glucose "targets" in pediatric glycemic control: Actual goals or retrospective definitions? kalia.ulate{at}seattlechildrens.org Kalia P. Ulate, MD, et al.	Preissig and Rigby question our choice of glucose ranges and definition of hypoglycemia, by stating that euglycemia has been defined as blood glucose >80 mg/dL and hypoglycemia <60 or 40 mg/dL. We defined hyperglycemia as glucose values >125 mg/dL, in accordance to American Diabetes Association Guidelines(1) and hypoglycemia as <60 mg/dL, as the release of counter-regulatory hormones is activated at glucose values of approximately 65 mg/dl and a decrease in mental efficiency is seen at levels <60 mg/dL(2,3). The definition of euglycemia must border the definition of hypoglycemia and hyperglycemia, as the end of one marks the beginning of the other, hence our definition of euglycemia of 60-125 mg/dL. Had we instead defined euglycemia as 80-125 mg/dL and hypoglycemia as values <40 or 60 mg/dL, a group of patients would not have been categorizable and we would have had to resort to authors more well versed in the current scientific vernacular to properly name that range. All glucose ranges must be accounted for and studied when aiming to find a safe potential glycemic target for future interventional studies, especially when one considers the much lower definition of euglycemia based on age adjusted normal fasting glucose ranges used in the recent tight glycemic control trial in pediatrics(4). We are concerned that Preissig and Rigby might have significantly misinterpreted our results. The purpose of our study was to find whether or not one could identify a more permissive glycemic range to be used as a potential target for future prospective trials. For that, we stratified patients according to median blood glucose measurements in a euglycemia group (60-125 mg/dL), a mild hyperglycemia group (126-139 mg/dL), a moderate hyperglycemia group (140-179 mg/dL), and a severe hyperglycemia group (>180 mg/dL). We then analyzed our entire sample in search of the ideal glycemic range, one that would be associated with the best outcomes and the lowest prevalence of hypoglycemia. A lower cutoff point below 90 mg/dL was associated with a higher occurrence of hypoglycemia and an upper cutoff point above 140 mg/dL was associated with increased morbidity and mortality, thus arriving at the 90-140 mg/dL range. We named this the “Permissive Target” group, as this would be our proposed safe target for use in a prospective randomized trial of glycemic control in children. We strongly believe that the approach to studying critical illness-related hyperglycemia in children should include population-specific glycemic control targets derived by the scientific method, and not based on investigator preference, personal bias, inference, intuition or position statements directed to those caring for adult patients(5,6). It should be clear to the reader that a retrospective study evaluating outcomes and their association to critical illness-related hyperglycemia such as ours could never be confused with another where investigators are actively manipulating caloric intake and insulin to achieve a particular blood glucose goal. It was never our intent to mislead; on the contrary, our aim was to add to the existing body of evidence and possibly help pave the way for future trials of glycemic control in pediatrics by providing scientific evidence of a target range that could prove to be both safe and effective. References 1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2005;28 Suppl 1:S37-42. 2. Mitrakou A, Ryan C, Veneman T, Mokan M, Jenssen T, Kiss I, et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol 1991;260(1 Pt 1):E67-74. 3. Ryan CM, Atchison J, Puczynski S, Puczynski M, Arslanian S, Becker D. Mild hypoglycemia associated with deterioration of mental efficiency in children with insulin-dependent diabetes mellitus. J Pediatr 1990;117(1 Pt 1):32-8. 4. Vlasselaers D, Milants I, Desmet L, Wouters PJ, Vanhorebeek I, van den Heuvel I, et al. Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study. Lancet 2009;373(9663):547-56. 5. Garber AJ, Moghissi ES, Bransome ED, Jr., Clark NG, Clement S, Cobin RH, et al. American College of Endocrinology position statement on inpatient diabetes and metabolic control. Endocr Pract 2004;10(1):77-82. 6. Moghissi ES, Korytkowski MT, DiNardo M, Einhorn D, Hellman R, Hirsch IB, et al. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Endocr Pract 2009;15(4):353-69. Conflict of Interest: None declared