Correspondence
Insulin Therapy in Very-Low-Birth-Weight Infants
N Engl J Med 2009; 360:535-537January 29, 2009
- Article
To the Editor:
Beardsall et al. (Oct. 30 issue)1 report the results of the Neonatal Insulin Replacement Therapy in Europe (NIRTURE) trial, which investigated the effects of a fixed-dose insulin (0.05 U per kilogram of body weight per hour) and glucose (20% dextrose) infusion as compared with usual care in very-low-birth-weight infants in the neonatal intensive care unit (ICU). Beardsall and colleagues, as well as Kashyap and Polin, in their accompanying editorial,2 interpret the negative results of this study as evidence against blood glucose control in premature babies. We do not agree with this interpretation. Pronounced hyperglycemia was present in the two study groups (average glucose level, 6.2 mmol per liter [112 mg per deciliter], despite insulin infusion, in the intervention group, and 6.7 mmol per liter [121 mg per deciliter] in the control group), as compared with the much lower normal (fasting) glucose levels in healthy newborns who are less than 4 weeks old (1.7 to 3.3 mmol per liter [31 to 59 mg per deciliter]) or in infants who are 4 weeks to 1 year old (2.2 to 5.0 mmol per liter [40 to 90 mg per deciliter]). Hence, the study intervention actually increased the glucose load and concomitant hyperinsulinemia in the presence of hyperglycemia, a combination that has been shown to be deleterious in patients as well as in animal models of critical illness.3-6 In contrast, achieving strict (age-adjusted) normoglycemia throughout an ICU stay, both in adults and in pediatric patients, has been shown to lower mortality in the ICU and to prevent severe infections and organ damage.3,5,6
6 ReferencesGreet Van den Berghe, M.D., Ph.D.
Dirk Vlasselaers, M.D., Ph.D.
Ilse Vanhorebeek, Ph.D.
Catholic University of Leuven, 3000 Leuven, Belgium
greet.vandenberghe@med. kuleuven. be 1
Beardsall K ,Vanhaesebrouck S ,Ogilvy-Stuart AL , et al. Early insulin therapy in very-low-birth-weight infants. N Engl J Med 2008;359:1873-1884
Full Text | Web of Science | Medline2
Kashyap S ,Polin RA . Insulin infusions in very-low-birth-weight infants. N Engl J Med 2008;359:1951-1953
Full Text | Web of Science | Medline3
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 | Medline4
Ellger B ,Debaveye Y ,Vanhorebeek I , et al. Survival benefits of intensive insulin therapy in critical illness: impact of maintaining normoglycemia versus glycemia-independent actions of insulin. Diabetes 2006;55:1096-1105
CrossRef | Web of Science | Medline5
Vanhorebeek I ,De Vos R ,Mesotten D ,Wouters PJ ,De Wolf-Peeters C ,Van den Berghe G . Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients. Lancet 2005;365:53-59
CrossRef | Web of Science | Medline6
Vlasselaers D, Milants I, Desmet L, et al. Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study. Lancet (in press).
To the Editor:
Beardsall and colleagues found that insulin supplementation in newborns increased the risk of hypoglycemia and offered no clinical benefit with respect to reducing mortality. The authors state that “insulin therapy in very-low-birth-weight infants may lead to a significant improvement in glucose control.” Variability of glucose concentrations was expressed only as the percentage of time above the threshold for hyperglycemia or below the threshold for hypoglycemia, a measure that does not show the effect of the dynamics and magnitude of changes in the glucose concentration. Glycemic variability has already been proved to be a risk factor in acute conditions, particularly in patients with apparent euglycemia.1 Since the NIRTURE investigators have reported no clinical signs of hypoglycemia among the study patients, it would seem reasonable to evaluate primary and secondary outcomes with respect to glycemic variability in more detail by using well-established measures, such as the mean amplitude of glycemic excursions or the mean of daily differences.2 A different approach would be to combine the duration of hyperglycemic and hypoglycemic episodes, as in the study by Hirshberg et al.3
3 ReferencesWojciech M. Fendler, M.D.
Wojciech M. Mlynarski, M.D., Ph.D.
Medical University of Lodz, 91-738 Lodz, Poland
wojciech.mlynarski@joslin. harvard. edu 1
Krinsley JS . Glycemic variability: a strong independent predictor of mortality in critically ill patients. Crit Care Med 2008;36:3008-3013
CrossRef | Web of Science | Medline2
Alemzadeh R ,Loppnow C ,Parton E ,Kirby M . Glucose sensor evaluation of glycemic instability in pediatric type 1 diabetes mellitus. Diabetes Technol Ther 2003;5:167-173
CrossRef | Medline3
Hirshberg E ,Larsen G ,Van Duker H . Alterations in glucose homeostasis in the pediatric intensive care unit: hyperglycemia and glucose variability are associated with increased mortality and morbidity. Pediatr Crit Care Med 2008;9:361-366
CrossRef | Web of Science | Medline
Author/Editor Response
Van den Berghe et al. highlight issues regarding interpretation of the results of the NIRTURE study. Although there was a reduction in the prevalence of hyperglycemia (from 33% in the control group to 21% in the early-insulin group, P=0.008), the reduction was not as large as we had anticipated from the pilot study. We agree that tighter glucose control may be important and requires further investigation, but it will need to be balanced against the risks of hypoglycemia.
There is no consensus regarding optimal glucose levels in preterm infants, but we are concerned by the recommendations of Van den Berghe et al. (1.7 to 3.3 mmol per liter). These data are based on fasting, healthy term newborns, in whom alternative fuels can be produced and used to minimize the absolute glucose requirement. This mechanism is impaired in preterm infants, who also have an increased glucose requirement because of their proportionately larger brains. They are therefore considered to be at increased risk from low blood glucose levels (<2.6 mmol per liter [47 mg per deciliter]),1 which have been associated with poor neurodevelopmental outcomes.2 Fetal glucose levels are 4 to 6 mmol per liter (72 to 108 mg per deciliter).3 We therefore aimed for a target glucose level of 4 to 8 mmol per liter (72 to 144 mg per deciliter).
Van den Berghe et al. suggest that excess dextrose was infused in these infants. Hyperglycemia may occur in preterm infants, despite glucose intakes below basal glucose requirements. The mean (±SD) carbohydrate intake in the early-insulin group was 51±13 kcal per kilogram per day, which would not be viewed as excessive according to widely accepted recommendations (50 to 60 kcal per kilogram per day).4 Promoting nutritional intake in preterm infants is critical for both survival and long-term health.
Van den Berghe et al. suggest that our intervention led to hyperinsulinemia. Insulin levels were not reported in the NIRTURE study, but in the pilot study, they were not significantly different from the levels in controls.5 We are aware of the controversy concerning the benefits of insulin administration as compared with glucose control in adults but would advise against extrapolating the findings in adults to those in preterm infants, in whom insulin plays an important role in growth and metabolism.
Fendler and Mlynarski raise the question of the effect of glucose variability on clinical outcomes. This was not a prespecified outcome, so it was not reported.
Overall, we agree with Van den Berghe et al. and Fendler and Mlynarski that the NIRTURE data do not provide conclusive evidence regarding the value of insulin therapy in preterm infants. Further studies are needed to assess whether reduced variability and tighter glucose control may provide benefits.
5 ReferencesKathryn Beardsall, M.R.C.P.
University of Cambridge, Cambridge CB2 0QQ, United KingdomFrancis de Zegher, Ph.D.
University of Leuven, B3000 Leuven, BelgiumDavid B. Dunger, M.D.
University of Cambridge, Cambridge CB2 0QQ, United Kingdom
dbd25@cam.ac. uk for the NIRTURE Investigators
1
Cornblath M ,Hawdon JM ,Williams AF , et al. Controversies regarding definition of neonatal hypoglycemia: suggested operational thresholds. Pediatrics 2000;105:1141-1145
CrossRef | Web of Science | Medline2
Lucas A ,Morley R ,Cole TJ . Adverse neurodevelopmental outcome of moderate neonatal hypoglycaemia. BMJ 1988;297:1304-1308
CrossRef | Web of Science | Medline3
Economides DL ,Nicolaides KH . Blood glucose and oxygen tension levels in small-for-gestational-age fetuses. Am J Obstet Gynecol 1989;160:385-389
Web of Science | Medline4
Thureen PJ . Early aggressive nutrition in very preterm infants. Nestle Nutr Workshop Ser Pediatr Program 2007;59:193-208
Medline5
Beardsall K ,Vanhaesebrouck S ,Ogilvy-Stuart AL , et al. A randomised controlled trial of early insulin therapy in very low birth weight infants, “NIRTURE” (Neonatal Insulin Replacement Therapy in Europe). BMC Pediatr 2007;7:29-29
CrossRef | Medline
Author/Editor Response
The normal glucose concentration in healthy newborn infants who are less than 4 weeks of age, as suggested by Van den Berghe et al., is lower than that which would be acceptable after the first few hours of life. Though the definition of hypoglycemia remains controversial in healthy term infants and routine monitoring is discouraged, maintaining glucose concentrations above 2.5 mmol per liter (45 mg per deciliter) is recommended for symptomatic infants.1 It is unclear what constitutes normoglycemia in very-low-birth-weight infants; however, glucose concentrations of 4.3 to 7.6 mmol per liter (77 to 137 mg per deciliter) are used as norms for euglycemia2,3 and hyperglycemia is defined as concentrations greater than 8.3 mmol per liter (150 mg per deciliter). Therefore, in our opinion, the very-low-birth-weight infants in the study by Beardsall et al., with mean glucose concentrations of 6.2 mmol per liter in the intervention group and 6.7 mmol per liter in the control group, did not have pronounced hyperglycemia.
3 ReferencesSudha Kashyap, M.D.
Richard A. Polin, M.D.
Columbia University College of Physicians and Surgeons, New York, NY 100321
Cornblath M ,Hawdon JM ,Williams AF , et al. Controversies regarding definition of neonatal hypoglycemia: suggested operational thresholds. Pediatrics 2000;105:1141-1145
CrossRef | Web of Science | Medline2
Mitanchez-Mokhtari D ,Lahlou N ,Kieffer F ,Magny JF ,Roger M ,Voyer M . Both relative insulin resistance and defective islet β-cell processing of proinsulin are responsible for transient hyperglycemia in extremely preterm infants. Pediatrics 2004;113:537-541
CrossRef | Web of Science | Medline3
Hay WW Jr . Intravenous nutrition of the very preterm neonate. Acta Paediatr Suppl 2005;94:47-56
CrossRef | Medline
- Citing Articles (1)
Citing Articles
1
Kathryn Beardsall, Carlo Acerini, David B Dunger. (2010) Physiological and clinical role of insulin in the neonate. Expert Review of Endocrinology & Metabolism 5:2, 197-207
CrossRef
