Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children

During the first 24-48 hours of life, as normal neonates transition from intrauterine to extrauterine life, their plasma glucose (PG) concentrations are typically lower than later in life.1Cornblath M. Reisner S.H. Blood glucose in the neonate and its clinical significance.N Engl J Med. 1965; 273: 378-381Crossref PubMed Scopus (116) Google Scholar, 2Srinivasan G. Pildes R.S. Cattamanchi G. Voora S. Lilien L.D. Plasma glucose values in normal neonates: a new look.J Pediatr. 1986; 109: 114-117Abstract Full Text PDF PubMed Scopus (225) Google Scholar, 3Stanley C.A. Rozance P.J. Thornton P.S. De Leon D.D. Harris D. Haymond M.W. et al.Re-evaluating “transitional neonatal hypoglycemia”: mechanism and implications for management.J Pediatr. 2015; 166: 1520-1525Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar Published guidelines for screening at-risk newborns and managing low PG concentrations in neonates focus on the immediate neonatal period, but do not address the diagnosis and management of disorders causing recurrent and prolonged hypoglycemia.4Canadian Paediatric SocietyScreening guidelines for newborns at risk for low blood glucose.Paediatr Child Health. 2004; 9: 723-740PubMed Google Scholar, 5Adamkin D.H. Postnatal glucose homeostasis in late-preterm and term infants.Pediatrics. 2011; 127: 575-579Crossref PubMed Scopus (424) Google Scholar, 6Wight N. Marinelli K.A. ABM clinical protocol 1: guidelines for glucose monitoring and treatment of hypoglycemia in breastfed neonates.Breastfeed Med. 2006; 1: 178-184Crossref PubMed Scopus (27) Google Scholar Distinguishing between transitional neonatal glucose regulation in normal newborns and hypoglycemia that persists or occurs for the first time beyond the first 3 days of life is important for prompt diagnosis and effective treatment to avoid serious consequences, including seizures and permanent brain injury.Moreover, the evaluation and management of pediatric hypoglycemia differ in several respects from that in adults, for whom guidelines were recently published.7Cryer P.E. Axelrod L. Grossman A.B. Heller S.R. Montori V.M. Seaquist E.R. et al.Evaluation and management of adult hypoglycemic disorders: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2009; 94: 709-728Crossref PubMed Scopus (704) Google Scholar First, persistent hypoglycemia most often results from a congenital or genetic defect in regulating secretion of insulin, deficiency of cortisol and/or growth hormone, or defects in the metabolism of glucose, glycogen, and fatty acids. Second, it may be difficult to identify and distinguish newborn infants with a persistent hypoglycemia disorder from those with transitional low glucose levels in the initial 48 hours of life, as detailed in the separate document on transitional neonatal hypoglycemia prepared by our committee.3Stanley C.A. Rozance P.J. Thornton P.S. De Leon D.D. Harris D. Haymond M.W. et al.Re-evaluating “transitional neonatal hypoglycemia”: mechanism and implications for management.J Pediatr. 2015; 166: 1520-1525Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar Third, the first few months of life are the most vulnerable period for developmental disability, which occurs in ∼25%-50% of children with congenital hyperinsulinism. Early recognition and treatment are crucial for preventing these sequelae.8Menni F. de Lonlay P. Sevin C. Touati G. Peigne C. Barbier V. et al.Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia.Pediatrics. 2001; 107: 476-479Crossref PubMed Scopus (271) Google Scholar, 9Steinkrauss L. Lipman T.H. Hendell C.D. Gerdes M. Thornton P.S. Stanley C.A. Effects of hypoglycemia on developmental outcome in children with congenital hyperinsulinism.J Pediatr Nurs. 2005; 20: 109-118Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 10Meissner T. Wendel U. Burgard P. Schaetzle S. Mayatepek E. Long-term follow-up of 114 patients with congenital hyperinsulinism.Eur J Endocrinol. 2003; 149: 43-51Crossref PubMed Scopus (157) Google ScholarTo address these deficiencies, the Pediatric Endocrine Society convened an expert panel of pediatric endocrinologists and neonatologists to develop guidelines for managing hypoglycemia in neonates, infants, and children, but excluding children with diabetes. The goals of these guidelines are to help physicians recognize persistent hypoglycemia disorders, guide their expeditious diagnosis and effective treatment, and prevent brain damage in at-risk babies.MethodsEvidence Retrieval and RatingThe committee searched for existing evidence synthesis reports, systematic reviews, and meta-analyses. The committee also evaluated guidelines published by the Endocrine Society, American Academy of Pediatrics, Canadian Pediatric Society, and others, and reviewed their bibliographies.4Canadian Paediatric SocietyScreening guidelines for newborns at risk for low blood glucose.Paediatr Child Health. 2004; 9: 723-740PubMed Google Scholar, 5Adamkin D.H. Postnatal glucose homeostasis in late-preterm and term infants.Pediatrics. 2011; 127: 575-579Crossref PubMed Scopus (424) Google Scholar, 6Wight N. Marinelli K.A. ABM clinical protocol 1: guidelines for glucose monitoring and treatment of hypoglycemia in breastfed neonates.Breastfeed Med. 2006; 1: 178-184Crossref PubMed Scopus (27) Google Scholar, 7Cryer P.E. Axelrod L. Grossman A.B. Heller S.R. Montori V.M. Seaquist E.R. et al.Evaluation and management of adult hypoglycemic disorders: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2009; 94: 709-728Crossref PubMed Scopus (704) Google Scholar Committee members identified additional individual studies.The committee adopted the framework of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group,11Atkins D. Best D. Briss P.A. Eccles M. Falck-Ytter Y. Flottorp S. et al.Grading quality of evidence and strength of recommendations.BMJ. 2004; 328: 1490Crossref PubMed Google Scholar in which guideline developers rate their confidence in the evidence as very low (+000), low (++00), moderate (+++0), or high (++++). Randomized trials start as high, and observational studies start as low.11Atkins D. Best D. Briss P.A. Eccles M. Falck-Ytter Y. Flottorp S. et al.Grading quality of evidence and strength of recommendations.BMJ. 2004; 328: 1490Crossref PubMed Google ScholarGrading the Strength of RecommendationsThe guideline developers considered the quality of the evidence. They also considered the balance between benefits and harms, patients' values and preferences, cost and resource utilization, and other societal and contextual factors, such as availability of technology and health services and implementation barriers. The recommendations according to the GRADE framework are either strong (GRADE 1), stated as “we recommend,” or weak (GRADE 2), stated as “we suggest.”Section 1: Which Neonates, Infants, and Children to Evaluate for Hypoglycemia1.1For children who are able to communicate their symptoms, we recommend evaluation and management only of those in whom Whipple's triad (see below) is documented. GRADE 1++++.1.2For infants and younger children who are unable to reliably communicate symptoms, we suggest evaluation and management only of those whose PG concentrations are documented by laboratory quality assays to be below the normal threshold for neurogenic responses (24 hours after a single episode of hypoglycemia or even longer after repeated episodes of hypoglycemia. A similar impairment in neuroendocrine responses to hypoglycemia also occurs during sleep and exercise.18Cryer P.E. Diverse causes of hypoglycemia-associated autonomic failure in diabetes.N Engl J Med. 2004; 350: 2272-2279Crossref PubMed Scopus (314) Google Scholar Thus, exposure to recurrent hypoglycemia can shift the usual glucose threshold for recognition of neurogenic symptoms of 55 mg/dL (3.0 mmol/L) to a lower level. Although previous exposure to hypoglycemia lowers the glucose threshold for neurogenic responses, the threshold for neuroglycopenic symptoms is not altered acutely; whether adaptation occurs with repeated exposure to hypoglycemia is unknown. Features of HAAF have been demonstrated in infants as young as age 10-13 weeks.19Hussain K. Bryan J. Christesen H.T. Brusgaard K. Aguilar-Bryan L. Serum glucagon counterregulatory hormonal response to hypoglycemia is blunted in congenital hyperinsulinism.Diabetes. 2005; 54: 2946-2951Crossref PubMed Scopus (49) Google ScholarPotential Artifacts in Measurements of PG ConcentrationTo diagnose hypoglycemia, PG concentration should be measured using a clinical laboratory method.12Cryer P.E. Hypoglycemia in diabetes: Pathophysiology, prevalence, and prevention.2nd ed. American Diabetes Association, Alexandria (VA)2013Google Scholar Important considerations are that whole blood glucose values are ∼15% lower than PG concentrations, and that because of red cell glycolysis, delays in processing and assaying glucose can reduce the glucose concentration by up to 6 mg/dL/hour (0.3 mmol/L/hour). Point-of-care meters provide a convenient screening method for detecting hypoglycemia, but their accuracy is limited to approximately ±10-15 mg/dL (0.6-0.8 mmol/L) in the range of hypoglycemia. Therefore, before establishing a diagnosis of hypoglycemia in neonates, infants, and children, it is essential to confirm low PG concentration using a clinical laboratory method.Normal PG Concentrations in Neonates Aged >48 Hours, Infants, and ChildrenAfter the first 48 hours of life, PG concentration and the physiology of glucose homeostasis do not differ to any great extent with age. Mean PG concentration in the postabsorptive state in normal neonates after ∼2 days of age and in infants and children does not differ from that in adults (70-100 mg/dL 3.9-5.5 mmol/L)17Chaussain J.L. Georges P. Calzada L. Job J.C. Glycemic response to 24-hour fast in normal children, III: influence of age.J Pediatr. 1977; 91: 711-714Abstract Full Text PDF PubMed Scopus (47) Google Scholar, 20Bonnefont J.P. Specola N.B. Vassault A. Lombes A. Ogier H. de Klerk J.B. et al.The fasting test in paediatrics: application to the diagnosis of pathological hypo- and hyperketotic states.Eur J Pediatr. 1990; 150: 80-85Crossref PubMed Scopus (119) Google Scholar, 21van Veen M.R. van Hasselt P.M. de Sain-van der Velden M.G. Verhoeven N. Hofstede F.C. de Koning T.J. et al.Metabolic profiles in children during fasting.Pediatrics. 2011; 127: e1021-e1027Crossref PubMed Scopus (55) Google Scholar; however, children under age 4 years may have a PG concentration 48 at for Hypoglycemia neonates can be identified by clinical as at high risk for severe hypoglycemia during the first 48 hours after M. Blanco-Sequeiros M. Krause U. Neonatal symptomatic and asymptomatic hypoglycaemia: a follow-up study of 151 children.Dev Med Child Neurol. 1972; 14: 603-614Crossref PubMed Scopus (124) Google Scholar, brain 2001; Full Text PDF PubMed Scopus (124) Google Scholar and a of those neonates are also at increased risk for persistent hypoglycemia beyond 48 hours of life in and infants with PubMed Scopus Google Scholar, D. V. D.M. et in for 1990; PubMed Scopus Google Scholar, A. A. to infants at risk of hypoglycemia before Pediatr. Full Text Full Text PDF PubMed Scopus Google Scholar, Thornton P.S. L. R.A. Stanley C.A. and insulin regulation in infants with a of prolonged neonatal hyperinsulinism.J Pediatr. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar include not only the infants with genetic hypoglycemia disorders, such as congenital hyperinsulinism or K. hypoglycaemia: genetic diagnosis and management.J Clin Pediatr Endocrinol. PubMed Scopus Google Scholar but also those with relatively more prolonged neonatal hyperinsulinism to as with intrauterine growth or in and infants with PubMed Scopus Google Scholar, D. V. D.M. et in for 1990; PubMed Scopus Google Scholar, Thornton P.S. L. R.A. Stanley C.A. and insulin regulation in infants with a of prolonged neonatal hyperinsulinism.J Pediatr. 2006; Full Text Full Text PDF PubMed Scopus Google and managing neonates at increased risk for a persistent hypoglycemia at increased risk of hypoglycemia and require glucose of for age delivery for or growth for or of of a genetic form of (eg, (eg, in whom to persistent hypoglycemia before hypoglycemia (eg, episode of symptomatic hypoglycemia or for dextrose to to PG concentration mg/dL up to 48 hours of age and mg/dL after 48 hours of of a genetic form of (eg, (eg, in a new provide a guide and in the of evidence in the committee a to the technical neonates with a risk of a genetic or other persistent form of