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Cited by 625Pancreatic function and diabetesMetabolism and Genetic DisordersDiabetes Management and Research

Recommendations from the Pediatric Endocrine Society for evaluation and management of persistent hypoglycemia in neonates, infants, and children

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Thornton, Paul S., Stanley, Charles A., De Leon, Diva D., Harris, Deborah, Haymond, Morey W., Hussain, Khalid, Levitsky, Lynne L., Murad, Mohammad H. +6 more·2015·The Journal of Pediatrics
DOI 10.1016/j.jpeds.2015.03.057PMC PMC11891912
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Abstract

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;

AI snapshot

Written from the paper’s full text.

TL;DR

This Pediatric Endocrine Society guideline provides expert recommendations for identifying and managing persistent hypoglycemia in neonates, infants, and children, excluding children with diabetes. It emphasizes distinguishing transitional neonatal hypoglycemia from persistent disorders, confirming low plasma glucose with laboratory assays, and using age- and diagnosis-specific treatment targets.

Key findings

  • For children able to communicate symptoms, evaluate/manage only when Whipple’s triad is documented (GRADE 1++++); for infants/young children unable to communicate reliably, evaluate/manage when laboratory-confirmed plasma glucose is <60 mg/dL (3.3 mmol/L) (GRADE 2+++0).
  • For high-risk neonates suspected of a persistent hypoglycemia disorder, delay diagnostic evaluation until ≥48 hours of age to allow transitional glucose regulation to pass (GRADE 2++00).
  • Treatment targets: maintain plasma glucose >70 mg/dL (3.9 mmol/L) in neonates with suspected congenital hypoglycemia disorder and older infants/children with confirmed disorder (GRADE 1++00); for high-risk neonates without suspected congenital disorder, target >50 mg/dL (>2.8 mmol/L) if <48 hours and >60 mg/dL (>3.3 mmol/L) if >48 hours (GRADE 2+000).
  • During fasting tests, plasma glucose of 50 mg/dL (2.8 mmol/L) is sufficiently low for diagnosis; in suspected hyperinsulinism, a glucagon-induced glycemic rise >30 mg/dL (>1.7 mmol/L) is nearly pathognomonic, and inappropriately low BOHB (<1.5 mmol/L [<15 mg/dL]) and FFA (<1.0–1.5 mmol/L [<28–42 mg/dL]) support the diagnosis.

Methods

  • An expert panel of pediatric endocrinologists and neonatologists convened by the Pediatric Endocrine Society developed guidelines for neonates, infants, and children, excluding children with diabetes.
  • The committee searched for existing evidence synthesis reports, systematic reviews, and meta-analyses; evaluated guidelines from the Endocrine Society, American Academy of Pediatrics, Canadian Pediatric Society, and others; reviewed bibliographies; and identified additional individual studies.
  • Recommendations were graded using the GRADE framework, with strong recommendations stated as “we recommend” (GRADE 1) and weak recommendations as “we suggest” (GRADE 2); a consensus process was used for technical suggestions where evidence was scarce.

Limitations

  • The paper states that evidence in this area is scarce and that the committee used a consensus process for some technical suggestions.
  • The paper states there is an absence of evidence on the short-term or long-term consequences of different treatment targets, so the committee focused on physiology, etiology, mechanism, and risk–benefit balance.
  • The text notes controversy over whether the newborn brain has greater or lesser susceptibility to hypoglycemic injury; evident from the text, several recommendations rely on expert consensus and extrapolation from adult/older-child physiology rather than direct pediatric outcome trials.

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Crossref · 10.1016/j.jpeds.2015.03.057

Cites

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  • Premisecitation
    § 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 concentrations are typically lower than later in life.

    “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.1–3”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1] Cornblath, 1965, Blood glucose in the neonate and its clinical significance, N Engl J Med source

      Not checked in the free run.

    • cites [2] Srinivasan, 1986, Plasma glucose values in normal neonates: a new look, J Pediatr source

      Not checked in the free run.

    • cites [3] Stanley, 2015, Re-evaluating “transitional neonatal hypoglycemia”: mechanism and implications for management, J Pediatr source

      Not checked in the free run.

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

    Published guidelines for screening at-risk newborns and managing low plasma glucose concentrations in neonates focus on the immediate neonatal period but do not address the diagnosis and management of disorders causing recurrent and prolonged hypoglycemia.

    “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.4–6”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [4] 2004, Screening guidelines for newborns at risk for low blood glucose, Paediatr Child Health source

      Not checked in the free run.

    • cites [5] Adamkin, 2011, Postnatal glucose homeostasis in late-preterm and term infants, Pediatrics source

      Not checked in the free run.

    • cites [6] Wight, 2006, ABM clinical protocol 1: guidelines for glucose monitoring and treatment of hypoglycemia in breastfed neonates, Breastfeed Med source

      Not checked in the free run.

  • Interpretationreasoning

    Exposure to recurrent hypoglycemia can shift the usual glucose threshold for recognition of neurogenic symptoms of 55 mg/dL to a lower level.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Cryer, 2004, Diverse causes of hypoglycemia-associated autonomic failure in diabetes, N Engl J Med source

      Not checked in the free run.

  • Premisereasoning

    Infants and young children have a 2- to 3-fold higher glucose utilization rate (4-6 mg/kg/min) per kilogram of body weight compared with adults.

    “Because of their disproportionately larger brain size relative to body mass, infants and young children have a 2- to 3-fold higher glucose utilization rate (4–6 mg/kg/min) per kilogram of body weight compared with adults.13”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Bier, 1977, Measurement of “true” glucose production rates in infancy and childhood with 6,6-dideuteroglucose, Diabetes source

      Not checked in the free run.

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

    The first few months of life are the most vulnerable period for developmental disability.

    “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.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [8] Menni, 2001, Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia, Pediatrics source

      Not checked in the free run.

    • cites [9] Steinkrauss, 2005, Effects of hypoglycemia on developmental outcome in children with congenital hyperinsulinism, J Pediatr Nurs source

      Not checked in the free run.

    • cites [10] Meissner, 2003, Long-term follow-up of 114 patients with congenital hyperinsulinism, Eur J Endocrinol source

      Not checked in the free run.

  • May combine two claims. 15
  • Classified as probably not a substantial claim. 6

  • May combine two claims.

    Interpretationreasoning

    Blunting or elimination of neurogenic responses leads to reduced or absent awareness of hypoglycemia and impairs hepatic glucose release, perpetuating hypoglycemia.

    “This leads to reduced or absent awareness of hypoglycemia and impairs hepatic glucose release, perpetuating hypoglycemia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Cryer, 2004, Diverse causes of hypoglycemia-associated autonomic failure in diabetes, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hypoglycemia-associated autonomic failure can persist for more than 24 hours after a single episode of hypoglycemia or even longer after repeated episodes.

    “HAAF can persist for >24 hours after a single episode of hypoglycemia or even longer after repeated episodes of hypoglycemia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Cryer, 2004, Diverse causes of hypoglycemia-associated autonomic failure in diabetes, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Previous exposure to an episode of hypoglycemia can blunt, and repeated episodes can eliminate, neurogenic responses to subsequent hypoglycemic episodes.

    “Previous exposure to an episode of hypoglycemia can blunt, and repeated episodes can eliminate, neurogenic responses to subsequent hypoglycemic episodes.18”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Cryer, 2004, Diverse causes of hypoglycemia-associated autonomic failure in diabetes, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In hypoketotic conditions such as hyperinsulinism or fatty acid oxidation disorders, ketones and lactate are not available in sufficiently high concentrations to substitute for glucose, and the risk of brain energy failure is greater.

    “However, in hypoketotic conditions, such as hyperinsulinism or fatty acid oxidation disorders, ketones and lactate are not available in sufficiently high concentrations to substitute for glucose, and the risk of brain energy failure is greater.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Hypoglycemia cannot be defined as a specific plasma glucose concentration.

    “Hypoglycemia cannot be defined as a specific PG concentration, because: (1) thresholds for specific brain responses to hypoglycemia occur across a range of PG concentrations, and these thresholds can be altered by the presence of alternative fuels, such as ketones, and by recent antecedent hypoglycemia;”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Point-of-care meters provide a convenient screening method for detecting hypoglycemia, but their accuracy is limited to approximately ±10-15 mg/dL in the range of hypoglycemia.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Cryer, 2013

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Previous exposure to hypoglycemia lowers the glucose threshold for neurogenic responses but does not acutely alter the threshold for neuroglycopenic symptoms.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Cryer, 2004, Diverse causes of hypoglycemia-associated autonomic failure in diabetes, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A further reduction of plasma glucose to 65-70 mg/dL elicits glucagon secretion and activation of the sympathoadrenal system, which increases glucose release from liver glycogen stores.

    “A further reduction of PG to 65–70 mg/dL (3.6–3.9 mmol/L) elicits glucagon secretion and activation of the sympathoadrenal system (reflected by increased epinephrine concentration), which increases glucose release from liver glycogen stores to raise the PG concentration.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Cryer, 2007, Hypoglycemia, functional brain failure, and brain death, J Clin Invest source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neonates at risk for persistent hypoglycemia include rare infants with genetic hypoglycemia disorders such as congenital hyperinsulinism or hypopituitarism, and those with relatively more common prolonged neonatal hyperinsulinism associated with birth asphyxia, intrauterine growth restriction, or toxemia.

    “These include not only the rare infants with genetic hypoglycemia disorders, such as congenital hyperinsulinism or hypopituitarism,31 but also those with relatively more common prolonged neonatal hyperinsulinism (also referred to as perinatal stress hyperinsulinism) associated with birth asphyxia, intrauterine growth restriction, or toxemia.27,28,30”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [31] Mohamed, 2012, Hyperinsulinaemic hypoglycaemia: genetic mechanisms, diagnosis and management, J Clin Res Pediatr Endocrinol source

      Not checked in the free run.

    • cites [27] Collins, 1984, Hyperinsulinsim in asphyxiated and small-for-dates infants with hypoglycaemia, Lancet source

      Not checked in the free run.

    • cites [28] Collins, 1990, Hyperinsulinaemic hypoglycaemia in small for dates babies, Arch Dis Child source

      Not checked in the free run.

    • cites [30] Hoe, 2006, Clinical features and insulin regulation in infants with a syndrome of prolonged neonatal hyperinsulinism, J Pediatr source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The mean plasma glucose concentration in normal newborns during the first hours after birth (~55-60 mg/dL) is similar to the threshold for neurogenic symptoms of hypoglycemia in older children and adults, but above the threshold for neuroglycopenic symptoms.

    “The mean PG concentration in normal newborns during the first hours after birth (~55–60 mg/dL [~3 mmol/L]) is similar to the threshold for neurogenic symptoms of hypoglycemia in older children and adults, but above the threshold for neuroglycopenic symptoms.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Cornblath, 1965, Blood glucose in the neonate and its clinical significance, N Engl J Med source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Expeditiously identifying the specific cause of hypoglycemia enables prompt institution of appropriate treatment and decreases the risk of permanent brain injury from persistent and recurrent severe hypoglycemia.

    “Expeditiously identifying the specific cause of hypoglycemia, as outlined above, will enable prompt institution of appropriate treatment and decrease the risk of permanent brain injury from persistent and recurrent severe hypoglycemia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    After the first 48 hours of life, plasma glucose concentration and the physiology of glucose homeostasis do not differ to any great extent with age.

    “After the first 48 hours of life, PG concentration and the physiology of glucose homeostasis do not differ to any great extent with age.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [17] Chaussain, 1977, Glycemic response to 24-hour fast in normal children, III: influence of age, J Pediatr source

      Not checked in the free run.

    • cites [20] Bonnefont, 1990, The fasting test in paediatrics: application to the diagnosis of pathological hypo- and hyperketotic states, Eur J Pediatr source

      Not checked in the free run.

    • cites [21] van Veen, 2011, Metabolic profiles in children during fasting, Pediatrics source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Treatment targets are generally aimed at avoiding activation of neuroendocrine responses and hypoglycemia-associated autonomic failure by maintaining plasma glucose concentration within the normal range of 70-100 mg/dL.

    “Therefore, treatment targets are generally aimed at avoiding activation of neuroendocrine responses and HAAF by maintaining PG concentration within the normal range of 70–100 mg/dL (3.9–5.6 mmol/L).7”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Cryer, 2009, Evaluation and management of adult hypoglycemic disorders: an Endocrine Society clinical practice guideline, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Plasma ketone levels are suppressed during hypoglycemia in high-risk neonates, making them particularly vulnerable to hypoglycemia-induced brain damage.

    “Of concern, as noted previously,3 plasma ketone levels are suppressed during hypoglycemia in high-risk neonates, making them particularly vulnerable to hypoglycemia-induced brain damage, and there is no assurance the plasma lactate level will be sufficiently elevated to compensate for low glucose.27,28,30,39”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [3] Stanley, 2015, Re-evaluating “transitional neonatal hypoglycemia”: mechanism and implications for management, J Pediatr source

      Not checked in the free run.

    • cites [27] Collins, 1984, Hyperinsulinsim in asphyxiated and small-for-dates infants with hypoglycaemia, Lancet source

      Not checked in the free run.

    • cites [28] Collins, 1990, Hyperinsulinaemic hypoglycaemia in small for dates babies, Arch Dis Child source

      Not checked in the free run.

    • cites [30] Hoe, 2006, Clinical features and insulin regulation in infants with a syndrome of prolonged neonatal hyperinsulinism, J Pediatr source

      Not checked in the free run.

    • cites [39] Harris, 2011, Cot-side electroencephalography monitoring is not clinically useful in the detection of mild neonatal hypoglycemia, J Pediatr source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The committee's review suggests that transitional neonatal hypoglycemia in normal newborns is a mild and transient form of hyperinsulinism in which the mean plasma glucose threshold for suppression of insulin secretion is approximately 55-65 mg/dL shortly after birth, compared with approximately 80-85 mg/dL in older infants, children, and adults.

    “As discussed previously,3 the committee’s review of available data on transitional neonatal hypoglycemia in normal newborns (ie, hypoketonemic hypoglycemia with inappropriately large glycemic responses to glucagon or epinephrine stimulation) suggests that it is a mild and transient form of hyperinsulinism in which the mean PG threshold for suppression of insulin secretion is ~55–65 mg/dL (3.0–3.6”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Stanley, 2015, Re-evaluating “transitional neonatal hypoglycemia”: mechanism and implications for management, J Pediatr source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some neonates can be identified by clinical features as being at high risk for severe hypoglycemia during the first 48 hours after delivery, and a subset of those neonates are also at increased risk for persistent hypoglycemia beyond 48 hours of life.

    “Some neonates can be identified by various clinical features as being at high risk for severe hypoglycemia during the first 48 hours after delivery,16,26 and a subset of those neonates are also at increased risk for persistent hypoglycemia beyond 48 hours of life (Table).27–30”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [16] Koivisto, 1972, Neonatal symptomatic and asymptomatic hypoglycaemia: a follow-up study of 151 children, Dev Med Child Neurol source

      Not checked in the free run.

    • cites [26] Vannucci, 2001, Hypoglycemic brain injury, Semin Neonatol source

      Not checked in the free run.

    • cites [27] Collins, 1984, Hyperinsulinsim in asphyxiated and small-for-dates infants with hypoglycaemia, Lancet source

      Not checked in the free run.

    • cites [28] Collins, 1990, Hyperinsulinaemic hypoglycaemia in small for dates babies, Arch Dis Child source

      Not checked in the free run.

    • cites [29] Hume, 1999, Failure to detect preterm infants at risk of hypoglycemia before discharge, J Pediatr source

      Not checked in the free run.

    • cites [30] Hoe, 2006, Clinical features and insulin regulation in infants with a syndrome of prolonged neonatal hyperinsulinism, J Pediatr source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Failure to investigate a neonate, infant, or child with suspected hypoglycemia increases the risk of delaying a definitive diagnosis and instituting effective treatment.

    “Failure to investigate a neonate, infant, or child with suspected hypoglycemia increases the risk of delaying a definitive diagnosis and instituting effective treatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In assessing possible hyperinsulinism, plasma BOHB and FFA are inappropriately low (BOHB <1.5 mmol/L and FFA <1.0-1.5 mmol/L), and there is an increased glycemic response to glucagon.

    “Because plasma insulin concentration is sometimes not above the lower limit of detection,34 it is important to include the following tests when assessing the possibility of hypoglycemia due to hyperinsulinism: plasma BOHB and FFA (both inappropriately low; BOHB <1.5 mmol/L [<15 mg/dL] and FFA <1.0–1.5 mmol/L [<28–42 mg/dL]), and an increased glycemic response to glucagon.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [33] Finegold, 1980, Glycemic response to glucagon during fasting hypoglycemia: an aid in the diagnosis of hyperinsulinism, J Pediatr source

      Not checked in the free run.

    • cites [34] De Leon, 2013, Determination of insulin for the diagnosis of hyperinsulinemic hypoglycemia, Best Pract Res Clin Endocrinol Metab source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The committee used a consensus process to make technical suggestions.

    “To provide a practical guide and in the light of scarce evidence in this area, the committee used a consensus process to make the following technical suggestions:”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The committee adopted the GRADE framework to rate confidence in the evidence.

    “The committee adopted the framework of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group,11 in which guideline developers rate their confidence in the evidence as very low (+000), low (++00), moderate (+++0), or high (++++).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Atkins, 2004, Grading quality of evidence and strength of recommendations, BMJ source

      Not checked in the free run.

20 of 20

  • The paper relies on this without support.

    Persistent hypoglycemia most often results from a congenital or genetic defect in regulating insulin secretion, deficiency of cortisol and/or growth hormone, or defects in the metabolism of glucose, glycogen, and fatty acids.

    “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.”

  • The paper relies on this without support.

    Hypoglycemia disorders in older infants and children are uncommon.

    “Hypoglycemia disorders in older infants and children are uncommon.”

  • The paper relies on this without support.

    Adrenal insufficiency, congenital or acquired, may manifest with hypoglycemia.

    “Adrenal insufficiency, congenital or acquired, may manifest with hypoglycemia.”

  • The paper relies on this without support.

    High plasma insulin level but low C-peptide level during hypoglycemia suggest exogenous insulin administration.

    “High plasma insulin level but low C-peptide level during hypoglycemia suggest exogenous insulin administration.”

  • The paper relies on this without support.

    The drugs most commonly associated with hypoglycemia include insulin, sulphonylureas, alcohol, beta-blockers, and salicylates.

    “The drugs most commonly associated with hypoglycemia include insulin, sulphonylureas, alcohol, beta-blockers, and salicylates.”

  • The paper relies on this without support.

    Not all commercially available insulin assays measure the insulin analogues; thus the finding of low insulin and C-peptide levels at time of hypoglycemia might not rule out surreptitious insulin administration.

    “Not all commercially available insulin assays measure the insulin analogues; thus, the finding of low insulin and C-peptide levels at time of hypoglycemia might not rule out surreptitious insulin administration.”

  • The paper relies on this without support.

    A plasma glucose concentration of 50 mg/dL is sufficiently low to elicit the metabolic and neuroendocrine responses required for diagnosis.

    “A PG concentration of 50 mg/dL (2.8 mmol/L) is sufficiently low to elicit the metabolic and neuroendocrine responses required for diagnosis.”

  • The paper relies on this without support.

    With few exceptions, blood tests performed while glucose concentrations are normal are not informative.

    “With few exceptions, blood tests performed while glucose concentrations are normal are not informative.”

  • The paper relies on this without support.

    Laboratory reference ranges for some tests (eg, insulin, BOHB) may be inappropriate for interpreting values obtained during childhood hypoglycemia.

    “Laboratory reference ranges for some of these tests (eg, insulin, BOHB) may be inappropriate for interpreting values obtained during childhood hypoglycemia.”

  • The paper relies on this without support.

    In cases of hyperinsulinism, glucagon can be expected to raise plasma glucose concentration to normal or above within 10–15 minutes and to maintain that concentration for at least 1 hour.

    “In cases of hyperinsulinism, glucagon can be expected to raise PG concentration to normal or above within 10–15 minutes and to maintain that concentration for at least 1 hour.”

  • The paper relies on this without support.

    Doses of glucagon 0.5–1.0 mg (independent of weight), given IV, intramuscularly, or subcutaneously, are usually effective; lower doses (0.03 mg/kg) may carry less risk of transient nausea and vomiting, but may be ineffective unless given IV.

    “Doses of 0.5–1.0 mg (independent of weight), given IV, intramuscularly, or subcutaneously, are usually effective; lower doses (0.03 mg/kg) may carry less risk of transient nausea and vomiting, but may be ineffective unless given IV.”

  • The paper relies on this without support.

    For disorders such as defects in glycogen metabolism and gluconeogenesis, maintenance of plasma glucose concentration in the normal range prevents metabolic acidosis and growth failure, and possibly the development of long-term complications.

    “For disorders such as defects in glycogen metabolism and gluconeogenesis, maintenance of PG concentration in the normal range prevents metabolic acidosis and growth failure, and possibly the development of long-term complications.”

  • The paper relies on this without support.

    There is no evidence that the concentration at which plasma glucose becomes limiting for brain function is different in neonates than in older children and adults.

    “There is no evidence that the concentration at which PG becomes limiting for brain function is different in neonates than in older children and adults.”
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Authors
Thornton, P. S., Stanley, C. A., De Leon, D. D., Harris, D., Haymond, M. W., Hussain, K., Levitsky, L. L., Murad, M. H., Rozance, P. J., Simmons, R. A., Sperling, M. A., Weinstein, D. A., White, N. H., & Wolfsdorf, J. I.
Affiliations
  • Cook Children's Medical Center (US)
  • Children's Hospital of Philadelphia (US)
  • Waikato District Health Board (NZ)
  • Texas Children's Hospital (US)
  • Great Ormond Street Hospital (GB)
  • Massachusetts General Hospital (US)
  • Mayo Clinic (US)
  • University of Colorado Anschutz (US)
  • Children's Hospital of Pittsburgh (US)
  • University of Florida Health (US)
  • Washington University in St. Louis (US)
  • Boston Children's Hospital (US)
Corresponding author
Thornton, Paul S.
ORCID
Venue
The Journal of Pediatrics
Publisher
Elsevier BV
Published
2015-08
Volume
167
Issue
2
Pages
238-245
ISSN
0022-3476 (ISSN-L)
DOI
10.1016/j.jpeds.2015.03.057
PMC
PMC11891912
OpenAlex
W1585861318
Semantic Scholar
ca2bf3a8781cb222c145d47ccfb2e95c216f9c0d
Cited by
625
References
44
Citations by year
2026: 54 · 2025: 36 · 2024: 71 · 2023: 62 · 2022: 73 · 2021: 80 · 2020: 72 · 2019: 54 · 2018: 46 · 2017: 33 · 2016: 31 · 2015: 11 · 2014: 1 · 2013: 1
FWCI
40.41
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Pediatrics (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK088139, R01DK055704)
  • National Institute of Environmental Health Sciences (P30ES013508)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
Keywords
persistent hypoglycemia, neonatal hypoglycemia, infants, children, plasma glucose, hypoglycemia management, hypoglycemia etiology, hypoglycemia screening, hypoglycemia treatment, hypoglycemia diagnosis, hypoglycemia
MeSH terms
Blood Glucose, Child, Child, Preschool, Endocrinology, Humans, Hypoglycemia, Infant, Infant, Newborn, Pediatrics, Societies, Medical

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