Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children
2015; Elsevier BV; Volume: 167; Issue: 2 Linguagem: Inglês
10.1016/j.jpeds.2015.03.057
ISSN1097-6833
AutoresPaul Thornton, Charles A. Stanley, Diva D. De León, Deborah L. Harris, Morey W. Haymond, Khalid Hussain, Lynne L. Levitsky, M. Hassan Murad, Paul J. Rozance, Rebecca A. Simmons, Mark A. Sperling, David A. Weinstein, Neil H. White, Joseph I. Wolfsdorf,
Tópico(s)Diabetes and associated disorders
ResumoDuring 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 (<60 mg/dL [3.3 mmol/L]). GRADE 2+++0.1.3For those neonates who are suspected to be at high risk of having a persistent hypoglycemia disorder, we suggest evaluation when the infant is ≥48 hours of age so that the period of transitional glucose regulation has passed and persistent hypoglycemia may be excluded before discharge home. GRADE 2++00.Clinical Definition of HypoglycemiaClinical hypoglycemia is defined as a PG concentration low enough to cause symptoms and/or signs of impaired brain function.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 Hypoglycemia may be difficult to recognize because the signs and symptoms are nonspecific, and a single low PG concentration may be an artifact. For these reasons, guidelines in adults emphasize the value of Whipple's triad for confirming hypoglycemia: symptoms and/or signs consistent with hypoglycemia, a documented low PG concentration, and relief of signs/symptoms when PG concentration is restored to normal. Young infants and children often cannot dependably recognize and/or communicate their symptoms, however; therefore, recognition of hypoglycemia may require confirmation by repeated measurements of PG concentration and formal testing. Nevertheless, suspected hypoglycemia should be treated promptly to avoid potential adverse consequences.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; (2) it is not possible to identify a single PG value that causes brain injury, and the extent of injury is influenced by other factors, such as duration and degree of hypoglycemia; and (3) potential artifacts and technical factors that lead to inaccuracies in glucose determination may complicate the interpretation of any single PG value.Symptoms of HypoglycemiaThe symptoms of hypoglycemia reflect responses of the brain to glucose deprivation and have been well delineated in adults.12Cryer P.E. Hypoglycemia in diabetes: Pathophysiology, prevalence, and prevention.2nd ed. American Diabetes Association, Alexandria (VA)2013Google Scholar Neurogenic (autonomic) symptoms result from the perception of physiological changes caused by the sympathetic nervous discharge triggered by hypoglycemia; these include adrenergic responses (eg, palpitations, tremor, anxiety) and cholinergic responses (eg, sweating, hunger, paresthesias). Neuroglycopenic signs and symptoms, including confusion, coma, and seizures, are caused by brain dysfunction resulting from a deficient glucose supply to sustain brain energy metabolism. Awareness of hypoglycemia depends chiefly on perception of the central and peripheral effects of neurogenic (as opposed to neuroglycopenic) responses to hypoglycemia. Brain glucose utilization becomes limited at a PG concentration of approximately 55-65 mg/dL (3.0-3.6 mmol/L).12Cryer P.E. Hypoglycemia in diabetes: Pathophysiology, prevalence, and prevention.2nd ed. American Diabetes Association, Alexandria (VA)2013Google Scholar Neurogenic symptoms are perceived at a PG concentration <55 mg/dL (<3.0 mmol/L), which in older children and adults triggers a search for food or assistance, an important defense against hypoglycemia. Cognitive function is impaired (neuroglycopenia) at a PG concentration <50 mg/dL (<2.8 mmol/L).Glucose UtilizationThe adult brain accounts for more than one-half of total glucose consumption. 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.13Bier D.M. Leake R.D. Haymond M.W. Arnold K.J. Gruenke L.D. Sperling M.A. et al.Measurement of “true” glucose production rates in infancy and childhood with 6,6-dideuteroglucose.Diabetes. 1977; 26: 1016-1023Crossref PubMed Google Scholar Although the brain has an obligate requirement for glucose, it also can use plasma ketones and lactate as energy sources if the concentrations of these substances are sufficiently elevated.14Veneman T. Mitrakou A. Mokan M. Cryer P. Gerich J. Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans.Diabetes. 1994; 43: 1311-1317Crossref PubMed Scopus (142) Google Scholar 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.Neuroendocrine Defenses against HypoglycemiaIn normal individuals, the maintenance of normal PG concentrations is highly protected. The first defense is suppression of insulin secretion when PG concentration falls below the normal postabsorptive mean of ∼85 mg/dL (4.9 mmol/L).15Cryer P.E. Hypoglycemia, functional brain failure, and brain death.J Clin Invest. 2007; 117: 868-870Crossref PubMed Scopus (223) Google Scholar 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. At a PG concentration 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 <70 mg/dL (3.9 mmol/L) and hyperketonemia after overnight fasting because of limited fasting tolerance.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 Other evidence that the normal PG concentration in children does not differ from that in adults include the following: (1) fasting hyperketonemia develops at a similar PG concentration in infants, children, and adults21van 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, 22Saudubray J.M. Marsac C. Limal J.M. Dumurgier E. Charpentier C. Ogier H. et al.Variation in plasma ketone bodies during a 24-hour fast in normal and in hypoglycemic children: relationship to age.J Pediatr. 1981; 98: 904-908Abstract Full Text PDF PubMed Scopus (45) Google Scholar (hyperketonemia does not occur during transitional neonatal hypoglycemia in normal newborns in the first 1-2 days of life3Stanley 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); (2) plasma lactate rises as PG falls below ∼70 mg/dL (∼3.9 mmol/L) in children with glucose-6-phosphatase deficiency23Wolfsdorf J.I. Plotkin R.A. Laffel L.M. Crigler Jr., J.F. Continuous glucose for treatment of patients with type 1 glycogen-storage disease: comparison of the effects of dextrose and uncooked cornstarch on biochemical variables.Am J Clin Nutr. 1990; 52: 1043-1050PubMed Google Scholar; and (3) lethargy and tachycardia are observed in patients with defects of fatty acid oxidation when PG decreases to 60-70 mg/dL (3.3-3.9 mmol/L).PG Concentrations in Neonates Aged 48 Hours Who May Be at Risk for Persistent Hypoglycemia DisordersSome neonates can be identified by various clinical features as being at high risk for severe hypoglycemia during the first 48 hours after delivery,16Koivisto 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, 26Vannucci R.C. Vannucci S.J. Hypoglycemic brain injury.Semin Neonatol. 2001; 6: 147-155Abstract Full Text PDF PubMed Scopus (124) Google Scholar and a subset of those neonates are also at increased risk for persistent hypoglycemia beyond 48 hours of life (Table).27Collins J.E. Leonard J.V. Hyperinsulinsim in asphyxiated and small-for-dates infants with hypoglycaemia.Lancet. 1984; 2: 311-313Abstract PubMed Scopus (101) Google Scholar, 28Collins J.E. Leonard J.V. Teale D. Marks V. Williams D.M. Kennedy C.R. et al.Hyperinsulinaemic hypoglycaemia in small for dates babies.Arch Dis Child. 1990; 65: 1118-1120Crossref PubMed Scopus (81) Google Scholar, 29Hume R. McGeechan A. Burchell A. Failure to detect preterm infants at risk of hypoglycemia before discharge.J Pediatr. 1999; 134: 499-502Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 30Hoe F.M. Thornton P.S. Wanner L.A. Steinkrauss L. Simmons R.A. Stanley C.A. Clinical features and insulin regulation in infants with a syndrome of prolonged neonatal hyperinsulinism.J Pediatr. 2006; 148: 207-212Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar These include not only the rare infants with genetic hypoglycemia disorders, such as congenital hyperinsulinism or hypopituitarism,31Mohamed Z. Arya V.B. Hussain K. Hyperinsulinaemic hypoglycaemia: genetic mechanisms, diagnosis and management.J Clin Res Pediatr Endocrinol. 2012; 4: 169-181Crossref PubMed Scopus (58) Google Scholar 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.27Collins J.E. Leonard J.V. Hyperinsulinsim in asphyxiated and small-for-dates infants with hypoglycaemia.Lancet. 1984; 2: 311-313Abstract PubMed Scopus (101) Google Scholar, 28Collins J.E. Leonard J.V. Teale D. Marks V. Williams D.M. Kennedy C.R. et al.Hyperinsulinaemic hypoglycaemia in small for dates babies.Arch Dis Child. 1990; 65: 1118-1120Crossref PubMed Scopus (81) Google Scholar, 30Hoe F.M. Thornton P.S. Wanner L.A. Steinkrauss L. Simmons R.A. Stanley C.A. Clinical features and insulin regulation in infants with a syndrome of prolonged neonatal hyperinsulinism.J Pediatr. 2006; 148: 207-212Abstract Full Text Full Text PDF PubMed Scopus (104) Google ScholarTableRecognizing and managing neonates at increased risk for a persistent hypoglycemia disorderNeonates at increased risk of hypoglycemia and require glucose screening:1.Symptoms of hypoglycemia2.Large for gestational age (even without maternal diabetes)3.Perinatal stressa.Birth asphyxia/ischemia; cesarean delivery for fetal distressb.Maternal preeclampsia/eclampsia or hypertensionc.Intrauterine growth restriction (small for gestational age)d.Meconium aspiration syndrome, erythroblastosis fetalis, polycythemia, hypothermia4.Premature or postmature delivery5.Infant of diabetic mother6.Family history of a genetic form of hypoglycemia7.Congenital syndromes (eg, Beckwith-Wiedemann), abnormal physical features (eg, midline facial malformations, microphallus)Neonates in whom to exclude persistent hypoglycemia before discharge:1.Severe hypoglycemia (eg, episode of symptomatic hypoglycemia or need for IV dextrose to treat hypoglycemia)2.Inability to consistently maintain preprandial PG concentration >50 mg/dL up to 48 hours of age and >60 mg/dL after 48 hours of age3.Family history of a genetic form of hypoglycemia4.Congenital syndromes (eg, Beckwith-Wiedemann), abnormal physical features (eg, midline facial malformations, microphallus) Open table in a new tab 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:For neonates with a known risk of a genetic or other persistent form of hypoglyce
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