Neonatal Hypoglycemia: Evidences and Practice

1. Neonatal Hypoglycemia: Evidences and Practice Prof. Pushpa Raj Sharma Department of Child Health

2. Why This Topic is Important? • Inability to breast feed and weight <2500 g were independently associated with hypoglycaemia. Mortality was 45.2% compared to 19.6% in normoglycaemic neonates (p < 0.001). • Osier FH, Berkley JA, Ross A, Sanderson F, Mohammed S, Newton CR.Abnormal blood glucose concentrations on admission to a rural Kenyan district hospital: prevalence and outcome.Arch Dis Child. 2003 Jul;88(7):621-5. • 41% newborn infants had mild (less than 2.6 mmol/l) and 11% had moderate hypoglycaemia: Hospital based study. • Pal DK, Manandhar DS, Rajbhandari S, Land JM, Patel N, de L Costello AM.Arch Dis Child Fetal Neonatal Ed. 2000 Jan;82(1):F46-51.

3. Koivisto M, Blaco-Sequeiros M, Krause U. Neonatal symptomatic hypoglycaemia: a follow-up study of 151 children. Dev Med. Child Neurol 1972; 14:603-14 • Their conclusions? TIME is most important factor affecting onset of sx and SYMPTOMATIC hypoglycemia with convulsions has poor prognosis for permanent CNS damage, while asymptomatic hypoglycemia without convulsions appears to have no influence on CNS pathology

4. Long term neurological outcomes • Lucus A, Morley R, Cole TJ. Adverse neurodevelopmental outcome of moderate neonatal hypoglycemia. British Medical Journal 1988; 297:1304-1308 • 661 preterm infants (BW <1850 g) surviving >48hrs • Weekly glucose level taken; reagent strips q6h for first 48-72 hours (if <1.5 or 2 low values below 2.5  blood test) • Treated by feeds/iv or bolus if less than 1 mmol/l or sx • At 18 months  92% assessed with Bayley motor and development scale • Results examined by statistical adjustment for differences between infants with and without hypoglycemia

5. Lucus A, Morley R, Cole TJ. • Their findings? <2.6 on 3 to 30 separate days  associated with reductions in Bayley motor ad mental development scores even after adjusting for confounding factors <2.6 on 5 or more consecutive days  increased risk (3.5 fold) of CP

6. Kinnala et al. Cerebral magnetic resonance imaging and ultrasonography findings after neonatal hypoglycemia. Pediatrics 103; 1999 • Investigated neuroradiologic changes in the brains of infants after transient neonatal hypoglycemia via MRI and U/S • Def’n of hypoglycemia: <2.5 mM WITH symptoms • Treatment included feeds, IV, hydrocortisone • MRI and US at fullterm and at 2m in 18 symptomatic fullterms (6 babies with SGA, 2 infants of diabetic mom) without any other pathology and 19 term controls

7. Results? 39% of hypoglycemic infants had abnormalities detected on MRI  4 showed patchy hyperintensity lesions in occipital periventricular white matter of the thalamus; lesions recovered by 2 months with only 1 neurologically affected Controls  10% had caudothalamic cysts Relative risk of hypoglycemic child compared with normoglycemic child to have ay abnormality detected in the brain was 3.7 (4x more often) Developmental assessment at 11 months  94% normal; 1 infant had rightsided hemiplegia ad tremors Kinnala et al. Cerebral magnetic resonance imaging andultrasonography findings after neonatal hypoglycemia. Pediatrics 103; 1999

8. Glucose Physiology in a Nutshell! FETUS: • Energy as glucose, lactate, FFAs, ketones, surplus amino acids • Gluconeogenesis & ketogenesis virtually absent • Energy stored at rapid rate (100 cal of fat/day in 9th month!) AT DELIVERY: • Adaptive response  surge in plasma glucagon & decrease in plasma insulin  mobilizes glucose & fatty acids from glycogen & triglyceride depots

9. Glucose Physiology II…. NEONATE: • Stores become insufficient so must rely on gluconeogenesis • Glucose is main oxidative fuel, but neonates can oxidize ketone bodies, lactate & amino acids • Glucose requirements exceed those of adults mainly b/c of increased ratio of brain to body mass • Low blood glucose values are usually NOT related to any significant problem but are 20 to normal process of metabolic adaptation to extrauterine life

10. Definition of neonatal hypoglycemia • The definition of clinically significant hypoglycemia remains one of the most confused and contentious issues in contemporary neonatology. Cornblath M, Hawdon JM, Williams AF, Aynsley-Green A, Ward-Platt MP, Schwartz R, Kalhan SC.Controversies regarding definition of neonatal hypoglycemia: suggested operational thresholds.Pediatrics. 2000 May;105(5):1141-5.

11. Approaches to defining neonatal hypoglycemia! Clinical Manifestations • Must fulfill Whipple’s Triad • Low glucose • S&S consistent with hypoglycemia (eg. Jitteriness, tremors, lethargy, seizures, apnea, cyanotic spells, hypotonia, difficulty feeding, hypothermia, coma) • Resolution of S&S after restoring glucose

12. Serum level? Epidemiological Approach • Def’n based on statistical definition of glucose values < or = to 2 SD below the mean in the population of well full term & LBW infants “in neonates any value below 40 mg/dL (2.8 mM) be viewed with suspicion”: Sperling MA. in Hypoglycemia; Chapter 77, page 420. Nelson’s Textbook of Paediatrics, 15th ed.

13. Operational Threshold • Indication for intervention • Based on evidence currently available in the literature Concentration of glucose in the blood or plasma at which the individual demonstrates a unique response to the abnormal milieu caused by the inadequate delivery of glucose to a target organ Cornblath et al. Controversies regarding definition of neonatal hypoglycemia: suggested operational thresholds. Pediatrics 105: 153-157, 2000 • Provides large margin of safety by designating the lower level of glucose that a neonate can safely tolerate based on physical maturity and influence of pathology

14. Proposed Operational Thresholds 1st 24 hours of life: Healthy preterm*/full term neonate: • NO clinical signs: <2.0 mM • Abnormal clinical signs: <2.5 mM Sick, Hypoxic, LBW, Infant of diabetic mom or premature neonate: <2.5 mM * >34 weeks

15. Proposed Operational Thresholds >24 hours of life:Others: 2.2  2.8 mM TPN: <2.5 mM Note: Level can be  in asymptomatic breast fed neonates because of concentrations of ketones (<1.7 or <2.0 mM  but there is controversy!!)

16. Operational Thresholds: How to use them? • Remember: INDICATION FOR ACTION! But, what is your goal? • THERAPEUTIC OBJECTIVE Raise glucose to > 2.6 mmol/l IF Recurrent, profound, sick or symptomatic neonates: > 2.8  3.3 Why is your Therapeutic Objective different from your Operational Threshold? • Higher therapeutic goal is chosen to include a significant margin of safety • Note: Response to Rx is NOT necessary

17. Who’s at Risk? What could be the cause? At Risk Groups: A. Increased Insulin • Intrapartum glucose • Drug Treatment (eg. Propranolol) • Infant of Diabetic Mother • Asphyxia ,SGA • Insulinomas • Beckwidth’s syndrome • Familial or sporadic hyperinsulinemia • Familial or sporadic hyperammonemic hyperinsulinemia • Severe erythroblastosis fetalis • Panhypopituitarism

18. At Risk Infants/Causes II… B.Decreased Stores • Placental abnormalities • IUGR • Preterms <32 weeks, <1500g • Smaller of discordant twins (especially if discordant by >25% with wt <2kg) C. Increased Needs • Very immature, SGA (high brain:liver ratio) • Severely ill (RDS, Septic) • Brain injury meningitis, trauma, hemorrhage, hypoxia-ischemia (increased brain glucose needs) • Hypothermia • Cyanotic heart disease • Drug withdrawal, CNS irritability

19. At Risk Infants/Causes III… D.Inadequate production or substrate delivery • Delayed/ inadequate feedings • Transient developmental immaturity of critical metabolic pathways • Deficient brain glucose transporters: posthypoxia-ischemia, inherited glucose transporter defects • Galactosemia • Glycogen storage disease • Fructose intolerance • Maple syrup urine disease • Long- or medium-chain acyl-CoA dehydrogenase deficiency To name a few!!! Many more ……………………..!!

20. When do you screen these “at risk” babies? FIRST OF ALL in ANY BABY: If symptomatic: SCREEN IMMEDIATELY If asymptomatic but AT HIGH RISK including infant of diabetic mom, septic, premature (<32 wks), <1500g: Screen at 30-60 min of life If asymptomatic but AT RISK: Screen baby at 3-4 hrs of life ALWAYS CHECK VALUE WITH LAB TEST!! ONE VALUE IS SUFFICIENT FOR ACTION!

21. Practical Points for Blood Glucose Estimation • Can it be used for neonate? Dextrostix. • False positive: hematocrit <35%, contamination with isopropylalcohal. • False negative: hematocrit >55%. • Glucose level can fall by 14-18 mg/dl/hr. • False results if done < 18degree C or >35 degree C.

22. So…….. you’ve got a low glucose, Now WHAT DO YOU DO???

26. All others at risk: Glucose <2 mM: CONFIRM in lab, tell senior  FEED: 1) If still <2.0 (FF) or <1.5-1.7 (BF): • Consider IV D10W 4-6 mg/kg/min • Supplement BF & Feed q3h • Recheck in 1 hour • If <2.0,  IV 2 mg/kg/min •  1 ml/hr if >2.5 mM 2) If now 2.0-2.5  feed q3h and supp. if BF

27. Just some tips…. • Frequent boluses of D10W will induce a INSULIN SURGE and REBOUND HYPOGLYCEMIA  Try to use a max of 2 boluses of D10W • Always think about your maintenance fluid. If at TFI 120cc/kg/day for premie and 100cc/kg/day in term in first 24 hours, consider switching to D12.5W or D15W.

28. What can be done to prevent it? • Early feeding • Supplements by gavage if can’t suck • IV D10W >60 cc/kg/day (if can’t feed) • Prevent cold stress

29. What if hypoglycemia occurs prolonged, recurrent or persistent? Recurrent of Persistent Hypoglycemia: • Require infusions of large amts of glucose (>1216 mg/kg/min) to maintain normoglycemia

30. What if hypoglycemia occurs prolonged, recurrent or persistent? • Persisting or recurring beyond the first 7-14 days of life **Prompt recognition is essential!! These conditions are associated with severe disease at substantial risk of developing severe mental retardation and epilepsy. These include many conditions stated previously including: Hormone deficiencies, Hyperinsulinism syndromes, Defects in carbohydrate, amino acid, fatty acid metabolism

31. What tests should you do?What is your management? • Assay for insulin, C-peptide, cortisol, growth hormone, B-hydroybutyrate, lactate, free fatty acids, T4, TSH, gas • Urine for reducing substances, ketones, organic acids Management includes: • Glucagon (0.3 mg/kg/dose bolus or infusion 1-2 mg/day); Add 1 mg to 24 ml of D10W and run at 1 ml/hour through separate lie • If resistant to glucagon or unable to wean: problem of reference (no endocrinal clinic at present in Nepal) • Consider Diazoxide 8-15 mg/kg/day PO TID-QID, Hydrocortisone 5 mg/kg/day IV QID or Prednisone 2 mg/kg/day PO

32. Research Topic for Anyone? Department? MD Thesis? • Need long term prospective controlled study to resolve questions and allow correlation between plasma glucose, acute changes in neurological function and outcomes in Nepalese Children. • Relation of cord blood glucose with blood glucose during first two/three hours of life.

33. Great References… http://www.neonatology.org Koivisto M, Blaco-Sequeiros M, Krause U. Neonatal symptomatic hypoglycaemia: a follow-up study of 151 children. Dev Med. Child Neurol 1972; 14:603-14 Lucas A, Morley R, Cole TJ. Adverse deurodevelopmental outcome of moderate neonatal hypoglycemia. BMJ 297: 1304-1308, 1988. Pal DK, Manandhar DS, Rajbhandari S, Land JM, Patel N, de L Costello AM. Neonatal hypoglycaemia in Nepal 1. Prevalence and risk factors.Arch Dis Child Fetal Neonatal Ed. 2000 Jan;82(1):F46-51. Cornblath et al. Controversies regarding definition of neonatal hypoglycemia: suggested operational thresholds. Pediatrics 105: 153-157, 2000 Conrblath M and Ichord R. Hypoglycemia in the neonate. Seminars in Perinatology 24: 136-151, 2000

34. “A man with a watch knows what time it is. A man with two watches is never sure” Thank you for your attention. I hope it was interesting. Please give your feed back,, you may not write your name.