Neonatal Hypoglycemia in newborn diagnosis and management

Neonatal hypoglycaemia

1. Hypoglycemia in newborn Somosri

2. Objectives Operational threshold Screening of high risk neonate Measurement of blood glucose Best practice for prevention Management of asymptomatic hypoglycemia Management of symptomatic hypoglycemia Evaluation in refractory & prolonged hypoglycemia

3. Adaptive changes at birth

4. Changes at birth

5. Preterm at high risk of hypoglycemia Low glycogen stores Activity of microsomal glucose-6-phosphatase (the final enzyme of glycogenolysis & gluconeogenesis) - extremely low i.c.t term C annot mount mature counter-regulatory ketogenic responses to low blood glucose levels in the first week Immaturity of counter-regulatory hormonal response H igher basal insulin secretion as compared to term

6. Clinical definition C linically significant hypoglycemia is diagnosed if Whipple’s triad (Whipple & Frantz 1935) is present: Presence of characteristic clinical manifestations clinical manifestations occurring in presence of low plasma glucose clinical signs resolve within minutes to hours, after normalization of blood glucose Limitations: May be different from the levels at which biochemical injury occurs Does not take into account “asymptomatic hypoglycemia ”

7. Metabolic definition The concentration of blood glucose at which counter-regulatory hormonal response is elicited Limitations: L ittle information available in neonates for - counter-regulatory hormonal stress response, autonomic , neuroglycopenic signs, impaired cognitive function i.c.t adults ( Mitrakou et al., 1991; Ward Platt & Deshpande , 2005 ) Preterms unable to mount a mature counter-regulatory response ( Hawdon et al., 1992).

8. Neurophysiological definition Koh et al. described abnormalities of brain-stem auditory or somatosensory evoked potentials in neonates having blood glucose less than 47mg/dl ( Koh et al., 1988 ). Researchers failed to reproduce distinct threshold on basis of evoked potentials in both term and preterm ( Pryds et al ., 1988; Cowett et al., 1997 ) .

9. Blood Glucose vs. CBF ( Pyrds et al 1990) Pryds et al: Hypoglycemic infants (N=13, mean B.Wt 1,500 g) Vs normoglycemic controls (N=12, mean B.Wt 1,310 g) Cerebral blood flow and plasma epinephrine concentrations were increased among hypoglycemic infants<30mg/dl

10. Plasma Glucose Values and Risk of CNS Injury Risk of neurological sequelae at plasma glucose < 25 mg/ dL ( Alkalay et al.2006 ) Minimal brain dysfunction at 8 yrs in IDM with plasma glucose < 27 mg/ dL ( Stenninger et al.1998 ) White matter injury in 94% with those with blood glc < 20 mg/ dL (Burns et al., 2008) Neuronal and glial injury with blood glucose < 20 mg/ dL (Anderson et al., 1968)

11. Brand et al Effect of transient hypoglycemia on neurodevelopment 75 healthy term LGA neonates Hypoglycemia only on postnatal day 1, value < 40 mg% Neurodevelopment at 4 years of age – Denver development scale No difference among hypoglycemia and no-hypoglycemic neonates Lucas et al n=661, < 1850 gms Blood glucose < 47 mg% RR 3.5 (95% CI: 1.3 to 9.4) for cerebral palsy or developmental delay for ≥ 5 days Duration of hypoglycemia Percent of all infants studies Percent with neurodevelopment impairment ≥ 3 days 15 29 ≥ 5 days 6 42 ≥ 7 days 3 40 Brand, ADC Fetal Neon Ed, 2004 Lucas, BMJ, 1988

12. Operational definition Cornblath’s description 1.Healthy term-<24 hr of age 30-35mg/dl acceptable, raised to >45 mg/dl if recurs after feed/in first 24 hr >24hr threshold 45 mg/dl 2.With abnormal sign symptoms-45mg/dl 3.Asymptomatic with risk factors- 36mg/dl 4.For any baby if plasma glucose<20-25mg/dl- IV glucose needed 5.In all other newborns, a screening glucose level of < 40mg/dl requires a follow up laboratory test 6.The therapeutic goal in all cases is to maintain a plasma glucose level above 40mg% on the first day of life and above 50mg% thereafter .

13. Operational threshhold Absence of concensus in literature of definition (AAP,2011) Infants>48 hour of life should have higher threshold (>60mg/dl) for plasma glucose ( Pediatric endocrine society,2015)

14. High risk newborns Low birth weight infants Preterm infants Small for gestational age infants Infant of diabetic mothers (IDM) Large for gestational age (LGA) infants Infants with Rh- hemolytic disease Infants born to mothers receiving therapy with terbutaline /propranolol/ labetolol /oral hypoglycemic agents Any sick - with perinatal asphyxia, polycythemia , sepsis, shock Infants on total parenteral nutrition

15. Indication and Frequency of RBS Monitoring ( Screening in High Risk) Condition Frequency Hyperinsulinemic States ( IDM, LGA +2SD, Hydrops, Mother received IP glucose> 20g/hr or maternal BS>120 md/dl) 1,3,6 hrs & hence 6 hrly for 48 hrs Preterm & SGA 1,3,6 hrs and hence 6 hrly for 72 hrs I VF and TPN 6 hrly DVET with CPD blood 2 hrs after DVET

16. Best practices for prevention of hypoglycemia Anticipation and prevention are key to management of hypoglycemia Stabilization- T ABC Keep baby warm – skin to skin Baby should be nursed in thermoneutral environment Feed baby within 30-60 minutes For ALL babies

17. Glucometer accuracy +10mg/dL 55 45 75% of the time, the glucometer overestimates blood glucose May may be be

18. Hatched area indicates safe areas for puncture site. Warm site with soft cloth, moistened with warm water for 3-5 minutes Cleanse site with alcohol prep. Wipe DRY with sterile gauze pad . Puncture skin, wipe off first drop of blood with sterile gauze use second drop of blood

19. Source of error Contamination by the alcohol antiseptic solution- erroneously high values In equal volume of blood and plasma, the glucose is 18% higher in plasma Glucose fall by 10-15mg/dl/ hr High hematocrit - falsely low blood glucose Presence of hemolysis - falsely low values. Deproteinization of the sample reduces the interference by hemolysates , uric acid, and bilirubin

20. CGMS Subcutaneous glucose oxidase based platinum sensor- Interstitial glucose is catalyzed & electrical current is produced every 10 sec –average of 5min displayed Other devices: Microdialysis Devices utilizing optical sensors- spectrophotometry Transdermal devices using reverse iontophoresis

21. Uettwiller F et al . Real-Time Continuous Glucose Monitoring Reduces the Duration of Hypoglycemia Episodes:A Randomized Trial in Very Low Birth Weight Neonates.PLoSONE 2015 .

22. Case 1: 29 weeker 900gmer girl baby born by PTVD due to placental abruption. Cried at birth. Stable o n CPAP 5/25% at CLR. Was on total IV fluid & caffeine. At 12 hour of age developed 1 episode of central apnoea. RBS was low. Baby was hypothermic. What will be your action?

23. Management of symptomatic hypoglycemia B olus of 2 mL/kg of 10% dextrose given . Followed by continuous glucose infusion at an initial rate of 6mg/kg/min . Ensure continuous glucose infusion using an infusion pump and without any interruption. Avoid using more than 12.5% dextrose infusion through a peripheral vein Two IV cannulas are necessary if baby is on GIR

24. What is GIR ? GIR= Glucose Infusion Rate ( mg/kg/min of glucose) Useful formulae: GIR = % of dextrose being infused x rate (mL/ hr ) body weight (in kg) x 6 GIR = IV rate (mL/kg/day) x % of dextrose 144 GIR= Fluid rate (mL/kg/day) x 0.007 x % of dextrose infused Example: 2 kg baby on 100 ml/kg/d IV fluids needs GIR 6 mg/kg/min 6hrly : Fluids= (100x2)/4= 50 ml Glucose= 6x2x 60x 6= 4320 mg Let x ml 10%D and y ml 5%D needed to make IV solution for 6hrs 1ml 10%D= 100 mg glucose and 1ml 5%D= 50 mg glucose

25. How to calculate GIR ? Example: 2 kg baby on 100 ml/kg/d IV fluids needs GIR 6 mg/kg/min 6hrly : Fluids= (100x2)/4= 50 ml Glucose = 6x2x 60x 6= 4320 mg Let x ml 10%D and y ml 5%D needed to make IV solution for 6hrs 1ml 10%D= 100 mg glucose and 1ml 5%D= 50 mg glucose So, Equation1 : x + y = 50 (6 hrly IV fluid) Equation 2: 100x + 50y= 4320 (6hrly Glucose requirement) Solving for x and y, x=36.4 ml ( 10% D q6hrly) y=13.6 ml ( 5% D q6hry) Alternative: 1. Ready reckoners and nomograms available 2. Calculator and apps

26. Blood glucose monitoring & hiking of GIR

27. Tapering & stopping of GIR Tapering has to be accompanied by concomitant increase in oral feeds. Once a rate of 4 mg/kg/min of glucose infusion is achieved and oral intake is adequate and the RBS are consistently >50 mg/ dL , the infusion can be stopped. Do not stop glucose infusion abruptly as severe rebound hypoglycemia may occur

28. Case 2: 37 weeker 1.9 kg boy baby born by emergency section (indication: severe PIH).Transition smooth. Roomed with mother. On breast feeding. Otherwise alert, active. Routine screening revealed RBS 32 mg/dl at 2hrs of age. What will be your action? When will you check RBS again? Depending on RBS what will do ?

29. Management of asymptomatic hypoglycemia ?

30. Treatment algorithm of hypoglycemia

31. CASE 3: 38 weeker 2 kg boy baby on GIR 12mg/kg/min, onset of hypoglycemia started by 6 hr , again showed RBS 36mg/dl on routine monitoring at 60 hr of life. What will be your next action? Do you want to re-examine the baby? (wide open AF, course facies , midline defect, micropenis , detail examination of genitalia, hemihypertrophy , organomegaly , cataract, urine odour) What investigation do you want to send?

32. Refractory/persistent hypoglycemia : (GIR>12 mg/kg /min or persisting >7days

33. Investigations for Refractory and Prolonged Hypoglycemia First Line Ix: Insulin, Cortisol, TFT, Urine for ketone and reducing substance Second Line Ix: (When other etiologies suspected) CAH: 17-OH-P 2. Suspected IEM- Blood gas, NH3, Lactate, GALT, TMS/GCMS 3. Hypopituitarism: GH, ACTH 4. Glucagon Deficiency: Glucagon Levels

34. Should we send insulin in first 48 hrs ? After birth , in normal newborns the mean plasma glucose drop by 25–30 mg/dl to a nadir of 55–60 mg/dl by 1–2 hours of age; then steadily rise to return to the normal range by day 3 . In normal newborn- in first 48 hours of age insulin (49 ± 19 μU /ml) were not suppressed at low plasma glucose levels of 44 ± 20 mg/dl Studies suggest that transitional neonatal hypoglycemia is associated with incomplete suppression of insulin secretion. Cornbalth M. New Engl J Med. 1965 Isles et al. Pediatr Res. 1968

35. Differentiation of an infant with a persistent hypoglycemia disorder may not be possible during the period of transitional neonatal hypoglycemia, but should become feasible after the period of transitional neonatal hypoglycemia has resolved by day of life 2 or 3. For this reason, the Pediatric Endocrine Society guide for hypoglycemia in neonates recommends that the focus for the first 24–48 hours of life should be on stabilization of glucose levels; whereas after 48 hours, neonates whose glucose values remain low or who have other risk factors should be evaluated to determine the etiology of hypoglycemia and ensure their safety prior to discharge .

36. P lasma insulin >2 μU / mLin presence of hypoglycemia (<50 mg/ dL ) and/or evidence of excessive insulin effect Increased glucose consumption rate (> 8 mg/kg/min) Hypofattyacidemia ( <1.5 mmol /L) Hypoketonemia ( <2.0 mmol /L) Glycemic response to 1 mg IV glucagon (Δ glucose >30 mg/ dL )

37. Drugs in refractory hypoglycemia Hydrocortisone 10 mg/kg/day IV or PO in two divided doses for 24 to 48 hrs Diazoxide - orally 10-25 mg/kg/day in three divided doses Glucagon 0.3mg/kg/dose (max-1mg)IM,IV,SC Octreotide ( 2-10 μg /kg/day subcutaneously 2-3 times a day.

38. Summary and Conclusions It is prudent to screen at-risk infants Operational and therapeutic thresholds are likely unique to each neonate Asymptomatic hypoglycemia should be treated with trial feed if RBS>25mg/dl Symptomatic hypoglycemia should be treated with bolus followed by glucose infusion Refractory hypoglycemia need detail investigation