1. Canadian Pediatric Society (CPS) Position Statement: Screening guidelines for newborns at risk for low blood glucose Dr. Hannah Weinstangel, PGY4 October 9, 2015

2. OBJECTIVES 1.Improve CanMeds competencies 2.Develop an approach to critical appraisal of practice guidelines and apply it to the CPS Neonatal Hypoglycemia guidelines 3.Define hypoglycemia 4.Develop an approach to diagnosis of neonatal hypoglycemia 5.Develop an approach to treatment of neonatal hypoglycemia

3. Source: Royal College of Physicians and Surgeons of Canada

4. CAN MEDS COMPETENCIES SCHOLAR: Gain knowledge about neonatal hypoglycemia and its diagnosis and treatment Gain knowledge about critical appraisal of practice guidelines HEALTH ADVOCATE: Advocate for effective diagnosis and treatment of neonatal hypoglycemia MANAGER: Allocate appropriate healthcare resources and manage neonatal hypoglycemia as part of a health care team, taking on a leadership role when appropriate

5. CAN MEDS COMPETENCIES COLLABORATOR: Approach the theory and practice of neonatal hypoglycemia and the CPS recommendations on this with members of the health care team COMMUNICATOR: Ask questions about and discuss neonatal hypoglycemia and the CPS approach to this issue Improve ability to discuss neonatal hypoglycemia with families and other members of the health care team PROFESSIONAL: Demonstrate professional behaviour during discussions about neonatal hypoglycemia

6. Source: U of A EBM toolkit, Critical appraisal of practice guidelines

7. Screening guidelines for newborns at risk for low blood glucose K. Aziz & P. Dancy Pediatrics & Child Health 2004

8. SEARCH STRATEGY MEDLINE search, up to 2004 Key words: Hypoglycemia, blood glucose, All infant: birth- 23 months Limits: Human, English, French Inclusion: all trials, reviews, clinical practice guidelines, follow-up studies, meta-analyses Cochrane Database Inclusion: articles relating to glucose and infant feeding *note: NO randomized clinical trials found

9. SEARCH STRATEGY Thorough search of a comprehensive database (Medline) + Cochrane database - Sensible process? Explicit process (clearly stated in methods) Inclusive (age birth – 23 months, types of studies) Excludes studies not in English or French Data now 11 years old

10. LEVELS OF EVIDENCE 1a: Systematic review of randomized controlled trials 1b: Individual randomized controlled trials (with narrow confidence interval) 1c: All cases affected before intervention, some or non affected after intervention 2a: Systematic review of cohort studies 2b: Individual cohort study (including low-quality randomized controlled trial) 2c: ‘Outcomes’ research 3a: Individual case-control studies 3b: Systematic review of case-control studies 4: Case series (and poor-quality cohort and case-control studies) 5: Expert opinion without explicit critical appraisal, or based on physiology, bench research or ‘first principles’ Source: Oxford Centre for Evidence-Based Medicine

11. LEVELS OF RECOMMENDATION A: Consistent level 1 studies B: Consistent level 2 or 3 studies or extrapolations from level 1 studies C: Level 4 studies or extrapolations from level 2 or 3 studies D: Level 5 evidence or troublingly inconsistent or inconclusive studies of any level Source: Oxford Centre for Evidence-Based Medicine

12. NEONATAL HYPOGLYCEMIA Level of blood glucose low enough to cause symptoms What are some symptoms of hypoglycemia?

13. NEONATAL HYPOGLYCEMIA Level of blood glucose low enough to cause symptoms CNS/autonomic: jitteriness, tremors, convulsions, limpness, lethargy, eye-rolling, diaphoresis, hypothermia, high-pitched cry RESPIRATORY: cyanosis, tachypnea, apnea CVS: pallor, cardiac failure/arrest GI/nutrition: feeding difficulty *note: all inter-related! *note: symptoms can be seen with other diagnoses, so always keep a differential in mind, consider other diagnoses if glucose administration does not improve symptoms

14. NEONATAL HYPOGLYCEMIA What blood glucose level is too low for a neonate? WHY?

15. NEONATAL HYPOGLYCEMIA No single blood glucose value will reliably lead to these symptoms in all clinical situations/in all infants

16. NEONATAL HYPOGLYCEMIA WHAT IS A SAFE RANGE FOR BLOOD GLUCOSE? NORMATIVE RANGES: Based on studies of exclusively breastfed, appropriate for gestational age, term babies Blood glucose at birth: 2/3 maternal level Within 1 hour after birth: falls to 1.8 mmol/L (based on individual cohort study, level 2B evidence) Then rises to > 2.0 mmol/L x 72 hours 12-14% of these babies have blood glucose < 2.6 mmol/L in first 72 hours of life Healthy newborns can have blood glucose levels as low as 1.8 mmol/L at 1 hour of life (based on systematic review of cohort studies, level 2a evidence)

17. NEONATAL HYPOGLYCEMIA WHAT IS A SAFE RANGE FOR BLOOD GLUCOSE? PRESENCE OR ABSENCE OF SEQUELAE: Based on studies of at-risk term, preterm (< 37 weeks GA), and small for gestational age (SGA, weight < 10%ile) infants Blood glucose < 2.6 mmol/L  short –term neurological sequelae (based on case series/poor-quality cohort and case-control studies, level 4 evidence)  long-term neurological sequelae (based on systematic review of cohort studies, level 2a evidence)  neuroimaging changes (based on case series/poor-quality cohort and case-control studies, level 4 evidence) PROSPECTIVE CLINICAL TRIALS: Does benefit of intervention outweigh risks?

18. NEONATAL HYPOGLYCEMIA WHAT IS A SAFE RANGE FOR BLOOD GLUCOSE? PRESENCE OR ABSENCE OF SEQUELAE: Based on studies of infants of diabetic mothers (IDMs): Blood glucose < 1.6 mmol/L  negative effect on long-term outcome Blood glucose < 1.5 mmol/L  neurological dysfunction, even if asymptomatic Based on studies of SGA infants: Blood glucose < 2.6 mmol/L  lower head circumference, lower developmental scores long- term Based on studies of preterm infants: Blood glucose < 2.6 mmol/L  adverse long-term effects (based on individual cohort studies, level 2b evidence)

19. NEONATAL HYPOGLYCEMIA WHAT IS A SAFE RANGE FOR BLOOD GLUCOSE? PROSPECTIVE CLINICAL TRIALS: Does benefit of intervention outweigh risks? No randomized controlled trials of interventions at differing thresholds

20. NEONATAL HYPOGLYCEMIA When considering these values, keep in mind… 10% variation between capillary, venous whole blood, and plasma glucose values – inconsistency in sampling methods across studies ASSOCIATION ≠ CAUSATION!

21. SCREENING…

22. SCREENING No study looks specifically at optimal timing and intervals for glucose screening Limited value in screening infants in the first few hours of life, as levels are not yet stable WHO recommendation, 1997: Screen at 4-6 hours of life (based on expert opinion without explicit critical appraisal, or based on physiology, bench research or ‘first principles’, level 5 evidence)

23. SCREENING Studies based on large for gestational age (LGA, weight > 90%ile) infants or IDMs: Earlier hypoglycemia, vulnerable until 12 hours of life + feeding/IV infusion established Studies based on preterm and SGA infants: Earlier hypoglycemia, vulnerable until 36 hours of life + feeding/IV infusion established CPS recommendation: Screen all symptomatic infants Screen asymptomatic at-risk (preterm, SGA, LGA, IDM) infants at 2 hours of life, after initial feed (breastfeed or 5-10 ml/kg formula or glucose water), and continue q3-6 hours until initial period of risk is over Period of risk for IDM and LGA: 12 hours of age Period of risk of preterm and SGA: 36 hours of age (based on expert opinion, level 5 evidence)

24. SCREENING “Point of care” (POC) testing: capillary blood “chemstrip” Pros: convenient, fast, cheap Cons: unreliable at low glucose levels, prone to sample & observer error, variations between types of blood and sample storage may confound results, repeating tests makes it less fast/cheap (Based on individual case-control study, level 3b evidence) CPS recommendation: If POC testing used, there must be a formal process in place to assure quality control at the bedside Rapid lab testing should be available to verify levels that require intervention

25. INTERVENTION…

26. WHEN TO INTERVENE Severity of sequelae  duration of hypoglycemia (based on individual cohort study, level 2b evidence) Historically, aim for blood glucose ≥ 2.6 mmol/L, intervene when blood glucose ≤ 2.0 mmol/L (based on expert opinion, level 5 evidence) CPS recommendation: If symptomatic and blood glucose < 2.6 mmol/L, treat immediately with IV dextrose If asymptomatic and blood glucose < 1.8 mmol/L – 2.5 mmol/L, initiate enteral supplementation and check levels q60 min If at risk (preterm, SGA, LGA, IDM) and asymptomatic: Give dextrose infusion if blood glucose < 1.8 mmol/L after one feed or < 2.0 mmol/L after subsequent feed Consider IV dextrose infusion if persistent blood glucose < 2.6 mmol/L despite feeding

27. HYPOGLYCEMIA INTERVENTION Prevention and treatment options: Increased breastfeeding frequency (ideally ad lib on demand) Supplementation with breastmilk or formula (PO or NG) *No clinical trials performed to evaluate benefit of one option over another *After feed, recheck blood glucose within 60 minutes to ensure response *Volumes based on size, age, gestation

28. HYPOGLYCEMIA INTERVENTION If enteral feeding not effective or if symptomatic: IV dextrose bolus 2 ml/kg 10% dextrose (based on case series, poor-quality cohort or case-control studies, level 4 evidence) 80 ml/kg/day of 10% dextrose = 5.5 mg/kg/min glucose) (based on systematic review of case-control studies, level 3b evidence) *recheck blood glucose within 30 minutes to ensure response If blood glucose > 2.6 mmol/L: Continue to monitor for 12 hours, then trial off IV dextrose

29. HYPOGLYCEMIA INTERVENTION If blood glucose still < 2.6 mmol/L: Stepwise increase in glucose supply and check levels q30 min: Increase by 25%: Change from D10 to D12.5 or from 80 ml/kg/day to 100 ml/kg/day If levels still low, keep increasing until you get to D12.5 at 120 ml/kg/day (10.4 mg/kg/min)

30. HYPOGLYCEMIA INTERVENTION If blood glucose still < 2.6 mmol/L: Consult endo Investigate for other diagnoses on your differential: endocrine pathology (hyperinsulinism), inborn errors of metabolism IV glucacon: bolus (0.1 mg/kg to 0.3 mg/kg) or infusion (10 -20 mcg/kg/h) to raise blood glucose and prevent further hypoglycemia *Fluid intake should not exceed 100 ml/kg/day without careful monitoring for fluid overload and dilutional hyponatremia Other treatments to consider: Hydrocortisone, diazoxide, octreotide (limited data)

31. Source: Nelson’s

32. FAMILY-CENTRED CARE Inform caregivers that their child is at risk and requires blood testing at regular intervals Educate caregivers about hypoglycemia – CPS has a great handout! http://www.caringforkids.cps.ca/handouts/blood_glucose_in_ne wborn_babies http://www.caringforkids.cps.ca/handouts/blood_glucose_in_ne wborn_babies Caregiver participation in monitoring when appropriate Keep caregivers informed about any changes in their child’s presentation, any treatment, and test results

33. RECOMMENDATIONS…

34. RECOMMENDATIONS: SCREENING No need to screen low-risk/healthy, asymptomatic infants for hypoglycmia (Grade C recommendation) Screen for hypoglycemia as soon as there are symptoms Screen asymptomatic, at-risk infants (preterm, SGA, LGA, IDM) at 2 hours of life, after initial feed (breastfeed or 5-10 ml/kg formula or glucose water), and continue q3-6 hours until initial period of risk is over [Level 5 evidence, Grade C (preterm, SGA, IDM) & D (LGA) recommendation]

35. RECOMMENDATIONS: SCREENING Screen IDM with stable blood glucose > 2.6 mmol/L once or twice per day before feeds until 12 hours of age Screen preterm and SGA infants with stable blood glucose > 2.6 mmol/L once or twice per day before feeds until 36 hours of age (Level 2b evidence, grade C recommendation)

36. RECOMMENDATIONS: SCREENING If POC testing used, there must be a formal process in place to assure quality control at the bedside Testing should be accurate within the range of 1-3 mmol/L Rapid lab testing should be available to verify levels that require intervention (level 3b evidence, grade D recommendation)

37. RECOMMENDATIONS: MANAGEMENT If symptomatic and blood glucose < 2.6 mmol/L, treat immediately with IV dextrose If asymptomatic and blood glucose < 1.8 mmol/L – 2.5 mmol/L, initiate enteral supplementation and check levels q60 min (Grade D recommendation) If at risk (preterm, SGA, LGA, IDM): Give dextrose infusion if blood glucose < 1.8 mmol/L after one feed or < 2.0 mmol/L after subsequent feed, even if asymptomatic Consider IV dextrose infusion if persistent blood glucose < 2.6 mmol/L despite feeding (Level 2b & level 5 evidence)

38. RECOMMENDATIONS: MANAGEMENT If initiating treatment, initiate concurrent workup of etiology If persistent blood glucose < 2.6 mmol/L despite IV dextrose, consult endo, investigate DDx, and treat with other medication (Grade C recommendation)

40. Source: U of A EBM toolkit, Critical appraisal of practice guidelines

41. DISCUSSION Please feel free to share stories from your own practice! Is the practice guideline of high quality? What do you think about the recommendation for screening? What do you think about 2.6 mmol/L as a low glucose cut off? What do you think about POC testing at the bedside? What improvements could we make to neonatal hypoglycemia screening and management? There are a lot of opportunities for research in this field! What are some of the barriers?

42. REFERENCES 1.Aziz, K & Dancey, P. Screening guidelines for newborns at risk for low blood glucose. Pediatrics and Child Health. 2004. 9(10):723-9. 2.CanMeds framework. Royal College of Physicians and Surgeons of Canada. Online. Accessed October 4, 2015. http://www.royalcollege.ca/portal/page/portal/rc/canmeds/framework http://www.royalcollege.ca/portal/page/portal/rc/canmeds/framework 3.Evidence-based medicine toolkit. University of Alberta. Online. Accessed October 4, 2015. http://www.ebm.med.ualberta.ca/CPG.htmlhttp://www.ebm.med.ualberta.ca/CPG.html 4.Oxford Centre for Evidence-Based Medicine. Levels of evidence and grades of recommendation. Online. Accessed October 4, 2015. http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence- march-2009/ http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence- march-2009/ 5.Williams, AF. Hypoglycemia of the newborn: A review. Bull World Health Organ. 1997. 75:261-290. 6.Nelson’s Textbook of Pediatrics, 19 th Ed. Kleigman et al. Elsevier, Philadelphia, Pa. Chapter 86: Hypoglycemia. Page 520.