W1A- Cases I Learned From

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1 W1A- Cases I Learned From David H Adamkin, MD Professor of Pediatrics Director, Division of Neonatology Director of Nutritional Research Rounsavall Chair of Neonatal Medicine Co-Director of Neonatal Fellowship University of Louisville Louisville, Kentucky

2 Disclosure of Relevant Relationship Dr. Adamkin (or spouse/partner) has disclosed the following commercial industry affiliation and/or financial relationship in the past 12 months: Company/Organizati on Individual with COI All COIs have been resolved prior to this presentation Dr. Adamkin will support this presentation and clinical recommendations with the best available evidence from medical literature. Dr. Adamkin does not intend to discuss an unapproved/investigative use of a commercial product/device in this presentation. Role Medolac Self Consulting Fee, Ownership interest

3 Cases I learned From ARS 50 th Pediatric Postgraduate Course: Perspectives in Pediatrics Miami, Florida March 2015 David H Adamkin Professor Of Pediatrics Director of Division of Neonatology Director of Nutritional Research Rounsavall Chair of Neonatal Medicine Co-Director of Neonatal Fellowship University of Louisville

4 Dr Adamkin is : Practice Question a) Intelligent b) Handsome c) Great teacher d) All of the above

5 Neonatal Hypoglycemia Relatively common and important disorder Most often temporary Infants of Diabetic Mothers Prematurity Small-for-gestational-age infants Long term concern - seizures and permanent brain injury Recognize genetic and non-genetic persistent hypoglycemia disorders

6 QUESTIONS Definition of Neonatal Hypoglycemia? (NH) Who is at risk? When should at risk be screened? How should screening be performed? Level of blood glucose requiring intervention? What interventions should be done when neonatal hypoglycemia is suspected? How frequently should asymptomatic be screened? How do we educate caregivers and standardize guideline

7 WHAT IS A NORMAL BLOOD GLUCOSE? 36 Mg/dl 20 (2.0) (mmol/l) (1.1) (2.5) Hypoglycemia 30 (1.7) Level duration (3.0) (6.0) damage? (2.2) 47 (2.6) (3.3) 50 (2.7) pragmatic intervention thresholds (that also provide a margin of safety) Operational threshold Nondisease term

9 OPERATIONAL THRESHOLDS Concentrations of glucose that have not been shown to be associated with any deviations in metabolic, physiologic or neurologic dysfunction. Significant hypoglycemia is not and can never be defined by a single number that can be applied universally to every individual patient Rather it is characterized by value(s) that are unique to each individual and varies with both their state of physiologic maturity and the influence of pathology Cornblath, Peds 2000

10 Screening and management of Postnatal Glucose Homeostasis in Late Preterm and Term SGA, IDM/LGA Infants [(LPT) Infants / 7 weeks and SGA (screen 0-24 hrs); IDM and LGA > 34 weeks (screen 0-12 hrs)] Symptomatic and <40mg/dl IV Glucose Birth to 4 hours of age ASYMPTOMATIC 4 24 hours of Age INITIAL FEED WITHIN 1 Hour Screen glucose 30 minutes after 1 st feed Initial Screen <25mg/dl Feed and check in 1 hour <25mg/dl 25 40mg/dl Continue feeds q2-3 hours Screen Glucose prior to each feed Screen <35mg/dl Feed and check in 1 hour <35mg/dl 35 45m/dl IV Glucose* Refeed/IV Glucose* as needed IV Glucose* Refeed/IV Glucose* as needed Target Glucose screen 45mg/dl prior to routine feeds *Glucose dose = 200mg/kg (dextrose 10% at 2ml/kg) and/or IV infusion at 5 8mg/kg/min (80 100ml/kg/d) Achieve plasma glucose 40 50mg/dl. Symptoms of Hypoglycemia include: Irritability, tremors, jitteriness, exaggerated moro reflex, high-pitched cry, seizures, lethargy, floppiness, cyanosis, apnea, poor feeding.

11 ARS QUESTION 1 Which one of the following is NOT a risk factor for developing Neonatal Hypoglycemia? A. Small for Gestational Age B. Late Preterm C. Large for Gestational Age D. Maternal Diabetes E. Oligohydramnios

12 Canadian Pediatric Statement (CPS) American Academy of Pediatrics (AAP) Infants considered at risk develop lower levels of blood glucose, particularly if levels persist or recur may be associated with adverse outcomes AT RISK SGA IDM LGA PT

13 Clinical Case Synopsis A term AGA infant is born by NSVD with Apgars of 8 and 9 to a 30 year old primigravida after an uneventful pregnancy including a normal glucose tolerance test during pregnancy. Mother wants to exclusively breast feed. She feeds the infant in the delivery room. At 2 hours of age before she attempts breast feeding again the nurse does a point-of-care glucose level in this asymptomatic infant and it is 36mg/dl. Nurse tells Mom the baby is hypoglycemic and that the baby needs to be supplemented with formula. Mother is very disappointed.

14 ARS QUESTION 2 Should this term AGA asymptomatic breastfeeding infant been screened for glucose level? A. Yes B. No

(Houston et al Early Human Development 1983) (15-20ml/k/d) Suckling

15 Breastfeeding Breastfeeding average intake of colostrum ± 7 mls/feed in the first 24 hours. (Houston et al Early Human Development 1983) (15-20ml/k/d) Suckling ketogenesis 12 14% of normal, AGA, breastfed newborns have a blood glucose level of <47mg/dl in the first 3 days of life

NEURONAL FUEL ECONOMY AVAILABLE ALTERNATIVE FUELS KETONE BODIES CONCURRENT NEONATAL CONDITIONS HYPOXIA SEPSIS LACTATE AA s ADAPTABILITY OF LOCAL MICROCIRCULATION Given

16 NEURONAL FUEL ECONOMY AVAILABLE ALTERNATIVE FUELS KETONE BODIES CONCURRENT NEONATAL CONDITIONS HYPOXIA SEPSIS LACTATE AA s ADAPTABILITY OF LOCAL MICROCIRCULATION Given complexity of defining adequacy of neuronal fuel adequacy concept of rigid threshold for blood glucose is challenged Clinical exam is more important than glucose level

17 Canadian Pediatric Statement (CPS) American Academy of Pediatrics (AAP) Infants considered at risk develop lower levels of blood glucose, particularly if levels persist or recur may be associated with adverse outcomes AT RISK SGA IDM LGA PT

18 ARS Question 3 The initial glucose screening test should be performed in the first hour of life? A. Yes B. No

19 ARS Question 4 Another infant has an initial point of care glucose of 27mg/dl (Plasma 36mg/dl) at one hour of age This probably is reflective of the nadir during Postnatal glucose homeostasis A. True B. False

20 British routine is initial screening glucose before second feed Insulin Glucagon Mobilize glycogen 1 Pildes 1986

Clinical Case Synopsis Term AGA infant after NSVD with Apgars of 5,7 and 8 received blow-by oxygen for cyanosis in the delivery room for approximately one minute.

21 Clinical Case Synopsis Term AGA infant after NSVD with Apgars of 5,7 and 8 received blow-by oxygen for cyanosis in the delivery room for approximately one minute. The pregnancy was not complicated by diabetes. The baby is well and goes to the well baby nursery. On arrival to the nursery at one hour of age because of the cyanosis in the delivery room the staff does a point-of-care glucose and it is 27mg/dl. A simultaneous plasma glucose was sent to the lab and comes back at 90 minutes of age and is 36mg/dl.

ARS Question 5 Which statement is true about the Plasma glucose level at one hour (35mg/dl) differing so much from the point-ofcare glucose level done simultaneously? A.

22 ARS Question 5 Which statement is true about the Plasma glucose level at one hour (35mg/dl) differing so much from the point-ofcare glucose level done simultaneously? A. Plasma levels are always lower than point-of care levels B. At higher levels of glucose there is more disparity between point-of- care levels versus plasma levels C. Bedside screening values are not as accurate as plasma levels and are particularly disparate at low levels of glucose.

23 Clinical Case Synopsis A term male infant weighing 4500grams (LGA by Weight) AGA by HC/L is delivered by C section to a 21year old primigravida who had no prenatal care. Apgars were 6 and 7. Baby went to the well baby nursery in good condition. At 6 hours of age the infant appears lethargic, feeding poorly at the breast and is jittery. A bedside glucose determination was performed and it was 10mg/dl. A plasma glucose level was sent to the lab. It comes back approximately 45 minutes later and was 15 mg/dl.

24 ARS Question 6 When should this macrosomic infant born to a diabetic mother with no prenatal care had its first screening bedside glucose? A. Immediately after delivery B. When it became symptomatic C. At 30 minutes after its first feeding which should have taken place by one hour of age.

25 ARS Question 7 This infant at 6 hours of age has signs that could be consistent with Hypoglycemia? A True B. False

26 ARS Question 8 Your plan now would be which one of the following A. Immediately feed this infant at 6 hours of age B. Wait for the plasma glucose to come back to make a decision. C. Provide intravenous glucose by minibolus and /or intravenous glucose infusion at 5-8 mg/k/min while following serial glucose levels hourly until glucose rises above 40 to 50 mg/dl.

27 CEREBRAL ENERGY DEFICIENCY and SIGNIFICANT HYPOGLYCEMIA Since the avoidance of and treatment of cerebral energy deficiency is the principle concern, greatest attention should be paid to neurologic signs (eg) -variation in tone -change in level of consciousness -seizures

28 Hypoglycemia Red Flags Most neonatal hypoglycemia is due to aberrant metabolic adaptation after birth. Strategies to enhance the normal adaptive processes should help prevent such episodes. Further investigations and specific interventions should be considered 1. hypoglycemia persists 2. is of unusual severity 3. OR occurs in the absence of identified risk factors.

29 Neonates in Whom to Exclude Persistent Hypoglycemia Prior to Discharge Neonates with severe hypoglycemia (e.g., an episode of symptomatic hypoglycemia or requiring iv dextrose to treat hypoglycemia) Neonates unable to consistently maintain pre-prandial plasma glucose concentrations > 50 mg/dl by day 3 * Family history of a genetic form of hypoglycemia Congenital syndromes (e.g., Beckwith-Wiedemann), abnormal physical features (e.g., midline facial malformations, microphallus) * AAP guidelines are for first 24 hours. Glucose levels rise to near infant and older child levels by day of life 3.

30 Changes you may want to make in your practice Only screen at risk asymptomatic babies and of course any neonate with symptoms that could be related to abnormal postnatal glucose homeostasis Always screen 30 minutes after the first feed which should always take place within the first hour of life. Determine institutional preferences for operational thresholds to practice within for asymptomatic infants.

31 ADDITIONAL QUESTIONS For the Homies POSTNATAL GLUCOSE HOMEOSTASIS PERSISTENT HYPOGLYCEMIC SYNDROMES PEDIATRIC ENDOCRINE SOCIETY RECOMMENDATIONS

32 2014 SUBTITLE Reevaluating the AAP Statement on Postnatal Glucose Homeostasis: The Pediatric Endocrine Society Weighs in. AAP Statement Pediatric Endocrine Society

33 ARS QUESTION 1 Supplement The first 48 hours of Transitional Hypoglycemia in a newborn infant can be characterized as a transitional hyperinsulinemia? A. True B. False

34 ARS QUESTION 2 Supplement This Transitional Hyperinsulinemia over the first 48 hours is characterized by all of the following except which one? A. Decreased beta hydroxybutyrate B. Decreased acetoacetic acid C. Increased Lactate D. Decreased glycerol

35 Peds Endocrine Society(2014) TRANSITIONAL HYPERINSULINISM FIRST 48 HOURS Mean plasma glucose for suppression of insulin secretion is first 48 hours of life vs in older infants. (Glucose sensor-insulin secretion) LOWER GLUCOSE THRESHOLD for SUPPRESION of INSULIN. It is the level neuroendocrine responses are activated in adult. neurogenic response Defines normal level for the first 48hours of life in their statement The decreased glucose concentrations are associated with Lactate β OH butyrate and acetoacetate (hypoketonemic) Glycerol DECREASED Large glycemic response to glucagon or epinephrine Which is identical to HYPERINSULINEMIA

36 ARS QUESTION 3 Supplement The initial metabolic response to stabilize glucose levels the first four hours of life in the neonate comes from Glycogenesis A.True B.False

37 Glucose Homeostasis in Newborn Abrupt interruption umbilical glucose delivery glycerol?trigger Catabolic Cascade FFA s Catecholamines glucagon insulin Glycogenesis (immediate) glycogen synthase glucagon Glycogenolysis glycogen phosphorylase Free AA s Gluconeogenesis (by 4-6 hours of life) Glucose (Term infants have enough hepatic glycogen to maintain glucose supply ~ 10hrs) (rapidly available 1 st few hrs) Blood glucose 1 st hrs Cortisol HGH Volume enteral feeds Adaptation to enteral feeds

38 ARS QUESTION 4 Supplement The following statements concerning Postnatal Glucose Homeostasis in the newborn are true with the exception of which one statement? A. The neonates reach a nadir of glucose level at approximately one hour of age B. There is an initial surge in insulin right after delivery C. Glucagon promotes gluconeogenesis which is active by 4-6 hours of age. D. Glycogenolysis is initial metabolic process for stabilizing glucose the first hours of life

39 Glucose Homeostasis in Newborn Abrupt interruption umbilical glucose delivery glycerol?trigger Catabolic Cascade FFA s Catecholamines glucagon insulin Glycogenesis (immediate) glycogen synthase glucagon Glycogenolysis glycogen phosphorylase Free AA s Gluconeogenesis (by 4-6 hours of life) Glucose (Term infants have enough hepatic glycogen to maintain glucose supply ~ 10hrs) (rapidly available 1 st few hrs) Blood glucose 1 st hrs Cortisol HGH Volume enteral feeds Adaptation to enteral feeds

40 ARS QUESTION 5 Supplement The mean plasma glucose at which suppression of insulin occurs is lower in the neonate the first 48 hours of life than days 3-5. A. True B. False

41 ARS QUESTION 6 Supplement The cord blood plasma glucose of the neonate is which percentage of the maternal level at delivery? A. 30% B. 40% C. 50% D.70%

42 Glucose Homeostasis in Newborn Basal glucose utilization 4 to 6 mg/kg/min (2x wt specific rates in adult) Birth ~ 70% maternal level first few hours as low as 30 mg/dl (1.7mmol/L) then attains Metabolic transition to independent glucose production and establishes POSTNATAL GLUCOSE HOMEOSTASIS Until exogenous supply of substrate provided, hepatic glucose output serves as most significant source of glucose to meet demands

43 ARS QUESTION 7 Supplement An infant that has had symptomatic hypoglycemia and or required intravenous glucose during its neonatal course should demonstrate normal glucose levels through many feeding-fast cycles prior to discharge A. True B. False

44 ARS QUESTION 8 Supplement Perinatal Stress Hyperinsulinism is characterized by all of the following except which one? A. Associated with being SGA at birth B. Being born by C section C. Persists only for a few days after birth D. Is very responsive to Diazoxide

45 PERINATAL STRESS HYPERINSULINISM (PSHI) Associated with Perinatal Stress Birth Asphyxia Intrauterine Growth Restriction, SGA C/S Median age (d) at initial hypoglycemia 1, range (0 to 168) Persistent hypoglycemia beyond 48 hours of age and can last for several weeks to months. Responsive to treatment with Diazoxide in contrast to severe neonatal onset hyperinsulinism associated with K ATP mutations.

46 ARS QUESTION 9 Supplement The following clinical situations raise suspicion that a Persistent Hypoglycemic Syndrome should be ruled out prior to discharge except which one? A. Required intravenous glucose for hypoglycemia during neonatal course B. Suffered symptomatic hypoglycemia during neonatal course C. Unable to maintain plasma glucose > 50 by day three D. Mother received drugs associated with neonatal hypoglycemia

Learning Objectives. At the conclusion of this module, participants should be better able to:

Learning Objectives. At the conclusion of this module, participants should be better able to: Learning Objectives At the conclusion of this module, participants should be better able to: Treat asymptomatic neonatal hypoglycemia with buccal dextrose gel Develop patient-specific approaches to intravenous