Neonatal Hypoglycemia.ppt

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					Neonatal Hypoglycemia:
Evidences and Practice


     Prof. Pushpa Raj Sharma
    Department of Child Health
      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.
  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
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
 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
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
Kinnala et al. Cerebral magnetic resonance
imaging andultrasonography findings after
neonatal hypoglycemia. Pediatrics 103; 1999

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
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
 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
          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.
      Approaches to defining neonatal
             hypoglycemia!
Clinical Manifestations
 Must fulfill Whipple’s Triad
a) Low glucose
b) S&S consistent with hypoglycemia
   (eg. Jitteriness, tremors, lethargy, seizures, apnea,
   cyanotic spells, hypotonia, difficulty feeding,
   hypothermia, coma)
c) Resolution of S&S after restoring glucose
                 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.
         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
      Proposed Operational Thresholds
1st 24 hours of life:

Healthy preterm*/full term neonate:
a) NO clinical signs: <2.0 mM
b) Abnormal clinical signs: <2.5 mM

Sick, Hypoxic, LBW, Infant of
diabetic mom or premature neonate:
<2.5 mM

* >34 weeks
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!!)
  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
    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
          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
         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 ……………………..!!
       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!
     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.
           So……..
you’ve got a low glucose,

Now WHAT DO YOU DO???
       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
       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.
       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
   What if hypoglycemia occurs prolonged,
            recurrent or persistent?


Recurrent of Persistent Hypoglycemia:

1) Require infusions of large amts of glucose
   (>1216 mg/kg/min) to maintain
   normoglycemia
     What if hypoglycemia occurs prolonged,
              recurrent or persistent?

1) 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
          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
       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.
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
“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
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