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Neonatal Hypoglycemia
Making Sense of Different Opinions
Other:
I am not a Neurologist nor a Developmental Pediatrician.
My goal is to prevent my patients from needing one.
BACKGROUND
1) NEONATAL HYPOGLCYEMIA IS THE MOST
COMMON METABOLIC PROBLEM IN
NEONATES
(1.1)
40 60
(2.2) (3.3)
30
47
(1.7) 50
(2.6)
45
(2.7)
55 – 110
“ pragmatic intervention thresholds”
(2.5) (that also provide a margin of safety)
(3.0) (6.0)
Level
Operational threshold
Hypoglycemia damage?
duration Nondisease term
Postnatal Glucose Homeostasis
Critical in AAP approach
Feed and Not Sample NADIR
Insulin
Glucagon (mobilize
glycogen)
1
Figure 1: Profile of blood glucose concentrations in the immediate
postnatal period
Pildes 1986
Transitional Neonatal Hypoglycemia
The Fetal Glucose “Set Point” Normally Persists For Up To 48
Hours And Then Transitions To An Adult Set Point
THE PES
USES MEAN
VALUES
AAP
CONSIDERS
LOWER
RANGES FOR Maternal
OPERATIONAL Glucose
THRESHOLDS Concentrations
and CLINICAL
Fetal Glucose
CONDITION
Concentrations
Marconi, 1996
Srinivasan, 1986
Transitional Neonatal Hypoglycemia
Suppression of insulin occurs at a LOWER plasma glucose
concentration in Term Newborns first 48 hours than Children or Adults
HYPERINSULINISM (First 48 hours) ( mmol x 18=mg/dl)
Normal Suppression of Insulin Secretion in Children (85 mg/dL); Term Baby (55-65mg/dl) First 48 hours only!
Hawdon, 1993
Transitional Neonatal Hypoglycemia
(TNH) Is Hyperinsulinemia
• Mean plasma glucose for suppression of insulin secretion is 55-65 first 48
hours of life.
• Therefore this Defines “normal” level for the first 48 hours of life
(PES)………55 to 65 mg/dl. Their recommendation is for glucose >
50mg/dl first 48 hours.
Suckling
Breastfeeding
Ketogenesis
Controversy
CALORIC DEPRIVATION VS 12 – 14% of
PROTECTION as normal, AGA,
ALTERNATIVE SOURCE OF breastfed
ENERGY. KETONES newborns
INCREASE after 24 hours have a blood
glucose level
of <47mg/dl in
Breastfeeding the first 3
average intake of days of life
colostrum ± 7
mls/feed in the first
24 hours. About 15
to 20 ml/k
(Houston et al Early
Human Development
1983)
Normal Newborn Fasting Glucose
Concentrations Are Stable (Mean)
Data from 1950s-1960s. Fasted 8 to 27 hours.
PES CONCLUDES glucose levels unaffected by Initiation or Feeding Interval
AAP believes lower glucose levels are affected by feedings
Glucose (mg/dL)
8 18 27
Duration of Fast (Hours)
2015: PES Neonatal Hypoglycemia Guidelines
Neonatal Regulation of Plasma Glucose TNH
“Beneficial Effects of Biochemical Hypoglycemia”
• Breast fed infants have lower plasma glucose concentrations than formula fed
infants, but ketone levels are increased in response to breast feeding.
• Normal physiologic response that all mammals have the first days of life
Approaches to Define “Hypoglycemia”
Epidemiological –Statistical
- Cross sectional data
- Longitudinal data
47mg/dl 2.6mmol/l
• BW <1850 g
• N= 661 infants, 6808 samples,
• Mean (SD) BW 1337 (315) g
• Mean (SD) gestation 30.5 (2.7) wks
• Large Nutrition Study (5 centers)
Sampling
- Daily for all requiring intensive care until clinically stable
(2nd to 3rd week)
- Weekly till discharge or weighed 2000g (9th week)
- Developmental Testing (18 mos)
Lucas A, Morley R, Cole TJ. BMJ 1988; 297: 1304-8.
EVOLUTION of the DEFINITION (1988)
of NH as 47
NEURODEVELOPMENTAL APPROACH
• BW <1850 g
• N= 661 infants, 6808 samples,
• Mean (SD) BW 1337 (315) g
• Mean (SD) gestation 30.5 (2.7) wks
• Large Nutrition Study (5 centers)
Sampling
- Daily for all requiring intensive care until clinically stable
(2nd to 3rd week)
- Weekly till discharge or weighed 2000g (9th week)
- Developmental Testing
Lucas A, Morley R, Cole TJ. BMJ 1988; 297: 1304-8.
NEURODEVELOPMENTAL APPROACH
Lucas A, Morley R, Cole TJ. BMJ 1988; 297: 1304-8.
• Maximum slope and significance were seen for PDI and MDI when a cut
off of 45mg/dl was used
• 2/3 had <47mg/dl ranging from 3 to 30 days. Median age onset was 2
days
• Reduced development scores were associated independently with number
of days on which level was < 47mg/dl.
(A number of infants had glucose < 20 for 5 days)
Control
110
105
100
95
90
General Locomotor Personal & Hearing & Eye-Hand Performance
Quotient Social Speech Coordination
• Dextrose gel and placebo gel ( gel x 2 still <47, admit to NICU)
254 (49%) 260 (51%) Also expressed milk prior to delivery for IDM
• These at risk groups represent over 25% of all newborns
Normal Low
Glucose Glucose • At least 12.5% of all newborns have a low glucose concentration
N=102 @ risk
>32 weeks
265 episodes
< 47 on CGM 81% 19%
107 episodes CGM
lasted > 30 mins, 75%
of those not detected on
blood sampling
BW < 1200g
- Efficacy test compared CGM combined with a paper guideline (n=20) to target glucose control
47-180mg/dl compared with standard care
RESULTS
1)Sensor performed well vs POC, Percent time in target range 77% CGM vs 59% in standard
2) Percent time >180mg/dl was 24% with CGM vs 40% in Standard
3) CGM also detected clinically unsuspected episodes of hypoglycemia (Up to 5 hrs with intermittent, none >
30 minutes on CGM)
CONCLUSION
Study suggests that CGM has sufficient accuracy and utility in preterm to warrant formal testing in RCT
Thomson et al (UK) Arch Dis Child Fetal 2018
Continuous Glucose Monitoring (CGM) in NICU: Not Quite
ready for ‘plug and play’ (editorial)
PREMISE : CGM in VLBW has the potential to minimize the incidence of hypo and hyperglycemic episodes
and increase glycemic stability providing new opportunities to improve long term neurocognitive outcomes
EDITORIAL
Instrumentation was developed for DM patients with glucose target aimed at 70-180mg/dl. This contrasts with
narrower range for VLBW and devices are not sufficiently accurate for these patients. Need testing and device
aimed at 0-47mg/dl range for term and LPT newborns at risk.
No firm or widely accepted cut-off values for low or high glucose concentrations in neonates or the meaning of
any glucose concentration below or above those values at one time or different durations.
Differences of > 15mg/dl between interstitial and blood glucose concentrations. So these should not replace
blood sampling. Future will see improved accuracy of these devices now used for research.
No study has demonstrated improved outcomes following treatment of asymptomatic hypoglycemia, it is even
possible CGM could increase diagnostics and treatments that are not warranted.
NEW ZEALAND
CHYLD
Children with Hypoglycaemia and their Later Development ,Courtesy Jane Harding
Key Findings From CHYLD @2y
At risk babies screened and treated with the aim of
keeping blood glucose concentrations >47 mg/dl:
CHYLD
McKinlay et al, NEJM 373: 2507, 2015 Children with Hypoglycaemia and their Later Development
Undetected Low Glucose
Concentrations
In at risk babies screened and treated with the aim of keeping blood
glucose concentrations > 47 mg/dl:
• 53% experienced blood glucose < 47mg/dl
• 23% had glucose concentrations <47mg/dl not detected on
intermittent blood testing.
• 25% of those treated had glucose concentrations < 47mg/dl for >5
hours in the first week
No events ≥1 Interstitial
Outcome RR (95%CI)
(N=108) episode (N=33)
First screen 1-2hr of age then q3 to 4 first 24hrs and q6-8 the following 24hrs.
Up to 7 days or until no ongoing clinical concerns. Masked CGM 7days
ASYMPTOMATIC
Birth to 4 hours of age 4 – 24 hours of Age
INITIAL FEED WITHIN 1 Hour Continue feeds q2-3 hours
Screen glucose 30 minutes after 1st feed Screen Glucose prior to each feed
Initial Screen <25mg/dl Screen <35mg/dl
Feed and check in 1 hour Feed and check in 1 hour
<25mg/dl 25 – 40mg/dl <35mg/dl 35 – 45m/dl
Symptoms of Hypoglycemia include: Irritability, tremors, jitteriness, exaggerated moro reflex, high-pitched cry,
seizures, lethargy, floppiness, cyanosis, apnea, poor feeding.
Dextrose Gel
GEL ADMINISTRATION @ALGH ( Provided by Cathy Bennet)
• Less treatment failure with Dextrose Gel, less NICU admissions NNT = 8
1) No evidence of a difference between dextrose gel and placebo gel for major
neurosensory disability at 2 year follow-up. ( One trial n =184 quality of evidence very
low)
2) Dextrose gel vs placebo gel or no gel did not alter the need for IV treatment for
hypoglycemia.
3) One trial (n=237) dextrose gel treated infants less likely to be separated from
mothers for treatment of hypoglycemia and more likely to be exclusively breast fed
after discharge.
Conclusion: Oral dextrose gel should be considered first line treatment for infants with
neonatal hypoglycemia
Glucose Gel in Infants at Risk for Transitional
Neonatal Hypoglycemia
Nursery protocol adopted 200 mg/kg gel for at risk infants. Compared to year
before no gel ( n=421) and year 2 after the addition of gel (n=383)
RESULTS
Hospital charges for the study population decreased from $801,276 to $387, 668
pre-gel vs gel ,respectively.
Makker et al Am J
Peri 2018
What Happens to Blood Glucose after Oral
Treatment for Neonatal Hypoglycemia?
Harris et al J Ped 2017
• Conclusion: Dextrose gel and breast feeding should be considered for first line oral
treatment of infants with hypoglycemia
Now Screening
Universal Screening
Association Between Transient Newborn Hypoglycemia
and Fourth-Grade Achievement Test Proficiency
A Population Based Study
Retrospective 1998 included all infants born @ University of Arkansas (1395 pairs)
At least 1 recorded glucose within first three hours of life was below cut off while next
value was above the cutoff.