Defining Neonatal Hypoglycaemia:
The Continuing Debate Win Tin
Professor of Paediatrics and Neonatal MedicineThe James Cook University Hospital
University of DurhamUnited Kingdom
Hot Topics in Neonatology Washington DC, USA7-10 December 2014
Faculty Disclosure I have no relevant financial relationships with industry to disclose.
-and-
I will not discuss off label use and/or investigational use in my presentation.
Outline
• Exploring our current knowledge• How do we define “norm” - limitations• Evolution of the definition • Blood glucose < 47 mg/dl or 2.6 mmol/l: Why
are we so neurotic about that?• The N.N.N.I. Study• Discussion
- One definition for all newborns??- The way forward
Exploring our current knowledge
Ask yourself: 1. Do I know the definition of Neonatal
Hypoglycaemia?
2. Do I know the evidence behind this definition?
3. What is/are the evidence/s that I know?
4. Have I ever critically appraise the evidence/s?
Approaches to define “neonatal hypoglycaemia”
• Based on clinical manifestation
• Based on epidemiological data (Epidemiological Definition)- Cross sectional data- Longitudinal data
• Based on acute changes in physiological responses
• Based on neurodevelopmental outcome (Functional Definition)- level at or below which can potentially cause injury (neurological)
Approaches to define “neonatal hypoglycaemia”
Based on clinical manifestation• often misinterpreted because the clinical
manifestations are not unique to “neonatal hypoglycemia”
• several newborns may well have low blood glucose (had this been measured), but without ever been known to have “neonatal hypoglycaemia”
Approaches to define “neonatal hypoglycaemia”
Based on epidemiological data (Epidemiological Definition)
• based on blood glucose concentrations measured on “normal” newborns, and using the “cut off” values of more than 2 standard deviations below the mean as neonatal hypoglycaemia
• Likely to be influenced by the feeding practices as well and management policies
• No correlation between the epidemiological definition and clinical outcomes
Approaches to define “neonatal hypoglycaemia”
Based on acute changes in physiological response• define neonatal hypoglycaemia as blood glucose
level below which the newborns demonstrate counter-regulatory responses:
- changes in cerebral blood flow - changes in hormonal response - abnormalities in neurophysiological function
• limited data
• correlation between these observed changes and the meaningful development outcome has not been established.
Approaches to define “neonatal hypoglycaemia”
Based on neurodevelopmental outcomes(Functional Definition)• Most relevant to clinicians
• Available data that correlates the glucose concentration with adverse neurodevelopmental outcome is limited
• Failed to consider other associated pathology
• Failed to include “non-hypoglycaemic controls”
Evolution of the definition of NH
Textbook of Neonatology. P 607 First Edition by NRC Roberton(Churchill Livingstone 1986)
• Hypoglycaemia in the newborn period is usually defined as a blood glucose concentration below 1.1 mmol/l (20 mg/dl) during the first 3 days in preterm or small for dates , and below 1.7 mmo/l (30 mg/dl) in term infants. (Cornblath & Schwartz, 1976)
• Not all investigators agree with these arbitrary definitions and some suggest that the lowest acceptable limit is 2.2 mmol/l (40 mg/dl) for all age groups. (Pagliara et al, 1973)
Evolution of the definition of NHThe Landmark Observation Study
Evolution of the definition of NH
Adverse neurodevelopmental outcome of moderate neonatal hypoglycaemia. Lucas A, Morley R, Cole TJ. BMJ 1988; 297: 1304-8.
• BW <1850 g• N= 661 infants, 6808 samples, • Mean (SD) BW 1337 (315) g• Mean (SD) gestation 30.5 (2.7) wks• Large study of feeding (5 centres)• Sampling
- Weekly till discharge or weighed 2000g (9th week) - Daily for all requiring intensive care till clinically stable (2nd to 3rd week)
Evolution of the definition of NHAdverse neurodevelopmental outcome of moderate neonatal hypoglycaemia. Lucas A, Morley R, Cole TJ. BMJ 1988; 297: 1304-8.
• Factors associated with “hypoglycaemia”- Birth weight <1000 g- SGA- Five minute Apgar <5- Neonatal Unit (8 folds between lowest and highest incidence)
• Regression analysis to explore minimal safe plasma glucose concentration in terms of development score at 18 months- Bayley Mental and Motor Score (dependent variable)- Days of “hypoglycaemia” (independent variable)- Plasma glucose cut offs between 0.5 and 4.0 mmol/l
Evolution of the definition of NH
Adverse neurodevelopmental outcome of moderate
neonatal hypoglycaemia.
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 2.5 mmol/l (45 mg/dl) was used
• Reduced development scores were associated independently with number of days on which level was ≤ 2.5 mmol/l (45 mg/dl)
Days of NH Adjusted RR
0 1
1 - 2 1.1 : 1
3 - 4 2.2 : 1
> 5 3.5 : 1
Adverse neurodevelopmental outcome of moderate neonatal hypoglycaemia.
Lucas A, Morley R, Cole TJ. BMJ 1988; 297: 1304-8.
Evolution of the definition of NH
Adverse neurodevelopmental outcome of moderate neonatal
hypoglycaemia.
Lucas A, Morley R, Cole TJ. BMJ 1988; 297: 1304-8.
• “the association between modest hypoglycaemia and poor neurodevelopment reported here might not be causal and might reflect our failure to adjust adequately for confounding factors”
Outcome of neonatal hypoglycaemia [letter].
Lucas A, Morley R. BMJ 1999; 318: 195.
• “when such observations generate hypotheses or legitimate clinical concerns, this should stimulate future studies.”
Adverse neurodevelopmental outcome of moderate neonatal hypoglycaemia. Lucas A, Morley R, Cole TJ. BMJ 1988; 297: 1304-8.
The last 4 lines of abstract states:
Evolution of the definition of NH
Only FIVE neonates in the study (Total=17)
THREE had measured blood glucose <2.6 mmol/l with normal BAER
“Hypoglycaemia” and Neural Dysfunction: Other Studies
• Brain stem auditory response in relation to neonatal glucose metabolism.
Cowett RH, Howard GM, Johnson J, Vohr B.
Biol Neonate 1997;71:31–6.
• Monitoring of early postnatal glucose homeostasis and cerebral function in newborn infants of diabetic mothers: a pilot study.
Stenninger E, Eriksson E, Stigfur A, Shollin J, Aman J.
Early Hum Dev 2001;62:23–32.
FAILED TO FIND ANY SUCH SPECIFIC THRESHOLD
The TRAP in Neonatal Medicine
HYPOTHESES
BELIEFS
LITOGEN• A DRUG THAT DOES NOT CAUSE
MALFORMATIONS, BUT DOES CAUSE LAWSUITS.
Dr. Robert Brent, Editor
TERATOLOGY 31:429, 1985.
WE HAVE BECOME “HUMAN LITOGENS”
Human Litogens
• “Unfortunately, untoward long-term outcomes in infants with one or two low blood glucose levels have become the grounds for alleged malpractice, even though the causative relationship between the two is tenuous at best.........................The definition of clinically significant hypoglycemia remains one of the most contentious issues in contemporary neonatology.”
Cornblath et al. Pediatrics 2000
The Northern Neonatal Nursing Initiative (N.N.N.I.) Study
1990 - 91
The NNNI “Hypoglycaemia” Study
Aim:
• To compare the neurodevelopmental outcome of preterm babies (<32 weeks) who had frequent low blood glucose levels (<2.6 mmol/l or 47 mg/dl) in the first ten days of life with that of matched controls.
The NNNI “Hypoglycaemia” Study
Methods:• “Prospective”, Observational Study• “All” children born before 32 weeks• North of England (1990-91)• Laboratory whole blood glucose was measured
(08:00 hrs) daily for first ten days• Results of additional samples taken at other
times were also recorded
The NNNI “Hypoglycaemia” Study
Methods:• Index – surviving child with blood glucose of
<2.6 mmol/l (47 mg/dl) in 3 or more days
• Control – surviving child who never had documented blood glucose of <2.6 mmol/l (47 mg/dl)
• “Matched”- hospital of early care
- gestation
- birth weight
The NNNI “Hypoglycaemia” Study
Methods: Assessment at Two Years• “All” surviving children were assessed at 2 years• Single assessor (no knowledge of “index” or “control”)• Assessments
- Griffiths Mental Developmental Scale (original version)
- Clinical examination
- Vision
- Hearing
- Growth measurements
The NNNI “Hypoglycaemia Study: Results
Fluid intake v Incidence of frequent low blood glucose*
• Total number of “Index” 48 • Overall incidence: 48/566 8.4%• “Liberal” Fluid regime 2.9%• “Intermediate” Fluid regime 8.5%• “Restrictive” Fluid Regime 11.7%
* Blood glucose <2.6 mmol/l (47 mg/dl) on 3 or more days
aa
Index Control20
40
60
80
100
120
140
20
40
60
80
100
120
140
GRIFFITHS GENERAL DEVELOPMENTAL QUOTIENTS OF 47 MATCHED PAIRS
Index = blood glucose of <2.6 (47 mg/dl) mmol/l in 3 or more days
Mean paired difference: – 0.2 (95% CI – 6.0 to 5.5)
General Quotients
Cerebral Palsy
90
95
100
105
110
GeneralQuotient
Locomotor Personal &Social
Hearing &Speech
Eye-HandCoordination
Performance
Index
Control
MEAN GRIFFITHS DEVELOPMENTAL QUOTIENTS OF 47 MATCHED PAIRS
Tin W. Early Human Develop 2005
The NNNI “Hypoglycaemia” Study
Conclusion 1:
• Neurodevelopmental outcome at TWO years of age of preterm babies who had “hypoglycaemia” in 3 or more days in the first ten days of life do not differ from that of matched controls
Tin W. Early Human Develop 2005
Lucas et al (1988) The NNNI Study (2005)
• N= 543• Birth Weight < 1850 grams• Bayley SID –II • 18 months corrected age
• Single Assessor (blinded)
• Follow up rate – 92%
• Sample collections
- weekly plasma samples
- daily for Infants receiving intensive care till STABLE
• N= 566• Gestation < 32 weeks• Griffiths MDS • 24 months corrected age• Single Assessor (blinded)• Follow up rate – 100%
• Sample collections
- daily for the first 10 days (at set time in the morning)
- Index v Matched controls
• Intellectual & Cognitive skills can NOT be assessed reliably
The NNNI “Hypoglycaemia” Study
Methods: Assessments at 15 year• Psychometric assessment (WISC-III)• Behaviour Problems• Daily Living and Adaptive Skills• Education attainments• Health Status
Follow up ascertainment• Outcome information on ALL but two children• Full Assessment on 38 pairs (82%)
The NNNI “Hypoglycaemia” Study
Index Controls
Gestation in Days (mean + SD) 207 + 13 205 + 15
Birth Weight in Grams (mean + SD) 1330 + 293 1267 + 434
Male (%) 55 63
Multiple births (%) 16 21
Ventilatory Support (%) 58 50
Proven Sepsis 21 16
Tin W et al. Pediatrics 2012
Mean paired difference of Full Scale IQ between index children and their matched counterparts was
-0.6 (95%CL: - 8.3 to + 7.2)
The NNNI “Hypoglycaemia” Study: Results 2
Full Scale IQ of 38 matched pairs
Tin W et al. Pediatrics 2012
The NNNI “Hypoglycaemia” Study: Results 2
Tin W et al. Pediatrics 2012
The NNNI “Hypoglycaemia” Study: Results 2
Tin W et al. Pediatrics 2012
The NNNI “Hypoglycaemia” Study
• The first study to compare the intellectual and cognitive skills, behaviour and adaptive skills in preterm infants who had low blood glucose and their matched counterparts
CONCLUSION:• No evidence to support the belief that recurrent
blood glucose levels of <2.6 mmol/l [<47 mg/dl] in the first 10 days pose a hazard to preterm babies
• Definition of “functional neonatal hypoglycaemia” remains elusive
Defining “norm”- Functional Definition
FACTS• No substantial evidence of what constitutes
clinically important low blood glucose levels
• Often occur with other conditions that are associated with brain injury
• Not possible to identify a specific value (level or a range) of blood glucose that can cause injury
• Evidence is lacking but clinical guidance is still needed
Adamkin D and COMMITEE ON FETUS AND NEWBORN (AAP), Pediatrics 2011
Operational Threshold
• The concentration of plasma or whole blood
glucose at which intervention should be
considered to increase the glucose level
[based on evidence currently available in the
literature].
Cornblath et al (2000)
Suggested “Operational Thresholds”
With clinical manifestations• Measure glucose
• Interventions aim at increasing glucose concentration if:
<45 mg/dl (2.5 mmol/l)
• Consider other pathological processes if “symptoms” persists despite improving glucose concentration
With risk factors• Monitoring
- within 2-3 hrs after birth and before feeding
• <36 mg/dl (2.0 mmol/l)
• If <25 mg/dl (1.4 mmol/l)
- IV glucose infusion
- “therapeutic objective” >45 mg/dl (2.5 mmol/l)
Cornblath et al. Pediatrics 2000
One size does not fit all!
• Bayley Scales of Infant and Toddler Development (Third Edition)
• Cognitive Scale: Subtest
• Must correctly identify at least 2 out of 3 to score
One functional definition of NH to “ALL”?
• Healthy Baby
• Infant of Diabetic Mother
• SGA Baby
• Pre-term Baby
• Babies With Perinatal Asphyxia
Exploring our knowledge
If I ask myself (25 years ago): 1.Do I know the definition of Neonatal
Hypoglycemia?
2.Do I know the evidence behind this definition?
3.What is/are the evidence/s that I know?
4. Have I ever critically appraise the evidences?
Exploring our current knowledge
Ask myself again: 1.Do I know the definition of Neonatal
Hypoglycemia?
2.Do I know the evidence behind this definition?
3.What is/are the evidence/s that I know?
4. Have I ever critically appraise the evidences?
Knowledge Gaps Glucose Metabolism and the Brain• The complex nature and maturational features of global
and regional brain energy use remain to be studied.
Clinical Issues• No evidence-based study to identify any specific
plasma/blood glucose to define “pathologic hypoglycaemia”.
Laboratory tests and Glucose monitoring• Inconsistency in source of sampling (capillary, venous,
arterial) and the methods used.• No bedside methods for measuring other energy
substrates• The role of neuroimaging and EEG studies
Hay Jr. et al Journal of Pediatrics 2009
The Way Forward
• Get out of the TRAP!!
• Accept the KNOLWLEDGE GAPS (and continue to address them)
• Prevent ourselves from becoming LITOGENS
• Develop RESEARCH AGENDA
• COLLABORATE to accomplish the research agenda
THANK YOU