Defining Neonatal Hypoglycaemia: The Continuing Debate Win Tin Professor of Paediatrics and Neonatal Medicine The James Cook University Hospital University

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)


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”


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


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.


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


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


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.



Adverse neurodevelopmental outcome of moderate neonatal

hypoglycaemia.


• “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:


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.


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


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


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


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


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%)


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







• 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

Documents

Defining Neonatal Hypoglycaemia: The Continuing Debate Win Tin Professor of Paediatrics and Neonatal Medicine The James Cook University Hospital University