Hypoglycemia in Infancy: The Need for a Rational Definition

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Hypoglycemia

in Infancy:

The Need

for a

Rational

Definition

A Ciba

Foundation

Discussion

Meeting

Marvin

Cornblath,

MD;

Robert

Schwartz,

MD;

Albert

Aynsley-Green,

MA, DPhil,

MBBS,

FRCP;

and June

K. Lloyd,

MD,

FRCP

Editors

From the Departments of Pediatrics, University of Maryland, The Johns Hopkins University, Baltimore, Maryland; Department of Pediatrics, Rhode Island Hospital, Brown University, Providence, Rhode Island; Department of Child Health, University of Newcastle Upon Tyne, The Medical School, United Kingdom; and Department of Child Health, Institute of Child Health, London, United Kingdom

A discussion meeting was held on October 17,

1989, to address the current status of the definition of significant hypoglycemia in infancy, especially in the normal- and low-birth-weight neonate.

Robert Schwartz introduced the complexity of

the problem by indicating the multiple variables

(duration, severity, cerebral blood flow, rates of

glucose uptake, availability of alternate substrates,

oxygen, etc) in equating a plasma glucose value

with neurodevelopmental consequences.

Marvin Cornblath reviewed the various defini-tions of hypoglycemic blood sugar levels reported

since 1911 which depend upon the method of blood

sugar analysis, clinical recognition and concerns.

Severe symptomatic hypoglycemia that persisted or

recurred was first reported in neonates in 1937.

Lower blood sugar levels, documented since the

1920s in both full-term and premature newborns,

had been considered physiologic. The recognition of transient significant hypoglycemia first in symp-tomatic and then in asymptomatic

small-for-ges-tational-age, neonates required new definitions in

the 1960s. These definitions were later modified as

changes in treating both the mother in labor and

at delivery and the neonate occurred. Intensive care and the survival of very-low-birth-weight newborns

have compounded the problem of definition.

Cur-rently methods are available to correlate plasma

glucose concentrations and glucose metabolism in

vivo in the brain with specific neurologic

dysfunc-Received for publication Nov 27, 1989; accepted Jan 8, 1990. Reprint requests to (MC.) 3809 St Paul St, Baltimore, MD 21218.

American Academy of Pediatrics.

tions. This should permit a better definition of the

continuum of significant hypoglycemia than has

been available before.

William Hay analyzed studies of the various

rapid bedside glucose oxidase stick techniques used to screen for blood glucose concentrations. He con-cluded that their dependence on the hematocrit,

their requirements for precision in performance and

timing, great variance (±5 to 15 mg/dL), and lack

of reproducibility, especially at blood glucose values less than 50 mg/dL, made their use in the neonate unsatisfactory (whether read by eye or by meter). In contrast, a single determination using a

labora-tory-quality glucose analyzer operated at the

bed-side by a trained neonatal nurse provided reliable blood glucose values, acceptable variance (±1.5 mg/

dL), and a sound basis upon which to make a

diagnosis.

In initiating the discussion, Satish Kalhan em-phasized the differences in glucose values between whole blood and plasma and between capillary and either single skin puncture or repeated indwelling catheter samples. A discussion ensued indicating

the need for automated laboratory-quality systems

for glucose analysis that are compatible with the

multiple other measurements monitored in

high-risk infants. Since cerebrospinal fluid glucose con-centrations reflect the amount of glucose available to the brain, further research needs to be performed

in which plasma glucose values are correlated with

those in the cerebrospinal fluid, as well as with

concentrations of alternate substrates (ketones, lactate, glycerol, amino acids) utilized by the brain.

In summarizing extensive experience with

exper-imental hypoglycemia in the adult rat, Bo Seisj#{246}

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electric) and prolonged (>30 minutes)

hypoglyce-mia was necessary to demonstrate cell necrosis in

the brain. He correlated these changes with cerebral blood flow, glucose uptake, oxygen consumption,

intracellular energy, and electrolyte changes. He

indicated that hypoglycemic neuronal damage

re-quired that cellular energy states be perturbed,

indicating that the mechanisms of cell necrosis were

the consequences of energy failure (decreases in

concentrations of phosphocreatine and adenosine

phosphates) and membrane depolarization,

char-acterized by an influx of calcium, an efflux of

po-tassium, with an ensuing acceleration of proteolytic and lipolytic reactions. However, the distribution

of the hypoglycemic neuronal necrosis, which was

unique and differed from that in ischemia or sei-zures, suggested the operation of a fluid-born

extra-cellular toxin, probably an excitatory amino acid

such as glutamate or aspartate. These accelerated cell death by causing a dendrosomatic lesion attrib-uted to calcium influx. These techniques and results provide leads for further research into new thera-peutic interventions and basic clinical studies.

Applying autoradiographic techniques to brains

of neonatal rats, Astrid Nehlig provided data on

oxygen uptake, glucose consumption, blood flow,

and utilization of alternate substrates in newborn,

10-, 14-, 17-, 21-, and 35-day-old animals. Glucose uptake and cerebral blood flow increased to day 17, then decreased to adult levels. Changes occurred at specific ages, correlating with beginning functions

in the brain, ie, auditory pathways with hearing

and visual pathways with eye opening and vision. Cerebral fl-hydroxybutyrate utilization was high in all areas of the brain during the suckling period,

peaking at 14 days of age. Therapeutic doses of

phenobarbital significantly decreased glucose

utili-zation at all ages, without any change in oxygen

consumption.

In the discussion that followed, Lynne Levitsky

reemphasized the clinical questions, pointing out

the multiple critical factors such as species

specific-ity, neonatal age in hours and days, and

develop-mental maturity in investigating these problems.

New positron emission tomography and magnetic

resonance imaging techniques permit studying

hy-poglycemia in vivo in the primate model and may

shortly be available in man. Questions were asked

concerning the effects of hypoglycemia on the

branching dendrites and newly forming synapses in

the newborn brain, as opposed to the adult brain,

and their implications on development.

Albert Aynsley-Green returned to the clinical

problem of defining neonatal hypoglycemia and

illustrated the current dilemma by citing various

definitions ranging from 18 to 72 mg/dL (1.0 to 4.0

mmol/L) glucose from 36 pediatric textbooks and

from 178 British pediatricians, a majority of whom

used levels of <36 mg/dL (2.0 mmol/L) in full-term

infants and <20 mg/dL (1.1 mmol/L) in premature small-for-gestational-age babies as their definition

of hypoglycemia. He discussed the limitations of

current definitions based on symptoms and

statis-tical surveys resulting in the acceptance of the

perception that low-birth-weight neonates can

tol-erate lower glucose levels than full-term neonates. He emphasized the urgent need for research both

in correlating plasma glucose concentrations with

specific neurologic dysfunction as well as with

be-havioral, mental, and neurodevelopmental

out-comes. His own preliminary studies correlating

blood glucose values with changes in patterns of

auditory and somatosensory-evoked potentials in

neonates, infants, and children indicate the

useful-ness of this particular approach, especially in

dem-onstrating that abnormal neurologic patterns can

occur in the absence of symptoms. At present, no

clinical criteria exist to identify the infant with low blood glucose concentrations at risk.

Alan Lucas then reviewed two previously

re-ported studies and his own collaborative data from

five centers to answer the query, “What are the

data on prognosis?” The limitations of these studies did not permit a definitive answer. However, utiliz-ing the first blood glucose concentration obtained on any given day in 661 infants with <1850 g birth

weight between birth and 2 or more months of age

and multiple regression analyses to screen out con-founding factors, he found that 5 or more days (not

necessarily consecutive) of a blood glucose value

less than 47 mg/dL (<2.6 mmol/L) was correlated with significantly reduced Bayley developmental scores and with an increased risk of

neurodevelop-mental abnormalities at 18 months of age. He

pointed out the long duration involved and the fact

that a blood glucose less than 47 mg/dL (<2.6

mmol/L) does not indicate central nervous system damage in itself. He concluded that the data might provide goals for achieving normoglycemia rather than define a critical level to diagnose hypoglyce-mia. However, formal intervention studies are re-quired to assess further the significance of devia-tions in neonatal blood glucose values.

Rosita Pildes presented data on the poor neuro-developmental outcome in infants <1250 g who had blood glucose values in excess of 125 mg/dL (>6.9 mmol/L). Infants rarely had hypoglycemia since all were given parenteral glucose support from birth.

Ole Pryd found different critical blood glucose levels based on the response measured, eg, a rise in epinephrine occurred below 45 mg/dL (<2.5 mmol/ L) glucose, whereas an increase in cerebral blood

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flow occurred below 30 mg/dL (<1.7 mmol/L). On the other hand, intravenous glucose administration produced a decrease in cerebral blood flow as meas-ured by infrared spectroscopy, without any effect on the cerebral redox state or glucose utilization.

Robert Schwartz reported follow-up studies of

newborn monkeys with profound hypoglycemia

(<16 mg/dL or 0.9 mmol/L) of 6 to 10 hours dura-tion immediately after birth resulting in little

im-pairment compared to normoglycemic controls,

again emphasizing species and age specificity.

Active discussion concerned the difference

be-tween acute neurologic dysfunction and pathologic

cerebral cellular damage, as well as the effect of

prolonged hypoglycemia, on adaptive or

coordi-nated functions vs acute necrosis. The importance

of long-term adverse effects of hyperglycemia was

discussed as well.

The final presentation by John Sinclair analyzed all of the published studies relating hypoglycemia

to neurodevelopmental outcome. He emphasized

that no clinically controlled prospective

interven-tion trial had ever been done addressing the

prob-lem of neonatal hypoglycemia. He graded each of

the published studies, using one scoring system for

criteria establishing causation and another for cri-teria evaluating studies of prognosis. He concluded that all of the studies were too flawed and made-quate to provide a definitive conclusion for defining hypoglycemia or for demonstrating a significant

correlation with neurodevelopmental outcome. The

need for a collaborative prospective controlled

study is apparent and urgent. The study design

must avoid blood sampling bias and include an

adequate cohort at inception as well as at follow-up with explicitly defined outcome criteria assessed

blindly and adjusted for extraneous prognostic

fac-tors.

In the formal discussion, Kari Raivio presented an overview of the day’s discussion. He still consid-ered symptomatic hypoglycemia as a more serious manifestation than asymptomatic hypoglycemia.

He recommended changing from blood to plasma

glucose values for defining hypoglycemia and hy-perglycemia. In his follow-up of sick, high-risk in-fants, he found positive significant correlations

be-tween compromised neurodevelopmental outcome

and hyperglycemia, but not with hypoglycemia. The concluding discussion related to ways to set up a clinical trial with various types of intervention at different blood glucose levels, including both hypoglycemic and hyperglycemic concentrations.

June Lloyd emphasized four major conclusions:

(1) eliminate the use of glucose oxidase reagent

sticks in the neonate, (2) discard the concept of

“cutoff” blood glucose values, (3) do a proper

pro-spective study comparing management regimens,

and (4) encourage the basic scientists to study

changes occurring with development.

The rational definition of hypoglycemia is clearly not a specific value but a continuum of falling blood glucose levels, creating thresholds for neurologic

dysfunction, which may vary from one cause of hypoglycemia or clinical circumstance to another. The hypoglycemia, if present with severe enough symptoms or for a long enough period of time may,

in fact, have an impact on neurologic outcome

during the first years of life. The impact on

long-term development is unknown. No specific values

can be derived from the current literature, and

previous recommendations based on data from the

1960s may no longer be relevant. A continuum of

severity from normal to abnormal must be

deter-mined now by measuring specific neurologic

func-tion and levels of plasma glucose and other

meta-bolic fuels and correlating the observations with

careful long-term follow-up studies.

It was concluded that a very large collaborative trial will be needed to provide sufficient numbers

of hypoglycemic and hyperglycemic infants,

ade-quate follow-up, and a large enough population base

to correct for confounding factors. This will be

necessary to establish whether or not certain

plasma glucose concentrations can be correlated

with neurologic, developmental, and/or mental

ab-normalities.

ACKNOWLEDGMENTS

This work was supported, in part, by R. K. Carvill Co,

London, England; Mead Johnson Nutritionals, Indian-apolis, IN; Nova-Nordisk, Copenhagen; Ross

Laborato-ries, Columbus, OH; Sandoz Research Institute, East

Hanover, NJ; Sullivan, Kelly and Associates, Los

Ange-les, CA; and The Ciba Foundation, London.

PARTICIPANTS

Chairmen

JUNE K. LLOYD

Dept of Child Health, Institute of Child Health,

London, United Kingdom ROBERT SCHWARTZ

Dept of Pediatrics, Rhode Island Hospital,

Provi-dence, Rhode Island

Speakers

ALBERT AYNSLEY-GREEN

Dept of Child Health, University of Newcastle upon

Tyne The Medical School, United Kingdom

MARVIN CORNBLATH

Depts of Pediatrics, University of Maryland, The

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WILLIAM W. HAY JR

Dept of Pediatrics, University of Colorado, Denver

ALAN LUCAS

Dunn Nutritional Laboratory, University of

Cam-bridge, United Kingdom

ASTRID NEHLIG

Institut de Pathologie et Biologie du

Developpe-ment Humain, Nancy, France

Bo

K. SIESJO

Laboratory for Experimental Brain Research,

Uni-versity Hospital, Lund, Sweden

JOHN C. SINCLAIR

Dept of Pediatrics, McMaster University,

Hamil-ton, Canada

Discussants

JANET A. EYRE

Dept of Child Health, University of Newcastle upon

Tyne The Medical School, United Kingdom

HAROLD GAMSU

Dept of Child Health, King’s College Hospital

Med-ical School, London, United Kingdom

DAVID HULL

Dept of Child Health, University Hospital, Queen’s Medical Centre, Nottingham, United Kingdom M. DOUGLAS JONES

Division of Neonatology, Dept of Pediatrics, The

Johns Hopkins Hospital, Baltimore, Maryland

SATISH KALHAN

Dept of Pediatrics, Cleveland Metropolitan General Hospital, Cleveland, Ohio

ANTHONY GRIFFITHS

Neville Hall Hospital, Abergavenny, Gwent, United Kingdom

JAMES LEONARD

Institute of Child Health, London, United Kingdom

LYNNE L. LEVITSKY

Dept of Pediatrics, University of Chicago, Wyler Children’s Hospital, Chicago, Illinois

JAMES L. MILLS

Prevention Research Program, National Institute

of Child Health and Human Development,

Na-tional Institutes of Health, Bethesda, Maryland

KYPROS NICOLAIDES

The Harris Birthright Unit, Dept of Obstetrics,

King’s College Hospital Medical School, London, United Kingdom

WILLIAM OH

Dept of Pediatrics, Brown University, Women and

Infants Hospital, Providence, Rhode Island

ROSITA S. PILDES

Dept of Pediatrics, Cook County Children’s

Hos-pital, Chicago, Illinois

OLE PRYDS

Dept of Neonatology, Rigshospitalet, Copenhagen,

Denmark

KARl RAIVI0

University of Helsinki, Children’s Hospital,

Hel-sinki, Finland

CHARLES A. STANLEY

Division of Endocrinology, Children’s Hospital of

Philadelphia, Philadelphia, Pennsylvania

JOSTEIN VIDNES

Central Hospital of Akershus, Dept of Pediatrics, Nordbyhagen, Norway

JOHN WALTER

Dept of Child Health, Royal Hospital for Sick Chil-dren, University of Bristol, United Kingdom

SELECTED REFERENCES

Cornblath M, Schwartz R. Disorders of carbohydrate metabo-lism in infancy. 2nd ed. Philadelphia: WB Saunders,

1976:155-205

Conrad PD, Sparks JW, Osberg I, Abrams L, Hay WW Jr. Clinical application of a new glucose analyzer in the neonatal intensive care unit: Comparison with other methods. J

Pe-diatr. 1989;1 14:281-287

Siesj#{246}BK. Hypoglycemia, brain metabolism and brain damage.

Diabetes Metab Rev. 1988;4:113-144

Nehlig A, Pereira-de-Vasconcelos A, Boyet S. Postnatal changes in local cerebral blood flow measured by the quantitative autoradiographic [‘4C]iodoantipyrine technique in freely moving rats. J Cereb Blood Flow Metab. 1989;9:579-588 Koh THHG, Aynsley-Green A, Tarbit M, Eyre JA. Neural

dysfunction during hypoglycaemia. Arch Dis Child

1988;63:1353-1358

Koh THHG, Aynsley-Green A, Tarbit M, Eyre JA. Neonatal hypoglycaemia: The controversy regarding definition. Arch Dis Child. 1988;63:1386-1388

Lucas A, Morley R, Cole JJ. Adverse neurodevelopmental out-come of moderate neonatal hypoglycaemia. Br Med J.

1988;297:304-308

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1990;85;834

Pediatrics

Marvin Cornblath, Robert Schwartz, Albert Aynsley-Green and June K. Lloyd