Hipoglicemia OMS

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    World Health Organization 1997

    This document is not a formal publication of the World Health Organization(WHO! and all rights are reserved b" the Organization# The document ma"!ho$ever! be freel" revie$ed! abstracted! reproduced or translated! in part or in$hole! but not for sale or for use in con%unction $ith commercial purposes#

    The vie$s e&pressed in documents b" named authors are solel" theresponsibilit" of those authors#

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    Contents

    7#'

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    ntravenous treatment##############################################################################################################)'

    7#*

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    +rugs######################################################################################################################################)*

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    -./.0-H ##########################################################################################################################)2

    -eferences###############################################################################################################################)7

    0c3no$ledgements#################################################################################################################27

    Acknowledgements

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    This revie$ has been compiled b" 0nthon" 4# Williams! +5hil! 4-5! /enior 6ecturer onsultant in 8eonatal 5aediatrics! /t# Georges Hospital :edical /chool! 6ondon! ;andung! 5rofessor0# 0"nsle"?Green (nstitute of hild Health! 6ondon! +r 0nthon" ostello (nstitute of hildHealth! 6ondon! +r 0rmida 4ernandes (6o3man"a Tila3 :unicipal :edical ollege! >omba"!+r @ane Ha$don (;niversit" ollege Hospital! 6ondon! 5rofessor W#W# Ha" (;niversit" ofolorado Health /ciences enter! olorado! +r @ane .# :cGo$an (;niversit" of 5enns"lvania!5hiladelphia! +r 0# :ehta (8ine$ells Hospital and :edical /chool! +undee! +r :# Ward 5latt(The -o"al Aictoria nfirmar"! 8e$castle! and +r /#8# Aani (>#@# :edical ollege and ivilHospital! 0hmedabad#

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    3

    Recommendtions !or "re#ention nd Mn$ement

    Hypoglycaemia of the Newborn

    Recommendations for Prevention and Management

    1# .arl" and e&clusive breastfeeding is safe to meet the nutritional needs of health" termne$borns $orld$ide#

    '# Health" term ne$borns $ho are breastfeeding on demand need not have their bloodglucose routinel" chec3ed and need no supplementar" foods or fluids#

    *# Health" term ne$borns do not develop Bs"mptomaticB h"pogl"caemia as a result ofsimple underfeeding# f an infant develops signs suggesting h"pogl"caemia (see point 17!loo3 for an underl"ing condition# +etection and treatment of the cause is as important ascorrection of the blood glucose level#

    )# Thermal protection (the maintenance of normal bod" temperature in addition tobreastfeeding is necessar" to prevent h"pogl"caemia#

    2# >reastfeeding should be initiated as soon as an infant is read"! preferabl" $ithin 1 hour ofbirth# mmediatel" after birth the bab" should be dried and held against the motherCs chest$ith s3in?to?s3in contact to provide $armth and to facilitate the initiation of

    breastfeeding#

    D# >reastfeeding should continue on demand# Health" term ne$borns sho$ signs ofreadiness to feed $hen the" are hungr"! but the interval bet$een feeds variesconsiderabl"! particularl" in the first fe$ da"s of life# There is no evidence that long

    interfeed intervals adversel" affect health" ne$borns $ho are 3ept $arm and $ho arebreastfed $hen the" sho$ signs of hunger# 0n infant $ho sho$s no signs of hunger or isun$illing to feed should be e&amined to e&clude underl"ing illness#

    7# 8e$borns at ris3 of h"pogl"caemia include those $ho are preterm andEor small forgestational age (/G0! those $ho suffered intrapartum asph"&ia or $ho are sic3! andthose born to diabetic mothers#

    ,# n ne$borns at ris3! h"pogl"caemia is most li3el" to occur in the first ') hours of life! asthe infant adapts to e&trauterine life# H"pogl"caemia $hich presents after the first da" oflife! or $hich persists or recurs! does not necessaril" indicate inadeFuate feeding# t ma"

    indicate underl"ing disease such as infection! or a $ide range of other conditions (seeTable * of main document# -eference should be made to standard te&ts#

    9# 4or ne$borns at ris3! breastmil3 is the safest and nutritionall" most appropriate food#Ho$ever it ma" need to be supplemented $ith specific nutrients for some ver" lo$ birth$eight infants#

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    %

    H&'o$(&cemi o! t)e Ne*+orn

    1# 0t?ris3 ne$borns $ho have a gestational age of *' $ee3s or more or $ho $eigh morethan 12 g at birth! ma" be able to breastfeed sufficientl" to satisf" their nutritional needs(but see also point 1'# f health"! the" should be given the opportunit" to breastfeed$ithin 1 hour of birth li3e term babies#

    11# 0t?ris3 ne$borns able to suc3le sufficientl" should continue to breastfeed $hen the"sho$ signs of hunger# Ho$ever! the" should not be allo$ed to $ait more than * hoursbet$een feeds# 8ormal bod" temperature should be carefull" maintained#

    1'# 0t?ris3 ne$borns notable to suc3le adeFuatel" and obtain all the mil3 that the" needfrom the breast! but $ell enough for oral feeds! can be fed e&pressed breastmil3 (.>:!or if necessar" an appropriate breastmil3 substitute! b" cup or b" gavage (orogastric ornasogastric tube feeding# 4eeds should commence $ithin * hours of birth! and shouldcontinue at least * hourl" thereafter#

    [-eference should be made to standard te&tsI for details of the feeding of ne$borns $ho are less than *'$ee3s gestational age! or $ho are ver" lo$ birth $eight! $ho are sic3 or born to diabetic mothers! or $ho

    are unable to feed enterall"]

    1*# 4or ne$borns at ris3! the blood glucose concentration should be measured at around )?Dhours after birth! before a feed! if reliable laborator" measurements are available#:easurements using glucose?o&idase based reagent paper strips have poor sensitivit" andspecificit" in ne$borns! and should not be relied upon as an alternative#

    1)# 4or ne$borns at ris3 who do not show abnormal clinical signs(Bas"mptomaticB! theblood glucose concentration should preferabl" be maintained at or above '#D mmol l?1()7 mg E1 ml#

    f the blood glucose concentration is belo$ '#D mmol l?1= The infant should be fed# This can be a breastfeed if the infant can suc3le

    adeFuatel"# f not! .>: or an appropriate breastmil3 substitute can be given b"cup or gavage#

    The blood glucose measurement should be repeated preferabl" after 1 hour andcertainl" before the ne&t feed * hours later# f it is still belo$ '#D mmol l?1!treatment $ith intravenous glucose should be considered#

    f facilities for administering intravenous glucose are not readil" available! asupplementar" feed should be given b" cup or gavage#

    >reastfeeding should continue#

    12# f reliable laborator" measurements of blood glucose are not available! ne$borns at ris3should be 3ept $arm and breastfed# f breastfeeding is not possible the" should be givensupplements of .>: or an appropriate breastmil3 substitute b" cup or gavage at leastever" * hours# The infant should continue to breastfeed as much as he or she is able#

    1D# f a ne$born is un$ell or sho$s signs of h"pogl"caemia= apnoea! c"anosis! %itteriness! orconvulsions (Bs"mptomatic h"pogl"caemiaB! the above guidelines are superseded# >loodglucose should be measured urgentl"! and if it is belo$ '#D mmol l?1! intravenous glucoseshould be administered as soon as possible#

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    Recommendtions !or "re#ention nd Mn$ement

    17# 4or management of Bs"mptomatic h"pogl"caemia!B $hen intravenous treatment isindicated and feasible! give 1J glucose intravenousl"# :onitor the blood glucose! andad%ust the rate of infusion accordingl"# ontinue normal feeding as soon as possible#

    1,# f reliable blood glucose measurement is not possible! intravenous glucose should be

    reserved for the treatment of ma%or complications associated $ith h"pogl"caemia (e#g#convulsions and for situations in $hich enteral feeds are contra?indicated# .nteraltreatment is other$ise preferable#

    4urther details about the above procedures $ill be found in the main document ?Hypoglycaemia of the Newborn: Review of the Literature (WHO/H!/"#$%&( WHO/''/"#$%&$

    efinition of terms

    !"clusive breastfeeding# 0n infant is given no food or drin3! including $ater! other thanbreastmil3! (e&cept an" medicinal drops or s"rups $hich ma" be indicated#

    Preterm# >orn before *7 completed $ee3s of gestation#

    $mall for gestational age %$&A'# >irth $eight belo$ the lthpercentile for infants of the samegestational age in the same population#

    (ery low birth weight# >irth $eight less than 12 grams#

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    H&'o$(&cemi o! t)e Ne*+orn

    Hypoglycaemia of the Newborn

    !"ecutive $ummary

    1# The term Bh"pogl"caemiaB refers to a lo$ blood glucose concentration# 8eonatalh"pogl"caemia is not a medical condition in itself! but a feature of illness or of failure toadapt from the fetal state of continuous transplacental glucose consumption to thee&trauterine pattern of intermittent nutrient suppl"# t is more li3el" to occur in conditions$here infants become cold! or $here initiation of feeding is dela"ed#

    '# :etabolic adaptation at birth involves mobilisation of gl"cogen reserves (glycogenoly)i)!hepatic s"nthesis of glucose from other substrates (gluconeogene)i)! and production ofalternative cerebral fuels such as 3etone bodies# The processes $hich ensure availabilit"of glucose and other fuels are collectivel" described as counterregulation# The" areactivated principall" b" glucagon and adrenaline# The concentration of glucose in the

    blood is onl" one piece in a comple& metabolic %igsa$ and cannot be interpreted inisolation#%$ection )*)+ $ection ,*)'

    *# 0 Bnormal rangeB for blood glucose values in the ne$born has not been properl" defined#Aalues are influenced b" birth $eight! gestational age! feeding method and postnatal age#4e$ studies have been made of breastfed infants and the" do not define feeding patternsor mil3 inta3e# %$ection -*.'

    )# There is controvers" over the definition of a BsafeB blood glucose concentration! i#e# avalue belo$ $hich there is ris3 of long?term neurodevelopmental impairment#

    H"pogl"caemia associated $ith abnormal clinical signs ()ymptomatic hypoglycaemia hasa poor short? and long?term outcome but evidence of ris3 in the absence of clinical signs(a)ymptomatic hypoglycaemia&is inconclusive# This is to be e&pected as maintenance ofcerebral function depends as much on abilit" to mobilise alternative fuels (e#g# 3etones ason blood glucose concentration# %Chapter .+ Chapter ,'

    2# t follo$s that the anticipated maturit" of the counterregulator" response and thepresence or absence of s"mptoms are as influential as the blood glucose concentration indeciding $hether to treat# 0 rigid definition of h"pogl"caemia relevant to all clinicalsituations cannot be made#

    D# There is no evidence that lo$ blood glucose concentrations among health" breastfed termbabies are detrimental to outcome# Health" term babies $ho are breastfed on demandreFuire no food or drin3 other than breastmil3# %$ection /*)*.'

    7# 0ll infants should be fed as soon as possible after birth# Those $ho are health" andmature enough to suc3le should be offered a breastfeed# There is some evidence that

    breastmil3 promotes 3etogenesis more vigorousl" than formula# %$ection )*,'

    ,# /creening for h"pogl"caemia using glucose?o&idase based reagent strips has poorsensitivit" and specificit"# t is preferable to ma3e occasional pre?feed laborator"measurements of blood glucose in infants at ris3# /creening health"! breastfed! term

    infants for h"pogl"caemia is furthermore inappropriate because a normal range of bloodglucose values has not been defined# %$ection -*.+ $ection 0*.*/'

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    Eecti#e Smmr&

    9# /ome evidence suggests that preterm babies and babies $ho are small for gestational agesho$ a constrained counterregulator" response to h"pogl"caemia# +etection andtreatment of h"pogl"caemia in these groups is therefore important# Other groups ofinfants at ris3 of earl" h"pogl"caemia are those $ho are infected! $ho have suffered

    intrapartum asph"&ia and $ho are infants of diabetic mothers# /upplementar" feedingma" be reFuired both to prevent and treat h"pogl"caemia in these groups# H"pogl"caemia$hich recurs or persists longer than ),?7' hours of age suggests an underl"ing medicalcondition (e#g# inborn error of metabolism or endocrine disorder# %$ection )*,+Chapter /+ Chapter 1'

    1# nfants at ris3 of h"pogl"caemia and $ho are mature enough to suc3le should bebreastfed on demand# 0 blood glucose estimation should be made before a feed at around)?D hours of age# urrent evidence suggests that supplementar" feeding should beconsidered if the value falls belo$ '#D mmol l?1 though there is no conclusive evidencethat brief e&posure to lo$er levels is harmful in as"mptomatic infants# 0 blood glucose

    measurement should be repeated 1 hour after feeding# f the blood glucose value still liesbelo$ '#D mmol l?1! treatment $ith an intravenous glucose infusion is necessar"# %$ection/*)+ $ection 1*.'

    11# nfants too immature to suc3le should be given supplementar" feeds either b" cup or b"gavage# >reastmil3 or formula is preferable to de&trose $ater as it has greater energ"densit" and contains fat $hich promotes 3etogenesis and reduces glucose o&idation# Thevolume of mil3 administered should be D ml 3g ?1 d?1on the first da"! 9 ml 3g?1d?1on thesecond da"! 1' ml 3g?1d?1on the third and 12 ml 3g?1d?1on the fourth# nfants in stablecondition $ithout respirator" distress ma" tolerate larger volumes! starting $ith1 ml 3g?1 d?1on the first da"# >lood glucose concentration should be measured at )?D

    hours of age# %$ection /*)'

    1'# /ic3 infants $ho have clinical features $hich contraindicate enteral feeding (e#gcardiorespirator" instabilit"K abdominal distension should receive an intravenous infusionof 1J de&trose! commencing at D ml 3g ?1d?1# This Fuantit" of glucose () mg 3g?1 min?1$ill maintain normogl"caemia in the ma%orit" of infants of appropriate $eight forgestational age# The infusion rate should be ad%usted according to blood glucoseconcentration# %$ection /*)+ $ection 1*.'

    1*# /creening and supplementar" feeding are inappropriate for infants $ho are health" butlarge for gestational age! unless 3no$n to be infants of diabetic mothers# %$ection 0*,+

    $ection 0*-+ $ection /*)*0'

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    0

    H&'o$(&cemi o! t)e Ne*+orn

    Hypoglycaemia of the NewbornReview of the Literature

    .* H2$34R2CAL 5AC6&R47N

    The term Bh"pogl"caemiaB refers to a reduction in the glucose concentration ofcirculating blood# t is almost a centur" since it $as first described in children andover fift" "ears since it $as recognised in ne$born and older infants (Hartmann @audon! 19*7# Given the numerous advances $hich have since occurred in thecare of ne$born infants it is surprising that so much controvers" still surroundsthe definition! significance and management of neonatal h"pogl"caemia#5arado&icall"! technological developments in the form of bedside glucosemonitoring have e&acerbated rather than eased the problem b" facilitatingscreening for an ill?characterised clinical entit"#

    .*. Patterns of hypoglycaemia

    The vulnerabilit" of premature infants and those of diabetic mothers toh"pogl"caemia $as recognised earl" in the histor" of neonatal medicine (e#g#:iller -oss! 19)K 8orval! 192K :cLuarrie! 192)K 4arFuhar! 192)# Thetransient nature of h"pogl"caemia and apparent infreFuenc" of clinicalmanifestations led man" to assume that lo$ blood glucose concentrations amongthese groups $ere innocuous and Bph"siologicalB! in contrast to h"pogl"caemiacaused b" metabolic and endocrine disease# Ho$ever! in 1929 ornblath et aldescribed eight! '?da" old infants born to mothers $ith pre?eclamptic to&aemia in$hom s"mptoms (apnoea! c"anosis! coma and convulsions $ere associated $ith

    reduced blood glucose concentrations (1?') mg dl

    ?1

    1

    # The" described a clinicalresponse to the infusion of intravenous glucose and dre$ attention to the Bself?limited but Fuite refractor"B course of h"pogl"caemia# The outcome of this smallgroup of infants $as poor# 4ive $ere normal $hen follo$ed?up at t$o $ee3s toeleven months but one died and t$o had persisting neurological abnormalities#4urther descriptions of neurological seFuelae associated $ith )ymptomatichypoglycaemia(i#e# that associated $ith clinical signs'$hich resolve at increased

    blood glucose concentration in the ne$born follo$ed#

    oncern arose that h"pogl"caemia without associated clinical signs'

    (a)ymptomatic hypoglycaemia might also lead to neurodevelopmental seFuelae#

    This led to an attempt to define h"pogl"caemia statisticall" as a blood glucoseconcentration more than ' standard deviations belo$ the mean for populations of$ell full?term and lo$ birth $eight infants# This! and the introduction in the earl"197Cs of reagent strip glucose assa"s (e#g# !e*tro)ti*T: for cotside screening ofne$borns at ris3! led to clinical classifications of neonatal h"pogl"caemia (e#g#4luge! 197)K Gutberlet ornblath! 1972# Gutberlet ornblath estimated the

    1 1, mg dl?1M 1 mmol l?1glucose#

    '' t is technicall" incorrect to spea3 of Bs"mptomsB in the conte&t of an infant becausethe term describes changes reported b" a patient# The term BsignsB more accuratel"describes clinical observations# -eference to Bas"mptomaticB and Bs"mptomaticB

    h"pogl"caemia has nevertheless been preserved throughout the manuscript as theseterms have become $idel" adopted in the literature#

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    Historic( c2$rond

    prevalence of h"pogl"caemia (defined as serum glucose concentrationN* mg 1 ml?1 as )#) per 1 total inborn live births! 12#2 per 1 lo$ birth$eight infants# 6ubchenco >ard (1971 arrived at much higher estimates=11#)J of all nurser" admissions and '#*J of those premature or lo$ birth$eight had blood sugar N* mg 1 ml?1if screened before feeding at D hours of

    age#

    .stimating the e&act freFuenc" of as"mptomatic h"pogl"caemia obviousl" begsthe Fuestion of numerical definition# This is addressed in /ection ) but it is $orthnoting at this %uncture that transitional h"pogl"caemia is a common problemobserved in both industrialised and less?developed countries# 4ormal studies in thelatter are fe$# Ho$ever! 0nderson et al (199* observed that *,J ofuncomplicated term infants born in r"ant! 1971#

    n a large retrospective case?control stud"

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    H&'o$(&cemi o! t)e Ne*+orn

    stri3ing difference in the number of small for gestational age infants (cases 7'#'J!controls ',#,J# This emphasises the $ea3ness of case?control methodolog" instud"ing $hether h"pogl"caemia itself affects outcome or is merel" a pro&" forother ris3 factors# /inclair (ornblath et al 199 has recentl" pointed out that allstudies to date have been too fla$ed to demonstrate definitive correlation

    bet$een h"pogl"caemia and developmental outcome# 0 randomised interventionstud" seems li3el" to be the onl" means of stud"ing this problem adeFuatel"#

    .*, Neonatal hypoglycaemia# current problems

    ymptomatic hypoglycaemia is associated $ith a ris3 of long?termneurodevelopmental seFuelae but evidence for a causative lin3 is $ea3#ontrovers" persists about the significance of a)ymptomatichypoglycaemia forseveral reasons# 4irst! glucose is onl" one of several brain fuels! and health" terminfants capable of mounting a counterregulator" response (/ection ' seemunli3el" to develop seFuelae if as"mptomatic# 0 corollar" is that preterm infants

    and infants that are small for gestational age (/G0 ma" be at greater ris3 ofseFuelae (6ucas et al! 19,, because of metabolic immaturit" (/ection '#/econd! it seems li3el" that infants $ho develop s"mptomatic h"pogl"caemia$ere h"pogl"caemic but as"mptomatic at an earlier stage of their clinical course#-igorous! dichotomous classification of s"mptomatic and as"mptomatich"pogl"caemia is thus philosophicall" difficult#

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    11

    G(cose Homeostsis nd Met+o(ic Ad'ttion t irt)

    )* &L7C4$! H4M!4$3A$2$ AN M!3A54L2C AAP3A324N A3 52R3H

    )*. 3he fetal nutritional and metabolic environment

    Glucose! amino acids and lactate are the principal energ" substrates during fetal

    life! glucose alone providing about half the total energ" reFuirement# Glucosecrosses the placenta b" facilitated diffusion along a concentration gradientbet$een maternal and fetal plasma! fetal plasma glucose concentrations being 7?,J of those in maternal venous plasma# 8et fetal glucose consumption is highl"dependent upon both the maternal blood glucose concentration and the placentalconcentration gradient but on average appro&imates 7 g 3g fetal $eight?1 d?1

    (2 mg 3g?1 min?1! $hich is close to the rate of endogenous glucose productionafter birth# .nz"me s"stems involved in gluconeogenesis and gl"cogenol"sis are

    present in the fetal liver! but remain inactive unless provo3ed b" e&treme maternalstarvation# Weight for $eight! fetal liver contains about three times moregl"cogen than adult liver and hepatic gl"cogen stores at birth comprise about 1J

    of the neonateCs energ" reserves at birth#

    The rate of placental fatt" acid transport varies bet$een species in proportion toadiposit" of the ne$born# 4at o&idation is believed Fuantitativel" less importantthan amino acidEglucose o&idation! and rates of 3etone bod" production are lo$during fetal life (Ha"! 1991# The fetal endocrine milieuis dominated b" insulin#nsulin does not cross the placenta! fetal secretion being influenced b"concentrations of both glucose and amino acids in fetal plasma# The fetal insulin

    a&is is therefore independent of the motherCs# The ?cells of the fetal pancreas

    become responsive to glucose relativel" late in gestation and ?cell mass increasesmar3edl" in the last trimester of pregnanc"# t has been speculated that this ma"

    be a critical developmental period at $hich substrate provision programme)pancreatic islet development irreversibl" influencing the metabolic response toglucose in later life and predisposing to certain patterns of adult disease (Hales >ar3er! 199'# nsulin promotes anabolism in the fetus b" stimulating upta3e ofglucose into muscle and adipose tissue (Table 1# Thus the last trimester of

    pregnanc" is a period of rapid fetal gro$th! particularl" deposition of fat inadipose tissue# n this $a"! energ" stores are laid do$n in preparation for birth#

    3able .

    Metabolic effects of insulin

    ( indicates stimulation! ? indicates inhibitionGlucose upta3e into muscle

    Glucose upta3e into adipose tissue

    -elease of amino acids from muscle

    -elease of fatt" acids from adipose tissue

    Gluconeogenesis

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    H&'o$(&cemi o! t)e Ne*+orn

    8ormall" blood glucose concentration is regulated $ithin a much narro$er rangethan other metabolic fuels! var"ing onl" t$o to three?fold# >" comparison 3etone

    bod" and non?esterified fatt" acid concentrations ma" var" ten to one hundred?fold under different ph"siological conditions# This tight control of blood glucoseconcentration during both the fed (or po)tpran+ial and fasted (or

    po)tab)orptive states is accomplished b" balancing the utilisation of glucose intissues $ith endogenous glucose production# The liver is the principal site ofendogenous glucose production! though after prolonged fasting up to 1J ofcirculating glucose ma" originate in the 3idne"# Glucose is produced b" gl"cogen

    brea3do$n (glycogenoly)i) or is s"nthesised from gl"cerol! lactate! p"ruvate andglucogenic amino acid precursors! of $hich alanine is Fuantitativel" mostimportant# The general term used to describe the processes b" $hich the bod"ma3es glucose available in the fasted state is counterregulation#

    '#'#1 ,lycogen metaboli)m# Gl"cogen ma" be s"nthesised either directl" from glucoseor indirectl" from other precursors such as lactate! p"ruvate and gl"cerol# The

    balance bet$een gl"cogen s"nthesis and brea3do$n is determined b" the relativeactivities of gl"cogen s"nthase and phosphor"lase respectivel"# 0 protein 3inase!activated b" increased c0:5 concentrations in the hepatoc"te! simultaneousl"activates hepatic phosphor"lase and inactivates gl"cogen s"nthase# Thus! a rise inhepatoc"te c0:5 levels stimulates gl"cogen brea3do$nK a fall stimulatesgl"cogen s"nthesis#

    hanges in hepatoc"te c0:5 levels are effected b" the hormones $hich regulateglucose metabolism# These fall into t$o groups= in)ulin and the so?calledcounterregulatory hormone)(Tables 1 '#

    3able )Counterregulatory hormones

    Glucagon

    atecholamines

    ortisol

    Gro$th hormone

    nsulin is secreted in response to a rise in blood glucose concentrations#Hepatoc"te c0:5 levels fall in the presence of insulin! thereb" stimulatinggl"cogen s"nthesis# The principal counterregulator" hormones are glucagon andadrenaline# >oth increase hepatoc"te c0:5 levels and favour gl"cogen

    brea3do$n# 0drenaline also promotes release of glucogenic substrates (lactate

    and alanine from peripheral tissues through stimulation of peripheral ?receptors#

    '#'#' ,luconeogene)i)# Glucose is s"nthesized from lactate or p"ruvate (some of $hichis derived from alanine essentiall" b" the reversal of the gl"col"tic path$a"#ertain regulator" steps are sub%ect to substrate andEor endocrine activation andinhibition# The" are= p"ruvate deh"drogenase! p"ruvate carbo&"lase!

    phosphoenolp"ruvate carbo&"3inase (5.5

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    G(cose Homeostsis nd Met+o(ic Ad'ttion t irt)

    these steps are complicated (for revie$ see Gerich! 199* but for the purpose ofthis discussion it is sufficient to note that the overall effect of insulin is toinhibitgluconeogenesis9 whilst glucagon directly activates it# 0part from theinsulinEglucagon ratio! intracellular accumulation of precursors (e#g# p"ruvate!acet"l o0 concentration and 80+HE80+ratio are regulator" influences# 4at

    and fatt" acids are not themselves converted to glucose# Ho$ever! fat o&idationpromotes gluconeogenesis b" increasing intracellular acet"l o0 concentrationand 80+HE80+ ratio# 0drenaline indirectl" stimulates gluconeogenesis b"stimulating peripheral mobilisation of non?esterified fatt" acids from adiposetissue and their subseFuent o&idation in the liver# 5lasma adrenalineconcentrations immediatel" after birth are higher than at an" other time of life!inductive proof of this hormoneCs 3e" role in perinatal metabolic and cardio?respirator" adaptation#

    '#'#* -eripheral gluco)e utili)ation# :ost tissues! including brain! ta3e up glucose inproportion to the concentration gradient across the cell membrane! but in muscle!

    adipose tissue! and liver the process is insulin sensitive# ntracellular glucose isphosphor"lated to glucose?D?phosphate (GD5 through the action of he&o3inase#When cells o&idise fat c"toplasmic glucose?D?phosphate (GD5 concentrationsincrease! inhibiting he&o3inase and reducing the cellCs abilit" to BtrapB glucose b"

    phosphor"lation# Thus provision of fat both reduces glucose upta3e into cells andfavours gluconeogenesis in the liver#

    '#'#) .urnover of gluco)e: the balance between pro+uction an+ utili)ation # n recent"ears it has been possible to measure rates of glucose production inne$born infants using stable (non?radioactive isotopes of glucose labelled $ithdeuterium ('H or 1* (D!D'H' glucose! 1?1* glucose and ;?1* glucose#

    .&periments $ith

    '

    H tracers "ield estimates of glucose production about 12Jhigher than those obtained $ith 1* tracers! as some 1* is rec"cled through theori c"cle# ;sing D!D'H'glucose! >ier et al (1977 estimated the rate of glucose

    production in infants over 1 da" old as )#*?,#2 mg 3g?1 min?1# n contrast!ier et al! 1977#

    nfusion of glucose into adults suppresses endogenous glucose production boththrough a direct effect of glucose concentration and through enhancement of

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    H&'o$(&cemi o! t)e Ne*+orn

    insulin secretion (see '#'#' above# The same phenomenon has been observed innormal ne$born infants though the degree of suppression is ver" variable and lessmar3ed in sic3! stressed infants! particularl" those $ho are ver" preterm (o$ettet al19,*K /unehag et al! 199)# This probabl" demonstrates variable e&pressionof the counterregulator" response in h"pogl"caemic and stressed ne$borns#

    '#'#2 ummary# :oment?to?moment endocrine control of blood glucose concentrationis achieved through the opposing actions of insulin and glucagon# 0drenalineBboostsB the counterregulator" response during stress# Other hormones act

    permissivel"K cortisol has little! short?term! direct effect on blood glucoseconcentrations but the effect of glucagon is reduced in cortisol deficienc"#/ubstrate concentrations directl" affect the rate at $hich gluconeogenesis

    proceeds# 0dministration of glucose suppresses gluconeogenesis $hereas it isactivated b" lactate! p"ruvate and glucogenic amino acids# ncreased o&idation ofnon?esterified fatt" acids facilitates gluconeogenesis indirectl" in the liver b"increasing acet"l o0 and 80+H concentrations# t also reduces peripheral

    glucose reFuirements#

    )*, Metabolic events at birth# the role of insulin and substrates other than glucose

    n)ulin# 0t birth the ne$born must s$itch abruptl" from a state of net glucoseupta3e and gl"cogen s"nthesis to one of independent glucose production# Themaintenance of normogl"caemia depends upon adeFuac" of gl"cogen stores!maturation of gl"cogenol"tic and gluconeogenic path$a"s! and an integratedendocrine response# The endocrine events believed to trigger the release ofglucose and the mobilisation of fat from peripheral stores are an increase inadrenaline secretion and a rapid fall in the insulin= glucagon ratio during the first

    fe$ hours of life! attributed to both a fall in the plasma insulin concentration and asurge in glucagon concentration (

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    1,

    G(cose Homeostsis nd Met+o(ic Ad'ttion t irt)

    4or e&ample! >eard et al(19DD alternatel" allocated term and preterm infants toan Bearl" feedingB group (fed $ith formula from D hours of age and a groupfasted for 7' hours# :ean blood glucose concentration at 7' hours $as ) mg dl ?1

    ('#' mmol l?1 in the fasted term infants! as compared to D, mg dl?1(*#, mmol l?1in the Bearl"?fedB group# 2,J of the fasted premature infants had a blood glucose

    concentration of N'2 mg dl?1

    (1#) mmol l?1

    b" 7' hours of age! as compared toonl" )J (1 infant among the earl"?fed groupK though no complications $erenoted# The fasted group also sho$ed a reduced increment in blood glucoseconcentration on in%ection of glucagon and adrenaline! suggesting a relativereduction in their gl"cogen stores# 4ree fatt" acid concentrations nevertheless rosein the fasted infants and over 2J of the fasted health" premature infants sho$ed3etonuria b" ),?7' hours of age# 5ersson Gentz (19DD similarl" notedincreases in free fatt" acid! gl"cerol and 3etone bod" levels among fasted terminfants# The highest values $ere noted in babies $ith the lo$est blood glucoseconcentrations# ncreases in the concentration of glucogenic precursors (alanineand lactate and 3etone bod" concentrations $ith starvation at this time of life are

    nevertheless smaller than those in older children $ith similarl" lo$ glucose levels(/tanle" et al! 1979K 0nda" et al! 19,1# :oreover it is important to emphasisethat the BprematureB babies of thirt" "ears ago $ere probabl" more mature as agroup than preterm infants of toda" $hose adaptive capacit" ma" be even less$ell developed#

    :ore recentl" Ha$don et al(199' conducted a cross?sectional stud" of wholebloo+glucose concentration among 12D health" term babies# This $or3 is ofimportance for man" reasons# 4irstl"! infants $ere +eman+1fe+# /econdl"!

    breastfed babies $ere studied ()DJ of the sample# Thirdl"! metabolic substratesother than glucose (gl"cerol! lactate! p"ruvate! alanine! non?esterified fatt" acids!

    3etone bodies $ere measured# 4inall"! infants $ere studied throughout the first$ee3 and not onl" in the first eight hours (/tanle" et al! 1979 to three da"s(>eard et al! 19DDK 0nda" et al! 19,1# t $as sho$n convincingl" that althoughhealth" term breastfed babies had significantl" lo$er blood glucose concentrationsthan those $ho $ere bottle?fed (breastfed= mean *#D mmol l?1! range 1#2?2#* mmoll?1K bottle?fed= mean )# mmol l?1! range '#2?D#' mmol l?1! their 3etone bod"concentrations $ere elevated in response# 0 statisticall" significant negativecorrelation bet$een PlogQ 3etone bod" and blood glucose concentration $asmeasured at '?* da"s of age! but not $ithin the first ') hours or after * da"s#6ucas et al(19,1 also found breastfed babies to have significantl" higher 3etone

    bod" concentrations than formula?fed babies studied on the si&th da" of life#

    n )ummary! blood glucose concentration falls in babies $ho are not fed# >uthealth" term babies of appropriate $eight for gestation (0G0 mobilisealternative metabolic substrates (free fatt" acids and 3etone bodies in response#>reastfed babies as a group have lo$er blood glucose concentrations (referred tolater as Bsuc3ling h"pogl"caemiaB and higher 3etone bod" levels than those $hoare bottle?fed# t is not clear $hether this reflects specific promotion of3etogenesis (e#g# b" breastmil3 fat or another mil3 component! or $hether it issimpl" the result of differences in blood glucose concentrations and postprandialincrements in plasma insulin concentration#

    )*- Abnormal glucose homeostasis

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    17

    G(cose Homeostsis nd Met+o(ic Ad'ttion t irt)

    '#)#' mall for ge)tational age (,2& infant)# This group has long been recognised tobe at increased ris3 of neonatal h"pogl"caemia (ornblath et al! 1929# :orerecentl" h"pogl"caemia has been detected during fetal life among infants small forgestational age at birth# 4actors $hich ma" account for this include a high

    brain=bod" mass ratio ($ith corresponding increase in glucose consumption!

    reduced fat stores! failure of counterregulation (including dela"ed maturation ofgluconeogenesis and h"perinsulinism#

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    10

    H&'o$(&cemi o! t)e Ne*+orn

    .ndocrine adaptation in /G0 babies has also been studied b" several authors#:ost have sho$n no differences bet$een 0G0 and /G0 infants in insulin andglucagon concentrations! though the range seen in both populations is $ide#

    8evertheless )ome /G0 babies appear to have both high plasma insulinconcentrations and high glucose reFuirements! consistent $ith h"perinsulinism

    (6e+une! 197'K ollins 6eonard! 19,)K ollins et al! 199# 0 prospectivestud" of /G0 infants admitted to a single neonatal unit over one "ear found that1 of '7 became h"pogl"caemic and that half of them had inappropriatel" high

    plasma insulin concentration at the time of h"pogl"caemia (ollins et al! 199#0lthough the assa" used did not discriminate insulin from its propeptides! andhence ma" have overestimated the BtrueB insulin concentration (Ha$don et al!1992! lo$ plasma free fatt" acid concentrations and high glucose reFuirements(e&ceeding 1 mg 3g?1 min?1 in t$o infants provided functional evidence ofh"perinsulinism#

    /ome of the babies also sho$ed lo$ plasma glucagon concentrations! raising the

    possibilit" that failure of the glucagon surge after birth pla"s as great a part in theaetiolog" of h"pogl"caemia in /G0 infants as does h"perinsulinism (:ehta!1991# :est"an et al(197D studied this possibilit" b" infusing glucagon intonormogl"caemic and h"pogl"caemic /G0 infants# Onl" the former groupresponded b" sho$ing a reduction in concentration of glucogenic amino acids# t$as suggested that /G0 infants ma" sho$ glucagon resistance (see /ection7#*#1#

    '#)#* tre)) hypoglycaemia# H"pogl"caemia ma" be present in a number of neonatalconditions associated $ith severe stress# The most common are sepsis and

    perinatal asph"&ia! but it is also seen in congenital heart disease (heart failure and

    severe c"anotic heart disease and neonatal cold in%ur" $ith fat necrosis#

    0lthough the catecholamine response to stress is a central feature ofcounterregulation! peripheral circulator" failure in sepsis and asph"&ia ma" lead to

    both reduced mobilisation of substrate from the peripher" and accumulation oflactate in the presence of anaerobic gl"col"sis# This leads to e&haustion of livergl"cogen and reduced capacit" for gluconeogenesis $hich ma" be compounded

    b" ano&ic liver in%ur"# H"perinsulinism and increased insulin sensitivit" ma" alsobe present in these circumstances#

    '#)#) .ran)ient hyperin)ulini)m# H"pogl"caemia associated $ith transienth"perinsulinism is seen most commonl" among infants born to diabetic mothers# t

    is also seen in infants affected b" er"throblastosis fetalis# atrogenic factors!including the use of glucose infusions in labour and maternal administration of

    s"mpathomimetics! ma" give rise to maternal h"pergl"caemia and associatedfetal h"perinsulinism# 6ess commonl"! h"perinsulinism is associated $ith the rare>ec3$ith?Wiedemann s"ndrome or ma" be idiopathic#

    The macrosomic infant of the diabetic mother (+: has a characteristic habitus#Whereas the infant $ho is simpl" large for dates has proportionate increases in

    both brain size and abdominal circumference! the macrosomic +: has increasedmuscle! fat and liver mass as might be predicted from the 3no$n effects of insulin(Table 1# Thus! in fetal life the +: has an increase in abdominal circumference=

    head circumference ratio (4raser! 199)# 4or man" "ears fetal h"perinsulinism hasbeen ascribed to maternal! and conseFuent fetal! h"pergl"caemia (5edersen et al!

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    19

    G(cose Homeostsis nd Met+o(ic Ad'ttion t irt)

    192)# :ore recentl" it has been speculated that other factors! including aminoacid concentrations! must operate as mid?trimester human pancreatic tissue sho$slittle insulin response to glucose concentration in vitro(:ilner et al! 197'# Theris3 of h"pogl"caemia in the neonatal period (4arFuhar! 192D ma" be reduced b"careful control of maternal blood glucose concentration during pregnanc" but is

    still greater in +: of appropriate $eight for gestational age than in the normalneonatal population# H"perinsulinism leads to reduced concentrations of free fatt"acids and 3etone bodies in association $ith h"pogl"caemia! $hich reflects both anincreased rate of glucose upta3e and a reduced rate of glucose production(lood glucose in the bab" $as amean #, mmol l?1(92J #2! 1#1 lo$er at ' hours of age than in babies bornto mothers $ho had received no glucose# The difference at 1 hour of age $as notstatisticall" significant# /maller differences in ' hour blood glucoseconcentrations $ere also apparent in the bab" even $hen N'2 g glucose h?1had

    been infused (mean #) mmol l?1! 92J ! #,! though the incidence ofh"pogl"caemia $as not significantl" different (mean odds ratio '#D! 92J #D1!

    11#*)#

    >oth prolonged oral (.pstein et al! 1979! and short?term intravenous!

    administration of ?agonists (5rociano" 5inheiro! 19,' used to suppresspreterm labour have been associated $ith increased cord plasma insulinconcentrations# This ma" be the result of both transplacental passage of the drugand the presence of h"pergl"caemia in the mother (Thomas et al! 1977#.pstein et al(1979 noted transient h"pogl"caemia in the bab"! but @ouppila et al(19, noted an increa)e in the bab"Cs blood glucose concentration $henfenoterol $as administered briefl" to suppress uterine contractions beforecaesarian section#

    '#)#2 -er)i)tent hyperin)ulini)m0 en+ocrine +i)or+er) an+ inborn error) ofmetaboli)m# 8eonatal h"pogl"caemia $hich persists or recurs after the first fe$da"s of life should raise the diagnostic possibilit" of an endocrine disorder orinborn error of metabolism (Table *#

    0mong the more common endocrine disorders are adrenocortical insufficienc"!h"popituitarism! and the B>?cell d"sregulation s"ndromeB (nesidioblastosis# Thefirst t$o ma" be associated $ith abnormalities of the e&ternal genitalia# /epto?optic d"splasia ma" also be associated $ith h"popituitarism# nfants $ith organich"perinsulinism have a habitus resembling the +: in the absence of features of

    gestational diabetes mellitus in the mother# nfants $ith congenital or acFuiredglucagon deficienc" also sho$ severe and protracted h"pogl"caemia (Aidnes

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    4

    H&'o$(&cemi o! t)e Ne*+orn

    O"saeter 1977! erger! 199*K ornblath /ch$artz!199*#

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    41

    G(cose Homeostsis nd Met+o(ic Ad'ttion t irt)

    3able ,Causes of recurrent and persistent neonatal hypoglycaemia

    (ornblath /ch$artz! 199*

    !ndocrine deficiencyH"popituitarismGro$th hormone deficienc"Glucagon deficienc"ortisol deficienc" E0TH unresponsiveness

    Hyperinsulinism>ec3$ith?Wiedemann s"ndrome

    > cell d"sregulation s"ndrome

    isorders of carbohydrate metabolismGl"cogen storage disease T"pe 4ructose intoleranceGalactosaemiaGl"cogen s"nthase deficienc"4ructose?1!D?diphosphatase deficienc"

    isorders of amino acid metabolism:aple s"rup urine disease

    5ropionic acidaemia:eth"lmalonic acidaemiaT"rosinaemia*?h"dro&" *?meth"lglutar"l o0 l"ase deficienc"

    isorders of fatty acid metabolism:edium chain ac"l o0 deh"drogenase deficienc"6ong chain ac"l o0 deh"drogenase deficienc"

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    44

    H&'o$(&cemi o! t)e Ne*+orn

    ,* !::!C3$ 4: H;P4&L;CA!M2A 4N 3H! C!N3RAL N!R(47$ $;$3!M

    +espite the lac3 of clinical evidence in human infants that h"pogl"caemia iscau)alin inducing seFuelae of s"mptomatic h"pogl"caemia (/ection1! evidencefrom animal studies andpo)t mortem studies of human infants indicate that severe

    and prolonged h"pogl"caemia can be correlated $ith particular neuroanatomicalpatterns of brain damage# n recent "ears much has also been learnt about thee&citoto&ic mechanisms $hich lead to in%ur" in h"pogl"caemia#

    ,*. Pathology of brain damage associated with hypoglycaemia

    The cerebral corte&! hippocampus! and caudate nucleus are the regions principall"affected b" e&perimentall"?induced h"pogl"caemia sufficient to create anisoelectric ..G# This differs from the distribution of h"po&icEischaemic damageKthe dentate g"rus is particularl" rarel" affected b" ischaemia but characteristicall"damaged in h"pogl"caemia# >rain stem and posterior fossa structures are least

    affected b" h"pogl"caemia (revie$ed b" 0uer /ies%o! 19,,K 0uer /ies%o!199*#

    t is no$ clear that neuronal death attributable to h"pogl"caemia is not simpl" theresult of metabolic attrition but an active e*citoto*ic process# .lectronmicroscop" reveals the a&on?sparing! dendritic lesion characteristic of this

    process# ;nderstanding the nature of the cellular in%ur" has potential importancein the prevention of h"pogl"caemic brain damage for pre?treatment $ithn1meth"l?d?aspartate (N:+0 antagonist drugs (notabl" dizocilpine maleate has

    been found protective in both cell culture and animal models (revie$ed b"5apagapiou 0uer! 199K 0uer /ies%o! 199*#

    ,*) Cerebral defences in hypoglycaemia

    2lternative )ub)trate)$H"pogl"caemia reduces cerebral glucose consumption inne$born animals $ithout a commensurate reduction in cerebral o&"genconsumption# This suggests that alternative metabolic fuels are utilised# The

    primar" candidates are lactate and 3etone bodies# 6actate reverses stuporassociated $ith insulin induced h"pogl"caemia in suc3ling?$eaning mice(Thurston et al! 19,* and has been sho$n to serve as a cerebral fuel in otherspecies of ne$born animals (Soung et al! 1991# nsulin?induced h"pogl"caemia(blood glucose N#2 mmol l?1 in ne$born dogs $as accompanied b" a more than

    2J fall in cerebral metabolic rate for glucose (:-gluc! and a more than 12?foldrise in cerebral metabolic rate for lactate (:-lac $hich became the predominantmetabolic fuel in this h"po3etonaemic situation (Hernandez et al! 19,# -ecentstudies in h"pogl"caemic! diabetic! human adults have also demonstrated that the

    brain consumes lactate (0miel! 199)# 6actic acidosis is believed to be protectiveduring the profound and protracted episodes of h"pogl"caemia observed ininfants $ith gl"cogen storage disease T"pe? (glucose?D?phosphatase deficienc"(4ernandes et al! 19,)#

    The ne$bornCs capacit" to promote 3etogenesis in the face of Bsuc3lingh"pogl"caemiaB has been described previousl" (/ection '#*# 8e$born terminfants rapidl" increase 3etone bod" flu& to rates observed in adults! but onl" afterseveral da"s of fasting! flu& (i#e# rate of 3etone bod" turnover being correlated$ith plasma 3etone bod" concentration (>ougneres et al! 19,D# 4urthermore!

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    43

    E!!ects o! H&'o$(&cemi on t)e Centr( Ner#os S&stem

    free fatt" acid! gl"cerol (5ersson Gentz! 19DD and 3etone bod" concentrations(Ha$don et al! 199' are inversel" related to blood glucose concentration#.&tensive evidence from animal species (+ombro$s3i et al! 19,9K 8ehlig et al!199*! including primates (6evits3" et al! 1977! demonstrates that 3etone bodiesare important cerebral energ" substrates# O$en et al(19D7 first demonstrated

    that the human brain consumes 3etones# The" catheterised the cerebral vessels ofthree adults and found that 3etone bodies became the predominant cerebral fuel$ith prolonged (2?D $ee3s starvation# /imilar catheterisation studies in infants(mean age 2 months undergoing elective surger" demonstrated higher rates of3etone bod" upta3e than those measured in adults (/ettergren et al! 197D#.nz"me s"stems necessar" for the metabolism of 3etones are present in humanfetal brain (5atel et al! 1972 and upta3e of 3etone bodies has been demonstratedin perfused brain obtained from fetuses aborted at 1'?'1 $ee3s of gestation(0dam et al! 1972# 4 is$ell matched to the local cerebral metabolic rate for glucose (:-gluc# nne$born dogs total cerebral blood flo$ $as conserved even at blood glucoseconcentrations N#2 mmol l?1 (Hernandez et al! 19,# Ho$ever! thedevelopmental time course of the mechanisms responsible ma" var" from speciesto species (revie$ed b" 8ehlig! 199* and e&trapolation to human neonates must

    be cautious# 5r"ds et al (19,,! 199 identified increased plasma adrenalineconcentrations and cerebral blood flo$ (measured using 1**e in preterm infants$hose blood glucose fell belo$ 1#7 mmol l?1# n further studies a fall in cerebral

    blood volume (measured using near infra?red spectroscop" accompaniedrestoration of normal blood glucose concentration in h"pogl"caemic preterminfants (/3ov 5r"ds! 199'# The authors speculated that the speed of changereflects the e&istence of a cerebral blood glucose BsensorB $hich maintainscerebral glucose suppl" b" recruitment of underperfused capillaries#

    ,*, $ummary

    H"pogl"caemic brain damage differs from ischaemic brain damage in both thedistribution and the mechanism of cellular in%ur"# The ne$born sho$s adaptiveresponses to h"pogl"caemia $hich ma" be protective to cerebral metabolism#These responses include an increase in cerebral blood flo$ and the use ofalternative metabolic substrates! particularl" 3etone bodies and lactate# ncreasingunderstanding of the mechanism of h"pogl"caemic brain in%ur" indicates that

    N:+0 antagonists ma" have a future clinical role in cerebral protection#

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    4%

    H&'o$(&cemi o! t)e Ne*+orn

    -* !:2N2324N 4: H;P4&L;CA!M2A

    onfusion about the definition of Bneonatal h"pogl"caemiaB $as $ell documentedb"

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    4,

    De!inition o! H&'o$(&cemi

    defined h"pogl"caemia in Bfull?sizeB term infants as a blood glucose value belo$* mg dl?1in the first ), hours and belo$ )?2 mg dl ?1after ), hours of age#/G0 babies $ere not considered as a specific group# H"pogl"caemia among lo$

    birth $eight babies $as defined as N' mg dl?1# These values dominated opinionover the management of neonatal h"pogl"caemia for man" "ears# 4urthermore!

    the acceptance of a lo$er threshold concentration for smaller babies has onl" beenchallenged relativel" recentl"#

    .arl" feeding $as commonl" discouraged in the era of this stud" (ornblath -eisner! 19D2# /rinivasan et al (19,D have more recentl" published pla)ma3

    glucose concentrations of *)) health" full?term! appropriate $eight forgestational age (0G0 infants# :ean and 92J confidence intervals (92J $ere calculated from a mi&ture of serial and cross?sectional data# The lo$erestimate of 92J for cord samples $as *#* mmol l ?1! falling to 1#) mmol l?1('Dmg dl?1 at one hour of age# 0fter t$o hours it e&ceeded '#* mmol l?1()' mg dl?1#The applicabilit" of even these data to the normal! breastfed! ne$born bab" is

    Fuestionable for the earl" care of the infants studied is described as follo$s=

    B0ll neonates $ere admitted to an observation nurser" $here $eight!temperature and other vital signs $ere recorded# The infant $as placed undera servo?controlled radiant $armer to maintain s3in temperature at *D#2 o#/3in care and bath $ere given after stabilisation of core temperature# 0llinfants $ere fed ' caloriesEoz formula at * to ) hours of ageK after feeding!the infants $ere transferred to their respective nurseries and fed ever" )hoursK 1?12J of the infants $ere breastfed#B

    Hec3 .renburg (19,7 made longitudinal measurements of serum glucoseconcentration in D) breastfed and 2 bottle?fed term infants during the first ),hours of life# >oth groups appear to have been fed first at ' hours of age and thenat BscheduledB *?) hour intervals# 0n unspecified number of the breastfed infants$ere given $ater or formula supplements (though not before blood sampling#4ifth centile blood glucose concentrations for the combined breastfed and bottle?fed groups $ere lo$est at D?1' hours of age (1#9 mmol l?1! rising to '#7 mmol l?1

    at ), hours# Aalues N'#' mmol l?1$ere obtained in 1DJ of the sample studied#nterestingl" the mean serum glucose concentration of bottle?fed babies $as#'' mmol l?1lowerthan that of the breastfed at 2?D hours of age# This statisticall"significant difference ma" have been attributable to higher postprandial insulinlevels in the bottle?fed babies (6ucas et al! 19,1#

    +ata published b" Ha$don et al(199' have been discussed in a previous section('#*# These authors measured cross?sectionall" a number of metabolic substrates!not %ust glucose! among health"! term! demand?breastfed and bottle?fed infants#The paper provides limited information about the management of breastfeeding inthe infants studied! stating onl" that the infants $ere Bdemand?fedB# 8osupplements of $ater or formula $ere given (@: Ha$don! personalcommunication# Wide variation in both blood glucose concentrations and thoseof other substrates prompted the authors to highlight a final problem in defininghypoglycaemiafor the purpose of clinical management=

    3 ;suall" 12?'J higher than blood glucose concentrations#/ection 2#1#2#

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    4-

    H&'o$(&cemi o! t)e Ne*+orn

    B###factors other than absolute blood glucose concentration are important in theneonatal period and! $hile guidelines are important for clinical management!rigid definitions Pof h"pogl"caemiaQ are inadeFuate and should be avoided#The influence of gestational age! feeding practices and counterregulator"abilit"#####must be considered in the interpretation of neonatal metabolicdata#B

    n )ummary! changing care practices account for the $ide variet" of thresholdplasma and blood glucose concentrations used in the past to defineBh"pogl"caemiaB statisticall"# There are ver" fe$ data on breastfed babies# :orerecent studies of the part pla"ed b" substrates other than glucose in perinatalmetabolic adaptation suggest that the Fuest to identif" a BsafeB blood glucoselevel b" defining a BnormalB range is not appropriate#

    -*) Metabolic definition

    f glucose is vie$ed as the primar" metabolic fuel! does the glucose concentration

    at $hich the counterregulator" response becomes activated indicate a BsafeBvalueU 0t present such a figure cannot be identified from the limited publisheddataK fe$ studies have measured concentrations of metabolic substrates other thanglucose and variabilit" in the concentration of some! for e&ample 3etone bodies!appears even greater than that of glucose#

    :etabolic studies nevertheless ma3e one essential point about the definition ofh"pogl"caemia# ounterregulator" responses differ significantl" bet$een term and

    preterm infants (Ha$don et al! 199'! suggesting that the threshold for a BsafeBblood glucose concentration in the preterm infant is higherthan that for a terminfant and not lo$er as implied b" earlier data (ornblath -eisner! 19D2#

    -*, Neurophysiological definition

    f the ultimate goal of identif"ing and treating h"pogl"caemia is the maintenanceof normal cerebral metabolism! can a threshold blood glucose concentrationassociated $ith disturbed neuroph"siological function be identifiedU

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    47

    De!inition o! H&'o$(&cemi

    n )ummary! current published evidence correlating neuroph"siologicaldisturbance $ith blood glucose concentration is eFuivocal and based on too fe$observations to set a BsafeB threshold for either term or preterm infants#

    -*- Neurodevelopmental definition

    The ma%orit" of studies e&amining neurodevelopmental prognosis afters"mptomatic or as"mptomatic h"pogl"caemia have compared control sub%ects$ith infants in $hom blood glucose concentration fell belo$ a defined value(/ection 1#'# ;sing a different approach 6ucas et al(19,, correlated plasmaglucose concentration $ith outcome in a large stud" of DD1 preterm infants$eighing N1,2 g at birth# >a"le" motor and mental developmental scoresascertained blindl" at 1, months of age $ere regressed upon lo$est recordedglucose concentrations bet$een #2 and )# mmol l?1ad%usting for se&! gestationalage! birth $eight! da"s of ventilation and other identifiable perinatal and social

    ris3 factors# :a&imum regression coefficient for plasma glucose concentrationand >a"le" scores $as observed at a threshold value of '#2 mmol l?1 but nocorrelation $ith outcome $as evident for plasma glucose concentrations R)#mmol l?1# /cores $ere also significantl" correlated $ith logarithm of number ofda"s on $hich plasma glucose levels N'#D mmol l?1 $ere recorded# 4reFuentBmoderateB h"pogl"caemia (plasma glucose N'#D mmol l?1 $as more strongl"associated $ith developmental deficit than more severe but less freFuenth"pogl"caemia# 6arge differences $ere seen bet$een eugl"caemic infants andthose in $hom plasma glucose fell belo$ '#D mmol l?1on five or more! notnecessaril" consecutive! da"s# :ean (/. scores in these respective groups for the>a"le" motor developmental inde& $ere 9D#1 (1#* v ,)#) (*#' (pN#1 and

    1'# (1#2 v ,2#D (*#7 (p N#2 for mental development# 4urthermore! theris3 of neurodevelopmental impairment (defined as cerebral pals" or >a"le"motorEmental development score N7 for infants $hose plasma glucose fell

    belo$ '#D mmol l?1 on five da"s or more $as *#2 (92J 1#*?9#)! pN#'relative to the ris3 for those in $hom h"pogl"caemia $as not recorded#

    This stud" is notable for its large sample size and unparalleled statistical po$er#8evertheless! it has a number of limitations as a guide to BsafeB plasma glucoseconcentrations# 4irst! it applies onl" to preterm infants and there is increasingevidence that the immature counterregulator" response of this group might ma3ethem more vulnerable to effects of h"pogl"caemia (/ection '#)#1# /econd! it is

    important to reiterate (/ection 1#* that evidence of an association bet$eenh"pogl"caemia and neurodevelopmental outcome in studies of this t"pe ma" notreflect causation# H"pogl"caemia ma" merel" have acted as a pro&" for otherunidentified ris3 factors not entered into the multiple regression model# t cannot

    be assumed that maintenance of a plasma glucose concentration R'#2 mmol l?1

    $ould have prevented neurodevelopmental seFuelae#

    -*0 $ummary

    There are insufficient data to define a normal range for blood glucose values inhealth" term breastfed babies# The fe$ studies $hich have e&amined this problem

    have not given detailed descriptions of breastfeeding management# .ven if anormal range of blood glucose concentrations could be set it $ould not establish a

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    49

    Screenin$

    0* $CR!!N2N&

    The development of reagent strip blood glucose tests in the 197Cs facilitated thepractice of screening for h"pogl"caemia in ne$born infants# Ho$ reliable arethese tests! and ho$ %ustifiable is screeningU

    0*. Methods for measuring bloodergme"er!

    197) have largel" superseded reductiometric methods in clinical practice $hereprecise measurement of blood or plasma glucose concentrations is reFuired#

    2#1#' ,luco)e o*i+a)e metho+# Glucose o&idase catal"ses the o&idation of glucose to"ield glucuronic acid and h"drogen pero&ide# The concentration of h"drogen

    pero&ide liberated is measured using a pero&idase step coupled to a colouredo&"gen acceptor or an electrode (>ergme"er! 197)# These reactions form the

    basis of both reagent strip and benchtop glucose electrode methods# Thelimitations of these s"stems are described in more detail belo$ (/ections 2#1#D!2#1#7#

    2#1#* He*o4ina)e metho+# He&o3inase catal"ses the phosphor"lation of glucose b"0T5# Glucose?D?phosphate is then reduced b" glucose deh"drogenase "ielding80+5HEH$hich can be measured using a suitable spectrophotometric indicators"stem# This method is precise and highl" specific for glucose (>ergme"er! 197)#

    2#1#) -reci)ion an+ )ource) of error in the +etermination of bloo+ 5 pla)ma gluco)econcentration)# -eFuirements for the ideal method for measurement of glucoseconcentrations in clinical practice are= accurac"! precision! and rapid processing ofsmall samples $ithout the need for preparator" steps# The method must also besufficientl" simple for medical and nursing personnel to underta3e it $ithoute&tensive training in laborator" s3ills# :ethods developed and used most

    e&tensivel" in the last t$o decades for cotside monitoring of blood and plasmaglucose concentrations include paper reagent strips and glucose electrodes# >othdepend on the glucose o&idase reaction (/ection 2#1#'# 0nother more recentl"developed method (the Hemoue photometer! /ection 2#1#, emplo"s glucosedeh"drogenase to reduce 80+ but measures indicator colour change b"transmission spectrophotometr" rather than the reflectance technolog" emplo"ed$ith paper strip methods#

    2#1#2 -ropertie) of the )ample an+ )ource) of error# 0rterial blood has a slightl" higherglucose concentration than venous# The magnitude of this difference varies $ithtissue glucose demands and $ill be greatest under anaerobic conditions# apillar"

    sampling is unreliable if peripheral blood flo$ is reduced# /amples must be al$a"sbe free?flo$ing as sFueezing the heel causes haemol"sis $hich interferes $ith the

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    3

    H&'o$(&cemi o! t)e Ne*+orn

    assa" unless deproteinisation is performed (see belo$# ontamination b" alcoholused for s3in preparation leads to erroneousl" high values (Grazaitis /e&son19,K Togari et al019,7# The sample should either be anal"sed immediatel" ordeproteinised (for e&ample using perchloric acid and chilled# Gl"col"sisother$ise continues# ommerciall" available sodium fluoride coated tubes do not

    al$a"s ensure a fluoride concentration sufficient to inhibit gl"col"sis (@oosten etal01991#

    One of the greatest problems $ith neonatal samples is that haematocrit ma" var"from N) to R7J# -ed cells contain less $ater than an eFuivalent volume of

    plasma (though the glucose concentrationin red cell $ater is the same as that inthe plasma# 5lasma glucose concentration is therefore higherthan that of $hole

    blood! on average b" about 1,J (0"nsle"?Green! 1991# 4urthermore! allmethods emplo"ing paper reagent strips are sub%ect to an intrinsic haematocrit

    biasK the higher the haematocrit value! the lo$er the result# 5ossible reasonsinclude discolouration of the test?pad and resistance to $iping or $ashing before

    reading# 0lso the higher sample viscosit" impedes diffusion of plasma into thetest?pad of the strip# 5reparation of a plasma sample! e#g# in a heparinised micro?haematocrit tube! overcomes this problem (ilirubin! uric acid! and haemol"sis also interfere $ith glucose o&idase?pero&idasebased strip methods# >ilirubin inhibits both steps of the assa" leading to falsel"lo$ values (4o& -edstone 197D# Haemol"sis also produces falsel" lo$ values#This ma" be attributable to presence of haemoglobin or to release of reducedglutathione $hich competes $ith the chromogen for h"drogen pero&ide releasedin the assa"# nterference b" haemol"sates! uric acid! and bilirubin can be

    prevented b" deproteinisation of the sample#

    2#1#D -aper )trip)# These $ere initiall" developed for monitoring blood glucoseconcentration in diabetes and not intended for detection of h"pogl"caemia# aremust be ta3en to avoid contamination b" alcohol s3in?cleansers! to cover the$hole surface of the test?pad! and to time the reaction precisel" before $iping thestrip# .ven $hen these precautions are adopted! all tend to under?estimates"stematicall" the mean of a series of measurements in the range of glucoseconcentrations relevant to the diagnosis of neonatal h"pogl"caemia (N'#D mmol l?1K appro& N 2 mg dl?1 and are imprecise! t"picall" giving values onl" to $ithin

    #2 mmol l?1 even $hen coupled $ith a reflectance metering s"stem (e#gReflolu*#

    /everal commerciall" available s"stems are available and have been evaluated forneonatal use including!e*tro)ti*(0mes o# (hantler et al! 19D7K Wil3ins

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    Screenin$

    4our studies have e&amined the problem in this $a"# One (0"nsle"?Green! 1991compared blood glucose measurements made using the6' glycemie %177 stripandReflolu*reflectance meter $ith autoanal"ser measurements across the rangeof blood glucose concentrations #,?'#, mmol l?1# The 92J confidence limits(precision across this range appro&imated #2 mmol l?1! and there $as a small

    s"stematic difference of #2 mmol l?1

    at all concentrations# 0nderson et al(199*compared 6' strip $ith the 8ellow pring) n)trument) glucose electrodes"stem#6' glycemie te)tgave results on average #*7 mmol l?1lo$er than thoseobtained $ith the glucose electrode in the range of concentrations 1?2 mmol l?1#onfidence limits $ere not given#

    0 third stud" (-e"nolds +avies! 199* e&amined the effectiveness of paperstrip s"stems in screening for neonatal h"pogl"caemia (see 2#' belo$! defined asa blood glucose concentration of N'# mmol l?1detected at the cotside $ith the

    6' glycemie %177 te)t(Table 2# The9o+a4 4tachems"stem $as used as acomparative laborator" reference# :ean6' glycemie te)tvalues understimated

    mean 9o+a4 4tachem values b" as much as 1#2 mmol l?1

    at a 6' glucoseconcentration of 1 mmol l?1 but $ere comparable at *#2 mmol l?1# 0t allconcentrations there $as a $ide scatter of results! such that the laborator" bloodglucose at a 6' value of '# mmol l?1 could have been bet$een 1#) and)#* mmol l?1 on 92J of occasions# Hameed et al (1992 similarl" comparedvenous and capillar" sample6'?test reflectance estimates $ith laborator" valuesobtained b" the he&o3inase techniFue and observed a tendenc" for the mean

    6'1 test value to underestimate $ith a $ide scatter of individual values (92J appro&imatel" V 1#D mmol l?1#

    n )ummary! reagent strip methods are prone to man" errors $hen used to screen

    for neonatal h"pogl"caemia# The mean of a series of measurements ma" beunderestimated b" as much as #2?1# mmol l?1# Conse=uently9 treatmentshould not be initiated on the basis of results obtained with these tests alone*

    2#1#7 ,luco)e electro+e )y)tem)# One stud" (onrad et al! 19,9 e&amined thereliabilit" of a glucose electrode based anal"ser (S/ (8ellow pring)

    n)trument)! :odel '*0 used b" nurses in a clinical setting# The device measures

    plasma glucose concentration on a $hole blood uncentrifuged '2l sample# 0n invitrostud" found good linear agreement (r M #99 over the range ?1 mg dl?1

    ( ? 2#D mmol l?1 bet$een S/ results and those obtained using a laborator"glucose o&idase method# The regression eFuation $as=

    S/ blood glucose (mg dl?1 M #92 laborator" value #7D mg dl?1#

    /tandard error of the estimate (nM)9 $as *# mg dl?1(#17 mmol l?1! significantl"better than agreement obtained bet$een S/ and reagent strip methods(,lucometer 0 hem)trip b,0 !e*tro)ti*0 ,luco)ti* for $hich standard error ofthe estimate ranged bet$een 12?' mg dl?1# nterference from bilirubin isnegligible at concentrations encountered in practice! and sample haematocrit doesnot affect the assa"# 4ull" automated s"stems are available but e&pensive (appro&12! compared to reflectance meters# Once purchased! the running costs ofthe S/ eFuate closel" to the cost of disposable reagent strips#

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    H&'o$(&cemi o! t)e Ne*+orn

    2#1#, Other be+)i+e )y)tem)$ The Hemoue ?glucose photometer (Hemo1ue 26!0ngelholm! /$eden is an optical method measuring $hole blood glucose on

    small (2l samples utilising disposable cuvettes# >lood is haemol"sed in thecuvette and 80+H formed b" enz"matic glucose o&idation reducesmeth"lthiazol"ldiphen"l tetrazolium to produce a formazan d"e! the concentration

    of $hich is determined spectrophotometricall"# Onl" one stud" has evaluatedapplication to neonatal samples (Aadsadi @acobs! 199*# 4urthermore! itsreliabilit" for detection of h"pogl"caemia cannot be established because too fe$observations $ere in the range of importance (N* mmol l?1 and results $eree&pressed onl" in terms of statistical correlation rather than limits of agreement(see comments in /ection 2#1#7# :oreover! the cost per test is high $hencompared $ith reagent strip or electrode s"stems# uvette storage temperatureand room temperature variation can introduce errors! though these are moresignificant at high than at lo$ glucose concentrations# 0 recent stud" (.llis et al!199D conducted in 8epal found that Haemouetended to overestimate bloodglucose concentrations of neonatal samples and $as unsuitable for the detection

    of h"pogl"caemia (N' mmol l?1#

    0*) !ffectiveness of screening based on reagent strip methods

    Table 2 summarises data on the effectiveness of screening from t$o publishedstudies# 0 positive predictive value (55A of #1, or #2' implies that a reagentstrip measurement predicted true h"pogl"caemia (i#e# confirmed b" laborator"

    measurement on onl" 1, or 2'J of occasions# The discrepanc" bet$een studiesin estimated positive predictive value probabl" reflects different incidence of

    h"pogl"caemia# n one (Holtrop et al0199 the proportion of true positives $as'1J of all tests! in the other (-e"nolds +avies! 199* it $as N1J# n general!

    the lo$er the incidence of a condition! the greater the li3elihood of a false positivediagnosis being made b" a screening test and the poorer its positive predictive

    value (Hall :ichel! 1992# /ensitivit" and specificit" values are unaffected b"the incidence of a condition and estimates in these t$o studies! of ,'J and ,DJ

    for sensitivit"! and 7J and 7,J for specificit"! $ere comparable# ;sing anaverage specificit" value of 7)J it can be calculated that appro&imatel" 1 in )

    normogl"caemic babies tested $ould have been erroneousl" classified ash"pogl"caemic# 0 third stud" (Ho et al! 1991K not sho$n in Table 2 using6'1te)t ,lycemie ;

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    3%

    H&'o$(&cemi o! t)e Ne*+orn

    Holtrop (199* studied the incidence of h"pogl"caemia in 6G0 and /G00merican ne$borns! identified as having birth $eight R9th or N1th centilerespectivel"# The definition of h"pogl"caemia chosen $as that suggested b"/rinivasan et al(19,D= a)erumglucose concentration of N*2 mg dl?1at N* hours

    of age! N) mg dl?1

    at *?') hours of age and N)2 mg dl?1

    at R') hours of age#H"pogl"caemia $as detected in ,#1J (')E'9, of 6G0 infants and 1)#7J(*E') of /G0 infants# n all but * /G0 infants it occurred in the first 1 hoursof life# 0lthough data on mean birth $eight and gestation $ere given! noinformation about feeding regimens $as presented#

    0 >ritish stud" of 1D) /G0 babies detected h"pogl"caemia (defined as+e&trosti& value N1#) mmol l?1 in onl" *E1) $ith birth $eight R'#* centile andDED $ith birth $eight N'#* centile# Onl" one of the 9 infants $as s"mptomatic!

    being described as B%itter"B# Ha$don et al(199'! revie$ing the literature! Fuoteincidences of Bh"pogl"caemiaB)in term infants ranging bet$een and ,J and

    bet$een * and 12J in preterm infants#

    nformation on the incidence of neonatal h"pogl"caemia in developing countries isver" limited# 0nderson et al (199* conducted a cross?sectional stud" of ''Dfull?term! uncomplicated ne$borns in a hospital in

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    3,

    Screenin$

    achieving this aim! prevention (/ection D b" earl" enteral feeding (or provision ofintravenous glucose for those unable to feed is more important than freFuent

    blood glucose testing# +ail" or t$ice dail" laborator" measurements arepreferable to freFuent but inaccurate reagent strip measurements# The" should besufficient in most cases to tailor feeding regimens to the individual infantCs

    reFuirement#

    mall for ge)tational age (,2& infant)# are should be ta3en in the diagnosis of/G0 (see /ection D#'#*# This group is ver" heterogeneous and not all are at ris3of h"pogl"caemia# Those N*rd percentile (birth $eight N' /+ from the mean forgestation (@ones -oberton! 19,DK ornblath /ch$artz! 199*! and those$ho are disproportionate (increased head circumference= bod" $eight ratio or$ith abnormal umbilical arter" +oppler flo$ velocit" profiles in fetal life(Ha$don et al! 199'! are probabl" most vulnerable# 5ol"c"thaemia is anadditional ris3 factor $hich is easil" e&cluded (/ection D#1# .&cessivel" freFuent

    blood sampling is not necessar" to identif" those at ris3# -eliable laborator"

    measurements of cord blood glucose and blood glucose at )?D hours of age(before the second feed are preferable (Ha$don Ward 5latt! 199*#

    Large for ge)tational age (L,2& term infant)# -are infants $ith organich"perinsulinism are t"picall" large at birth! and this association has led toscreening of infants $hose birth $eight e&ceeds the 9thpercentile for gestationalage# Occasionall" 6G0 is associated $ith hitherto undetected maternalgestational diabetes# >ut the ma%orit" of 6G0 infants are simpl" large! normalhealth" infants (see /ection '#)#)# 0s in 0G0 infants (Ha$don et al! 199'!

    blood glucose concentrations ma" fall belo$ ' mmol l?1 in this group! usuall"$ithin the first , hours of life (Holtrop! 199*# There is no evidence that transient

    h"pogl"caemia in this group is detrimental to outcome# onseFuentl"! reagent?strip screening! supplementar" feeding and treatment of transient! mildh"pogl"caemia in the absence of s"mptoms are inappropriate#

    nfant) of +iabetic mother)# :ost of these infants displa" transienth"perinsulinism and are conseFuentl" at ris3 of h"po3etonaemic h"pogl"caemia#/creening should be underta3en for at least the first ') hours of life and the bloodglucose concentration maintained at R'#D mmol l?1# Testing ma" be discontinuedonce satisfactor" blood glucose concentrations are maintained $ithoutsupplementar" feeds or intravenous therap"#

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    3-

    H&'o$(&cemi o! t)e Ne*+orn

    /* PR!(!N324N

    /*. Peripartum factors

    D#1#1 ntrapartum factor)$0lthough man" intrapartum factors predisposing to neonatal

    h"pogl"caemia are unavoidable (e#g# ?s"mpathomimetics to suppress preterm

    labour! caesarean section some are avoidable# One such is e&cessive maternalglucose infusion during labour# -estriction to N1 g h?1 should not have asignificant effect on either the cord blood insulin concentration or the incidence ofh"pogl"caemia (/ection '#)#)#

    D#1#' arly po)tpartum management# The bab" should be dried immediatel" to reduceevaporative heat loss $hich increases energ" demands# /3in?to?s3in contact

    bet$een the mother and her bab" as soon as possible after deliver" are importantin the maintenance of core temperature (van den >osch >ullough! 199# .arl"enteral feeding should have the highest priorit" in health" infants! $hether term or

    preterm (/mallpeice +avies! 19D)K Wharton >o$er! 19D2#

    D#1#* Neonatal ri)4 factor)# /ection '#) discussed factors $hich increase the ris3 ofneonatal h"pogl"caemia# 4eeding regimens for categories of babies at ris3 aresuggested belo$ (/ection D#'# 5ol"c"thaemia (pac3ed cell volume! or 5A! ofR#D2 ma" be associated $ith h"pogl"caemia in some babies! particularl" those$ho are small for gestational age and infants of diabetic mothers# Themanagement of neonatal pol"c"thamia is controversialK some authorities (Glader 8aiman! 1991 recommend partial dilutional e&change $ith 2J albumin ininfants $ho are Bs"mptomaticB (including those $ho are h"pogl"caemic but thereis no consistent evidence of short? or long?term benefit in those $ho are $ell(+o"le Xipurs3"! 199'#

    /*) :eeding regimens

    The most effective method of preventing h"pogl"caemia is feeding $ith mil3 assoon as possible after deliver"# 5rolonged fasting is associated $ith a progressivefall in mean blood glucose in both term and preterm infants and in thoseappropriate or small for gestational age (>eard et al! 19DD# >reastmil3 is

    preferred to formula because it appears to promote 3etogenesis (Ha$don et al!199'# 4urthermore! there is some evidence that earl" blood glucose values interm babies fed formula are lo$er than those in babies breastfed (Hec3 .renburg! 19,7# This ma" reflect the insulinogenic effect of protein in formula

    (6ucas et al! 19,1 (/ection )#1#

    .erm infant)# There is no %ustification for giving health" term infants 1Jde&trose $ater or an" other form of prelacteal feeds# 0lthough the practice $asonce routine! particularl" in 8orth 0merican nurseries! it is outdated# +e&trose$ater is of lo$er energ" densit" than mil3 $hich contains fat# The practice offeeding de&trose $ater presumabl" arose through concern about aspiration of thefirst feed but there is no evidence that aspiration of colostrum is an" more harmfulthan aspiration of de&trose or $ater#

    n some parts of the $orld! notabl" the ndian sub?continent! prelacteal feedingand $ithholding of colostrum is common# n an ndian ouncil of :edical-esearch collaborative stud" of infant feeding! onl" *'J of mothers suc3led their

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    37

    "re#ention

    bab" $ithin the first ') hours and onl" 1*J in the first , hours# /event"?one percent of mothers offered an alternative to breastmil3! such as hone" or sugar $ater(0nderson et al! 199*# /uch practices seem ver" li3el" to increase the incidenceof neonatal h"pogl"caemia though no intervention studies appear to havedocumented this#

    D#'#' -reterm infant)# t is over thirt" "ears since t$o >ritish studies documented thatBearl"B feeding $ith e&pressed breastmil3 reduced the incidence of h"pogl"caemia(blood glucose N' mg dl?1 in preterm infants (/mallpeice +avies! 19D)KWharton >o$er! 19D2# n the 19)Cs and 192Cs preterm infants $ere starvedfor the first ') hours of life in order to reduce the incidence of aspiration#/mallpeice +avies (19D) sho$ed that nasogastric tube feeding of small infants(birth $eight 1?' 3g using graded volumes of mil3 $as safe and reduced thefreFuenc" of h"pogl"caemia! %aundice and deh"dration $hen compared $ithhistorical controls# The feeding schedule the" adopted! commencing $ithD ml 3g?1 d?1and increasing dail" in steps of * ml 3g?1d?1to 12 ml 3g?1d?1on thefourth da" of life! is still $idel" recommended in standard neonatal te&ts though

    has never been s"stematicall" evaluated# Wharton >o$er (19D2 found that thispractice halved the incidence of as"mptomatic h"pogl"caemia (immediate?fedgroup 2E))K late?fed group 1E2) and abolished s"mptomatic h"pogl"caemia(E)) immediate?fedK )E2) late?fed though $as associated $ith an increased ris3of mortalit"! often associated $ith aspiration#

    0n alternative ma" be to provide 1 ml 3g?1d?1on the first da"! 72 ml 3g ?1d?1onthe second and 2 ml 3g?1d?1on the third as the volume of breastmil3 obtained b"suc3ling increases (@: Ha$don! : Ward 5lattK personal communications! 199D#oncern about the relationship bet$een high earl" feed volume and necrotisingenterocolitis ma" be un%ustified! being based on case?control data (0nderson

    ,/ weeks of gestation # /ustained coordination ofsuc3ling and s$allo$ing is present from about *' $ee3s of gestation (-ennie!199' and man" such infants ma" be allo$ed an opportunit" to suc3le# The abilit"of small babies to feed at the breast is often underestimated# 5earce >uchanan(1979 reported that 1' of 17 ver" lo$ birth $eight babies consecutivel" admittedto a neonatal unit started breastfeeding at a mean $eight of 1#*') V #99 3g(mean! /+ and a mean age of 11 da"s# Ten $ere full" breastfed at a mean age of

    '7 da"s $hen the" $eighed 1#D V #1*9 3g#

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    30

    H&'o$(&cemi o! t)e Ne*+orn

    The breast should be offered as soon as possible after birth and at *?hourl"intervals thereafter# There is little point in persisting if the infant is sleep"!undemanding and un$illing to attach or suc3le# Total reFuirements ma" not beobtained directl" and supplementar" feeds should be given after breastfeedsduring the earl" da"s of life# The volume of supplement should be reduced assuc3ling improves and birth $eight is regained (see guidelines in D#'#' above#

    4eeds should be offered b" cup or gavage in preference to a bottle# .&pressedbreastmil3 is the food of choice but formula is preferable to de&trose $ater if it isnot available#

    Healthy preterm infants under ,) weeks of gestation # The ma%orit" of these$ill not suc3le effectivel" and reFuire gavage feeding though cup?feeding is

    possible from * $ee3s of gestation (6ang et al! 199)# f reFuired! a gastric tubeshould be passed orall" and not nasall" (/toc3s! 19,# On the first da" a volumeof D ml 3g?1 d?1 divided into hourl" aliFuots should be given# f facilities forintravenous therap" are available! a 1J glucose infusion should be initiated assoon as possible after birth /ection D#)# 0bsolute contraindications to feeding

    include bile?stained gastric aspirate and abdominal distension! most commonl"attributable to ileus# 4eeds should be stopped and intravenous 1J glucoseinfusion commenced (or parenteral nutrition $hen available# .nteral feeding ma"

    be recommenced $hen signs resolve! assuming that necrotising enterocolitis(8. has been e&cluded# 8. and other conditions associated $ith ileus (e#g#sepsis! respirator" disease should be treated according to standard te&ts#

    :ost infants N', $ee3s of gestation sho$ immature patterns of bo$el motilit"though earl" feeding has been sho$n to hasten adaptation to the pattern seen inmore mature babies (>issett et al! 19,9# 0 randomised controlled stud" of babiesN1,2 g birth $eight found human mil3 feeds more rapidl" tolerated than formula

    feeds (6ucas! 19,7#

    Management of the mother# f the bab" is unable to suc3le! mothers shoulde&press their breastmil3 as soon as possible after deliver" and continue at least *?hourl" even at night# 0ll mil3 e&pressed should be given to the bab"# f the bab" iscapable of suc3ling but appears unable to obtain hisEher total reFuirements themother should e&press aftereach feed# /3in?to?s3in contact (B3angaroo careBhas been sho$n in a randomised controlled stud" to increase the duration oflactation among mothers of ver" small preterm infants (Whitela$ et al! 19,,#

    D#'#* mall for ge)tational age (,2& infant)

    2dentifying $&A babies# ;suall" /G0 babies are defined as those $hose birth$eight is belo$ the 1th centile for gestational age# This crude classificationignores the strong effect of maternal height and $eight on birth $eight# There is adifference of appro&imatel" 2 g bet$een the mean birth $eights at term of

    babies born to mothers of ) feet 1 inches or 2 feet 1 inches# f the e&tremes ofmid?pregnanc" $eight are also ta3en into account! the difference approaches 1 3g(0ltman oles! 19,# 0 stud" of >ritish babies (Gardosi et al! 199'estimated that ',J of infants conventionall" classified as /G0 $ere ofappropriate $eight $hen maternal race! height! $eight! and parit" $ere ta3en intoaccount# /imilarl"! ')J of babies conventionall" classified as appropriate $eight

    for gestational age (0G0 $ere trul" /G0# deall"! birth $eight should bead%usted at least for the effect of maternal height! parit" and mid?pregnanc"$eight (0ltman oles! 19, before babies are labelled /G0#

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    "re#ention

    0s the endogenous glucose production rate and glucose reFuirements correlatemore closel" $ith brain $eight than bod" $eight! the /G0 babies at greatest ris3of h"pogl"caemia are probabl" those of disproportionate appearance $ith highO4E:0 (head circumference= mid?arm circumference or O4Ebod" $eightratio# ;nfortunatel" there are insufficient data at present to establish a sufficientl"

    precise threshold identif"ing an at?ris3 population# :oreover the calculation ofsuch an inde& from t$o independent parameters doubles the potential formeasurement error#

    Management of $&A infants# -easons for the increased incidence ofh"pogl"caemia among /G0 infants $ere discussed in /ection '#)=counterregulator" response and 3etogenesis are blunted b" comparison $ith 0G0infants but appear to mature on feeding# onseFuentl"! earl" feeding is believed to

    be as important in this group as in preterm infants of normal $eight# Glucoseproduction rates in /G0 infants are higher than in 0G0 infants (/ection '#'#)#We therefore commence enteral feeding in health" /G0 infants at 9 ml 3g ?1d?1as

    *?hourl" feeds on the first da" and increase in * ml 3g?1

    steps dail"#

    n a ambridge stud" (Whitb" et al019,' of 'D9 infants $eighing 1#,?'#2 3g$ho $ere provided $ith D ml 3g ?1 d?1of mil3 on the first da" (increasing b"aliFuots of * ml 3g?1 d?1 onl" 2 developed h"pogl"caemia2# 0ll $ereas"mptomatic# 22J of the infants $ere B$$ma4ing )ome attempt to brea)t1fee+ at+i)charge#B 0 further ambridge stud" of 1D) infants belo$ the 2thcentile birth$eight at *7 $ee3s fed according to this regimen observed onl" 9 cases ofh"pogl"caemia (footnote)! most of $hich $ere in infants N' standard deviations

    belo$ mean birth $eight for gestation# .ight of the 9 $ere as"mptomatic and one$as described as B%itter"B#

    There are no properl" controlled studies of the incidence of h"pogl"caemiaamong small (/G0 and preterm babies e&clusivel" breastfed on demand or

    breastfed $ith supplements# These are urgentl" needed to uncover the incidenceand outcome of h"pogl"caemia! the incidence of adverse effects associated $ithformula supplementation! and the size of an" negative effect on breastfeeding#0nother area $orth" of stud" might be the role of simple anthropometr" (e#g#head circumference= arm circumference or length ratios in identif"ing more

    precisel" those small for gestational age infants at ris3#

    D#'#) nfant of the +iabetic mother# These infants displa" transient h"perinsulinism# The

    ris3 is greatest among those $ho are macrosomic (/ection '#)# H"pogl"caemia isnot li3el" to occur after the first ') hours of life# 0ffected infants should bebreastfed as soon as possible after birth and thereafter on demand# f a pre?feedblood glucose estimation at * hours of age is normal it is unli3el" thatsupplements $ill be reFuired# >ut if the plasma glucose is N'#D mmol l?1at thisage! supplementar" feeds (9 ml 3g?1 d?1 should be instituted for the first ')?),hours of life! bearing in mind that the abilit" of these infants to $ithstandh"pogl"caemia can be compromised b" h"po3etonaemia# t is reassuring to notethat most studies have found neurodevelopmental outcome among infants ofdiabetic mothers similar to that of controls! provided that h"pogl"caemia $asappropriatel" treated#

    2 !e*tro)ti*value of N'2 mg dl?1#

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    H&'o$(&cemi o! t)e Ne*+orn

    D#'#2 Large for ge)tational age (L,2& infant)$ 6G0 is usuall" defined as birth $eightR9th centile for gestational age# nfants $ith persistent h"perinsulinism (e#g#attributable to >?cell d"sregulation s"ndrome are t"picall" 6G0! as are those

    born to mothers $ith unrecognised gestational diabetes# :etabolic adaptation hasnot been studied so intensivel" in 6G0 infants as a group as it has been! for

    e&ample! in /G0 or preterm infants# The incidence of h"pogl"caemiaD

    in an0merican stud" (Holtrop! 199* of 6G0 infants $as ,#1J but no details offeeding regimens $ere given# n the same stud" 1)#7J of /G0 infants $ereh"pogl"caemic using the same criteria# H"pogl"caemia in 6G0 infants $as earl"(mean age '#9 hours and no cases occurred in infants over , hours old# 5ersistentorganic h"perinsulinism in other$ise health" infants is ver" rare and it is doubtfulthat screening and supplementar" feeding of breastfed 6G0 infants is %ustified#

    /*, Additives for milk feeds

    The effectiveness of supplementing feeds $ith carboh"drate $as investigated in a

    randomised controlled trial involving 1* full?term! 6G0 infants7

    (/inghal et al!1991# nfants $ere admitted to a nurser" for the first ') hours of life and fedstandard formula! either alone or supplemented $ith 2 g po$dered BsugarB per1 ml# >oth groups $ere fed , ml 3g ?1')h?1b" bottle or gastric tube! ma3ingthe average glucose suppl" of the t$o groups 2 or 7#, mg 3g? 1 min?1 respectivel"#>lood glucose concentrations (determined on an 0utoanal"ser of the t$o groupsat 1' hours of age $ere 2*#* 7#1 and 71#D D#2 mg dl?1respectivel"# :oreo