Physiological and Phased Approach to Newborns At‑Risk of

193© 2019 Journal of Clinical Neonatology | Published by Wolters Kluwer - Medknow

A neonatologist plays a critical role in the management of babies withhypoglycemia.Although neonatal hypoglycemia has been conventionally definedas glucose ≤2.5 mmol/L, levels ≤2.8 mmol/L among neonates raise concerns ofneuroglycopenia,supportingthePediatricEndocrineSocieties’suggestiontotargetplasmaglucoselevels>2.8mmol/Linat‑riskinfants<48hofageand>3.3mmol/Lforthoseaged>48h.Theneonatologistneedstoidentifyat‑riskbabiesandenrollthem into a pathway that ensures safe, physiological transition to extrauterinelife. Physiological transition constitutes early enteral feeding, navigating theglucose nadir while maintaining mother–child bonding. Smooth umbilical toenteral transitionofglucosehomeostasis followingbirthneedsadequateglycogenstores and appropriate counter‑regulatory hormone responses. When stores areinadequate and counter‑regulatory responses fail, glucose regulation becomesmore dependent on appropriate β‑cell responses. However, β‑cell dysregulationmay cause inappropriate insulin secretion when hypoglycemic (hyperinsulinemichypoglycemia [HH]) that can be transient, prolonged, or persistent.ThemajoritycomprisetransientandprolongedformsofHHthatrecoverindaystoweekswithfeedsor short‑termparenteralglucose infusionor rarelywithuseofKATP channelagonist,diazoxide.Theminoritywithpersistentformsmayhavegeneticmutationsin at least 12 genes (ABCC8,KCNJ11,GLUD1,GCK,HADH,SLC16A1,UCP2,HNF4A,HNF1A,HK1, PGM1, and PGMM2) and need medical and/or surgicalintervention,aswellas long‑termmultidisciplinaryspecialistcare.Although thereis complexity to a management framework that begins in the first hours to daysof life, a gentle, physiological, andphased approach can lead to better outcomes.Thisreviewarticledescribessuchanapproach.

Keywords: Congenital hyperinsulinism, diazoxide, hyperinsulinemic hypoglycemia, octreotide, resolution fast study, safety fast study

Physiological and Phased Approach to Newborns At‑Risk of Hyperinsulinemic Hypoglycemia: A Neonatal PerspectiveSuresh Chandran1,2,3,4, Victor Samuel Rajadurai1,2,3,4, Khalid Hussain5, Fabian Yap2,4,6

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Website: www.jcnonweb.com

DOI: 10.4103/jcn.JCN_37_19

Address for correspondence: Prof. Suresh Chandran, Department of Neonatology, Neonatal Hypoglycaemia Prevention

Program and Hyperinsulinemic Hypoglycaemia Center, KK Women’s and Children’s Hospital, 100 Bukit Timah Road,

Singapore 229899. E‑mail: [email protected]

fuels (ketone bodies). Hypoglycemia is known tocause irreversible neuronal injury warranting promptrecognition and treatment. Knowledge of glucosehomeostasis, appropriate laboratory investigations forintermediary metabolites during hypoglycemia, and

Review Article

Introduction

Hypoglycemia remains the most commonmetabolic problem in neonates. Congenital

hyperinsulinism (CHI), due to dysregulated insulinsecretion from pancreaticβ‑cells, has increasingly beenreported to cause intractable hypoglycemia in infants.Glucose is the principal neuronal energy source, andin hyperinsulinism, there is an increase in consumptionof glucose and inhibition of glycogenolysis,gluconeogenesis, and ketogenesis, depriving the brainof both its primary (glucose) and secondary energy

Departmentsof1Neonatologyand6Endocrinology,KKWomen’sandChildren’sHospital,2DepartmentofNeonatology,Duke‑NUSMedicalSchool,3DepartmentofNeonatology,YongLooLinSchoolofMedicine,4DepartmentofNeonatology,LeeKongChianSchoolofMedicine,Singapore,5DepartmentofPediatricMedicine,DivisionofEndocrinology,SidraMedicine,Doha,Qatar

How to cite this article: Chandran S, Rajadurai VS, Hussain K, Yap F. Physiological and phased approach to newborns at‑risk of hyperinsulinemic hypoglycemia: A neonatal perspective. J Clin Neonatol 2019;8:193‑202.

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Received:03rdApril,2019Revision:14thJuly,2019Accepted:31stJuly,2019Publication:04thOctober,2019

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Chandran, et al.: Approach to hyperinsulinemic hypoglycemia in at‑risk neonates

194 Journal of Clinical Neonatology ¦ Volume 8 ¦ Issue 4 ¦ October-December 2019

prompt initiation of medical therapy are vital in themanagementofhyperinsulinemichypoglycemia(HH).[1‑4]

Neonatalhypoglycemiahasbeenconventionallydefinedas glucose ≤2.5 mmol/L, and levels ≤2.8 mmol/Lamong neonates raise concerns of neuroglycopenia,often prompting immediate clinical action.[5,6] However,glucose levels of 1.4–1.7 mmol/L in well term infantsin the first 2 h of life represents a physiological nadirthat does not requiremedical intervention.[7]Navigatingthrough this critical transition period requires enteralfeeding and appreciation of the nadir because it isunknownhowparenteralglucoseduringaglucosenadirwouldinfluenceβ‑cellfunction.

Infants at‑risk of hypoglycemia include infants born todiabeticmothers(IDM),largeforgestationalage(LGA),small for gestational age (SGA), preterm (PT), andinfantsborntooverweightmothers(IOM).[8]Mechanismof hypoglycemia in IDM, LGA, and IOM is related toinappropriate insulin levels that causeHH. In SGA andPT infants, reasons for hypoglycemia are multifactorialbut primarily related to substrate deficiency.The at‑riskinfants comprise approximately one‑third of newbornsand may require intervention that includes earlyparenteraldextrose.Asparenteralglucoseexertsadirecteffect on the β‑cell, while gut peptide hormones andfirst‑pass through the livermodulateβ‑cell responses toenteral feeds, it is not unreasonable to expect transientdysregulation of β‑cell function among infants whoreceiveearlyparenteralglucose.[9]

Although there is complexity in the hypoglycemiamanagement framework that begins in thefirst hours todays of life, a more gentle, physiological, and phasedapproachcanleadtobetteroutcomesinthemanagementof infants at‑risk for hypoglycemia. This reviewarticle describes a stepwise, practical workflow on themanagementof theseat‑risk infants that isbasedon thephysiologyoffetalandneonatalglucosehomeostasis.

Glucose homeostasis and insulin secretion in fetus and newbornFuel for fetal metabolism is generated mostly byoxidation of glucose. Maternal plasma glucose (PG)levels maintain continuous glucose supply to the fetus,exposing the fetal brain to PG concentration onlyslightlybelowthatofmaternalplasmawithfetomaternalPG difference of 0.5 mmol/L.[10] During the umbilicalto enteral transition at birth, in well‑term infants, thePG levels drop to a nadir of 1.4–1.7 mmol/L by 1 hof age and then steadily rise to 3–3.3 mmol/L by 2 hof age and continue to rise and maintain PG in therange of 3.9–5.9 mmol/L.[7] Transitional hypoglycemiain newborn infants is expected to resolve within 48 h

of life. In the immediate neonatal period, hepaticglycogenolysis provides glucose, whereas β‑oxidationof fatty acids and lactate generation due to proteolysisprovidesubstrateforgluconeogenesis.[11]

Effect of PG on insulin secretion by β‑cells ofpancreas is the key factor in understanding the medicalmanagement of HH. Glucose, amino acid, and fattyacid metabolism results in the production of adenosinetriphosphate (ATP), which controls the stimulusresponse‑coupling action of theATP‑sensitive potassiumchannels in theβ‑cells of the pancreas regulating insulinrelease precisely to keep the fasting PG concentrationsbetween 3.5 and 5.9 mmol/L [Figure 1].[11,12] Followingraised PG level, glucose enters the β‑cells throughfacilitative glucose transporter (GLUT 2) and isconverted to glucose‑6‑phosphate by the enzymeglucokinase.[13] Glycolysis results in the generation ofhigh‑energy molecules such asATP leading to a rise intheATP:ADPratio.FunctionalintegrityofthepancreaticATP‑sensitive potassium (KATP) channel depends on theinteractions between the pore‑forming inward rectifierpotassium channel subunit (Kir6.2) and the regulatorysulfonylureareceptor1(SUR1),encodedbyKCNJ11andABCC8 genes, respectively.The increase in the cytosolicATP:ADP ratio leads to activation of plasmamembraneSUR1andclosureofKATPchannelcausingdepolarizationofcellmembraneallowinginfluxofcalcium.Thisleadstoreleaseofinsulinbyexocytosisfromstoragegranules.[14]

The gut also regulates glucose homeostasis.Glucagon‑like peptide 1 (GLP1) is secreted from theL‑cells of the small intestine,which binds to theGLP1receptors in pancreatic β‑cells, thereby stimulating thesecretionofinsulin.[15,16]

Figure 1:Glucoseandproteinmediatedinsulinsecretionfromβ‑cellsofpancreas.SUR1–Sulfonylureareceptor;Kir6.2–Potassiumchannelinwardlyrectifier;GLUT2–Glucosetransporter2;G‑6‑P–Glucose6phosphate;GDH–Glutamate dehydrogenase;SCHAD– short‑chain3‑hydroxyacyl‑CoA dehydrogenase; HADH‑L3 – Hydroxylacyl‑CoenzymeAdehydrogenase;GK–Glucokinase



195Journal of Clinical Neonatology ¦ Volume 8 ¦ Issue 4 ¦ October-December 2019

Definition of hypoglycemia in at‑risk infantsAfter the first 72 h life, normal fasting bloodglucose concentrations in term well infants aremaintained within a narrow physiological range of3.5–5.5mmol/L.[17]However, recommended target levelsarecurrentlyvariable in infants at‑riskofhypoglycemia.TheAmericanAcademyofPediatrics(AAP)2011clinicalguidelines recommend target PG levels ranges from 1.4to 2.2mmol/L in asymptomatic infants<4 h of age and1.9–2.5mmol/Linthosewhoare4–24hoflife.[18]Morerecently in 2015, the Pediatric Endocrine Society (PES)recommended target PG concentration of >2.8 mmol/Lforthoseaged<48h,>3.3mmol/Linhigh‑riskneonateswithout a suspected congenital hypoglycemia disorderaged >48 h of life, and >3.9 mmol/L when there issuspicionofgeneticformofHH.[6,19]

Given the importance of navigating the physiologicalnadir[7] and the risks of neuroglycopenia among at‑riskinfants,[6] we adopted the AAP guidelines for the first4hoflifeandthePESguidelinesafter4hoflife.

Diagnosis of hyperinsulinemic hypoglycemiaA diagnosis of HH is made when serum insulin/C‑peptide isdetectable in thepresenceofhypoglycemiain infants >48 h of life receiving a glucose infusionrate (GIR) of >8 mg/kg/min concurrently withhypoketonemia, hypofattyacidemia, and a positiveglycemicresponsetoglucagon[Table1].[20]

HH in infants can be transient, prolonged, orpersistent (congenital). Transient HHmay be observedin IDM, IOM, SGA, LGA, infants with perinatalasphyxia, or Rh isoimmunization and even in thosewithout risk factors.[21] Although no clear definitionis given for the duration of transient hypoglycemia,resolution occurs within days following increment offeedsorshort‑termglucoseinfusion.ProlongedHHmaybe observed in SGA infantswho require highGIR and

demonstrate diazoxide responsiveness where resolutionisobserved inweeks tomonths.PersistentHH, seen inCHI,mayhavemoreseverephenotypeswithmutationsin at least 12 genes (ABCC8,KCNJ11,GLUD1,GCK,HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1,PGM1, and PMM2) that alter β‑cell function havebeen reported. In addition, geneticmutations have alsobeen reported which cause syndromic diseases withHH. Histologically, genetic forms of HH can be focal,diffuse,oratypical.[22‑25]

Genetics of hyperinsulinemic hypoglycemiaChannelopathies: KATP channel defectsMutations inABCC8 andKCNJ11 genes encodingKATPchannel proteins are themost common cause of severeCHI. Medically unresponsive HH is mainly caused byrecessive inactivating loss‑of‑function mutations, whilemilder formsofCHIarecausedbyautosomaldominantmutations in thesegenes.Mutations in theKATP channelregulating genes cause CHI that is unresponsive todiazoxide.[25]

Metabolopathies1. Hyperinsulinemia–hyperammonemia (HI/HA)

syndrome:GLUD1geneencodesforthemitochondrialenzyme GDH, which catalyzes the oxidativedeamination of glutamate to α‑ketoglutarate andammonia.GDH is allosterically activated by leucineand inhibited by guanosine‑5‑triphosphate (GTP).In HI/HA syndrome, mutations in GLUD1 genedecreases the sensitivity of inhibitor GTP, causinggain‑of‑function of GDH, resulting in activationof insulin secretion by leucine. They present withleucine sensitive symptomatic hypoglycemia andhyperammonemia. HI/HA cases respond well todiazoxide[26,27]

2. L‑3‑Hydroxyacyl‑Coenzyme ADehydrogenase (HADH) gene mutations:Short‑chain 3‑hydroxy acyl‑CoA dehydrogenase,encoded by the gene HADH, is an enzyme thatcatalyzes the penultimate step of mitochondrialfatty acid oxidation. HADH gene is expressedin β‑cells and has an inhibitory effect on GDH.Autosomal recessive loss‑of‑function mutationslead to rise in intracellularATP and inappropriateleucine‑sensitive HH. The serum ammonialevel is normal. HH is protein‑induced, canbe mild to severe in infants, and is diazoxideresponsive[Figure1][27,28]

3. HNF4A, HNF1A, and GCK mutations: HNF4Aand HNF1A genes encode for hepatocyte nuclearfactor (HNF) 1‑α and 4‑α proteins, whichare transcription factors expressed in β‑cells.Heterozygous loss‑of‑function mutations in HNF4A

Table 1: Diagnostic criteria for hyperinsulinemic hypoglycemia

Glucoseinfusionrateof>8mg/kg/mintomaintainplasmaglucose≥3.3mmol/Lininfants>48hoflifeInappropriateinsulin/c‑peptidelevelswhenplasmaglucose<3.3mmol/L(insulin>1.6mU/L)Hypoketonemia‑<0.6mmol/LHypofattyacidemia‑<0.5mmol/LLowserumlevelsofIGFBP‑1GlucagonstimulationtestWhenplasmaglucoselevel<3.3mmol/LGiveglucagon1mgIM/IVCheckplasmaglucoseevery10min.Ariseof>1.5mmol/Lwithin20minsupportsadiagnosisofhyperinsulinemichypoglycemia

IGFBP‑1–Insulingrowthfactorbindingprotein1;IM–Intramuscular;IV–Intravenous




and HNF1A have biphasic phenotype: HH innewborninfantsandmaturity‑onsetdiabetesinyoungadults.The transient‑to‑severeHHdue to thesegenemutationsarediazoxide‑responsive[29‑31]

4. Heterozygous‑activating mutations of GCK gene,which encodes for glucokinase enzyme, raise theATP/ADP ratio, leading to inappropriate secretionof insulin.Affected patients can be symptomatic ininfancywithfastinghypoglycemiaandarediazoxideresponsive[32,33]

5. Exercise‑inducedCHI:Monocarboxylasetransporter1protein (MCT1) is involved in the transport ofpyruvate and lactate across the β‑cell. MCT1,encoded by SLC16A1 gene, is normally silencedin β‑cells, preventing lactate and pyruvate fromstimulatinginsulinrelease.Dominantgain‑of‑functionSLC16A1 mutations lead to exercise‑induced CHIduetoreleaseofinhibitionbythemutatedgene.ThisformofHH ischaracterizedby inappropriate insulinsecretion that is exaggerated following exercise.Most of these patients are diazoxide responsive andareadvisedtoavoidstrenuousexercises[34,35]

6. Recently reported gene mutations causing CHIinclude HK1, PGM1, PMM2, FOXA2, andCACNA1D[36‑40]

7. Syndromic infants having CHI includeBeckwith‑Wiedemann, Kabuki, Sotos, Usher,Timothy,andCostellosyndrome[41]

8. MetaboliccausesofHHincludecongenitaldisordersofglycosylationType1a,1band1dand tyrosinemiaType1.[42,43]

Clinical presentationInfants at‑risk of hypoglycemia are screened 2 h afterbirth till prefeed PG levels remain stable on feeds.Even though most infants with HH present withhypoglycemia during the first 48 h of life, SGA infantsmay present later.[23,44] Symptoms of hypoglycemiaare often nonspecific and include jitteriness, lethargy,apnea, irritability,poorfeeding,seizure,coma,andevensuddendeath.Presenceofhepatomegalymaypoint toadiagnosis of glycogen storage disorder in the presenceofhypoglycemia.[45]

Management of infant’s at‑risk of hypoglycemiaInfants at‑risk of hypoglycemia should be monitoredfor hypoglycemia from birth. Asymptomatic high‑riskneonates should be given a feed (breast or formulamilk) during the phase of glucose nadir at 1 h of lifeand glucose levels checked at 2 h of age.[23,44] Parentalhistory of consanguinity, family history of early‑onsetdiabetes, a sibling with a history of seizures/suddencollapse (inborn error of metabolism) may point to aninherited cause for hypoglycemia. History of maternal

diabetes, obesity, perinatal asphyxia, gestational age,andbirthweight(SGA/LGA)mightindicatetheetiologyof hypoglycemia.[46,47] Physical examination may revealsyndromesassociatedwithHH.[41]

Asymptomatic infantsIn asymptomatic infants, the mainstay of medicaltreatment of hypoglycemia is to provide adequatecarbohydrate to maintain PG levels in thenormoglycemic range. Sometimes, to ensure regularfrequent feeds, feeding via nasogastric tube may beneeded.[48] Oral buccal glucose gel (Rapilose, PenlanHealthcare,UK) isuseful in the initialmanagementofthese infants with hypoglycemic episodes. Administer0.5 ml/kg of glucose gel to the buccal mucosa ininfants >35 weeks gestation, and follow with afeed.[49] Parenteral glucose infusion is indicated if2h PG level <1.4mmol/L or if there is no rise in PGlevel following glucose gel administration and top upfeeds.Avoid intravenousmini‑boluses inasymptomatichypoglycemic infants and use intravenous dextroseinfusion to avoid increased glucose variability andthe rapidity with which low glucose concentrationsare corrected.[50] Beyond 48 h of life, any infantwith persistence or recurrence of hypoglycemia is anindicationforinvestigationsandspecifictherapy.

Symptomatic infantsNeonates presenting with symptomatic hypoglycemia,especially seizures, are treated with “mini‑bolus” ofintravenous 10% dextrose at 2 ml/kg over 3 min,followed by glucose infusion targeting GIR of4–7mg/kg/minand titratingupasneeded.[46,51]ConsiderHH if theGIR is>8mg/kg/min.BabieswithconfirmedHH should be managed at specialized centers as theywillneedcentralvenousaccess.ForconfirmationofHH,infantsmayneedtoundergocontrolledGIRreductiontoinduce hypoglycemia to collect critical blood samples.In infants with suspected amino acid‑induced HH,protein‑loadingtestisindicated.[52]

Once the diagnosis of HH is confirmed, attemptsshould be made to wean dextrose infusion as toleratedbecause transient forms may resolve within 5–7 days.Instead, ifGIR is risingevenafter aweekofparenteralglucose ± feeds, a trial of diazoxide therapy (3mg forSGA and 5 mg/kg/day for AGA infants) with thiazidediureticsisinitiated.Ifunabletoachievedesiredglucoselevels,incrementinthedosageofdiazoxidecanbemadeby2.5mg/kguptoamaximumdosageof15mg/kg/day.If the patient is diazoxide responsive, gradually weanGIR until full oral feeds are established.[47,53,54] Around50% of infantswith CHI have feeding problemswhichare independent of neurodevelopmental delay or modeoftreatment.[48,55]




While on full feeds if prefeed PG levels are stable,age‑appropriate safety fast study (SFS) (6‑h) is done toconfirm the infant’s ability to maintain normoglycemiaduring an inadvertent fast at home. If PG levels aremaintained during the SFS and biochemical responseis appropriate, the patient can be discharged with homeglucosemonitoring. If a baby develops hypoglycemia orbecomessymptomaticduringSFS,thestudyisabandoned,parenteral“miniglucose”bolustherapyisgiven,anddoseofdiazoxideisincreased.OncePGremainsstable,theSFSis repeated before discharge. Home glucose monitoringcontinues and on follow up plan to stop diazoxidewhenthe dose of diazoxide is “self‑weaned” with stable PGlevels.Considerwithdrawalofdiazoxideifthedailydoserequired (3–5mg/kg/day) “self‑weans” to half the initialdose (1.5–2.5 mg/kg/day). In others on higher initialdose>5mg/kg/day,discontinuationshouldbeconsideredwhen the dose has self‑weaned to <2.5mg/kg/day.After3 days of discontinuation of diazoxide, while on homeglucose monitoring, infant is admitted to the hospitalfor resolution fast study (RFS). RFS should be done for8–18 h (shorter for infants below 6months). The infantpasses the RFS if he maintains normal PG levels andadequate biochemical responses until the end of the fast.If the infant pass RFS, neurodevelopmental assessmentfollow‑upisgiven.[19,56]

Diazoxide,atthemaximumdoseof15mg/kg/dayshouldbe triedbeforeconsideringgenetic testing.[57] If theGIRcannot be weaned on maximum doses of diazoxide,infants are considered as diazoxide‑unresponsive, andoctreotide therapy is indicated. Responsiveness todiazoxide is a standard means of distinguishing KATPchannelmutationsfromothers.Sinceoctreotideisunableto perform this differentiating role, it is not a primarymodality of treatment in HH. DNA of the infant andparents is collected for molecular testing for mutationsin genes causing CHI. In diazoxide‑unresponsive HH,in addition to octreotide, some of these infants mayneed glucagon infusion to transition from diazoxide tooctreotide.Successfulglycemiccontrolusingcontinuousglucagon infusion in genetic forms of HH has beenreported.[56]Nifedipine is currently not recommended inthe treatmentofCHI,even thoughsomecase reportsofHHwithout genetic study claims treatment response.[58]Other medications, including sirolimus, GLP1 receptorantagonist, and ketogenic diet, are still being evaluatedfor efficacy and safety in infants and are not routinelyrecommended. Genetic mutations in KATP channelregulatinggenesaremoreoftendetected.[45]Homozygousand compound heterozygous mutations in ABCC8and KCNJ11 genes usually cause diffuse disease andpaternally inheritedmutations in these two genes resultin focal disease.[57] Once genetic study suggests focal

disease,imagingusing18F‑DOPA‑PET‑CTscanhastobedonetolocalize,facilitatingprecisesurgicalexcisionandcure.[59,60] The therapeutic approach to the managementof diffuse formsofCHI ismuchmore challenging, andatrialofmedicaltherapyusingoctreotide/lanreotideandsirolimusmay be attempted before resorting to surgicaloptions.[61]Figure2outlinesthepracticalworkflow.

Infants on and after medical treatment for CHIshould have long‑term follow‑up due to high‑riskof neurodevelopmental delay, cerebral palsy, andepilepsy.[62,63] All the familial forms of CHI should beofferedgeneticcounseling[Figure3].

Medical treatment of hyperinsulinemic hypoglycemia [Table 2]DiazoxideDiazoxide remains the first‑line medical therapy forHH. Diazoxide acts on the SUR1 subunit of the KATPchannel, preventing cell membrane depolarization, andthereby inhibiting insulin secretion. It is effective for avariety of HH subtypes such as syndromic forms and“metabolopathies” since KATP channels are functionalin these patients. However, it is generally ineffectivefor the most severe, recessive, and focal forms due toinactivatingmutationsinABCC8orKCNJ11genes.[51]

Diazoxide isusedorally at thedoseof5–15mg/kg/dayin three divided doses.[57] Diazoxide is metabolizedin the liver and excreted by kidneys, warranting closemonitoring of hepatic and renal functions. Whenusing diazoxide in infants having hepatic dysfunctionor hypoalbuminemia, it is initiated at lower doses of3mg/kg/dayasdiazoxide is90%proteinbound.[54]Oraldiazoxide is available in suspension (Proglycem, TevaPharmaceuticals, USA) form and desired dosage ofdiazoxidecanbeachievedpreciselywithsuspension.

Tolerance to diazoxide is usually good. Hypertrichosisoccurs in most patients but is reversible ondiscontinuation. Others include tachycardia, neutropenia,thrombocytopenia, and hyperuricemia. Pulmonaryhypertension(PH)wasreportedwithafrequencyof2.4%,especially in infantswhohadPHrisk factors; respiratoryfailure and structural heart disease. Fluid retention sideeffect of diazoxide can cause serious complicationssuch as pericardial effusion warranting use of thiazidediuretics.[64,65] As SGA infants are very sensitive todiazoxide,itissafertostartdiazoxideat3mg/kg/day.[54]

Somatostatin analogsSomatostatin is secreted by δ‑cells of the pancreaticislets and inhibits both insulin and glucagon secretions.The mechanisms leading to decrease in the insulinsecretion is mediated through inhibition of theintracellularmobilizationofcalciumaswellasdecrease




Table 2: Drugs used in medical management of hyperinsulinemic hypoglycemiaMedication Route of administration Dose Side effectsDiazoxide Oral 3‑15mg/kg/day Fluidretention

HypertrichosisThiazidediureticsChlorothiazide Oral 5‑10mg/kg/day ElectrolyteHydrochlorothiazide Oral 1‑2mg/kg/day Imbalance

Octreotide SCbolus,IVorSCinfusion

5‑35µg/kg/day FeedintoleranceSteatorrheaCholelithiasisGrowthsuppression

Long‑actingoctreotide(LAR/Lanreotide) DeepSCIM

30‑60mg/doseEvery4weeks

Sameasoctreotide

Sirolimus Oral 0.5‑1mg/m2/day HeapticandrenalimpairmentImmunosupression

Glucagon SCorIMBolusIVorSCinfusion

0.5‑1mg/dose1‑20µg/kg/h

SkinrashThrombocytopeniaFeedintolerance

Nifedipine Oral 0.25‑2.5mg/kg/day DizzinessHypotension

SC–Subcutaneous;IM–Intramuscular;IV–Intravenous;Ca++–Calcium;LGA–Largeforgestationalage

Figure 2: Proposedalgorithmformanagementoftransitionalandperisitenthyperinsulinemichypoglycemia.GIR–Glucoseinfusionrate;IDM–Infantofdiabeticmother;SGA–Smallforgestationalage;LGA–Largeforgestationalage;IOM–Infantofobesemother




in the insulin gene promoter activity.[66,67] Octreotidehas short half‑life requiring its administration either bymultiplesubcutaneousinjectionsevery6–8hourlyorbycontinuous infusion. Recommended dose of octreotideis 5–35 µg/kg/day and it is used as the second line ofmedicaltherapyforchildrenwithdiazoxide‑unresponsiveHH.[47]

Two long‑acting somatostatin analogs, long‑actingrelease octreotide and the lanreotide acetate, have beenintroduced and can be administered every 28 days.[68]Theyaresafeandeffectivealternativetooctreotidepumptherapy inpatientswithCHI,offeringbettercomplianceandanimprovedqualityoflife.[69]

Side effects of octreotide include vomiting, diarrhea,abdominal distension and fatal necrotizing enterocolitisinneonates.[70‑72]

GlucagonPancreatic α‑cells secrete glucagon as acounter‑regulatory hormone of insulin. It can beadministered by intravenous, subcutaneous, orintramuscular route and has been used at dosesof 1–20 µg/kg/h mainly for short‑term control ofdiazoxide‑unresponsive HH patients. In symptomatic

hypoglycemicLGAinfants,intramuscularadministrationof glucagon may be used as a single dose between0.5 and 1 mg. Side effects of glucagon include feedintolerance and erythemanecrolyticum.Glucagon beingan insulin secretagog in high doses, long‑term use isrecommendedonlywithsomatostatinanalogs.[73,74]

GlucocorticoidsEvidencefortheuseofcorticosteroidinthemanagementof hypoglycemia is limited. Glucocorticoids reduceinsulin secretion and enhance glycogenolysis andgluconeogenesis.[75] Current recommendations supportthe use of glucocorticoids when there is documentedhypocortisolism while hypoglycemic or when there isprovenadrenalinsufficiencyviaaSynacthentest.

NifedipineNifedipine, an L‑type calcium channel blocker, hasbeen used at a dose of 0.25–2.5 mg/kg/day as atherapeutic option in patients for whom diazoxidetherapy was unsuccessful. The clinical response tothis drug is highly variable. Response to nifedipinein patients with HH have been reported, but they alllack genetic study, fasting tolerance, and follow‑up.Güemes et al. reported 11 patients who had ABCC8gene mutation who were treated with nifedipine eitherasmonotherapyorincombinationbutwithnoresponseon glycemic profile.[58] Common side effects with theuseofnifedipine includeflushing, feed intolerance,andhypotension.[66,76,77]

Mammalian target of rapamycin inhibitor: SirolimusMammaliantargetofrapamycin(mTOR)isamemberoftheserine/threoninekinasefamily.Apossiblemechanismof hyperinsulinism and β‑cell hyperplasia in diffuseHH involves the constitutive activation of the mTORpathway, which causes increased glucose uptake andglycolysis. The use of the mTOR inhibitor, sirolimus,helps inboth thereductionofbeta‑cellproliferationandtheinhibitionofinsulinproduction.[78,79]

Sirolimus is started at an initial dose of 0.5 mg/m2 ofbodysurfacearea/day.Thedoseis titrateduptargetingaserum trough levelof5–15ng/mlwith stablePG levels.Adverse effects of mTOR inhibitors include stomatitis,increased risk of infection, and pneumonitis. Thesuccessfuluseofsirolimus,eitheraloneorasanadjuvanttherapy with octreotide, for patients with diffuse HHmaybeafeasiblepotentialalternativetopancreatectomy[Table2].[61]

Glucagon‑like peptide 1 receptor antagonistIncretin hormone, GLP1, amplifies postprandial insulinsecretion. GLP1 receptor antagonist, exendin‑9‑39,by decreasing cAMP levels and thereby inhibitinginsulin secretion, is effective for the treatment of CHI.

Figure 3: Phased‑approach to managing newborns at‑risk ofhyperinsulinemichypoglycemia.HH–Hyperinsulinemichypoglycemia;GIR–Glucoseinfusionrate;DZX–Diazoxide




However,furtherclinicalstudiesareneededtoassessitspharmacokinetics,effectiveness,andsafety.[80,81]

Ketogenic dietInCHI,thereisshortageofcerebralenergyfuelsandcanlead to severe neurological sequelae. By reproducing afasting‑likecondition inwhichenergy ismainlyderivedfrom beta‑oxidation, ketogenic diet provides alternativeenergy source to neurons. There are reports showingclinical improvement and seizure free periods whenketogenic diet is used. However, additional studies areneeded to confirm the efficacy of this novel therapeuticapproachforitsneuroprotectiveeffectinCHI.[82,83]

ConclusionThe management of infants at‑risk of hypoglycemia,which begins in the first hours to days of life with thepotential to leadtoadiagnosisofHH,isoffundamentalinterest to doctors looking after newborn babies.Althoughthereiscomplexityintheoverallframeworkofcare,thecriticalcheckpointsinthepathwayareupstreamand include recognizing and navigating the glucosenadir, choosing the appropriate form of therapy duringhypoglycemia, and ensuring a precise diagnosis of HH.The middle of the process involves the assessment ofDiazoxide responsiveness, which takes center stage anddeterminestreatmentandprognosis.Furtherdownstream,the safety and resolution fasting studies play importantrolesinthetransitionfromhospitaltohomecare.

AcknowledgmentWe express our gratitude to Dr. Shrenik Vora, StaffPhysician, Department of Neonatology, KK Women’sandChildren’sHospital,Singapore, forhelpingwith thepreparationofthemanuscript.

Financial support and sponsorshipNil.

Conflicts of interestTherearenoconflictsofinterest.

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