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Generalclinicalsituations 3 General clinical situations The metabolic emergency In the neonate,theearlyclinicalfeaturesofacutemetabolicdecompensationarealmostalways non-specific;theyinclude“unwell”,lethargy,feedingproblems,vomiting,abnormalbreathing, hypotoniaandseizures.Disordersofglucose,proteinandfatbreakdown(intermediarymetabolism)intheneonatalperiodtypicallyhaveanasymptomatic interval,withclinicalmanifestations fromtheseconddayoflifeonwards(“intoxicationtype”),althoughhyperammonaemiainparticularmaypresentasearlyasday1.Thebaby’sgeneralconditionwillusuallydeterioraterapidly despitenormalornon-specificfindingsinroutineinvestigations(laboratorysignsofinfection, lumbarpuncture,chestX-ray,cranialultrasound)andantibiotictherapy.Thefamily historymay revealsiblingswhodiedwithsimilarclinicalmanifestations(“sepsis”,“SIDS”)orunexplained disordersinotherfamilymembers(progressiveneurologicaldisease,maternalPKU,multiplemiscarriages,HELLPsyndrome,etc.).Consanguinityincreasestheriskofarecessivedisorder. Metabolicdisordersafter the neonatal periodmaypresentwithrecurrentvomitingandlethargyprogressingtocomawithoutfocalneurologicalsignsortypicalpatternsoforgandysfunction. Initialmanagementmayfollowsimilarprinciplesasinneonates.Caremustbetakentoidentify theconditionsthattriggeredmetabolicdecompensationsuchasvomitingandfeverorchangesin thediet. A metabolic disorder should be considered, along with other diagnoses (e.g. infection, CNSpathology)... ... inallneonateswithunexplained,overwhelmingorprogressivediseaseparticularlyafter normalpregnancyandbirth; ... inallchildrenwithacutedeteriorationofthegeneralconditionand/orreducedconsciousness,particularlywhenprecededbyvomiting,feverorfasting; ... inallchildrenwithsymptomsandsignsofacidosisorhypoglycaemia. Appropriate diagnostic and therapeutic measures must be initiated as soon as possible to avoidlong-termdamage. Post-mortem investigations:seepage 25 Phase 1: Basic metabolic emergency investigations and first line management Stopintakeofpotentiallytoxiccompounds(protein,fat,galactose,fructose) Insert i.v. line and take blood samples for urgent analysis of: • Electrolytes,glucose,CRP,CK,ALT,AST,creatinine,urea,uricacid,acid-base status,coagulationstudies • Ammonia,lactate • Storeplasmasampleforaminoacids,acylcarnitines,etc. • Storefilterpapercard(“Guthrie”cardfornewbornscreening)withdriedbloodspotsforacylcarnitines(aminoacids,possiblyDNAstudies) • Storetherestoftheothersamplesforpossibleadditionaltests(informlaboratory) 4 Diagnosisandmanagementofmetabolicdisorders Obtain urine sample: • Checkcolourandodour • Performstandardteststripanalyses(e.g.ketonebodies,glucose,protein;pH>5duringacidosis→DDrenaltubularacidosis) • Storeurinesamplefromtheacutephasefororganicacidsoradditionalmetabolictests If lumbar puncture is performed: • StoreCSF(freezeimmediately) Startwith10% glucose infusion, 150 ml/kg/day(10mg/kg/min,~60kcal/kg/day),withappropriateelectrolytes. Glucosesupplyinthisinfusionisattherateofnormalhepaticglucoseproductionandisusuallysufficientfordisordersofreducedfastingtolerancesuchasglycogenstoragedisordersor MCADdeficiency.Itmaynotbesufficientindisordersthatareexacerbatedbycatabolism,e.g. organicaciduriasorureacycledefects.Itmaybepotentiallydangerousinmitochondrialdisorders(specificallypyruvatedehydrogenasedeficiency)asahighglucosesupplymayenhance lacticacidosis.Thebenefitsofthehigh-glucoseinfusionoutweightherisksbutlactateandacid-basestatusshouldbecheckedregularly. Orderadditionalinvestigationsasindicated,e.g.ECG,echocardiogram,cranialimaging. Results of emergency investigations should be available within 30(–60) min.Atthatstage,decideon specialistinvestigationsandadditionaltherapeuticmeasures. Phase 2: Treatment and investigations according to the initial findings If the emergency investigations show ... ...hypoglycaemia:seepage 5 ...hyperammonaemia:seepage 7 ...metabolicacidosis:seepage 10 ...elevatedlactate:seepage 12 ...severeliverdisease:seepage 19 If results are inconclusive but metabolic disease remains a possibility: • Continueglucoseinfusion • Reviewthehistoryandclinicalsigns.Phoneregionalmetaboliccentreforadvice. • Afterdiscussion,sendsamplesforspecialistmetabolicinvestigations(resultsrelevanttothe diagnosisoftreatablemetabolicdisordersshouldbeavailablewithin24[atmost48]hrs): – Driedbloodspotsforacylcarnitinesandaminoacids(urgentanalysis) – Plasmasampleforaminoacidsandacylcarnitines – Urinesampleforsimplemetabolictestsandorganicacids • Monitorelectrolytes,glucose,lactate,acid-basestatus(keepsodiumwellabove135mmol/lto avoidcerebraloedema) 5 Generalclinicalsituations Hypoglycaemia Definition Bloodglucose<2.6mmol/l(45mg/dl)atallages Glucoseconcentration: 1mmol/l=18mg/dl 10mg/dl=0.55mmol/l Consider • In the neonate:evidenceofnon-metaboliccauses? • History:timesincelastmeal(hypoglycaemiapostprandial,afterfasting),drugs,erratic? • Examination:hepatomegaly,liverfailureorcirrhosis,smallgenitals,hyperpigmentation,short stature? • Glucose requirements: >10 mg/kg/min indicates (persistent or transient) hyperinsulinism (page 88)unlesstherearemarkedlosseselsewhere(e.g.urine) • Rule out(intheneonate):septicaemia,severesystemicillness,smallforgestationalage,maternaldiabetes Laboratory investigations during symptomatic hypoglycaemia Adequatelaboratorytestsmustbecarriedoutduring symptomatic hypoglycaemiatoidentifythe underlyingcause,orelsemanydiagnosesmaybemissed. Essential • Free fatty acids + 3-hydroxybutyrate (serumorplasma);ketones(teststrip).Amarkedelevationoffree fatty acidsindicatesactivelipolysisandthatthehypoglycaemiaisassociated withafastingreaction.Inthissituation,“normal”(low)valuesofplasma ketones(3-hydroxybutyrateissufficient)arestronglysuggestiveofadisorderoffattyacidoxidationorketogenesis.Normalvalues:seepage 167. • Acylcarnitines(driedbloodspotsorplasma).Thistestisdiagnosticofmost(butnotall)fattyacidoxidationdisordersandvariousorganicacidurias. • Hormones(serum).Insulin(normal:insulincompletelysuppressedwhenglucose<2.6mmol/l [45 mg/dl]),cortisol(normal>270nmol/l). • Lactate(blood,NaFtube).Elevationsmayindicateliverdamageorimpairedglycogenolysis/ gluconeogenesisbutmayalsobefoundafteraseizureordifficultbloodsampling(seepage 12). • One spare tube(serumorplasma)foranythingfrombeloworforgottenorlost • Organic acids(urine)→variousmetabolicdisordersthatmaycausehypoglycaemia Others • Bloodgases,bloodcount,CRP,electrolytes,phosphate,liver/renalfunctiontests,CK,uricacid, triglycerides,carnitinestatus,growthhormone • Ammonia(EDTAblood)→e.g.liverdamageorglutamatedehydrogenasedeficienthyperinsulinism • Aminoacids(plasma) • Considertoxicologicalinvestigations(incl.C-peptide) 6 Diagnosisandmanagementofmetabolicdisorders Differential diagnosis Hypoglycaemiainprematurechildrenisfrequentlycausedbyproblemsofadaptationandmay notrequireextensivelaboratorytests.Themostfrequentcausesofpersistentneonatalhypoglycaemiaarehormonaldisturbances,e.g.hyperinsulinismorhypopituitarism.Hypoglycaemiaof hyperinsulinismisaccompaniedbylowconcentrationsoffreefattyacidsandketonebodiesdue toinhibition of lipolysis.Regulatory disturbances(e.g.ketotichypoglycaemia,glycogenstorage diseasetypeIII,hypopituitarismafterthefirstyearoflife)resultinhypoglycaemiawithparticularlystrongketosis.Defects of fatty acid utilisation(carnitine shuttle,fatty acid oxidation,ketogenesis)arecharacterisedbyhypoglycaemia,highlevelsoffreefattyacidsandlowketonesduringlipidcatabolism.Gluconeogenesis defects(e.g.glycogenstoragediseasetypeI)showmarked hypoglycaemiawithlacticacidosis;ketonelevelsmaybeloworelevated. As always:Thereareexceptionstoeveryruleorsimplification. Ketones“normal”(low)or insufficientlyelevated Ketoneselevated Free fatty acids relatively low:hyperinsulinism,↓ counterregulatoryhormones Free fatty acids greatly elevated:disordersoffattyacid oxidationandketogenesis “Ketotichypoglycaemia”,organicacidurias,↓ counter-regulatoryhormones(afterthefirstyear),glycogenstoragedisease typesIIIand0,ketolysisdefects Without Organicacidurias,ketolysisdefects,respiratorychaindefects, Lactate hepatomegaly long-chainfattyacidoxidationdisorders(especiallyLCHAD) elevated (>2mmol/l) Isolated Glycogenstoragediseases,gluconeogenesisdefects hepatomegaly Liver disease Treatment Fructoseintolerance,respiratorychaindefects,long-chain fattyacidoxidationdisorders,tyrosinaemiatypeI • Glucosei.v.7–10mg/kg/min(glucose10%:110–150ml/kg/day),keepbloodsugar≥5.5mmol/l (100 mg/dl). Ifglucosebolusisneeded:Donotgivemorethan200mg/kg(glucose20%:1 ml/kg). • Awaitresultsofspecialistinvestigationsandtreataccordingly • Highglucoserequirement>10mg/kg/minorincompletelysuppressedinsulinattimesofhypoglyaecemiaisabnormalandsuggestshyperinsulinism(seepage 82) • Fordisordersoffattyacidoxidationandketogenesisseepage 91