Download General clinical situations

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