GammahydroxybutyrateGHBanunusualcauseofhighaniongapmetabolicacidosisLaurenceCarlierMDVincentVanBelleghemMDKathleenCroesPharmDPhDFrederikHooftMDMatthiasDesmetMDOlivierHeylenPharmDSt ID: 955779
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APPORTDECAS Gamma-hydroxybutyrate(GHB),anunusualcauseofhighaniongapmetabolicacidosisLaurenceCarlier,MD*;VincentVanBelleghem,MD*;KathleenCroes,PharmD,PhDFrederikHooft,MD*;MatthiasDesmet,MD*;OlivierHeylen,PharmD;StijnLambrecht,PharmD,;StefaanCarlier,MD* Thecausesofhighaniongapmetabolicacidosis(HAGMA)arewelldescribedintheliterature.However,sometimesmorefrequentcausesofHAGMAcannotexplainitsoccurrence.InthecaseofHAGMAandsevereneurologicaldepressionintheabsenceofothercausesofHAGMA,cliniciansshouldconsideranintoxicationwithgamma-hydroxybutyrate(GHB)asapossiblecause.GHBisendogenoustothemammaliancentralnervoussystem(CNS).SyntheticGHBwasinitiallyusedasananestheticbutisnowonlylicensedformedicaluseinalimitednumberofindicationssuchasthetreatmentofnarcolepsy.Becauseofitseuphoriceffects,itbecamepopularforrecreationaluseunderthestreetnames:LiquidEcstasy,GeorgiaHomeBoy,andLiquidG.WedescribetheclinicalcaseofapatientwhosufferedfromsevereneurologicaldepressionandHAGMA. Lescausesdelacidosemétaboliqueàtrouanioniqueélevé(AMTAE)sontbienprésentéesdansladocumentationmédicale.Toutefois,ilarrivequedescausesplusfréquentesdAMTAEnepeuventexpliquercetrouble.DanslescasdAMTAEetdedépressionneurologiquegraveenabsencedautresfacteursétiologiques,lescliniciensdevraientenvisagerlapossibilitédintoxicationparlegammahydroxybutyrate(GHB).LeGHBestunesubstanceendogènedusystèmenerveuxcentraldesmammifères.QuantauGHBdesynthèse,ilétaitutiliséaudébutcommeanesthésique,maissonemploiàdesnsmédicalesnestautorisémain-tenantquedansunpetitnombredindicationstellesqueletraitementdelanarcolepsie.Enn,lutilisationàdesnsrécréativesduGHB,communé-mentappelé«ecstasyliquide»,«GeorgiaHomeboy»ou«LiquidG»,agagnébeaucoupdeterrainenraisondeseseffetseuphorisants.Seraexposéiciuncascliniquededépressionneurologiquegrave,accompagnéeduneacidosemétaboliqueàtrouanioniqueélevé.gamma-hydroxybutyrate,highaniongapmetabolicacidosis,neurologicaldepression CASEREPORTA54-year-oldmalewasfoundinhiscarnearhishouseandwasadmittedintheemergencydepartment.Thepatientwasseenbyhissonshortlybeforeheleftandheseemedtobeneatthatmoment.Thepatienthadahistoryofalcoholabuse.Exceptforalaminectomyandarterialhypertension,thepatienthadnomedicalhistory.Hishomemedicationwaslosartanandapainkillerwhennecessary.Hehadnoknownallergies.Atthemomentthathewasfound,hewasunres-ponsivetoverbalcommandandpainfulstimuliwithaGlasgowComaScaleof3/15.Hisheartrateandbloodpressurewerenormal,andclinicalexaminationdidnotrevealmajorinjury.Toprotecttheairway,thetracheawasimmediatelyintubatedonthespot,andthepatientwasventilated.Toruleoutseveretraumaticbraininjury,aCTscanwasperformed,whichdidnotrevealposttraumaticinjury.A12-leadelectrocardiogramshowednosignsofischemiaorrhythmdisturbances.Peripheralbloodcountandliverbiochemistrywerewithinnormallimits.Thepatienthadanestimatedglo-merularltrationrateabove1.50ml/s/m,whichwasnormal.Becauseserumprolactinlevelswereslightlyele-vated(2146.55pmol/L,normalvalues[N]:165-1010pmol/L),anelectroencephalogramwasperformed.Therewerenosignsofseizureactivity.Lactatewaswithinnormalrange(1.67mmol/L,N:0.50-2.20),aswellasglucose(6.16mmol/L,N:3.9-6.6mmol/L).Ethanolonthissamplewasslightlyelevated(10.2mmol/L,N:2.17mmol/L).Theserumosmolalitywas287mOsm/kg(N:280-300mSsm/kg)andserumcreatininewas83.1micromol/L(N:51.3-107.0micromol/L).Anarterialbloodgasanalysisrevealedthefollowing:pH7.07(N:7.35-7.45),bicarbonate12.6(N:;22.0-26.0mmol/L),sodium136(N:136-145mmol/L), Fromthe*DepartmentofAnesthesiology,DepartmentofEmergencyMedicine,andDepartmentofIntensiveCare,AZG
roeninge,Kortrijk,Belgium;and§Clinicallaboratoryandtoxicology,AZGroeninge,Kortrijk,Belgium.Correspondenceto:LaurenceCarlier,AZGroeninge,PaterDamiaanstraat98500Kortrijk,Belgium;Email:Laurence.carlier@student.kuleuven.be©CanadianAssociationofEmergencyPhysiciansDOI10.1017/cem.2017.10 2018;20(S2) K W W S V G R L R U J F H P 3 X E O L V K H G R Q O L Q H E \ & D P E U L G J H 8 Q L Y H U V L W \ 3 U H V V potassium4.11(N:3.50-5.10mmol/L),chloride95.2(N:98.0-107mmol/L),andpCO244.2(N:35.0-45.0mmHg),indicatingaHAGMAwithananiongapof28.2mmol/L(N:11.0-21mmol/L).Carbonmonoxide(CO)intoxicationwasunlikelybecausethepatientscarwasparkedoutsidebeforeleavingandwasruledoutbyanormalCOhemoglobinlevel(3.7%)(N:5to6%TIETZ)uponarrivalatthehospital.Anarterialbloodgasanalysislessthan12hoursaftertherstarterialbloodgasanalysiswasnormal(Table1).Becauseketoacidosisisawell-knowncauseofHAGMA,urinewastestedforketonesandglycose.ThetestwastheRocheComburTestMstrip,anditwasnegative.Subsequenttoxicologicalscreeningofserumforacetaminophen,salicylate,benzodiazepines,barbitu-rates,andtricyclicantidepressantswasnegative.Urinewasscreenedforbarbiturates,benzodiazepines,acetaminophen,tricyclicantidepressants,(meth)amphetamine,cocaine,opiates,andmethadoneandwasfoundnegativeaswell.Theanalysisof(toxic)alcoholswasperformedbyheadspacegaschromatographywithameionizationdetection(HS-GC-FID)andallowedsimultaneousdetectionofmethanol,ethanol,npropanol,isopropanol,andacetone.Theanalysisofglycols(ethyleneglycolandpropyleneglycol)wasperformedbyGC-FID.Serumconcentrationsofacetone,allalcohols,andglycolstestedwere0.86mmol/Latthismoment(Tables2and3).Onthebasisofthelaboratoryresultsofbloodandurinesamplesandclinicalexamination,commoncausesofHAGMA(ethyleneandpropyleneglycol,lactate,methanol,salicylate,renalfailure,andketoacidosis)wereruledout(seeTables2and3).ThediagnosisofasevereGHBintoxicationcausingHAGMAwasestablishedaftergaschromatographic-massspectrometricanalysis(GHBserum:10.64mmol/L,GHBurine33.53mmol/L).ThesampletestedforGHBwastaken210minutesaftertherstbloodgas.Aplasmalevelof0.048mmol/Landaurinelevelof0.096mmol/Lwasusedasacut-offconcentrationofnormalendogenousGHBconcentrations.Supportivetherapywithsedation,ventilation,replacement,andbicarbonatewasgiven.Thepatientfullyrecoveredafter17hoursandwasdischargedtothewardonthefollowingday.QuestioningofthepatientandofhissonconrmedthehypothesisthatthepatientaccidentallyingestedGHB.Hethoughtthebottlethathefoundunderthebedofhissonwasabottleofgin.Thebottlewasnotsubmittedforanalysis. Table1.ArterialbloodgasanalysisArterialbloodgasanalysisTime1850(day1)2341(day1)0535(day2)pH7.077.277.37pCO244.2mmHg36.8mmHg34.5mmHgpO2155.5mmHg88.2mmHg137.2mmHgO2-saturation98.2%96%98.9%CoHb3.7%--Bicarbonate12.6mmol/L16.6mmol/L19.7mmol/LBaseexcess-17mmol/L-9.5mmol/L-4.8mmol/LGlucose111mg/dl123mg/dl115mg/dlLactate1.9mmol/L2.3mmol/L1.7mmol/L Table3.ToxicologyresultsobtainedonurineParameterResultsMethodsantidepressantsNegativeMicrogenicsDRIimmunoassayBenzodiazepinesNegativeRocheimmunoassayOpioidsNegativeRocheimmunoassayPhenylalkylamineNegativeRocheimmunoassayCocaineNegativeRocheimmunoassayMethadoneNegativeRocheimmunoassaySalicylatesNegativeColorimetricassayBarbituratesNegativeRocheimmunoassayAcetaminophenNegative(micromol/L)RocheenzymaticCreatinine530.4micromol/LRochecolorimetric Table2.ToxicologyresultsobtainedonserumToxicologyonbloodResultsMethodsEthanol10.2mmol/LRocheenzymaticassayantidepressantsNegativeMicrogenicsDRIimmunoass
ayBenzodiazepinesNegativeRocheimmunoassayAcetaminophenRocheenzymaticassay2mg/LRocheenzymaticassayBarbituratesNegativeRocheimmunoassay1.56mmol/LHS-GC-FIDEthyleneglycolheadspacegaschromatographywithameionizationdetection;gaschromatographywithameionizationdetection.GHBandHAGMA CJEMJCMU2018;20(S2)S3 K W W S V G R L R U J F H P 3 X E O L V K H G R Q O L Q H E \ & D P E U L G J H 8 Q L Y H U V L W \ 3 U H V V DISCUSSIONGHBisendogenoustothemammalianCNS,butnormalendogenousbloodandurineconcentrationsarelow(0.096mmol/L).Interpretationofbloodlevelscanbefalseduetocollectiontubeadditivesandstoragetemperature,whichcanaffecttheGHBlevels.TheoptimalspecimenfortestingforthepresenceofGHBisaurinesample.ItshouldbetakeninconsiderationthaturineconcentrationsafteringestionofGHBvarywidely.Gaschromatographic-massspectrometricanalysisisthebestwaytoconrmthepresenceofGHBinbloodorurine.GHBisrapidlyabsorbedandeliminatedfromthebody.Theeliminationofbiologicalhalf-lifeis30-50minutes.Becauseofitsfastelimi-nation,GHBcanusuallynotbedetectedinplasmamorethan250minutesafteringestion.TheconcentrationofGHBinurineiscomparablewiththeconcentrationinthebloodduringthetimethaturinewasproducedinthekidneyandstoredinthebladder.ThiscanexplainwhytoxicologyforGHBcanbepositiveinurineandnegativeinblood.Gamma-hydroxybutyricaciduriaistheonlyknownmetabolicdiseasewithhighendogenousGHBcon-centrations.SyntheticGHBwasinitiallyusedasananestheticbutisnowonlylicensedformedicaluseinalimitednumberofindicationssuchasthetreatmentofBecauseofitseuphoriceffects,itbecamepopularforrecreationaluseunderthestreetname,LiquidEcstasy.OtherpopularnamesforGHBarecherrymeth,growthhormonebooster,scoop,LiquidX,LiquidG,andGeorgiaHomeBoy.GHBassuchisawhitecrystallinepowderbutismostfrequentlyvendedasasolution.TheseliquidformshavewidelyvariableGHBconcentrations.ItisalsousedasasleepaidandisingestedchronicallytoincreaseleanbodymassbybodyThepresentationofaGHBintoxicationiswelldescribedintheliterature.Lowdoseshavearelaxanteffectsimilartothatofalcohol,andhigherdoseswillleadtosevereCNSdepression.Thedrughasasteepdose-responsecurvewithasmalltherapeuticwindowleadingtoanabruptdecreaseinthelevelofconsciousness.TheabsorptionofGHBisfast,andthetimetoreachthemaximumplasmaleveldependsonthedosethatisadministered.Ittakesapproximately30to60minutestoreachpeakplasmalevelsafteringestionof50mg/kg.TheclinicalpresentationofaGHBintoxicationcanbeobscuredduetoconcomitantdruguse.Inacaseseriesstudy,Galiciaetal.demonstratedthat76%ofthepatientscombinedGHBwithotherdrugssuchasalcohol,cocaine,ketamine,cannabis,andsoforth.Thismultipledrugabuseleadstoamoresevereclinicalpresentationandwillincreasetheneedofmoreinvasivetherapy.NotonlyCNSsymptomscanbepresentinaGHBintoxication,butalsocommonothersymptoms,includingvomiting,urinaryandfecalincontinence,bradycardia,hypoventilation,miosis,mydriasis,andhypothermia.Thesymptomsdependontheingesteddose(Tables4and5).GHBisaphysiologicalmetaboliteofgamma-aminobutyricacid,whichplaysaroleinthecontrolmechanismofthepituitaryhormones.Thereleaseofdopamine,whichisaprolactin-releaseinhibitingfactor,isblockedbyGHB.Asaconsequence,GHBinducesareleaseofprolactin.Prolactincanalsoberaisedafterageneralizedtonic-clonicseizureandafteranon-epilepticseizureaswellasafterasyncope,indicatingthatincreasedprolactinlevelscannotbeusedtodif-ferentiatebetweenseizures,syncope,andGHBintoxi-Patientswhosufferedfromageneralizedtonic-clonicinsulthaveamarkedelevationoflactateandoftensufferfromlactateacidosis.Th
etreatmentofGHBintoxicationsissupportivebecausenoantidoteisavailable.Inourpatient,thepHwascorrectedwithbicarbonateinfusions.Inoneothercasereport,dialysiswasusedtocorrectthepHbecausebicarbonatetherapywasunsuccessful.HAGMAcouldalsobecausedbythepresenceofmethanolorethyleneglycolmetabolites,whiletheparentcompoundwasfullymetabolized.However,giventhetoxicityofmethanolandethyleneglycol, Table5.GHBpeakplasmaconcentrationanditsclinicalGHBconcentration(mmol/L)Clinicaleffects0-0.95Awake0.61-1.56Lightsleep(occasionaleyeopening)1.45-2.81Mediumsleep(blinking)2.34-3.79Deepsleep(noresponsetostimuli)gamma-hydroxybutyrate. Table4.Dose-relatedsymptomsofGHBDoseSymptoms10mg/kgShort-termamnesia,hypotonia20-30mg/kgDrowsiness,sleep50-70mg/kgProfoundhypnosis,deepcomaCarlieretal S42018;20(S2)CJEMJCMU K W W S V G R L R U J F H P 3 X E O L V K H G R Q O L Q H E \ & D P E U L G J H 8 Q L Y H U V L W \ 3 U H V V fullrecoveryofthepatientwithoutsequelaewouldbeunlikely.Anintoxicationwithpropyleneglycol,asolventforintravenousdrugs,isveryrareandisunlikelytoprovokeacoma.HAGMAafterGHBintoxicationisrarelyreportedintheliterature.Toourknowledge,thisisonlythesecondcasedescribedintheliterature.Therstcasewasagamma-butyrolactone(GBL)intoxicationwithahighaniongapandosmolalgap.However,becauseGBLisreadilyconvertedtoGHBinthebody,onlyGHBwasdetected,inthiscase.ThepKaofGHBis4.7,meaningthatinphysio-logicalconditions99%ofGHBisionized,leadingtoexcessanionscausingHAGMA.andclinicalteachingdonotincorporateGHBasapossiblecauseofHAGMA.Mehtaetal.suggesteda21stcenturymnemonicforHAGMA:GOLDMARK(glycols,oxoproline,L-lactate,D-lactate,methanol,aspirin,renalfailure,ketoacidosis).WesuggestshouldstandnotonlyforglycolsbutalsoforGHB. CONCLUSIONInthecaseofHAGMAandsevereneurologicaldepressionintheabsenceofothercausesofHAGMA,cliniciansshouldconsideranintoxicationwithGHBasapossiblecause.Competinginterests:Nonedeclared. REFERENCES1.HallerC,ThaiD,JacobP,etal.GHBurineconcentrationsaftersingle-doseadministrationinHumans.JAnalToxicol2.BusardoFP,JonesAW.GHBpharmacologyandtoxicology:acuteintoxication,concentrationsinbloodandurineinforensiccasesandtreatmentofthewithdrawalsyndrome.CurrNeuropharmacol3.CorkeryJ,LoiB,ClaridgeH,etal.GHB,GBL,1,4-BD:aliteraturereviewwithafocusonUKfatalitiesrelatedtonon-medicaluse.NeurosciBiobehavRev2015;53:52-78.4.BenzerT,CameronS,ScottRussiC,etal.Gamma-hydroxybutyratetoxicity.Medscape;2015.Availableat:5.GaliciaM,NogueS,MirO.Liquidecstasyintoxication:clinicalfeaturesof505consecutiveemergencydepartmentEmergMedJ6.TakaharaJ,YunokiS,YakushijiW,etal.Stimulatoryeffectsofgamma-hydroxybutyricacidongrowthhormoneandprolactinreleaseinhumans.JClinEndocrinolMetab1977;44:1014-7.7.VukmirRB.Doesserumprolactinindicatethepresenceofseizureintheemergencydepartmentpatient?JNeurol8.ChenDK,SoYT,FisherRS.Useofserumprolactinindiagnosingepilepticseizures.9.BabaR,ZwaalJW.Severemetabolicacidosisafterasingletonic-clonicseizure.10.HeytensL,NeelsH,VanRegenmortelN,etal.Near-fatalpersistentanion-andosmolal-gapacidosisduetomassivegamma-butyrolactone/ethanolintoxication:acasereport.AnnClinBiochem11.KrautJA,KurtzI.Toxicalcoholingestions:clinicalfeatures,diagnosisandmanagement.ClinJAmSocNephrol2008;3:208-5.12.MehtaAN,EmmettJB,EmmettM.GOLDMARK:ananiongapmnemonicforthe21stcentury.GHBandHAGMA CJEMJCMU2018;20(S2)S5 K W W S V G R L R U J F H P 3 X E O L V K H G R Q O L Q H E \ & D P E U L G J H 8 Q L Y H U V L W \ 3 U H