SRITISHMEDICALJOURNALVOLUME2852OCTOBER1982TABLEIINormalborderlineandabnormalvaluesintestsofcardiovascularautonomicfunctionNormalBorderlineAbnormalTestsreflectingparasympatheticfunctionHeartrateres ID: 937033
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BRITISHMEDICALJOURNALVOLUME2852OCTOBER1982RegularReviewDiagnosisandmanagementofdiabeticautonomicneuropathyDJEWING,BFCLARKEAstheclinicalimportanceofdiabeticautonomicneuropathyhasbecomerecognisedtheneedhasgrownforsimpleobjectiveteststoconfirmitspresenceorabsence.Thisarticleisintendedtogiveapracticalguidetothosetestswhichweconsiderreliable,reproducible,simple,andnon-invasive.Thesecriteriahavesofarbeenfulfilledonlyintestsbasedoncardio-vascularreflexes.Theyalsoneedtoreflectdamageelsewhereintheautonomicnervoussystem,andcurrentlyavailableevidencesuggeststhatthisisSO.12Thoughtestsusingcardio-vascularreflexesaremostoftendoneondiabetics,theyareequallyapplicableinthediagnosisofautonomicdamagecausedbyotherdisorders.ThetestsdescribedintableIarebasedontheresponsesoftheheartrateandbloodpressuretoavarietyofstimuli.Thefirstthreereflectcardiacparasympatheticintegrity,whiletheothertwostarttogiveabnormalresultswithmoreseveresympatheticnervedamage.Whileeachtestmaybeusedindividuallywethinkthatallfiveshouldbeperformedwhenpossible,sogivingfullerinformationaboutthestateoftheautonomicnervoussystem.TestsreflectingcardiacparasympatheticdamageHeart-rateresponsetoValsalvamanoeuvreDuringthestrainperiodoftheValsalvamanoeuvrethebloodpressuredropsandtheheartraterises.Afterreleasethebloodpressurerises,overshootingitsrestingvalue,andtheheartslows.Thoughthesereflexchangesarecomplex,theresponseoftheheartratecanbeabolishedbyatropinebutitisunaffectedbypropranolol,suggestingthatitismediatedbythevagusnerve.3Inpatientswithautonomicdamagethebloodpressureslowlyfallsduringstrainandslowlyreturnstonormalafterrelease,withnoovershootriseinbloodpressureandnochangeinheartrate.Thetestisperformedbythepatientblowingintoamouth-piececonnectedtoananeroidmanometeroramodifiedsphygmomanometerandholdingitatapressureof40mmHgfor15secondswhileacontinuouselectrocardiogramisrecorded.Themanoeuvreisperformedthreetimeswithone-minuteintervalsbetween.Thetestshouldbeavoidedinpatientswithproliferativeretinopathy,becauseoftheriskofretinalhaemorrhage.Problemsmayalsooccurwithpatientswithpoorvisionwhoareunabletoseethemanometer.Patientscancheatbystickingthetongueoverthemouthpiece,butthisisusuallyobvioustotheobserver.TheresultisexpressedastheValsalvaratio,4whichistheratioofthelongestR-Rintervalafterthemanoeuvre(reflectingtheovershootbradycardiafollowingrelease)totheshortestR-Rintervalduringthemanoeuvre(reflectingthetachycardiaduringstrain),measuredwitharulerfromtheelectrocardio-gramtrace.ThemeanofthethreeValsalvaratiosistakenasthefinalvalue.InterpretationofthisandtheothertestresultsisshownintableII.Heart-rate(R-Rinterval)variationduringdeepbreathingNormallytheheartratevariescontinuallybutthisdependsonanintactparasympatheticnervesupply.Thevariationisabolishedwithatropinebutuninfluencedbypropranololandismorepronouncedatslowheartrates,duringdeepbreathing,andinyoungerpatients.3Diabeticswithautonomicneuropathymayhaveanoticeablereductionin,andsometimescompleteabsenceof,heart-ratevariation.Heart-ratevariationcanbestudiedduringquietbreathing,deepbreathing,orafterasingledeepinspiration.Deepbreathingatsixbreathsaminuteisthemostconvenientandreproducibletechnique.5Thepatientsitsquietlyandbreathesdeeplyatsixbreathsaminute(fivesecondsinandfivesecondsout)foroneminute.Anelectrocardiogramisrecordedthroughouttheperiodofdeepbreathing,withamarkerusedtoindicatetheonsetofeachinspirationandexpiration.TABLEI-FlowplanforperformingtestsofcardiovascularautonomicfunctionApproximateTestPositiontimeoftestApparatusrequired(infollowingorder)(min)Heart-rateresponsetoValsalvamanoeuvreSitting5Aneroidmanometer,electrocardiographHeart-ratevariationduringdeepbreathingSitting2ElectrocardiographBlood-pressureresponsetosustainedhandgripSitting5Handgripdynamometer,sphygmomanometerImmediateheart-rateresponsetostandingL..ElectrocardiographBlood-pressureresponsetostandingLyingtostandngSphygmomanometer916 SRITISHMEDICALJOURNALVOLUME2852OCTOBER1982TABLEII-Normal,borderline,andabnormalvaluesintestsofcardiovascularautonomicfunctionNormalBorderlineAbnormalTestsreflectingparasympatheticfunctionHeart-rateresponsetoValsalvamanoeuvre(Valsalvaratio)�1-211-11-1-2010Heart-rate(R-Rinterval)variationduringdeepbreathing(maximum-minimumheartrate).. Tj;&#x 64.;7 T;&#xz -0;&#x.48 ;&#xTs 1;.68;&#x 0 T; 00;15beats/min11-14beats/minbeats/minImmediateheart-rateresponsetostanding(30:15ratio) T;&#xj /F; 8.;€ T; 67;&#x.42 ;&#xTz -;�.60;&#x Ts ;.5; 0 ;&#xTd 0;1-041-01-1-031-00TestsreflectingsympatheticfunctionBlood-pressureresponsetostanding(fallinsystolicbloodpressure)mmHg11-29mmHg T;&#xj /F; 7.; T; 14;.25;&#x Tz ;.2; 0 ;&#xTd 0;30mmHgBlood-pressureresponsetosustainedhandgrip(increaseindiastolicbloodpressure) T;&#xj /F; 7.; T; 14;.25;&#x Tz ;.2; 0 ;&#xTd 0;16mmHg11-15mmHgmmHgThemaximumandminimumR-Rintervalsduringeachbreathingcyclearemeasuredwitharulerandconvertedtobeatsaminute.Theresultisthenexpressedasthemeanofthedifferencebetweenmaximumandminimumheartratesforthesixmeasur
edcyclesinbeatsaminute.Thetesthastheadvantageofbeingobjective,simpletoperform,andrequiresverylittleco-operationfromthepatient.Heart-ratevariationhasalsobeenmeasuredastheratiooftheheartrateatexpira-tiontothatatinspiration,theso-calledE:Iratio,butthisdoesnotappeartohaveanyadvantages.5Immediateheart-rateresponsetostandingDuringthechangefromlyingtostandingacharacteristicimmediaterapidincreaseinheartrateoccurswhichismaximalataboutthe15thbeatafterstanding.Arelativeovershootbradycardiathenoccurs,maximalataboutthe30thbeat.6Thisresponseismediatedbythevagusnerve.7Diabeticswithautonomicneuropathyshowonlyagradualornoincreaseinheartrateafterstanding.Thetestisperformedwiththepatientlyingquietlyonacouchwhiletheheartrateisrecordedcontinuouslyonanelectrocardiograph.Thepatientisthenaskedtostandupunaided,andthepointatstartingtostandismarkedontheelectrocardiogram.TheshortestR-Rintervalatoraroundthe15thbeatandthelongestR-Rintervalataroundthe30thbeatafterstartingtostandaremeasuredwitharuler.Thecharacteristicheart-rateresponseisexpressedbythe30:15ratio.Otherwaysofmeasuringthisresponseareunderdebate,butwestillrecommendthe30:15ratio.Thistestissimpleandobjective,requireslittlepatientco-operation,isreproducible,anddoesnotdependoneitherageortherestingheartrate.TestsreflectingsympatheticdamageBlood-pressureresponsetostandingOnstandingpoolingofbloodinthelegscausesafallinbloodpressure,whichisnormallyrapidlycorrectedbyperipheralvasoconstriction.3Inpatientswithautonomicdamagethebloodpressurefallsonstandingandremainslowerthaninthelyingposition.Thetestisperformedbymeasuringthepatient'sbloodpressurewithasphygmomanometerwhileheislyingdownquietlyandagainwhenhestandsup.Theposturalfallinbloodpressureistakenasthedifferencebetweenthesystolicbloodpressurelyingandthesystolicbloodpressurestanding.Thissimpletestgivesanabnormalresultonlywithsevereperipheralsympatheticdamage.Blood-pressureresponsetosustainedhandgripDuringsustainedhandgripasharpriseinbloodpressureoccurs,duetoaheart-rate-dependentincreaseincardiacout-putwithunchangedperipheralvascularresistance.3Shouldthenormalreflexpathwaysbedamaged,asindiabeticswithextensiveperipheralsympatheticabnormalities,therisein.bloodpressureisabnormallysmall.Themaximumvoluntarycontractionisfirstdeterminedusingahandgripdynamometer.Handgripisthenmaintainedat300%ofthatmaximumforaslongaspossibleuptofiveminutes.Bloodpressureismeasuredthreetimesbeforeandatone-minuteintervalsduringhandgrip.Theresultisexpressedasthedifferencebetweenthehighestdiastolicbloodpressureduringhandgripexerciseandthemeanofthethreediastolicblood-pressurereadingsbeforehandgripbegan.Theautonomic"battery"ofcardiovasculartestsTableIshowshowallfivetestscanbeperformedsimplyandquickly.Thetotaltimerequiredisabout20minutes,andtheequipmentneededincludesasphygmomanometer,anelectrocardiograph,ananeroidmanometer,ahandgripdynamometer,pluscouchandchair.Oncethetestshavebeenperformedtheresultscanbecalculatedeitherbyhand,or,iffacilitiesareavailable,usingamicroprocessorsystemtomeasuretheR-Rintervalsdirectlyfromtheelectrocardiogramrecord.TableIIgivesthenormal,borderline,andabnormalvalueswhichweuseforeachtest.Theresultscanthenbecategorised,andusuallyfallintooneoffourgroups:normal;earlyparasympatheticdamagewithresultsofoneofthethreetestsofparasympatheticfunctionabnormal;definitepara-sympatheticdamagewithresultsofatleasttwoofthetestsofparasympatheticfunctionabnormal;andcombinedpara-sympatheticandsympatheticdamage,whereinadditiontoabnormalparasympathetictestresultsfindingsinoneorbothofthesympathetictestsareabnormal.Inourexperiencewithover500diabeticsveryfew(20;40%)couldnotbeplacedintooneofthesecategoriesusingthisbatteryoftests.Thenaturalhistoryofautonomicdamageindiabetesisbecomingclearer,withparasympatheticdamageoccurringearlyandsympatheticdamagelater.89Thesesimpletestsallowclinicianstogivesomediagnosticprecisiontotheautonomicabnormalitiespresentindiabetics.Lestitbethoughtthatthisisonlyoflimitedimportance,mostlargeserieshavefoundthat20%to4000ofalldiabeticshavesomeabnormalitiesofautonomicfunction.10-13917 918BRITISHMEDICALJOURNALVOLUME2852OCTOBER1982TreatmentofsymptomsPosturalhypotensionisprobablythemostdisablingsymptomofautonomicdamage.Thedifferenttreatmentsproposedincludeelasticstockings,ephedrine,tyrosine,indomethacin,andbeta-blockers.Indiabeticsthemosteffectivetreatmentisprobablyfludrocortisone,01-0-3mgdaily,whichislessthanthedoseusuallyrequiredforprimaryorthostatichypotension.Thisdrugincreasesbloodvolumeandminimisesthefallinbloodpressure.Manydiabeticshaveconsiderablefallsinbloodpressurewithoutsymptomsanddonotneedtreatment.Iffluidretentiondevelops,aswithcongestivecardiacfailureorthenephroticsyndrome,posturalhypotensioncandisappearandsomakedrugtreatmentunnecessary.Treatmentwithinsulincansometimesaggravateposturalhypotension,andchangingthetimingofinjectionsmayhelp.Gastricsymptoms-Experimentalstudieshaveshownthatmetoclopramideincreasesgastricmotilityandmayimprovesymptomsinsomepatientswhohavesymptomaticgastricatonyandgastricretention.'4Adoseof10mgthreetimesdailybeforemealsisusuallyadequate.Diarrhoea-The
mechanismofdiarrhoeaindiabeticauto-nomicneuropathyisobscure.Broad-spectrumchemotherapysuchastetracycline,givenfortheepisodesoronaninter-mittent(oneweekinfour)basis,oftenrelievessymptoms,butimprovementmaycoincidewithnaturalremission.Recentlymetoclopramidegivenforgastricproblemshasbeennotedtolessendiarrhoeainsomepatients.Thisseemsaneffectivewayoftreatingdiabeticdiarrhoea,sometimeswithdramaticresults,andwenowrecommenditinadoseof10mgthreetimesdaily.Onlyifthisisnoteffectiveshouldchemotherapybegiven.Sweating-Troublesomeexcesssweatingcanbehelpedwithanticholinergicdrugssuchaspropanthelinehydrobromideorpoldinemethylsulphate,thoughthesedrugsdohavesideeffectssuchasurinaryretention.Somediabeticswithgustatorysweatingfindthataprophylacticdoseofeitherdrugtakenbeforeaheavymealiseffective.Bladderdysfunctionandurinaryretention-Patientswithautonomicdysfunctionofthebladdershouldbeencouragedtovoideverythreetofourhoursduringtheday,ifnecessaryusingmanualsuprapubicpressure.Long-termchemotherapyissometimesrequiredforurinaryinfection.Iftheresidualurinevolumeisincreasedthepatientisbesttreatedbybladder-neckresection,providedthatheisfitforoperation,soallowingtheweakbladdermusclestoovercomeoutflowresistanceatthebladderneck.Impotence-Onceimpotencehasdevelopedindiabeticswithautonomicneuropathyitisusuallyirreversible,andcounsellingprobablyisthemosthelpfulcourseofaction.PenileprosthesesClarkeBF,EwingDJ,CampbellIW.Diabeticautonomicneuropathy.Diabetologia1979;17:195-212.2EwingDJ,CampbellIW,ClarkeBF.Thenaturalhistoryofdiabeticautonomicneuropathy.QJMed1980;49(Winter):95-108.3EwingDJ.Cardiovascularreflexesandautonomicneuropathy.ClinSciMolMed1978;55:321-7.4LevinAB.AsimpletestofcardiacfunctionbasedupontheheartratechangesinducedbytheValsalvamaneuver.AmJCardiol1966;18:90-9.5EwingDJ,BorseyDQ,BellavereF,ClarkeBF.Cardiacautonomicneuropathyindiabetes-comparisonofmeasuresofR-Rintervalvariation.Diabetologia1981;21:18-24.6EwingDJ,CampbellIW,MurrayA,NeilsonJMM,ClarkeBF.Immediateheart-rateresponsetostanding:simpletestforautonomicneuropathyindiabetes.BrMedJ1978;i:145-7.EwingDJ,HumeL,CampbellIW,MurrayA,NeilsonJM,ClarkeBF.Autonomicmechanismsintheinitialheartrateresponsetostanding.JApplPhysiol1980;49:809-14.EwingDJ,CampbellIW,ClarkeBF.Assessmentofcardiovasculareffectsindiabeticautonomicneuropathyandprognosticimplications.AnnInternMed1980;92:308-1.havebeendevelopedintheUnitedStatesbutEuropeanexperienceoftheseislimited.Cardiorespiratoryarrests-Suddenandunexpecteddeathsoccurindiabeticswithautonomicneuropathy,andthesemaybeduetocardiorespiratoryarrestinassociationwithhypoxia.215Anydiabeticwhohasautonomicneuropathyisaconsider-ableanaestheticrisk,andparticularcareneedstobetakenduringandaftertheoperationtotrytopreventsuchepisodes,whichmaybeduetosuddenchangesoftheinspiredoxygenconcentration.PreventionorreversalofautonomicdamageBythetimesymptomshavedevelopedautonomicnervedamageisprobablyirreversibleandcarriesapoorprognosis.2Assomeautonomicdamageoccursinmanydiabetics,however,preventionofthelatestagesisclearlydesirable.Preliminarystudiessuggestthatverygoodmetaboliccontrolcanachievesomereversalofautonomicabnormalities.Diabeticswithabnormalitiesofautonomicfunctionshouldthereforebeencouragedtokeeptheirdiabetesaswellmaintainedaspossible.Asecondapproachtopreventionofautonomicdamagehasbeenwithcertaindrugs,suchasthoseofthealdosereductaseinhibitorgroup,butasyetitistooearlytosaywhetherornotpreventionorreversalofthedamageispossiblebythismeans.ConclusionsSubclinicalautonomicnervedamageoccursmorewidelyindiabeticsthanwashithertosuspectedandisassuminggreaterimportancebecauseoftheimplicationsformorbidityandmortality.Symptomaticautonomicneuropathycarriesaworseprognosisthananyothercomplicationofdiabetes.2Thesimplebedsidetestsdescribedabovecanprovideanobjectiveguidetowhetherornotautonomicdamageispresent,andtowhatdegree.Someofthetroublesomesymptomsinthelaterstagescannowbemoresuccessfullytreatedthanbefore.Thelonger-termaimofmanagementshould,however,bethepreventionorreversalofautonomicdamage,particularlyinitsearlystages.DJEWINGWellcomeTrustseniorlecturerBFCLARKEConsultantphysicianUniversityDepartmentofMedicineandDiabeticandDieteticDepartment,RoyalInfirmary,EdinburghEH39YWEwingDJ,CampbellIW,ClarkeBF.Heartratechangesindiabetesmellitus.Lancet1981;i:183-6.'0Sharpey-SchaferEP,TaylorPJ.Absentcirculatoryreflexesindiabeticneuritis.Lancet1960;i:559-62.EwingDJ,IrvingJB,KerrF,WildsmithJAW,ClarkeBF.Cardiovascularresponsestosustainedhandgripinnormalsubjectsandinpatientswithdiabetesmellitus:atestofautonomicfunction.ClinSciMolMed1974;46:295-306.2HilstedJ,JensenSB.Asimpletestforautonomicneuropathyinjuvenilediabetics.ActaMedScand1979;205:385-7.13DyrbergT,BennJ,ChristiansenJS,HilstedJ,NerupJ.Prevalenceofdiabeticautonomicneuropathymeasuredbysimplebedsidetests.Diabetologia1981;20:190-4.14SnapeWJ,BattleWM,SchwartzSS,BraunsteinSN,GoldsteinHA,AlaviA.Metoclopramidetotreatgastroparesisduetodiabetesmellitus-adoubleblind,controlledtrial.AnnInternMed1982;96:444-6.'5PageMM,WatkinsPJ.Cardiorespiratoryarrestanddiabeticautonomicneuropathy.Lancet1978;i:14-6