120 Vol.20,No.1,2006

CARVEDILOL AGGRAVATES ORTHOSTATIC HYPOTENSION IN A DIABETIC PATIENT WITH CHRONIC RENAL FAILURE

Tsuan-ShihYu,Chin-FengTseng,Lai-KingYeung,Kuo-ChengLu,Chuan-ChiehLiu

A 64-year-old male was admitted because of progressive dyspnea, bipedal edema and reduced urine output. His medical history included coronary artery disease with coronary artery bypass graft, hypertension and type 2 diabetes mellitus with chronic renal failure and retinopathy. During admission, he developed severe postural dizziness. Positional blood pressure and heart rate measurements revealed fluctuations in systolic blood pressure greater than 20 mmHg but no significant heart rate change. Two days after stopping carvedilol, systolic blood pressure declined by only 10 mmHg and heart rate increased significantly with positional changes. Orthostatic hypotension due to autonomic neuropathy was suspected. Nerve conduction velocity study showed severe sensorimotor polyneuropathy. Sympathetic skin response and RR interval variability tests indicated autonomic dysfunction.

Combinations of alpha- and beta-blockers should always be administered with caution in diabetics, who are likely to have autonomic nervous system dysfunction and in whom the use of such medications may increase the risk of orthostatic hypotension. (Acta Nephrologica 2006; 20: 120-125)

Key words: orthostatic hypotension, carvedilol, diabetes, renal failure, autonomic neuropathy

DepartmentofMedicine,CardinalTienHospital,SchoolofMedicine,Fu-JenCatholicUniversity,Taipei,TaiwanReceived:May,2005 Revised:July,2005 Accepted:January,2006Addressforreprintsandcorrespondence:Dr.Chuan-ChiehLiu,DepartmentofMedicineCardinalTienHospital,SchoolofMedicine,Fu-JenCatholicUniversity,Taipei,Taiwan,No362,Chung-ChengRd,HsinTienCity,TaipeiCounty,TaiwanTel:886-2-22193391Fax:886-2-29451602E-mail:youtsuanshih@yahoo.com.tw

INTRODUCTION

TheAmericanAutonomicSocietyandtheAmericanAcademy of Neurology defines orthostatic hypotension (OH)asadeclineinsystolicbloodpressureofat least20mmHgbeyond3minutesof standingorpassivehead-uptiltpositionat60degrees.1,2ManyfactorshavebeenlinkedtoOH,includingage,prolongedbedrest,lowbodymassindex,systemicdiseases(e.g.,diabeticautonomic neuropathy, stroke, multiple sclerosis,amyloidosis, adrenal insufficiency)andmedications(e.g., antipsychotic agents, peripheral vasodilators,specificallyalpha-blockersandnon-dihydropyridinecalciumchannelantagonists).3

IfapatientsuspectedofhavingOHishypertensiveand requires antihypertensive medications, pre-treatmentmeasurementsarenecessary to identify thepresenceofbaselineOH.IfnobaselineOHisdetected,antihypertensivemedicationsmaybeprescribedwhileregularlymonitoring forOH. Ifpre-treatmentOH isfound,clinicians shouldbalance thepossible riskof

worseningposturalhypotensionduetoantihypertensivetherapy against the hemodynamic benefits of improved bloodpressurecontrol.

Wereportapatientwithdiabeticnephropathyandneuropathy,whopresentedcarvedilolaggravatedOH.

CASE REPORT

A 64-year-old male was admitted because ofprogressivedyspnea,bipedaledemaandreducedurineoutputof threeweeksduration.Hehasahistoryofcoronaryarterydiseasewith3-vesseldiseaseforwhichhehad receivedcoronaryarterybypassgraft surgeryoneyearprior to thisadmission.Healsohashadtype2 diabetes mellitus for the past 16 years; diabeticretinopathy,chronicrenalfailureandhypertensionhadbeennotedsince2yearsbeforethisadmission.At thetimeofadmission,hismedicalprescription includedcombined regular and intermediate acting insulinpreparations,digoxin0.125mg/day,irbesartan150mg/day,pravastatin20mg/day,clopidogrel75mg/day,and

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ActaNephrologica CarvedilolandOrthostaticHypotension 121

furosemide80mg/day.Hehadsmokedaboutonepackofcigarettesdailyforthepast40yearsbuthadstoppedtakingalcoholicdrinksforthepast10years.

Uponpresentation,BPwas90/50mmHg,HRwas89beats/min,andrespiratoryratewas18/min.Physicalexamination revealed a jugular venous pressure ofabout6cmabovethesternalborder,anoldmid-sternallongitudinal surgical scarandpittingedemaofbothlowerextremities.Hemoglobin levelwas lowat4.9g/dlandhematocritwasonly15%.Bloodbiochemistryrevealedelevated levelsofbloodureanitrogen level(150mg/dl)andserumcreatinine(4.4mg/dl)butnormallevelsofserumsodium(140mmol/L)andpotassium(4.3mmol/L).Serumdigoxin levelwasslightly lowat0.4ng/ml.Twenty-fourhoururinecreatinineclearance(CCr)was22.65ml/min.

Electrocardiogram revealed sinus rhythm withaheart rateof90/min,QT intervalof320msec,andaQTcof393msec.Echocardiogramrevealeda leftventricularejectionfractionof62%andregionalwallmotion abnormality. On the third hospital day, thepatientdevelopedtarrystoolsbutuppergastrointestinalpanendoscopy revealed only duodenitis and superficial gastritis.He receiveda transfusionofeightunitsofpackedRBCforsevereanemia.Hemoglobinlevelontheseventhhospitaldaywas10.2g/dl.Allantihypertensivemedicationswerediscontinueduponadmissionduetohypotensionbutwereresumedon thesecondhospitaldayduetorecurrenceofhighbloodpressure.Carvedilol(25mg/day)wasgivenstartingonthethirdhospitaldayduetopersistentlyhighbloodpressure.Increasedurineoutputandgradual resolutionofbipedaledemawerenotedfollowingintravenousfurosemideadministrationalthoughmildperipheraledemapersisted.Thejugularvenouspressure level remainedapproximately5cmabovethesternalborderandtherewasnoevidenceofvolumedepletion.

After one week of carvedilol administration,he developed progressively severe dizziness withvertigo,particularlywithchanges inposition.On the9thdayofcarvedilol treatment,hewasnoted tohavesensoryataxiawithinvoluntaryfallingepisodes.Uponneurological consultation, polyneuropathy due tounderlyingdiabeteswithchronic renal failureand/orvertebrobasilar insufficiencywere suspected.Nerveconductionvelocitystudyshowedseveresensorimotorpolyneuropathy.Carotiddopplerscanningrevealed50%stenosisoftheleftcommoncarotidarteryandmoderatetosevereatherosclerosisofbothcommoncarotidandinternalcarotidarteriesalthoughtotalvertebralarteryblood flow was adequate. Positional blood pressure and heartratechangesweremeasuredinthesupine,sittingandstandingpositionsfor2consecutivedays.Systolic

bloodpressuredeclinedbymore than20mmHgwithchanges in position but heart rate did not changesignificantly (Table 1). Upon review of his medications, carvedilolwassuspectedas themostprobablecauseofOHandwas therebydiscontinued.Twodaysafterstoppingcarvedilol, thepatient claimed thathe feltmuchbetter.Electrocardiographywasdone to recordR-Rintervalinthesupine,sitting,andstandingpositionsforatleast3minutes(Fig.1).SupineQTwas356msecandQTcwas430msec.SittingQTwas326msecandQTcwas428msec.StandingQTwas312msecandQTcwas414msec.Simultaneousbloodpressure readingsshoweda10mmHgdeclineinsystolicbloodpressure;tachycardiawasalsonotedwithchanges inposition(Table1).Nofurtherepisodesofposturaldizzinessorsensoryataxiawerenotedonfollow-up.Wesuspectedthat the10mmHgfall insystolicbloodpressureafterstoppingcarvedilolmightbeduetounderlyingdiabeticautonomicneuropathy.Thus,sympatheticskinresponse(SSR)andRRintervalvariability(RRIV)studieswereperformed.Results revealedRRIV4.84%against anormalvalue>10%(Fig.2).NormalSSRwasseenon rightupperextremities. (Fig.3) andabsentSSRon the leftupperandboth lowerextremities. (Fig.4)These twostudies indicate thepresenceofautonomicdysfunction in thisdiabeticpatientwithchronicrenalfailure.

DISCUSSION

Diabetes is the leadingcauseofneuropathyin theWesternworld,andneuropathy is themostcommoncomplication and the greatest source of morbidityandmortality indiabetics.2Diabeticneuropathymaymanifestassensorimotorneuropathy,distalsymmetricalpolyneuropathyor autonomicneuropathy involvingthecardiovascular,gastrointestinalandgenitourinarysystems.Autonomicneuropathymayinvolveboth thesympatheticandparasympathetic innervationsof theheartandcoronaryvessels,4withhallmarksymptomsoforthostatichypotensionanddecreasedheart ratevariability.Theincidenceofcardiovascularautonomicneuropathyappears tobearound15% in type1and20% in type 2 diabetes patients.5 Cardiovascularautonomicneuropathymaycontributetoleftventriculardysfunction, silent or asymptomatic myocardialinfarction,andexerciseintolence.4,6

Autonomicnervoussystemdysfunctionmayalsodevelop inpatientswithuremia.7 Impotence,posturaldizziness, feeling of gastric fullness or delayedemptying,boweldysfunction, and reducedsweatingare themostcommonsymptoms.7Hemodialysismayimproveautonomic function inuremicpatients.8The

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122 T.S.Yu,C.F.Tseng,L.K.Yeung,K.C.Lu,C.C.Liu Vol.20,No.2,2006

Table1.ComparisonofposturalBPandposturalHRbeforeand2daysafterdiscontinuationofcarvedilolsupine sitting standing

BP(mmHg)

HR(beats/min)

BP(mmHg)

HR(beats/min)

BP(mmHg)

HR(beats/min)

Before134/82 82 128/78 80 100/70 80

142/76 88 100/68 86 90/62 82

After120/60 90 100/50 104 90/46 106

108/54 92 98/50 100 88/48 108

Abbreviations:BP,bloodpressure;HR,heartrate

Fig.1. Electrocardiography2daysafterdiscontinuationofcarvedilol.(a)insupineposition,QTc430msec,(b)threeminutesafterchangefromsupinetosittingposition,QTc428msecand(c)threeminutesafterchangefromsittingtostandingposition,QTc414msec.

(a)

(b)

(c)

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ActaNephrologica CarvedilolandOrthostaticHypotension 123

Fig.2. R-Rintervalvariabilitytest Fig.3. SSRofrightupperextremities

Normal responseMin: 79 bpm Mean: 81 bpmMax: 82 bpm SD: 0.9 bpmRate Variance: 4.84%Rate [bpm]

90

80

70

Time [see]

0 30 60 90 120

Fig.4.

SSR of left lower extremities

SSR of right lower extremities

SSR of Left upper extremities

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124 T.S.Yu,C.F.Tseng,L.K.Yeung,K.C.Lu,C.C.Liu Vol.20,No.2,2006

incidenceofOHindiabeticswithchronicrenalfailureis37.5%.9Ourpatienthadchronic renal failureduetodiabeticnephropathyandpresentedwithazotemiawhichmayhaveaggravatedhisunderlyingautonomicneuropathy.

The regulationofbloodpressure andheart ratewithchanges inposition involves thecardiovascular,musculoskeletal,renal,endocrinologicalandautonomicnervous systems. Conditions that predispose anindividual to OH include advanced age, decreasedbaroreflex sensitivity, impaired β-adrenoceptor-mediated response,10 increasedvascularstiffness11anddecreasednumberofpacemaker cells in the sinoatrial node.12

DrugswhichmaycauseOHorworsenpositionalbloodpressurechangesincludepsychoactivemedicationssuchas tricyclicantidepressants,13antiparkinsonismagentsandcardiovascularmedications,suchasvasodilators.14,15Someantihypertensivemedicationsmayinterferewithposturalhaemodynamicstability , therebyaggravatingpositionalbloodpressureandpredisposingtoOH.3Ontheotherhand,certainantihypertensivemedicationsmay improve baroreflex sensitivity16 and decreasevascular stiffness,17whichmayamelioratepositionalbloodpressurechangesandlessentheriskofOH.

It iswellknown thatnon-selectivebeta-blockersreducebloodpressure,heartrateandmyocardialoxygendemand.However,animalstudieshaveshownthat thealpha-1blockersmay inducevasodilatation, increaseperipheralvascularbloodflowanddecreasedthelimbvascularresistance.18,19Sinceperipheralvasoconstrictionis an important counter-mechanismduringposturalchanges,patients receivingalpha-blockersmaybeatincreasedriskofdevelopingOH.

Carvedilolmaypreserve renal functionwithouteliciting reflex stimulationof the renin-angiotensin-aldosteronesystemor fluidretention.Carvedilolalsodoes not affect glucose tolerance or carbohydratemetabolismandisthereforesuitableforthetreatmentofhypertensivepatientswith type2diabetesmellitus. Invitroandanimalstudieshavealsoshownthatcarvedilolhas cardioprotective andneuroprotectivepropertiesthatmaybebeneficial inpatientswithanginapectorisorcongestiveheart failure.18Ourpatienthascoronaryarterydisease, type2diabetesmellituswithchronicrenalfailureandhypertensionandweusedcarvedilolfortheabovereasons.However,carvedilolisanonselectivebeta-adrenoreceptorwithalpha-blockingactivityandmaybeassociatedwitha40%increasedriskofOHinelderlypatients.20

In one study, patients on 25 mg of carvediloldailydevelopedadose-dependentfall insupinebloodpressure and standing blood pressure. In contrast,beta-blockerswith intrinsicsympathomimeticactivity

producedsimilarreductionsinsupinebloodpressurebutless significant reductions in standing blood pressure.20

Ourpatienthad systolicbloodpressure fluctuationsgreater than20mmHgwithchanges inpositionbutno significant change in the heart rate.After oraladministration,thehalf-lifeofcarvedilolis2to8hoursalthoughitmayonlybe2to5hoursintheelderly(age>65years).18Twodaysafterstoppingcarvedilol,ourpatient feltmuchbetterclinically.Followupsystolicbloodpressuredeclinedbyonly10mmHgandheartrate increased significantlywithpositionalchanges.The 10 mmHg fall in systolic blood pressure afterstoppingcarvedilolismostprobablyduetounderlyingautonomicneuropathy.Ourpatienthasa longhistoryofdiabetesandnerveconductionvelocityexaminationshowedseveresensorimotorpolyneuropathy.TheSSRtestprovidesuseful informationregardingsympatheticpostganglionic functionandanabsentSSRsupportsadiagnosisofdiabetic autonomicneuropathy.21,22AlowerRRIVmayalsobeseenindiabeticswithcardiacautonomic neuropathy and absent SSR.23,24 In ourpatient,absentSSRand lowRRIVboth indicate thepresenceofautonomicdysfunctionclinicallypresentingasOH.

Inconclusion,physiciansmustkeep inmind thatcarvedilolmayaggravateorthostatichypotensioninthediabeticpatientwithchronicrenalfailure,particularlythosewithunderlyingautonomicneuropathy.IfOHisaproblem, theuseofangiotensinconvertingenzymeinhibitors,angiotensinreceptorblockers,25beta-blockerswithintrinsicsympatomimeticactivity(e.g.,pindolol)26and calcium blockers such as verapamil27 may beconsidered.

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