malignant vasovagal syncope: a randomised trial of - heart

Heart 1997;77:268-272

Malignant vasovagal syncope: a randomised trialof metoprolol and clonidine

Mauro Biffi, Giuseppe Boriani, Paolo Sabbatani, Gabriele Bronzetti, Lorenzo Frabetti,Romano Zannoli, Angelo Branzi, Bruno Magnani

AbstractObjective-To evaluate the efficacy ofhead up tilt guided treatment with meto-prolol and clonidine in preventing therecurrence of syncope in patients withmalignant vasovagal syncope.Patients-20 patients (9 men and 11women, mean age 33 (SD 17), range 14 to62 years) with severe symptoms.Design-Randomised double blind cross-over trial; efficacy was assessed by headup tilt testing.Results-Metoprolol was more effectivethan clonidine in abolishing syncope(19120 v 1/20, P < 0.001) but clonidineshowed some beneficial effects on time tosyncope and severity of hypotension in 12patients. During an average follow up of15 (3) months there was a significantreduction in the recurrence of symptomscompared with the previous year inpatients who had tilt up guided treatment(18 metoprolol, 1 clonidine).Conclusions-Treatment guided by headup tilting is a reliable method of treatingpatients with malignant vasovagal syn-drome. Metoprolol was an effective longterm treatment for preventing syncope.High doses were more effective and acareful dose titration period helped tominimise withdrawal symptoms and sideeffects.

(Heart 1997;77:268-272)

Keywords: neurocardiogenic syncope; head up tilt test;P blockers; clonidine

Institute ofCardiology, PoliclinicoS Orsola, University ofBologna, ItalyM BiffiG BorianiP SabbataniG BronzettiL FrabettiR ZannoliA BranziB MagnaniCorrespondence to:DrM Biffi, Institute ofCardiology, Policlinico SOrsola, via Massarenti No 9,40138 Bologna, Italy.Accepted for publication3 October 1996

Vasovagal syncope is a common clinical prob-lem forming the pathophysiological basis ofsyncope in up to 25% of patients seen at an

emergency department for this condition,' andit may account for nearly half the cases of syn-cope.2

Although it usually has a favourable prog-nosis, it may be a highly limiting clinical prob-lem in a particular subset of patients amongwhom syncopal recurrences are frequent andwithout prodromic symptoms, or have a trau-matic outcome. For this subgroup of patientsthe term "malignant vasovagal syncope" hasbeen proposed to identify these characteris-tics.3 The treatment of these highly sympto-matic patients is necessary to avoid dangerousinjuries and to improve their quality of life.The treatment of vasovagal syncope is con-

troversial and different approaches have been

proposed. Among these, ,3 blockers, cardiacpacing, disopyramide, clonidine, and scopol-amine are the most frequently employed.4-12 Inthis study we investigated the efficacy of meto-prolol and clonidine in a randomised doubleblind crossover study to prevent syncoperecurrence in a highly symptomatic groupof patients with "malignant" vasovagal syn-drome.

Since there is clinical evidence for the use ofmetoprolol,45 10 we tested the hypothesis that asympathetic modulator such as clonidinemight also be effective, as reported byFitzpatrick et al in a randomised trial.8 The useof clonidine has strong pathophysiologicalsupport because of its partial selective a2 ago-nist activity (a2 receptors predominate in largecapacitance vessels, and clonidine would sig-nificantly reduce venous capacitance, thusdecreasing the likelihood of triggering thevasovagal reflex following gravitational stress).Beneficial effects were observed by Robertsonet al in patients with severe orthostatic hypo-tension, who showed a great improvement insystolic blood pressure and functional capacitywith clonidine treatment.'3

MethodsPatients with frequent recurrences of syncope(one or more per month) or injuries caused bysyncopal events due to vasovagal syncope seenat our hospital from March 1993 to May 1995were screened for enrolment in the study.

Exclusion criteria were a clinical history ofasthma or chronic obstructive airways disease,atrioventricular block greater than first degree,sinus rate less than 40 beats/min, structuralheart disease with contraindications for /3blocking agents, hypersensitivity to /3 blockers,and patients' refusal to participate.Twenty patients fulfilled the entry criteria

for randomisation (more than 12 syncopalepisodes or more than one syncopal event withtraumatic outcome in the previous year, orboth). The diagnosis of vasovagal syncope wasruled out by a standardised cardiological andneurological approach in all the patients. Thework up consisted of clinical examination, lab-oratory screening, 12 lead electrocardiogram(ECG), cross sectional echocardiography, and24-hour Holter monitoring. Electrophysio-logical study was performed when clinicallyindicated.

Vasovagal syncope was confirmed by headup tilt test (HUT) according to a previouslypublished classification'4; after baseline HUT,patients were randomised to receive either

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Malignant vasovagal syncope: a randomised trial of metoprolol and clonidine

Study design. Acute phase

Study drug 1

Metoprolol(10 patients)

Baseline HUT(20 patients)

Clonidine(10 patients)

Study drug 2

Metoprolol(10 patients)

Wash out Chronic phase

Clonidine(10 patients)

metoprolol or clonidine in a double blindcrossover manner. The study consisted of twodistinct phases: the acute drug evaluationphase, and the chronic treatment phase.During the acute phase, the efficacy of bothtreatments was assessed in a double blind, ran-domised, crossover manner. During thechronic phase the study was carried out in sin-gle blind manner.

Patients were instructed by the referral physi-cian to take the drugs orally on a progressivelyincreasing dose schedule over a 10 day period;HUT was then repeated on the 15th day. Afive-day wash out period was allowed, and thenpatients crossed over to the second treatmentwith a similar dosage titration period; on the15th day, HUT was repeated as in phase 1 (fig-ure).Both patients and physicians performing the

HUT were blinded to the treatment taken bythe patients. Metoprolol and clonidine weregiven twice daily, increasing from 50 mg up to400 mg daily for metoprolol and from 0 150mg up to 1-2 mg daily for clonidine.

Patients were instructed to report potentialside effects of the study drug; dosage titrationwas limited by the onset of intolerable sideeffects or excessive bradycardia (resting heartrate < 40 beats/min).

HUT PROTOCOLHUT was performed by a standardised proto-col in our laboratory. Tests were performed at10:30 in a comfortable quiet room at 22°C; car-diac rhythm was continuously monitored on aMarquette unit (Case 12) and blood pressureby a Finapress unit (Ohmeda 2300).The HUT protocol consisted of two phases:

basal HUT and a pharmacological test. BasalHUT was performed as follows: after 10 min-utes of rest, the bed was tilted to 700 for 25minutes; in case of negative response, the phar-macological test ensued. The pharmacologicaltest was accomplished by isoprenaline infusionin five progressive steps, from 1 up to 5 jig/min(0 15 to 0 07 ug/kg/min) at 800 tilt. Each stepconsisted of five minutes supine and 10 min-utes tilt at constant infusion rate.Our protocol was based on data in published

reports.3-5 111215-17 The most recent studies con-firm the sensitivity, specificity, and repro-ducibility ofHUT results by this degree of tabletilting and test duration, either in the basal con-dition or during isoprenaline testing.18 19

After the acute drug evaluation phase wascompleted, patients were allocated to thechronic treatment phase on the study drugwhich had changed the baseline HUT to anegative response, or on study drug 2 if theyresponded to both. If neither drug was effec-tive, the patient was treated on the basis of thereferring physician's judgement.

Statistical analysisResults are given as mean (SD). The haemo-dynamic effect of the two study drugs wascompared by analysis of variance.The effect of the two study drugs during the

acute phase (the number of patients whorespectively converted from a positive to nega-tive HUT) was evaluated by contingencytables.The results during the follow up period

were evaluated by McNemar's test.

ResultsTwenty of 203 consecutive patients referredto our outpatient clinic for syncope of unex-plained origin fulfilled the clinical entry criteriafor enrolment into the study. Mean age was33 (17) (range 14 to 62) years; there werenine males and 11 females. None of thepatients had any relevant clinical abnormali-ties or organic heart disease. All 20 patientshad negative tests on the preliminary diagnos-tic work up, but vasovagal syncope was con-firmed by a positive baseline HUT in all cases.Among these 20 patients, 14 had had morethan 12 syncopal attacks in the year precedingbaseline HUT, while six had two traumaticsyncopes. Among the latter there was a meanof 3 (13) (range 2 to 4) syncopes in 4 (2 8)months (range 1 to 9) since the first syncopalepisode.

Baseline HUT elicited syncope in all thepatients, in 11 (55%) during basal HUT, andin nine (45%) during pharmacological testing.Among these latter, syncope was reproducedat an isoprenaline infusion rate of 1 6 (0 9),ug/min (range 1 to 3 4ug/min).

At baseline HUT, 14/20 patients (70%)showed a vasodepressive pattern of syncope,4/20 (20%) a mixed pattern, and 2/20 (10%) acardioinhibitory pattern (table 1).During the acute phase, HUT was consid-

ered negative if both basal HUT and the five



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Table 1 Head up tilt responses at baseline and during treatment

Vasodepressive Mixed Cardioinhibitory Negative

Baseline 14 4 2 0Metoprolol 0 1 0 19*Clonidine 11 7 1 1

*P < 0-001 v baseline and clonidine.

Table 2 Haemodynamic variables at baseline and during drug evaluation. Values aremeans (SD) and range

Baseline Metoprolol Clonidine

Heart rate (beats/min) 78 (12) 58 (8)* 60 (8)*(range) (60 to 105) (44 to 73) (46 to 74)Mean blood pressure(mm Hg) 105 (10) 100 (14) 103 (11)

(range) (87 to 126) (80 to 128) (85 to 123)

*P < 0-005 v baseline (ANOvA).

steps of pharmacological testing failed toreproduce symptomatic hypotension.

During the two drug titration periods, one

syncopal and two near-syncopal episodesoccurred in three patients, in all cases duringclonidine titration (one during study drug 1,two during study drug 2). No patient droppedout because of syncope recurrence or drugrelated side effects; the maximum tolerateddosage was reached in all the patients. Theaverage metoprolol dose reached was 280 (52)mg (range 200 to 400 mg), whereas the aver-

age clonidine dose reached was 0-742 (0-157)mg (range 0-600 to 1-200 mg).

Resting heart rates on the two drugs were

comparable, and significantly lower than atbaseline HUT (table 2). Resting mean bloodpressure was slightly but not significantlydecreased on the two treatments compared tobaseline (table 2).

During metoprolol treatment, 19/20patients converted to a negative HUT,whereas 1/20 showed a persistent mixedresponse; during clonidine treatment, only onepatient (a responder to both treatments) had anegative response (P < 0-001 v metoprolol;table 1).Among the 19 patients not responding to

clonidine, 10 showed a favourable effect of thedrug in terms of time to onset of symptomsand severity of symptoms. A prolongation oftime to syncope was observed in 10 patients(six who fainted in basal conditions had a pos-itive HUT during isoprenaline testing; fourwho fainted during isoprenaline testing had a

positive HUT at the following isoprenalinestep); no change occurred in three patients,and a shortening in time to syncope occurredin six patients. Among these six patients, twowho had syncope after 25 minutes and 19minutes at baseline HUT developed syncopeafter 11 minutes and 12 minutes on clonidine,respectively, whereas four who had syncopeduring isoprenaline testing at baseline HUTdeveloped syncope at an earlier step of isopre-naline testing on clonidine.No difference in baseline HUT was

observed in patients who had a prolongation oftime to syncope, no change, or a shortening intime to syncope with clonidine.

In terms of severity of symptoms, eightpatients had severely symptomatic hypoten-

Table 3 Data atfollow up (15 (SD 3) months)

Previous year Follow up

Syncopes 193 0*Near syncopes 182 7*

*P < 0-001.

sion (average blood pressure 48 (4) mm Hg,range 38 to 55), but no syncope; among these,six had a prolongation and two no change intime to positive HUT compared to baselineHUT. Overall, at least a partial effect wasobserved in 12/20 patients on clonidine(60%).During metoprolol treatment 19/20 patients

converted to negative HUT; only 1/20 had apersistent mixed response with no change intime to syncope compared to baseline or cloni-dine. This patient was taking 200 mg of meto-prolol as the maximum tolerated dose.

At repeated HUT on clonidine, a slightlyhigher prevalence of mixed patterns (7/20) wasobserved compared to baseline HUT; this wasassociated with a decrease (11/20) of vaso-depressor responses (table 1).

FOLLOW UP DATADuring follow up, patients were instructed torecord every syncopal and near-syncopalepisode (defined as lightheadedness whichrequired the patient to lie supine to abort syn-cope, or forthcoming syncope aborted byhealth professionals or trained personnel) andto contact the referral physician as soon aspossible in case of symptom recurrence.Nineteen patients were followed up to 15 (3)months (range 11 to 24), 18 on metoprololand one on clonidine. No syncopal episodeshave been reported; near-syncopal episodeshave occurred in four patients, although to adramatically lesser extent than in the year pre-ceding baseline HUT (table 3). No with-drawals occurred during the follow up periodbecause of treatment related side effects.

DiscussionThe treatment of "malignant vasovagal syn-drome" is still controversial, mainly because ofa lack of controlled trials. Controlled studiesmay be difficult to carry out in patients withonly sporadic syncopal events; on the otherhand, placebo treatment is unacceptable inseverely symptomatic patients, such as ourstudy population, especially when effectivetreatment may be identified by provocativetests. Tilt up guided treatment may be veryhelpful in assessing the effectiveness of treat-ments to prevent syncope recurrence in highrisk subgroups."2 17 20

In our study, we evaluated the efficacy ofmetoprolol and clonidine in a randomised,double blind, crossover manner.

ACUTE PHASEThe results confirm that metoprolol is veryeffective in preventing syncope in these highlysymptomatic patients, whereas clonidineseems less effective. However, we wouldemphasise that clonidine should not be con-



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sidered to be ineffective; in fact, 10 patientshad a prolongation of time to syncope at HUTon clonidine, and in eight patients severesymptomatic hypotension occurred but wasnot followed by syncope. These results are inagreement with the findings of Fitzpatrick etal,8 who showed that time to syncope was pro-longed in a randomised trial of clonidine,atenolol, scopolamine, and placebo. In thisstudy, clonidine and scopolamine were moreeffective than atenolol, which shortened timeto syncope. Some important differences, how-ever, must be noted. The number of persistentpositive HUT tests was 6/13 for clonidine andscopolamine, 8/13 for atenolol, and 9/13 forplacebo. This is a much poorer response thanin our study population, which appears to be a"sicker" population from the point of view ofclinical presentation (in Fitzpatrick's study theaverage rate of syncopes was 3 (SD 4) perannum).As pointed out by Fitzpatrick et al,8 the

lipophilic characteristics of metoprolol may beof paramount importance compared toatenolol when considering central P blockingeffects. In fact, there is growing evidence that/3 blockers have central serotonin blockingproperties.2' 22 Recent research has shown thatthe pivotal event of neuromediated hypo-tension-sympathetic withdrawal-may beinduced by both intracerebral and systemicadministration of serotonin.2324 Following thisconcept, Grubb and Kosinski have treatedpatients with refractory neurocardiogenic syn-cope with serotonin reuptake inhibitors-flu-oxetine and sertraline hydrochloride-withbeneficial long term clinical effects.25 Thesefindings provide new insight in the pharmaco-dynamics of P blockers and may explain theobserved differences between metoprolol andatenolol. Moreover, one important point mustbe kept in mind: whereas the clonidine doseused by Fitzpatrick et a18 was similar to that inour study (0-742 (0 67) mg), our dose ofmetoprolol was clearly higher than that ofatenolol (50 mg) used in that study. Apartfrom any special pharmacokinetic-pharmaco-dynamic features of atenolol, its apparent inef-ficacy may reflect the lower dose given. Thedose of metoprolol used in our study was alsohigher than that reported by Sra et al4 5; in factthe success in abolishing syncope repro-ducibility assessed by HUT was higher in ourstudy (95%).

In a recent paper by Sra et al,4 however,only patients with cardioinhibitory responsewere considered, and this may represent a sub-group in which prevention of vasovagalepisodes may be more difficult. Moreover, theefficacy of P blocking agents was tested byrepeated HUT during steady state esmololinfusion. Although Sra et al have shown thatacute intravenous esmolol administration ishighly predictive of success with chronic meto-prolol treatment,5 this may have caused asmall underestimate of the overall efficacy of /3blockers, as observed in our patients.

Indeed, in a previous study with HUTrepeated during steady state oral metoprololadministration, Sra et al themselves have

reported an overall efficacy comparable to thatin our study: a negative HUT test on metopro-lol in 25/26 patients.'0 From this standpoint, itis conceivable that the prevention of the vaso-vagal reflex may be accomplished only withcomplete blockade of its afferent limb, whichmay require full adrenergic blockade over sev-eral days of consistent drug administration. Inthe same way, the relative weight of centralantiadrenergic and serotonin blocking effectsis much more highly expressed at high meto-prolol doses.

In a recent paper by Mahanonda et al,atenolol caused substantial improvement insymptom recurrence in a randomised con-trolled trial of 42 patients, when given at50-100 mg daily.26 In this study, 62% ofpatients had a negative HUT on atenolol com-pared to 5% on placebo; this is a much higherefficacy than the 38% reported by Fitzpatricket al.8 The likelihood of dose related differ-ences in HUT response on atenolol was notinvestigated by Mahanonda et al; nonethelessit may be a reasonable explanation for thesedifferences.26

It is interesting to note that drugs such asmetoprolol and clonidine may cause a changein the pattern of presentation of the vasovagalreflex, even when they are not effective atabolishing it. In fact three out of 14 patientswith vasodepressive HUT at baseline had amixed HUT on clonidine, in our experience.This could reflect spontaneous variability ofthe autonomic reflex, but it seems more likelyto be due to the drug effect on the sinus node,causing additional bradycardia if vagal hyper-activity occurs. This has also been shown formetoprolol in a case report by Dangovian et al,who observed conversion from a mixedresponse at baseline HUT to prolonged asys-tole during metoprolol treatment at 100mg/day.27 Such an adverse effect has neverbeen observed in our patients, irrespective ofthe response at baseline HUT. This observa-tion seems to underline the potentially harm-ful effect of antiadrenergic drugs whenunderdosed: if prevention of the vasovagalreflex does not occur, the pharmacologicaleffect may cause the vagal hyperactivity to bemuch more cardioinhibitory. This impliesthat, in order to reach the highest therapeuticindex these drugs should be prescribed athighest tolerated dose, since this offers theoptimal efficacy and the same risks as at lowerdoses.

CHRONIC PHASEDuring long term follow up, no syncopalepisodes occurred during a consistent evalua-tion time of 15 (3) (range 11 to 24) months.One might speculate that this reflects theimproved capability of patients to abort syn-cope, although most of our patients with trau-matic syncope had no prodromal symptoms,and sudden loss of consciousness occurredeither during clinical episodes or at baselineHUT. However, the striking observation thatrules out any improved capability to abort syn-cope and a possible "placebo" effect is thedramatic reduction in the number of near-syn-



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copes. This was clinically highly significant,and reflects prevention of triggering of thevasovagal reflex. This finding is clinically sig-nificant, since it confirms the value of "HUTguided treatment" as a reliable means of treat-ing patients with vasovagal syncope, due to thehigh reproducibility of tilt up testing.15-'7 Infact, the absence of symptom recurrence afterconversion to a negative HUT during pharma-cological treatment has been reported previ-ously by Grubb et al.20 Whether this is due tothe peripheral or to the central blocking effectsof metoprolol cannot be determined from ourdata.

Patient compliance during follow up wasvery good, which was probably related to thegreat improvement in quality of life. Early sideeffects during the acute phase were limited byprogressive dose titration, and only twopatients complained of mild fatigue on someoccasions during long term treatment.

CONCLUSIONSTreatment guided by head up tilting is a reli-able method of treating severely symptomaticand high risk patients with malignant vaso-vagal syndrome. Metoprolol is a very effectivelong term treatment for preventing recurrenceof syncope, and high doses are recommendedfor optimal efficacy; a careful dose titrationperiod helps to minimise drop out and sideeffects. Although there is strong pathophysio-logical support for its use, clonidine seemsclinically less effective than metoprolol.However, clonidine may be considered a use-ful alternative treatment when ,B blockade iscontraindicated, since beneficial effects areobserved in terms of time to syncope andseverity of hypotension. Further studies arenecessary to investigate the underlying mecha-nism of action of metoprolol in patients withmalignant vasovagal syncope.

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18 Natale A, Akhtar M, Jazayeri M, Jazayeri M, Dhala A,Blanck Z, et al. Provocation of hypotension during head-up tilt testing in subjects with no history of syncope orpresyncope. Circulation 1995;92:54-8.

19 Sheldon R, Rose S, Flanagan P, Koshman ML, Killam S.Risk factors for syncope recurrence after a positive tilt-table test in patients with syncope. Circulation 1996;93:973-81.

20 Grubb BP, Temesy-Armos P, Moore J, Wolfe D, Hahn H,Elliot L. Head-upright tilt-table testing in evaluation andmanagement of the malignant vasovagal syndrome. Am JCardiol 1992;69:904-8.

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26 Mahanonda N, Bhuripanyo K, Kangkagate C, Wansanit K,Kulchot B, Nademanee K, et al. Randomized double-blind, placebo-controlled trial of oral atenolol in patientswith unexplained syncope and positive upright tilt tabletest results. Am HeartJ 1995;130:1250-3.

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