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Malignant vasovagal syncope: a randomised trial of metoprolol and clonidine
  1. Green Lane Hospital,
  2. Auckland,
  3. New Zealand

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Sir,—In a recent article, Biffi et al concluded that treatment guided by head up tilting is a reliable method of treating severely symptomatic and high risk patients with malignant vasovagal syndrome.1 They also found metoprolol to be superior to clonidine treatment according to their protocol. Their “pharmacological test” comprised isoprenaline infusion in five progressive steps, from 1–5 μg/min at 80° head up tilt. The specificity of isoprenaline challenge with steep angles of head up testing has been questioned. Natale et alinvestigated the effects of both differing degrees of head up tilt and progressive rates of isoprenaline infusion in normal volunteers with no history of syncope or presyncope.2 Testing at a 70° angle with a low dose isoprenaline infusion provided an adequate specificity of 88%, this fell to 60% during 80° head up testing. Limiting test duration at 80° to 10 minutes would have reduced the false positive rate to 16%. Furthermore, increasing the dose of isoprenaline to 3 and 5 μg/min at 70° head up tilt resulted in positive tests in 28% and 56%, respectively, of normal volunteers at a mean time of 8.2 to 9.7 minutes. Kapoor and Brant reported a similar experience (65% positive tests) in two control groups, each of 20 people, with a protocol using 80° head up tilt for a maximum of 15 minutes and mean isoprenaline doses of 1.7 and 1.9 μg/min, respectively.3

My understanding of the reported results by Biffi et al is that at least 14 of the 19 “failures” during tilt testing on clonidine occurred during isoprenaline infusion. I appreciate that their duration of head up tilt was limited to 10 minutes during testing. However, the apparently better results reported in the metoprolol group (average dose 280 mg) might partially or completely represent protection from the false positive effects of isoprenaline, rather than an intrinsic advantage of β blockade.

The use of the term “malignant vasovagal syncope” also merits comment. The original description emphasised a prolonged asystolic response during head up tilt.4 The term has now been broadened to denote clinical characteristics (frequent syncope without warning and/or traumatic outcome). As a following article in the same issue reports,5 the term malignant may be more emotive than scientifically accurate and consensus on its appropriateness is overdue.


This letter was shown to the authors, who reply as follows:

The question about the sensitivity and specificity of pharmacological testing with isoproterenol in patients with neurocardiogenic syncope is old and debated. Although false positive results have been reported in two studies,1-1 1-2 several observations have confirmed the high specificity and reproducibility of isoproterenol testing.1-3-1-6 Moreover, the average isoproterenol infusion rate at syncope was 1.6 μg/kg/min in our study,1-7 which is well within the limit of “specificity” obtained by Natale et al,1-2moreover, no patient in our study developed syncope at infusion rates greater than 3 μg/kg/min either during baseline head up tilting or during the two treatment phases. Once again, this is clearly within the limits of specificity claimed in the paper by Natale et al.1-2 With respect to the second point, the occurrence of failures during clonidine treatment at isoproterenol infusion rates comparable to those at baseline head up tilting rules out any false positivity and confirms the intrinsic advantage of β blockade.

To substantiate our observation, we report here follow up data with respect to baseline head up tilting. According to Dr Smith’s view, one would expect a higher recurrence of symptoms in patient who fainted during isoproterenol testing compared with those who fainted under basal conditions. In our experience, among the 19 patients who responded to drugs, four had recurrent symptoms: two of 11 who fainted under basal conditions and two of nine who fainted during isoproterenol testing at baseline head up tilting (NS); the former had four near syncopes and the latter three near syncopes at follow up (NS). Thus, the response to isoproterenol testing may not be considered a false positive, nor may it represent a predisposing factor to the positive effect of β blockers.

No consensus has been achieved regarding the term malignant vasovagal syncope. Prolonged asystole has been reported by many authors, and in our series we observed sinus arrest up to 39 seconds. Although this may indeed raise emotive reactions, it is rarely a marker of serious outcome or poor prognosis as in the paper by Pentousis et al,1-8 nor is it reproducible as demonstrated by Dhala et al.1-9 On the contrary, severe injuries due to sudden hypotension without prodromes occurred in eight of our patients in the absence of significant bradycardia. We believe therefore that, in the absence of universally accepted definitions, the interpretation of malignancy based on syncope outcome is far less emotive than the mere observation of some degree of asystole.


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