14th International Congress
THE "NEW FRONTIERS"
OF ARRHYTHMIAS 2000

Jan. 29 - Feb. 5, 2000
Marilleva, Trento, Italy

RT-79

Pharmacological pump for treatment of vasovagal syncope: is phenylephrine the right drug?

Antonio Raviele, Franco Giada, Aldo Bonso, Gianni Gasparini, Sakis Themistoclakis, Andrea Corrado.
Division of Cardiology, Umberto I Hospital, Mestre-Venice, Italy

Background

Vasovagal events, like many other autonomic nervous system disturbances, have a cyclic and unpredictable course with usually brief periods of symptom recrudescence (so-called “clusters”) alternated to sometimes very long periods of quiescience and asymptomatic status¹. Thus, a chronic therapy with drugs does not appear useful in the majority of cases and is often associated with important or intolerable side effects as well as poor patient compliance, especially in young people¹1. Moreover, prevention of vasovagal reaction usually requires high drug plasma levels at the time of event occurrence that are difficult to reach with a chronic oral administration¹. As a matter of fact, only occasionally drugs have proven to be effective in the few double-blind, randomized, placebo-controlled trials performed till now^2-6. It is also noteworthy that electrical treatment with pacemaker, even when effective, rarely leads to a complete elimination of symptoms⁷, because of the hypotensive effects of the vasodepressor reflex that is practically present in all subjects, generally precedes cardioinhibition and bradycardia and is not amenable for correction or reversion by cardiac pacing. For all these reasons, it seems logical and desirable to develop an implantable drug delivery system for treatment of vasovagal syncope¹. Such a device would allow the automatic “on demand” delivery of a bolus of a vasoactive drug, previously recognized to be effective and safe in preventing tilt induced syncope, possibly together with the activation of a sequential cardiac pacing.

The ideal agent for a drug delivery system should have the following properties: it should be fast-acting, to minimize as much as possible intervention delay to reach the goal of aborting syncope; it should have a short action duration, to eliminate or reduce side effects and to permit repeated drug infusions, if necessary¹; and, finally, it should be stable over time at body temperature and its effective dose should be contained in a small volume, to prevent frequent refilling of the drug reservoir¹.

Among the theoretically potential candidates, phenylephrine, an alpha-agonist agent with potent vasoconstrictor effect, currently used to treat hypotensive crises in the operating room and to asses baroreflex sensitivity after myocardial infarction^8,9, is probably the most appropriate drug for this application. Its action is almost immediate¹⁰, the half-life is 5 minutes¹¹ and the drug is safe and well tolerated at a recommended dosage of 0.5-1.0 mg (as bolus)^10-14. Finally, in sterile water for injection phenylephryne is stable for a long period of time (up to 84 days at 60°)¹⁴ and the effective dose may be concentrated in a small volume (1 ml of the drug preparation contains 10 mg of the active principle).

In order to establish the value of phenylephrine as pharmacological agent for a drug delivery system for treatment of vasovagal syncope, we have performed a pilot study in which the efficacy and safety of this drug in aborting tilt-induced syncope have been tested. Two previous studies have already suggested the potential usefulness of phenylephrine in preventing syncope during head-up tilt testing^15,16.