N mediated hypotension is a common clinical problem that can be diagnosed by head-up tilt (HUT) table testing.1–3 In patients with neurally mediated syncope, sympathetic stimulation is believed to cause ventricular hypercontractility, which activates mechanoreceptor C-fibers located within the ventricles.4 Mechanoreceptor activation elicits the release of serotonin (5-HT), which impinges on 5-HT3 receptors on the afferent vagus nerve at the position of the right ventricle and propagates the stimulus to the dorsal vagal nucleus of the brain stem.4,5 This results in vagal overdrive and sympathetic withdrawal, which causes hypotension, bradycardia, and syncope.4 In animal models of neurally mediated syncope, 5-HT3 stimulation has been shown to cause bradycardia and hypotension.6–8 Paroxetine (SmithKline Beecham, Philadelphia, Pennsylvania), a selective serotonin reuptake inhibitor, has been evaluated in humans with 61.8% of patients being successfully treated (38.2% placebo group) after 1 month of therapy.9 However, paroxetine is believed to work indirectly by specifically increasing serotonin levels for 5-HT2 receptor stimulation rather than antagonism at the 5-HT3 receptor. We recently reported that granisetron, a 5-HT3 receptor antagonist, can inhibit the Bezold-Jarisch reflex (bradycardia and hypotension preceded by sympathetic stimulation) in a hemorrhagic rabbit model.10 Whether granisetron can prevent neurally mediated hypotension in humans undergoing HUT is unknown. The present study evaluates whether the specific 5-HT3 receptor antagonist granisetron can prevent neurally mediated hypotension in patients induced by HUT. • • • Patients with $2 episodes of syncope or presyncope of unexplained etiology who underwent diagnostic HUT and had a positive test for neurally mediated hypotension were evaluated for study inclusion. Patients were excluded from the study if they: (1) were on b blocker or selective serotonin reuptake inhibitors, (2) had prestudy systolic blood pressures (BP) ,90 mm Hg, (3) contraindications to isoproterenol or granisetron therapy, and (4) had an implanted permanent pacemaker. The study protocol was approved by the Institutional Review Board at Hartford Hospital, and informed consent was obtained from all patients. After an overnight fast and after cardioactive or vasoactive drugs known to cause hypotension or syncope were discontinued for 5 half-lives, HUT was performed between 8 and 10 A.M. to minimize confounding diurnal variation. After small gauge intravenous cannula placement, the patient was allowed to rest quietly in the supine position for 20 minutes. A physiologic recorder continuously monitored heart rate. BP was determined every minute by automatic cuff and confirmed with manual determinations when the patient became symptomatic. The tilt protocol consisted of a 70 upright tilt for 30 minutes. If the patient did not develop syncope or presyncope, the table was lowered to the supine position and an isoproterenol infusion was initiated and titrated upwards between 1 and 2 mg/min until a heart rate of 100 beats/min or an increase in heart rate of .25% from baseline occurred. Upon achieving the target heart rate, the isoproterenol infusion rate was maintained while the patient was retilted at 70 for 15 minutes. A positive response to upright tilt (with or without concomitant isoproterenol infusion) was defined as a sudden loss of consciousness or the development of impending faint in association with a decrease in systolic BP to ,70 mm Hg. Patients who developed a syncopal or presyncopal response during initial or isoproterenol HUT were given intravenous granisetron over 5 minutes. The first 9 consecutive patients received 40 mg/kg and the final 8 consecutive patients received 160 mg/kg of granisetron. The repeat HUT commenced 5 minutes after the granisetron infusion concluded. If isoproterenol HUT was used to induce syncope and/or presyncope, the full tilt protocol (initial first, then isoproterenol) was repeated to assess the impact of granisetron on the time to onset of syncope or presyncope, ability to prevent the recurrence of syncope or presyncope, and effect on hemodynamic (heart rate and BP) and electrocardiographic parameters. In the 160 mg/kg group, the QT and RR intervals were measured 4 minutes after the granisetron infusion concluded. Data are expressed as means 6 SD. A Student’s t test was used to compare continuous variables. A p value of ,0.05 was considered significant. Patient (n 5 17) demographics and clinical characteristics are summarized in Table I. In the total cohort, 47% of patients responded to granisetron therapy, whereas 44% and 50% of patients in the 40 mg/kg dose group and 160 mg/kg dose group had suppression of HUT induced syncope, respectively. The response From the Department of Pharmacy and Division of Cardiology, Hartford Hospital, Hartford; University of Connecticut School of Pharmacy, Storrs; University of Connecticut School of Medicine, Farmington, Connecticut; and Chinese University of Hong Kong, Shatin, Hong Kong. Dr. White’s address is: Drug Information Center, 80 Seymour Street, Hartford Hospital, Hartford, Connecticut 06102–5037. Email: cmwhite@harthosp.org. Manuscript received September 14, 1999; revised manuscript received and accepted December 8, 1999.
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Jun 1, 2003
Angelo Di Iorio + 9
Open Access