Beneficial Effects of Dextro-Amphetamine inthe Treatment of Vasodepressor Syncope

ARMANDO SUSMANO, ANNABELLE S. VOLGMAN, andTHOMAS A. BUCKINGHAM

From the Section of Cardiology, Department of Medicine, Rush-Presbyterian St. Luke's MedicalCenter, Chicago, Illinois

SUSMANO, A., ET AL.: Beneficial Effects of Dextro-Amphetamine in the Treatment of VasodepressorSyncope. Three patients with history of documented hypolension, near syncope, or syncope be/ore orafter the administration of isoproterenoi during head-up tilt table are reported. Severe bradycardia wasalso noted in one patient. AJl three patients responded to the administration of 2.5 mg of oral dextro-amphetamine 45 minutes prior to a repeat head-up tilt table study. The potent central and peripheraladrenergic agonist pharmacological properties o/this drug permitted the prevention of severe vasodepres-sor syncope in these patients. (PACE, Vol. 16. June 1993)

syncope, vasodepressor, dextro-amphetamine, head-up lilt testing

IntroductionVasodepressor syncope represents approxi-

mately 5%-10% of all forms of syncope'-^ and al-though in most instances has a benign outcome,it can be a frightening and dramatic event due tosudden and usually brief loss of consciousness.Morbidity from syncope induced trauma can besignificant, particularly in elderly patients,

Vasodepressor or vasovagal syncope can beprecipitated by a variety of psychologicalstresses,^'* drugs,^ as well as physiological fac-tors.^"" Neurally induced hypotension and brady-cardia,^ increased beta adrenergic hypersensitiv-ity,^" increased circulating levels of catechola-mines,^^ sudden changes in central volume,^^changes in vagal tone, or stimulation of ventricularmechanoreceptor'^"^^ are among the most com-mon cited mechanisms.

The recent introduction of the head-up tilt teststudy^"^"^" in evaluating patients with syncope hasadded a new and practical technique that can beused to assess the effectiveness of various drugsin the treatment of this condition.

Address for reprints: Armando Susmano, M.D., 1725 W. Harri-son St., Suite 1159, Chicago, IL 60612. Fax: (312] 942-5829.

Received October 27, 1992; accepted lanuary 4, 1993,

Beta blockers,^^ disopyramide,^^ scopolam-ine,^^ insulin,^'' ephedrine,^"^^ probanthine,^^and theophylline,^^ have been used with varyingresponses.

We recently had the opportunity to studythree patients with vasodepressor syncope inwhom an alpha agonist, dextro-amphetamine. waseffective in preventing the development of syn-cope during tilt table testing.

Case Report

Patient No. 1

Y.C. is a 74-year-old female with a history offainting for several decades. She was afraid ofcrowds or entering into large and enclosed areaswith many people where she would have a ten-dency to faint. Many years ago she was given acombination of amphetamine and barbiturate tocontrol her symptoms with apparent success.

While being examined in an ophthalmolo-gist's office chair about 1 month after cataract re-mova! she had a sudden loss of consciousnesswith no loss of pulse, lasting only few minutes andrecovered while placed in a supine position. Therewas no history of high blood pressure, diabetes,coronary artery disease, mitral valve prolapse,

PACE, Vol. 16 June 1993 1235

SUSMANO, ET AL.

smoking, or alcoholic intake. Laboratory data waswithin the normal limits. A baseline head-up tilttable study demonstrated a sudden drop in pres-sure with sinus bradycardia of 49 beats/min [con-trol 84 beats/min) 8 minutes after 60° tilt (Fig. 1).She experienced dry mouth, mild hyperventila-tion, was apprehensive, and had near syncopewith systolic blood pressure of 80 mmHg [140/72control). An electrophysiological [EP) study wasdone under local anesthesia through the rightgroin, using 6 French quadripolar catheters in theright atrium and in the right ventricle; the studyshowed no evidence of sinus or AV nodal diseaseor inducible tachycardias, A repeat tilt tahle studywas done immediately after EP studies with TEDstockings on. Again (as during baseline) she devel-oped hypotension bradycardia and near syncopeafter symptoms of dry mouth and nausea. Systolicblood pressure was 60 mmHg at the point [128/84mmHg control) after 8 minutes of tilt. AV pacingwas hegun at a rate of 100 beats/min only afterpatient had developed symptoms, bradycardia,and hypotension. The systolic blood pressure nor-malized within 3 minutes of the patient heingplaced in the supine position in both instances.Following this episode 10 mg of IV metoprolol wasgiven hut did not prevent the patient from devel-oping hypotension [80 mmHg systolic) mild drop

E 1SDE

SYNCOPE ' ,

9 12

- - T E D SIOCmxGS

Figure 1. Diagram of systolic blood pressure in patientY.C., at control and under different conditions produc-ing syncope during head-up tilt at 60°. Dextro-amphet-amine clearly prevents hypotension and syncope. Asimilar effect was documented in [wootherpatients(seetext}.

in heart rate (from 80 to 65 beats/min) and nearsyncope during head-up tilt. The following day arepeat tilt table study was done after 2.5 mg p.o. ofdextro-amphetamine was given. [Patient also hadTED stockings on as well.) Although there was amild drop in pressure while on a 60° tilt, with sys-tolic blood pressure of 95 mmHg and dry mouthwith mild hyperventilation, she did not experi-ence significant hypotension, bradycardia, or nearsyncope after 30 minutes of tilt as in the previoustwo studies prior to dextro-amphetamine adminis-tration,

Patient was discharged home on dextro-am-phetamine 2.5 mg p.o. daily. Ten months later shehad not experience any more episodes of syncopeon a routine dose of dextro-amphetamine.

Patient No. 2

T.I. is a 55-year-old Indian male who sufferedan episode of sudden death while at church onemorning. He was resuscitated by two physiciansthat were present who claim that the patient hadno palpable pulses and no spontaneous respira-tion. They administered CPR and he regained con-sciousness in a few minutes. After admission tothe hospital, all laboratories values were normalas was the chest X ray. An ECG revealed a normalsinus rhythm with nonspecific ST changes and in-verted T waves over the precordial leads but thesewere unchanged over a period of 3 years. A two-dimensional echocardiogram revealed mild con-centric left ventricular [LV) hypertrophy but it wasnormal otherwise. Twenty-four hour Holter moni-tor was normal and there was also a negative sig-nal-averaged ECC. Selective LV and coronary arte-riogram revealed normal coronary arteries with LVhypertrophy but no outflow obstruction. An EPstudy was performed, revealing normal sinusnode, AV nodal function and no inducible signifi-cant atrial or ventricular arrhythmias,

A tilt table study revealed presyncopal symp-toms with significant hypotension of 60/40 mmHg(control 110/64 mmHg) after 10 minutes of head-up tilt at 60° while on isoproterenol at 2 jig/minwith reproduction of his symptoms. He wasstarted on atenolol 50 mg/day and a head-up tilttest was repeated 3 days later on isoproterenol at2 |jLg/min revealing a mild and transient drop inblood pressure to 86/58 mmHg (control 120/70

1236 June 1993 PACE, Voi. 16

TREATMENT OF VASODEPRESSOR SYNCOPE

mmHg) not accompanied by symptoms or brady-cardia, and the test was interpreted as negative. Hewas placed on atenolol 50 mg/day, then reduced to25 mg/day due to severe tiredness. Patient thendeveloped marked impotence after 4 weeks oftherapy and it was discontinued after 8 weeks oftherapy. A repeat head-up test on December 7.1991 with 2.5-mg dexedrine 45 minutes prior tothe test failed to produce hypotension, bradycar-dia, or reproduction of presyncopal symptoms.

The patient was placed on long-term therapywith dextro-amphetamine 2.5 mg p.o. every day.His impotence has resolved and no side effect fromdextro-amphetamine has developed as of thiswriting.

Patient No. 3

I.W. a 70-year-old male, sustained a syncopalepisode while in his office, the day of his admis-sion to Rush-Presbyterian St, Luke's Medical Cen-ter. He had no preceding symptoms. He has hadone similar episode 8 and 12 years before. He hasbeen symptom free since his last syncopal epi-sode. He is known to have high blood pressure forsome time. A 24-hour Holter monitor revealed apremature atrial contraction and two runs of su-praventricular tachycardia, 5 and 11 beats each.There was no AV block or ventricular tachycardia.Chest X ray was normal. An ECC showed sinusbradycardia with a small Q wave in the inferiorleads and an inverted T wave in V4 through VB. Atreadmill exercise test was normal and the thal-lium scan revealed an abnormality in the inferiorwall with no reversible ischemia. Abdominal andcarotid ultrasound did not reveal any abnormali-ties. Selective coronary angiography showed dif-fuse intimal disease in the left anterior descendingwith a distal plaque of 70%. The obtuse marginalhranch had between 60% to 70% obstructing dis-ease. The right coronary artery was normal. Theleft ventricle had mild but diffuse hypokinesis. Anelectrophysiological study was normal with no in-ducible atrial or ventricular arrhythmias. A head-up tilt test with isoproterenoi produced markeddrop in the blood pressure to 88 mmHg (control166/90 mmHg) with reproduction of his symptomsand near syncope. A second study was done thefollowing day with similar results after isoprotere-noi with a significant fail in blood pressure to 74/

40 mmHg (control 140/52 mmHg). He was thenplaced on dexedrine 2.5 mg p.o., 45 minutes priorto a repeat tilt table test that failed this time toproduce a drop in blood pressure, after 30 minutesof head-up tilt during isoproterenoi infusion.

Discussion

Dextro-amphetamine (dexedrine)^^ is an am-phetamine with sympathomimetic effects: power-ful central nervous system stimulation with effectson alpha and beta peripheral receptors. It also haspressor effects as well as bronchodilating and re-spiratory stimulating effect. Cardiac output is gen-erally unchanged with little change in cerebralblood flow. A potent effect is depression of ap-petite.

The effect after an oral dose appears within30-60 minutes. In our three patients the hypoten-sive effect of head-up tilt table changes or the ef-fects of isoproterenoi were effectively counter-acted hy dexto-amphetamine and the near syncopeor syncope was prevented from developing. Al-though the central CNS effects are greater than itsperipheral action, this drug appears to have a sig-nificant activity in preventing syncope by its ef-fects on alpha receptor and, therefore, maintainingthe systolic pressure in the normal range and pre-venting its fall during tilt.

Vasodepressor syncope is a common occur-rence in patients with syncope. Although itsmechanism of action has not been completely ex-plained yet, it appears that the withdrawal or inhi-bition of normal peripheral vasoconstrictive activ-ity takes place as a primary phenomenon. A vari-ety of sympathomimetic drugs have recently beenused in the treatment of vasodepressor syncopebased on the hypothesis that adrenergic agonistactivity can prevent these episodes. Ephedrine,phenylephrine, scopolamine, ethiinephrine, the-ophylline, etc., have been used with various re-sults. Increased cholinergic activity and excessiveadrenergic stimulation of ventricular mechanore-ceptors can play a significant role in the pathogen-esis of vasodepressor syncope. It is for that reasonthat disopyramide, with its anticholinergic andnegative inotropic effect has heen used to treat thehypotension and bradycardia associated with up-right tilt.^"

Adenosine may be an important mediator in

PACE, Vol. 16 June 1993 1237

SUSMANO, ET AL.

tbe hypotensive bradycardia of patients with vaso-depressor syncope. Theophylline, with its adeno-sine receptor blockade properties, has also beenshown to prevent tilt induced vasodepressor syn-cope.^^ Althougb this therapy appears to be effec-tive over a short term, its long-term effects are notyet known, particularly the frequency of side ef-fects. Similarly, the side effects of beta blockerssuch as sexual dysfunction with impotence, aswith Patient No. 2, can preclude the beneficial ef-fects of long-term use.

Phenylephrine and alpha agonists bave notproven to be efficacious alone in patients with or-tbostatic hypotension, but when used in combina-tion witb monoamine oxidase inhibitors such astranylcypromine have been reported to be effec-tive in three patients.^'^ In diabetics, insulin mayproduce syncope by enhancing the hypotensiveeffect produced by an autonomie neuropathy ordysfunction witb altered vasoconstrictive re-sponses and may also inhibit the vasoconstrictiveresponse to alpha agonist (phenylepbrine) andtilting.^-"

Finally, ephedrine with low dose oral admin-istration may be effective in preventing vasode-pressor syncope during head-up tilt, possibly byblocking tbe cardioinbibitory and vasodepressorcomponents.

Our tbree patients bad more demonstrable se-vere hypotension than significant bradycardia,wbich occurred in only one patient. Therefore, thebeneficial effects of dextro-ampbetamine may wellbe related to its powerful central nervous systemstimulating properties, by counteracting tbe "vas-odepressor component" while baving only a mildblocking effect on the "cardioinhibitory compo-nent." Tbe mechanism of action of dextro-amphet-amine in this form of vasodepressor syncope willneed further investigation.

References

1. Kapoor WM, Karpf M, Wieand S. et al. A prospec-tive evaluation and follow-up of patients with syn-cope. N Engll J Med 1983; 309:197-204.

2. Manolis AS, Linzer M, Salem D. et al. Syncope:Current diagnostic evaluation and management.Ann Intern Med 1990; 112:850-863.

3. Engel GL. Psychologic stress, vasodepressor (vaso-vagal) syncope, and sudden death. Ann Intern Med1978; 89:403-412.

4. Linzer M. Varia I. Pontinen M, et al. Medically

Although idiosyncratic reactions had oc-curred and the side effects profile includes centralnervous, cardiovascular, and gastrointestinal sys-tems, the drug is safe wben used in relatively lowdoses (usually up to 5 mg two or three times perday for chronic use).

However, as with any other drug, side effectsand addiction may occur and close supervision isimportant to obtain the desired pharmacologicaleffects. Two of tbe patients have been on tbis ther-apy for almost a year and had not experienced anysyncope or untoward side effects with low doseintake of dextro-ampbetamine.

One patient [No. 1) had used the medicationfrequently but only for preventive purposes (suchas before going to a concert hall or expecting to bein the presence of large group of people) and hadnot experience any syncope.

In summary, the administration of low dosedextro-amphetamine in three patients was effec-tive in preventing tbe development of significanthypotension, bradycardia, orsyncopal episodes inthem. One patient who responded to treatmentwith beta blockers did not tolerate this medicationbut did respond to and tolerated dextro-amphet-amine. Since two of the patients bad only a bistoryof rare syncope, we are not certain at this timeabout the development of side effects or the long-term effectiveness of this drug. Although it will benecessary to accumulate further experience in alarger number of patients, it appears that based onthe effects and preliminary results obtained in ourpatients, dextro-amphetamine sbows promise forthe prevention and treatment of vasodepressorsyncope.

Acknowledgmeiil; The authors are very grateful to Ms. Lil-lian Linares for her secretarial assistance.

unexplained syncope: Relationship to psychiatricillness. Am J Med 1992; 92[Suppl; 1A);18S-25S.

5. Hanlon |I, Linzer M, MacMillan JP, et al. Syncopeand presyncope associated with probable adversedrug reactions. Arch Intern Med 1990; 150:2309-2312.

6. Weissler AM, Warren JV, Stes EH Jr, et al. Vasode-pressor syncope factor influencing cardiac output.Circulation 1957; 15:875-882.

7. Goldstein DS, Spanarkel M, Pitterman L, et al. Cir-

1238 June 1993 PACE, Vol. 16

TREATMENT OF VASODEPRESSOR SYNCOPE

culatory control mechanism in vasodepressor syn- 19.cope. Am Heart J 1982; 104:1071-1075.

8. Glick G, Yu P. Hemodynamic changes duringspontaneous vasovagal reactions. Am ] Med 1963;34:42-51. 20.

9. Almquist A, Gornick C, Benson DW. et al. Carotidsinus hypersensitivity: Evaluation of the vasode-pressor component. Circulation 1985; 71:927-936.

10. Perry JC, Garson A. The child with recurrent syn- 21.cope: Antonomic function testing and beta-adren-ergic hypersensitivity, J Am Coll Cardiol 1991; 17; 22.1168-1171.

11. Chosy IJ, Graham DT. Catecholamines in vasovagalfainting. J Psycho Res 1965; 9:189-194,

12. Lipsitz LA. Orthostatic hypotension in the elderly. 23.N EngI J Med 1989; 321:952-956.

13. Abbond FM. Ventricular syncope: Is the heart asensory organ? N Engl J Med 1989; 320;390-392.

14. Scheidt VW, Bohm N, Schneider B, et al. Gholiner- 24,gic baroreflex vasodilatation: Defect in heart trans-plant recipients due to denervation of the ventricu-lar baroreceptor. Am J Cardiol 1992; 69;247-252. 25.

15. Scherrer U, Vissing S, Morgan BJ, et al. Vasovagalsyncope after infusion of a vasodilator in a hearttransplant patient. N Engl J Med 1990; 322: 26.602-604,

16. Almquist A, Coldenberg IF, Milstein S, et al. Prov-ocation of bradycardia and hypotension by isopro-terenoi and upright posture in patients with unex- 27.plained syncope. N Engl J Med 1989; 320;346-351.

17. Calkins H, Kadish A, Sousa J, et al. Comparison ofresponses to isoproterenoi and epinephrine duringhead up tilt in suspected vasodepressor syncope. 28,Am ] Cardiol 1991; 67:207-209.

18. Raviele A, Gasparini G, Di Pede F, et al. Usefulnessof head-np tilt test in evaluating patients with syn- 29.cope of unknown origin and negative electrophysi-ologic study. Am | Cardiol 1990; 65:1322-1327.

Waxman MB, Yao L, Cameron DA, et al. Isoprotere-noi induction of vasodepressor type reaction invasodepressor prone persons. Am J Cardiol 1989;63;58-65.Ponsiglione G, Fish AF, Strasburger JF, et al. Heartrate and blood pressure response to uprigfit tilt inyoung patients with unexplained syncope. J AmColl Cardiol 1990; 16;165-170,Keinzle MG. Syncope; Mechanisms and manifesta-tions. Hospital Practice 1990; Dec. 15:77-88,Milstein S, Buetikofer J, Dunnigan A, et al. Useful-ness of disopyramide for prevention of upright tiltinduced hypotension-bradycardia. Am | Cardiol1990; 65:1339-1344.Abi-Samra FM, Maloney JD, Fouad FM, et al. Tbeusefulness of head up tilt testing in hemodynamicinvestigation in tbe work-up of syncope of un-known origin. PACE 1988; Il;12o2'-1214,Yamamoto M, Asayama K, Kanai M, et al. Effectsof insulin on vasoconstrit:tor responses to alphaagonist and tilting. Angiology 1990; 41:394-400.Janosik D, Holt D, Fredman C, et al. Efficacy of oralephedrine sulfate in preventing neurocardiogenicsyncope. Circulation 1991; 84(Suppl. fll:234.DiMarco |P, Garan H, Ruskin JN. Intracardiac elec-trophysiology in patients witb recurrent unex-plained syncope. Ann Intern Med 1981; 95;542-548.Nelson SD, Stanley M, Love CJ, et al. The auto-nomie and hemodynamic effects of oral theopbyl-line in patients witb vasodepressor syncope. ArchIntern Med 1991; 151:2425-2429,Goodman LS, Gillman A, The Pharmacologic Basisof Therapeutics. Fifth Ed. New York, MacMillanPublishing Co., 1975, p, 496,Itskovictz HD, Wartenburt A. Combined phenyl-epbrine and tranylcypromine for postural hypo-tension. Am Heart | 1983; 106:598-599.

PAGE, Vol. 16 June 1993 1239