Use of Intravenous Esmolol to Predict Efficacy of Oral Beta-Adrenergic Blocker Therapy in Patients with Neurocardiogenic Syncope

402 JACC Vol. 19, No. 2 February 1992:402-8 REPORTS ON THERAPY

Use of Intravenous Esmolol to Predict Efficacy of Oral Beta Adrenergic Blocker Therapy in Patients With Neurocardiogenic Syncope

JASBIR S. SRA, MD, VISHNUBHAKTA S. MURTHY, MD, PHD, MOHAMMAD R. JAZAYERI, MD, FACC, YUE-HUA SHEN, MD, PAUL J. TROUP, MD, FACC, BOAZ AVITALL, MD, PHD, MASOOD AKHTAR, MD, FACC Milwaukee, Wisconsin

The usefulness of esmolol in predicting the efficacy of treatment Irrespective of their response to esmolol infusion, all patients with an oral beta-adrenergic blocking agent was evaluated in 27 had a follow-up tilt test with oral metoprolol after an interval of consecutive patients with neurocardiogenic syncope. Seventeen ~5 half-lives of the drug. All 16 patients (100%) with a negative patients had a positive head-up tilt test response at baseline and 10 tilt test response during esmolol infusion had a negative tilt test patients required intravenous isoproterenol for provocation of response with oral metoprolol. Of the 11 patients with a positive hypotension. All patients were then given a continuous esmolol tilt test response during esmolol infusion, 10 (90%) continued to infusion (500 JLg/kg per min loading dose for 3 min followed by have a positive response with oral metoprolol. 300 Jlg/kg per min maintenance dose) and rechallenged with a It is concluded that in the electrophysiology laboratory, es head-up tilt test at baseline or with isoproterenol. molol can accurately predict the outcome of a head-up tilt Of the 17 patients with a positive baseline tilt test response, 11 response to oral metoprolol. This information may be helpful in continued to have a positive response to esmolol challenge. Sixteen formulating a therapeutic strategy at the initial head-up tilt test in patients (including all10 patients with a positive tilt test response patients with neurocardiogenic syncope. with isoproterenol) exhibited a negative response to upright tilt (JAm Coli Cardio/1992;19:402-8) during esmolol infusion.

Syncope, defined as transient loss of consciousness, is Methods responsible for up to of emergency room visits in the 3% all Study patients. Twenty-seven consecutive patients (18 United States (1). Because of the intermittent and episodic female and 9 male, 12 to 75 years of age) were included in nature of syncope, a definitive etiology is difficult to docu this study. All patients were referred for evaluation of ment and the use of noninvasive techniques is frequently unexplained syncope and had a positive head-up tilt test unrewarding (2). Recently, the head-up tilt test alone or with isoproterenol challenge has been used as a diagnostic response at baseline study (17 patients) or after intravenous method in a subset of patients with unexplained syncope administration of isoproterenol (10 patients). Twenty-six (3-6). In these patients, neurocardiogenic mechanisms seem patients had two or more episodes and one patient had one to be the underlying cause of syncope that may respond to episode of syncope in the preceding year. In addition, 20 treatment with an oral beta-adrenergic blocking agent (7). patients had a history of recurrent presyncope. Comprehen The future efficacy of such agents in patients with neuro sive physical examination, neurologic evaluation, surface cardiogenic syncope is difficult to predict at the initial tilt electrocardiogram (ECG) and electrophysiologic evaluation test. This study was designed to determine if intravenous did not identify the cause of syncope in any of these patients. esmolol, an ultrashort-acting cardioselective beta-blocker, Two patients had coronary artery disease. The mean ejec would help in assessing the response of patients with neuro tion fraction was 63.2% (range 45% to 73%). cardiogenic syncope to long-term oral beta-blocker therapy. Head-up tilt test. During the head-up tilt test, arterial blood pressure was monitored by means of an intraarterial cannula inserted percutaneously into the brachial or femoral artery. Each patient was tilted to 70° for a maximum of From Sinai Samaritan Medical Center, Milwaukee, Wisconsin. This study was presented in part at the 63rd Annual Scientific Session of the American 15 min. If the baseline tilt test response was negative, the Heart Association, Dallas, Texas, November 1990. patient was returned to the supine position and intravenous Manuscript received April30, 1991; revised manuscript received June 19, isoproterenol infusion was started at 1 JLg/min. The infusion 1991, accepted July 12, 1991. Address for reprints: Jasbir S. Sra, MD, Sinai-Samaritan Medical Center, rate was gradually increased until a 20% increase in heart 950 North 12th Street, P.O. Box 342, Milwaukee, Wisconsin 53201. rate was achieved and the head-up tilt test was repeated.

Table 1. Clinical and Electrophysiologic Characteristics of 27 Patients Syncope Results of HUT Pt Age (yr)/ Heart Provocation No. Gender Disease (min to provocation) Esmolol Metoprolol 58/M NSHD HUT (10) 2 40/F NSHD HUT (15) 3 40/M NSHD HUT (6) 4 33/F NSHD HUT (7) 5 15/F NSHD HUT (14) 6 75/F NSHD HUT(S) 7 58/F NSHD HUT and Iso (8) 8 73/F NSHD HUT and Iso (14) 9 37/F NSHD HUT and Iso (6.5) 10 40/F NSHD HUT and Iso (6) 11 12/M NSHD HUT and lso (5 .5) 12 35/F NSHD HUT and lso (9) 13 71/F NSHD HUT and lso (3) 14 43/M NSHD HUT and lso (6.5) 15 38/F NSHD HUT and lso (3 .5) 16 38/F NSHD HUT and Iso (8) 17 34/F NSHD HUT(6) + 18 39/F NSHD HUT(6.5) + + 19 55/M NSHD HUT(6) + + 20 42/M NSHD HUT(3) + + 21 20/M NSHD HUT(2) + + 22 22/F NSHD HUT (10) + + 23 72/F CAD HUT(7) + + 24 71/F NSHD HUT (10) + + 25 43/M NSHD HUT(5) + + 26 63/M CAD HUT(7) + + 27 54/F NSHD HUT(3) + + CAD = coronary artery disease; F = female; HUT = head-up tilt test; Iso = isoproterenol; M = male; NSHD = no structural heart disease; Pt = patient; - = negative head-up tilt test response; + = positive tilt test response.

A response was considered positive if significant arterial lenged with head-up tilt alone or with isoproterenol as hypotension in association with syncope or presyncope was before. All patients, irrespective of the results with esmolol, encountered. All patients with a positive tilt test response were then started on treatment with oral metoprolol. then received an infusion of esmolol at 500 p.g/kg for 3 min Twenty-six patients received metoprolol, 50 mg twice daily, followed by a maintenance dose of 300 JLg/kg per min. Five and one patient who weighed 46 kg received 25 mg twice minutes after the start of the infusion, patients were rechal- daily. After ;;::5 half-lives of the drug, the head-up tilt test

Figure 1. Mean arterial pressure at initi 150 p=NS 150 p<0.00001 150 p<0.004 ation (lnit.) and termination (Term.) of LLI tilt test at baseline tilt (left IX the head-up 125 panel), during esmolol infusion (middle ~ 125 125 Cl) panel) and with oral metoprolol (right LLI panel) in 16 patients who demonstrated a 100 100 f.-. ±11 ±13 negative response to the head-up tilt test ..JOI "l~I .. '" during esmolol challenge. The slight de ~ ~ 75 75 75 crease in arterial pressure during esmolol ffie 58 infusion is insignificant as compared with 1-"- I± 12 a: 50 50 50 the baseline level. Furthermore, none of o( the patients had syncope or presyncope z and in no patient was the decrease in ~ 25 25 25 arterial pressure during esmolol chal :& 0 ..._ ...__ .... _ lenge > 13 mm Hg. Similarly, arterial 0 0 pressure changes with metoprolol were I nit. Term. I nit. Term. lnit. Term. insignificant in comparison with the level BASELINE ESMOLOL METOPROLOL during baseline tilt. 404 SRA ET AL. JACC Vol. 19, No. 2 ESMOLOL IN NEUROCARDIOGENIC SYNCOPE February 1992:402-8

180 p<0.0007 180 p<0.03 180 p=NS

160 160 160

- 140 140 140 E Figure 2. Heart rate changes in the 16 pa .8' 120 120 tients who had a negative head-up tilt re sponse during esmolol infusion. A signifi 100 Ill 100 cant decrease in heart rate was seen at 1- I±18.. c baseline tilt, with one patient having asys a: 80 ±17MI 80 t: tole. In comparison, a minimal increase or c 60 60 no significant change was seen when the Ill same patients were rechallenged with a :t: 40 40 40 head-up tilt test during esmolol infusion and subsequently with oral metoprolol. Format 20 20 20 and abbreviations as in Figure 1.

0 0 0 I nit. Term. I nit. Term. lnlt. Term.

BASELINE ESMOLOL METOPROLOL was repeated under similar circumstances as before (that is, 15). The mean time to a positive head-up tilt test with at baseline study or after intravenous isoproterenol). isoproterenol provocation was 6.8 ± 3.2 min (range 2 to 15). Statistical analysis. The data are expressed as mean val Patients with a negative head-up tilt test response during ues ± SD. Paired and unpaired t test analysis was used to esmolol infusion. Changes in mean arterial pressure and compare heart rate and blood pressure within the same heart rate during the head-up tilt test at baseline, during group and between different groups. A p value < 0.05 was esmolol infusion and during oral metoprolol therapy are considered significant. depicted in Figures 1 and 2. A decrease in mean arterial pressure of 43 ± 13 mm Hg at baseline from the initial upright position to termination of the tilt test was signifi Results cantly greater than the change recorded during esmolol Patient characteristics. Table 1 shows the clinical and infusion (-5 ± 5 mm Hg; p < 0.00001 vs . baseline tilt) or electrophysiologic characteristics of the 27 patients included with oral metoprolol (I ± 7 mm Hg; p < 0.00001 vs. baseline in this study. Two patients had documented sinus pauses tilt) (Fig. 3). Furthermore, none of these patients had syn (3 .5 to 6 s duration), one had complete heart block and two cope or presyncope when rechallenged with head-up tilt had significant sinus bradycardia and syncope while being during esmolol infusion or oral metoprolol. Similarly, heart monitored in the hospital for earlier episodes of syncope that rate during baseline tilt decreased in all patients except two, had occurred outside the hospital. with Patient 5 having asystole (Fig. 4). A decrease in heart Seventeen patients had a positive baseline head-up tilt rate of 23 ± 21 beats/min at baseline tilt was significant in test response and 10 required intravenous isoproterenol (I to comparison with the change during esmolol infusion (8 ± 13 3 pg/min, mean 1. 7) for provocation of hypotension and beats/min; p < 0.0004 vs. baseline tilt) and during oral syncope or presyncope. The mean time to a positive head-up metoprolol therapy (4 ± 14 beats/min; p < 0.0008 vs. tilt test response at baseline was 7.4 ± 3.4 min (range 2 to baseline tilt) (Fig. 3). w E a: +60 0 HUT, Baseline Q, +60 ;:) a HUT+ Esmolol .a ~ c; +40 - HUT + Metoprolol +40 (I) w :1: +20 w +20 Figure 3. Mean maximal changes in mean ar- a::e terial pressure (left panel) and heart rate (right A. E o CJ ... _ z 0 panel) in the 16 patients who demonstrated a c( negative head-up tilt (HUT) response during :! (I) -20 :1: -20 a::w (.) esmolol infusion. In comparison with baseline ~ CJ -40 w -40 tilt, insignificant changes in mean arterial pres- a::z -23±21 sure and heart rate are seen during esmolol and c( c( -60 -43±13 ~ -60 oral metoprolol challenge. z:t: a: ..___, ...___, c((.) -80 ...___, ...... _, 1- -80 p<0.0004 pzNS p < 0.00001 p < 0.01 w a: p

1 HC. A B - nl1111 ~-,--~.~------~-r~~ 150 125- 100 3 75 :z:3 50 a 25 TILT (•)= 70 0 TIME(')= +0.5 1 HR (bpm)= 80 ( Syncope ) Asystole : 9 seconds BP (mmHg)= 125/80 (Banllne)

D E F .. r rr-n 1+ I" ,. 1..--.v 150 125- 100 3 75 3:z: 50 a 70 TILT (•)= 70 70 70 25 - +15 TIME(')= +0.5 +15 +0.5 0 55 74 1 HR (bpm)= 63 75 110/70 BP (mmHg)= 110/80 120/85 115/75 (Eamolol) ( Metoprolol ) 50 mg Bid

Patients with a positive head-up tilt test response during Figure 4. Patient 5. Negative head-up tilt response to esmolol patients with a positive baseline infusion and oral metoprolol. From top to bottom, tracings represent esmolol infusion. Eleven lead V and arterial pressure. The heart a positive surface electrocardiographic 1 head-up tilt test response continued to exhibit rate (HR) and blood pressure (BP) at the initiation of head-up tilt are response during esmolol infusion. All of these patients depicted in panel A. At 14 min (panel B), cardiac asystole ensues, except Patient 17 continued to show a positive response lasting for 9 s. After resumption of the supine position and stabili when rechallenged with head-up tilt after an interval of ~5 zation of heart rate and blood pressure, a repeat head-up tilt test (panels C and D). oral metropolol. during esmolol infusion shows a normal response half-lives of tilt test response is seen after 3 days of oral changes from the Similarly, a negative Mean arterial pressure and heart rate metoprolol therapy (panels E and F). initial upright position to termination of the tilt test at baseline, during esmolol infusion and with oral metoprolol are shown in Figures 5 and 6. The magnitude of the decrease Similarly, differences in the decrease in heart at baseline tilt in mean arterial pressure at baseline tilt (-54 ± 22 mm Hg) (-27 ± 36 beats/min), during esmolol infusion ( -13 ± 25 was similar to that seen during esmolol infusion ( -40 ± beats/min) and with oral metoprolol ( -18· ± 26 beats/min) 12 mm Hg) and with oral metoprolol (-48 ± 20 mm Hg). were insignificant (Fig. 7).

150 p<0.00001 150 p<0.00001 150 p<0.00001 Ill a: ;:) 125 125 fl) 125 Figure 5. Mean arterial pressure changes fl) in 11 patients who continued to demon- Ill a: 100 100 100 98 strate a positive head-up tilt response Q..-.. ±19... I ±12I de- ..JOI during esmolol infusion. A significant c:z: crease in mean arterial pressure is seen at -E 75 75 75 baseline tilt, during esmolol infusion and ffiE ...... _. ,. I±10 57 with oral metoprolol. The broken line 50 49 a: 50 46 50 I±15 represents a patient who had a positive cC I±10 head-up tilt test response during esmolol z cC 25 25 25 infusion but a negative response with oral Ill metoprolol. Format and abbreviations as ~ in Figure 1. 0 0 0 I nit. Term. I nit. Term. I nit. Term. BASELINE ESMOLOL METOPROLOL 406 SRA ET AL. JACC Vol. 19, No. 2 ESMOLOL IN NEUROCARDIOGENIC SYNCOPE February 1992:402-8

180 p < 0.02 180 p<0.05 180 p<0.02

160 160 160

140 140 Figure 6. Heart rate changes in the 11 pa 1~ / 1~ / tients who continued to have a positive / head-up tilt test response during esmo1ol infu sion. Changes in heart rate at baseline tilt, during esmolol infusion and with oral meto 1:: 79r~/,"" 1:: U ±15 IM prolol were significant. Two patients had ±48 ±29 asystole at baseline tilt and with oral meto 60 60 53 ±29 prolol. One of these patients also had asystole 40 40 on esmolol. The broken line is as defined in Figure 5. Format and abbreviations as in 20 20 20 I Figure I. 0 ...._. __ ....,_ I nit. Term. I nit. Term. I nit. Term.

BASELINE ESMOLOL METOPROLOL

There were no significant differences in age (44 ± 18 vs. therapy. Head-up tilt testing is increasingly being used as a 46 ± 17 years) or ejection fraction (62 ± 14% vs. 64 ± 13%) diagnostic tool in patients with unexplained syncope; previ between the groups with a negative or positive head-up tilt ous reports (4) have shown its high reproducibility rate in test response during esmolol infusion. such patients. In most patients, the phenomenon of neuro Baseline heart rate (72 ± 14 vs. 74 ± 10 beats/min) was cardiogenic syncope is characterized by prodromal symp similar between the groups with a negative and or positive toms of pallor, yawning, nausea and sweating; in others, loss head-up tilt test response during esmolol infusion. Similarly, of consciousness may be abrupt. We recently reported (7) on mean maximal changes in heart rate from the supine to the the long-term efficacy of oral beta-blocker and disopyramide initial upright position (21 ± 14 vs. 19 ± 19 beats/min) and therapy in patients with unexplained syncope and a positive from the supine to the upright position during 70° upright tilt head-up tilt test response. However, not all patients respond positioning (32 ± 19 vs. 28 ± 26 beats/min) did not differ to initial therapy and it may actually worsen the presenting between the two groups. Mean maximal changes in heart symptoms in some (Fig. 8). Because of the potential for rate during esmolol infusion from the supine to the upright serious injury and incapacitating symptoms, it is imperative position also did not differ between the two groups (11 ± 13 that an effective therapeutic strategy be identified at the vs. 12 ± 10 beats/min). initial test. Beta-blocker therapy and neurocardiogenic mechanisms of syncope. Using esmolol challenge, we identified two distinct Discussion groups with a favorable or unfavorable response to oral The head-up tilt test. This study highlights the usefulness beta-blocker therapy at the initial tilt test in our study. It is of esmolol in combination with the head-up tilt test in unclear how beta-blockers prevent hypotension and brady predicting patient response to long-term oral beta-blocker cardia in patients with neurocardiogenic syncope. Several w E a: +60 r::::J HUT, Baseline a. +60 ~ ~ HUT + Esmolol .a ~;+40 -HUT+ Metoprolol +40 U) w :::1: +20 w +20 Figure 7. Mean maximal changes in mean ar a: E terial pressure (left panel) and heart rate (right a._,_ E o z 0 panel) in the 11 patients who continued to "cc demonstrate a positive head-up tilt (HUT) re ~ U) -20 :::1: -20 a::w (J sponse during esmolol infusion. Changes in w" -40 w -40 mean arterial pressure and heart rate at base li:z ... line tilt, during esmolol infusion and with oral cc cc -60 cc -60 metoprolol are significant and almost of the a: -27±36 z:::t -48±20 same magnitude. Format as in Figure 3. cc(J -80 -54± 22 ... -80 w a: :::E -100 ....._____...... ___. cc-w 100 ....._____...... __. p < 0.02 p=NS :::1: p=NS p= NS p=NS p=NS JACC Vol. 19, No. 2 SRA ET AL. 407 February 1992:402-8 ESMOLOL IN NEUROCARDIOGENIC SYNCOPE

I. A 8 C +-+1I -+-tl1-+-1 I I I I -+---r------r---1r-

150 125- ~ 100 3 T5 3 .. ~ nLT (")= 70 70 70 .. - 0 nME (')= +0.5 +4.5 +5 (Syncope) Asystole : 11 seconds l HR (bpm)= 75 55 BP (mm Hg)= 150/85 110/50 (Baseline) 11. D E F +-~~- ~r-,~-- 11---r------

125- 100 3 MU 75 3 ~ .. ~ nLT (")= 70 .. - 70 70 0 nME (')= +0.5 +3 +3.5 (Syncope) Asystole : 11 .5 seconds r HR (bpm)= 52 58 BP (mmHg)= 125/85 100/50 (Esmolol) Ill. G H I

125- 100 3 T5 3 ~ ~ .. :z: G TILT(")= 70 70 70 .. - 0 nME (')= +0.5 +5.5 +8 (Syncope) Asystole : 13 seconds r HR (bpm)= 58 88 BP (mm Hg)= 120/85 90/80 ( Oral Metoprolol ) 50 mgm Bid

animal experiments (8-13) have suggested that propranolol Figure 8. Patient 25. Positive head-up tilt test response after esmolol can decrease the discharge frequency of mechanoreceptors infusion and oral metoprolol. Panel I shows the heart rate (HR) and tilt (A, B and are thought to initiate hypotension and bradycardia in blood pressure (BP) response during baseline head-up that C). At 5 min, the patient has 11 s of asystole. After resumption ofthe susceptible persons. The investigators reported that this supine position and stabilization of heart rate and blood pressure, effect of propranolol was maintained even with isoproteronol the patient is rechallenged with esmolol and the head-up tilt test is and during increased left ventricular end-diastolic pressure repeated (panel 11). Cardiac asystole again ensues at 3.5 min (F). when maximal mechanoreceptor activity was demonstrated. After 5 days of oral metoprolol therapy, the tilt test is repeated as recently demonstrated (14) a significant increase in before (panel Ill). As depicted, the patient becomes syncopal and We cardiac asystole again ensues 6 min after the start of the head-up tilt epinephrine concentrations with little or no change in nor test. epinephrine levels at the time of tilt-induced hypotension in patients with neurocardiogenic syncope. Echocardiographic data from our laboratory (15) have also suggested that a clear. All patients with a positive head-up tilt test response marked increase in left ventricular fractional shortening with isoproterenol had a negative response during esmolol along with a decrease in left ventricular systolic volume infusion. However, no other significant differences were always preceded the onset of hypotension in these patients. demonstrated between the two groups. Significant bradycar From these observations, it is thus conceivable that beta dia and asystole in some patients and hypotension preceding blockers by their negative inotropic effect may at least bradycardia in the majority of the patients during the base partially inhibit the mechanoreceptor activity that is trig line positive tilt test response were seen in both groups of gered by ventricular deformity and stretch. patients (Fig. 7 and 8). Baseline supine heart rate and mean Sixteen patients had a negative head-up tilt test response maximal changes in heart rate from the supine to the upright during esmolol infusion and 11 patients continued to show a position at baseline tilt and with esmolol were similar be positive response to upright tilt during the infusion. The tween the two groups. underlying reason for these interpatient differences is un- Because the esmolol dose was titrated according to body 408 SRA ET AL. JACC Vol. 19, No. 2 ESMOLOL IN NEUROCARDIOGENIC SYNCOPE February 1992:402-8 weight, variations in dose could not have accounted for the treatment strategies could be considered. Otherwise, these differences in response. Furthermore, all patients who re patients should be closely monitored while taking oral me quired isoproterenol for provocation of hypotension and toprolol because the long-term clinical efficacy of beta syncope after a negative baseline head-up tilt test response blockers under these circumstances is not clear. had a negative response with esmolol and oral metoprolol. These observations suggest that hypersensitivity of the We are indebted to Barbara Alexander and Brian Miller for their valuable help mechanoreceptors rather than the increased adrenergic tone in preparation of the manuscript. may determine which patients will respond favorably to beta-blockers. Head-up tilt response to esmolol and metoprolol. Esmolol quite accurately predicted the outcome of oral metoprolol References therapy in our patients. In contrast, intravenous metoprolol I. Stults BM, Gandolfi RJ . Diagnostic evaluation of syncope. West J Med at the initial tilt test has been ineffective in predicting the 1986;144:234-8. response to oral beta-blockers in patients with neurocardio 2. Silverstein MD, Singer DE, Mulley AG, Thibault GE, Barnett GO. genic syncope (16). This discordant response of patients Patients with syncope admitted to medical intensive care units. JAMA 1982 ;248: 1185-9. receiving intravenous metoprolol or esmolol may be due to 3. Abi-Samra F, Maloney JD, Fouad-Tarazi FM, Castle LW. The usefulness several factors. Metoprolol is a lipid-soluble beta-blocker of head-up tilt testing and hemodynamic investigations in the work up of with a large volume of distribution (that is, 4.2 ± 0. 7 syncope of unknown origin. PACE 1988;11:1202-14. liters/kg) (17,18). After intravenous administration, its initial 4. Fitzpatrick A, Sutton R. Tilting towards a diagnosis in recurrent unex plained syncope. Lancet 1989;1:658-60. distribution may be favored to tissues with a high blood flow 5. Waxman M, Yao L, Cameron DA, Wald RW, Roseman J. Isoproterenol and lipid content. This may cause a delay in the development induction of vasodepressor type reaction in vasodepressor-prone persons. of an adequate degree of beta-receptor blockade in some Am J Cardiol1989;63 :58-85. tissues. A sevenfold interpatient variation 6. Almquist A, Goldenberg I, Milstein S, et al. Provocation of bradycardia in plasma levels of and hypotension by isoproterenol and upright posture in patients with metoprolol has been reported (19). These characteristics of unexplained syncope. N Engl J Med 1989;320:346-51. metoprolol could account for the variable reported results. 7. Sra JS, Anderson AJ, Sheikh SH, et al. 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Reflex control of the also dissipate rapidly, as demonstrated by increased levels of peripheral circulation. Prog Cardiovasc Dis 1976;18:371-403. its metabolite ASL-8123, in a dose-dependent fashion 12. Thoren P. Role of cardiac vagal C-fibers in cardiovascular control. Physiol Biochem Pharmacoll979;86:1-94. (19,20). These properties make esmolol a more dependable 13. Thames M. Effect of d- and 1- propranolol on the discharge of cardiac and safe beta-blocker during the head-up tilt test. vagal C fibers. Am J Physiol 1980;238:8465-70. It is difficult to estimate the exact oral dose of metoprolol 14. Sra JS, Jazayeri MJ, Murthy VS , et al. Sequential catecholamine changes that will be effective in an individual patient. There is no during upright tilt: possible hormonal mechanisms responsible for patho genesis of neurocardiogenic syncope (abstr). JAm Coli Cardioll991 ;17: persistent interpatient correlation between the dosage of 216A. metoprolol and the therapeutic response (21) , and titration of 15. Shalev Y, Gal R, Tchou PJ , et al. Echocardiographic demonstration of the metoprolol dose , which might be useful in patients with decreased left ventricular dimensions and vigorous myocardial contrac tion during syncope induced by head-up tilt. J Am Coli Cardiol 1991 ;18: hypertension or angina, may not be practical in patients with 746-51. neurocardiogenic syncope. However, 50 mg twice daily 16. Van Wyhe G, McKinnie J, Avitall B, et al . Unexpected discordance seems to be an adequate dose in patients with neurocardio between acute intravenous and long term oral beta blockade for control of genic dysfunction because results with this dose of oral neurocardiogenic dysfunction diagnosed during head-up tilt testing (abstr). Circulation 1989;80(suppl II):II-656. metoprolol correlated favorably with results with esmolol, 17. Metoprolol tartrate. Am Soc Hosp Pharm 1988;45:826-30. which was given at a very high dose. 18. Frishman WH. Clinical Pharmacology of the ~Adrenoceptor Blocking Conclusions. In the electrophysiologic laboratory, es Drugs, 2nd ed. New York: Appleton-Century-Crofts, 1984:13-26. molol can accurately predict the head-up tilt response to oral 19. Murthy VS, Hwang TW , Sandage B, Laddu A. Esmolol and the adren metoprolol. This information can be useful in formulating an ergic response to perioperative stimuli. J Clin Pharmacoli986;26:A27-35. 20. Turlapaty P, Laddu A, Murthy VS , Singh B, LeeR. Esmolol: a titratable appropriate therapeutic strategy at the initial head-up tilt test short-acting intravenous beta blocker for acute critical care settings. Am in patients with neurocardiogenic syncope. Patients with a Heart J 1987;114:866-85. negative head-up tilt test response can be safely treated with 21. Bengtsson C, Johnsson G, Regardh CG. Plasma levels and effects of metoprolol on blood pressure and heart rate in hypertensive patients after metoprolol. However, in patients who continue to demon an acute dose and between two doses during long-term treatment. Clin strate a positive response with esmolol challenge, alternative Pharmacol Ther 1975;17:400-8.