Value of Head-Up Tilt Testing Potentiated With Sublingual Nitro lycerm to Assess the Origin of Unexp ained 1 Syncope Antonio Raviele, MD, Carlo Menozzi, MD, Michele Brignole, MD, FESC, Gianni Gasparini, MD, Paolo Alboni, MD, FACC, Giacomo Musso, MD, Gino Ldi, MD, Daniele Oddone, MD, Maurizio Dinelli, MD, and Roberto Mureddu, MD This study was undertaken to assess the value of sub- lingual nitroglycerin administration during u as a simple practical test for the diagnosis o P right tilt vasova- gal syncope. To this purpose, 235 patients with syn- cope of unknown origin and no evidence of organic heart disease (110 men, mean age 52 f 20 years) and 35 asymptomatic control subjects underwent head-up tilt testing with nitroglycerin challenge. Patients and subjects were tilted at 60” for 45 + 20 minutes; the ini- tial 45 minutes were without medication and the final 20 minutes after 300 pg of sublingual nitroglycerin. During the drug-free phase of the test, 59 patients (25%) and no controls had a positive response. After drug ad- ministration, a positive response (syncope in associa- I n recent years head-up tilt testing has gained great popularity as a means of diagnosing vasovagal syn- c0pe.l The reported sensitivity and specificity of head- up tilt without pharmacologic provocation range from 32% to 74% (mean 47%) and from 90% to 100% (mean 95%), respectively.2-g The addition of isoproterenol to head-up tilt increases the test sensitivity up to 87%,‘O but decreases its specificity to values between 55% and 100% (mean 76%).6,1o-” This has prompted the use of other drugs as provocative agents during upright tilt.14-16 In a previous study,16 we reported on the usefulness of nitroglycerin infusion in conjunction with head-up tilt; the test proved to be more sensitive and feasible than the isoproterenol test, and equally specific, but the protocol used was quite complicated and time-consuming.16 The aim of the present study was to assessthe diagnostic val- ue of a new simplified, more rapid and practical protocol for the nitroglycerin test, consisting of sublingual ad- ministration of the drug after an initial period of con- ventional unmedicated head-up tilt. METHODS Study population: Two hundred thirty-five consecu- tive patients with syncope of unknown origin and no evi- dence of organic heart disease and 35 asymptomatic con- From the Division of Cardiology, Ospedale Umberto, I MestreVenice; Section of Arrhythmolog , Ospedale S. Maria Nuova, Reggio Emil- ia; Section of Arrhythmo ogy, Ospedali Riuniti, LavagnaGenoa; Divi- Y sion of Cardiology, Ospedale Civile,, Cento-Ferrara; and Section of Arrhythmology, Ospedale Civile, Imp&rip, Italy. Manuscript received February 14, 1995; revised manuscript received and accepted May 22, 1995. Address for reprints: Antonio Raviele, MD, Divisione di Cardi- ologia, Ospedale Umberto I, 30174 Mestre (Venezia), Italy. tion with sudden hypotension and brad cardia) occur- red in 60 patients (26%) and in 2 contra s (6%), where- T as an exaggerated or false-positive response (minor or different symptoms in association with slowly increas- ing hypotension alone) was observed in 33 patients (14%) and in 5 controls (14%). We conclude that the sublingual nitroglycerin head-up tilt test is a useful tool to unmask the vasovagal origin of unexplained syn- cope in dition o r tients without organic heart disease. The ad- nitroglycerin to upright tilt allows the positive rate of passive tilting to be doubled (5 1% vs 25%) while maintaining a high specificity (94% vs 100%). (Am J Cardiol 1995;76:267-272) trol subjects were included in the study. Of the 235 patients, 110 were men (47%) and 125 were women (53%). The mean age (+ SD) was 52 + 20 years (range 12 to 86). The mean number of syncopal episodes per patient (+- SD) was 5.1 + 8.2 (range 1 to 98, median 3) and the reported duration of symptoms ranged from 1 to 480 months (mean +- SD 57 + 87, median 24). Loss of consciousness was recurrent in most patients (179,72%). Patients were diagnosed as having unexplained syn- cope if no cause was detected after a standardized diag- nostic evaluation including careful history and physical examination, full neurologic assessment, routine labora- tory tests, supine and orthostatic blood pressure deter- minations, 1Zlead surface electrocardiography, bilateral bedside and upright carotid sinus massage, a minimum of 24-hour Holter monitoring and echocardiography. Other cardiac and neurologic investigations, such as exercise stress testing, electrophysiologic study, angiog- raphy, electroencephalography, Doppler flowmeter of neck vessels, and computerized axial tomography of the head were performed only when clinically indicated. The protocol used for atrial and ventricular stimulation and the abnormalities regarded as exclusion criteria from the study have been previously described.4,16 Of the 35 control subjects, 18 were men (51%) and 17 were women (49%). The mean age (+ SD) was 54 + 19 years (range 20 to 82). All control subjects were ap- parently healthy and had no history of syncopal or pre- syncopal episodes during their lifetime. They were re- cruited from outpatient medical clinics and were matched for age with the patients. Head-up tilt test with sublingual nitroglycerin provoca- tion: After giving informed consent, all patients and con- trol subjects underwent head-up tilt testing with sublin- gual nitroglycerin provocation. ARRHYTHMIAS & CONDUCTION DISTURBANCES/SUBLINGUAL NlTROGlYCERlN HEAD-UP TILT TEST 267
Transcript
Value of Head-Up Tilt Testing Potentiated With Sublingual Nitro lycerm to Assess
the Origin of Unexp ained 1 Syncope Antonio Raviele, MD, Carlo Menozzi, MD, Michele Brignole, MD, FESC,
This study was undertaken to assess the value of sub- lingual nitroglycerin administration during u as a simple practical test for the diagnosis o P
right tilt vasova-
gal syncope. To this purpose, 235 patients with syn- cope of unknown origin and no evidence of organic heart disease (110 men, mean age 52 f 20 years) and 35 asymptomatic control subjects underwent head-up tilt testing with nitroglycerin challenge. Patients and subjects were tilted at 60” for 45 + 20 minutes; the ini- tial 45 minutes were without medication and the final 20 minutes after 300 pg of sublingual nitroglycerin. During the drug-free phase of the test, 59 patients (25%) and no controls had a positive response. After drug ad- ministration, a positive response (syncope in associa-
I n recent years head-up tilt testing has gained great popularity as a means of diagnosing vasovagal syn-
c0pe.l The reported sensitivity and specificity of head- up tilt without pharmacologic provocation range from 32% to 74% (mean 47%) and from 90% to 100% (mean 95%), respectively.2-g The addition of isoproterenol to head-up tilt increases the test sensitivity up to 87%,‘O but decreases its specificity to values between 55% and 100% (mean 76%).6,1o-” This has prompted the use of other drugs as provocative agents during upright tilt.14-16 In a previous study,16 we reported on the usefulness of nitroglycerin infusion in conjunction with head-up tilt; the test proved to be more sensitive and feasible than the isoproterenol test, and equally specific, but the protocol used was quite complicated and time-consuming.16 The aim of the present study was to assess the diagnostic val- ue of a new simplified, more rapid and practical protocol for the nitroglycerin test, consisting of sublingual ad- ministration of the drug after an initial period of con- ventional unmedicated head-up tilt.
METHODS Study population: Two hundred thirty-five consecu-
tive patients with syncope of unknown origin and no evi- dence of organic heart disease and 35 asymptomatic con-
From the Division of Cardiology, Ospedale Umberto, I MestreVenice; Section of Arrhythmolog , Ospedale S. Maria Nuova, Reggio Emil- ia; Section of Arrhythmo ogy, Ospedali Riuniti, LavagnaGenoa; Divi- Y sion of Cardiology, Ospedale Civile,, Cento-Ferrara; and Section of Arrhythmology, Ospedale Civile, Imp&rip, Italy. Manuscript received February 14, 1995; revised manuscript received and accepted May 22, 1995.
Address for reprints: Antonio Raviele, MD, Divisione di Cardi- ologia, Ospedale Umberto I, 30174 Mestre (Venezia), Italy.
tion with sudden hypotension and brad cardia) occur- red in 60 patients (26%) and in 2 contra s (6%), where- T as an exaggerated or false-positive response (minor or different symptoms in association with slowly increas- ing hypotension alone) was observed in 33 patients (14%) and in 5 controls (14%). We conclude that the sublingual nitroglycerin head-up tilt test is a useful tool to unmask the vasovagal origin of unexplained syn- cope in dition o r
tients without organic heart disease. The ad- nitroglycerin to upright tilt allows the positive
rate of passive tilting to be doubled (5 1% vs 25%) while maintaining a high specificity (94% vs 100%).
(Am J Cardiol 1995;76:267-272)
trol subjects were included in the study. Of the 235 patients, 110 were men (47%) and 125 were women (53%). The mean age (+ SD) was 52 + 20 years (range 12 to 86). The mean number of syncopal episodes per patient (+- SD) was 5.1 + 8.2 (range 1 to 98, median 3) and the reported duration of symptoms ranged from 1 to 480 months (mean +- SD 57 + 87, median 24). Loss of consciousness was recurrent in most patients (179,72%).
Patients were diagnosed as having unexplained syn- cope if no cause was detected after a standardized diag- nostic evaluation including careful history and physical examination, full neurologic assessment, routine labora- tory tests, supine and orthostatic blood pressure deter- minations, 1Zlead surface electrocardiography, bilateral bedside and upright carotid sinus massage, a minimum of 24-hour Holter monitoring and echocardiography. Other cardiac and neurologic investigations, such as exercise stress testing, electrophysiologic study, angiog- raphy, electroencephalography, Doppler flowmeter of neck vessels, and computerized axial tomography of the head were performed only when clinically indicated. The protocol used for atrial and ventricular stimulation and the abnormalities regarded as exclusion criteria from the study have been previously described.4,16
Of the 35 control subjects, 18 were men (51%) and 17 were women (49%). The mean age (+ SD) was 54 + 19 years (range 20 to 82). All control subjects were ap- parently healthy and had no history of syncopal or pre- syncopal episodes during their lifetime. They were re- cruited from outpatient medical clinics and were matched for age with the patients.
Head-up tilt test with sublingual nitroglycerin provoca- tion: After giving informed consent, all patients and con- trol subjects underwent head-up tilt testing with sublin- gual nitroglycerin provocation.
ARRHYTHMIAS & CONDUCTION DISTURBANCES/SUBLINGUAL NlTROGlYCERlN HEAD-UP TILT TEST 267
The procedure was performed in the morning, after overnight fasting in a quiet, slightly darkened room out- side the electrophysiologic laboratory. No other investi- gations were undertaken on the same day. All cardioac- tive and vasoactive drugs were stopped for 25 half-lives before the study, with the exclusion of drugs that patients had been taking at the time of symptom presentation.
The tilt test was performed by means of an electroni- cally controlled tilt table with a footboard for weight- bearing. Restraining belts were placed at chest and thigh levels. Blood pressure, heart rate, and rhythm were con- tinuously monitored and recorded every 2 to 5 minutes, or more often if symptoms developed. Blood pressure was measured by means of an Ohmeda Finapress 2300 (Louisville, Colorado) photoplethysmographic device that provides continuous noninvasive beat-to-beat deter- mination of finger arterial pressure by the Pen&z volume- clamp method. An appropriately sized finger cuff was used and the hand was supported in a sling to keep the cuff at heart level in the upright position. No intravas- cular instrumentation was used during the test.
Head-up tilt was performed after an initial observa- tion with the patient in the supine position for 10 min- utes. The test consisted of 2 consecutive phases. During the first phase, participants were tilted at 60” for up to 45 minutes without medication, in accordance with the Westminster drug-free protocol5 (control phase). If syn- cope did not develop, participants received 300 pg of sublingual nitroglycerin during the second phase and continued to be tilted at the same angle for a further 20 minutes (pharmacologic phase). The end points of the test were positive or exaggerated response (see later) and completion of the protocol. If syncope occurred during the test, the tilt table was rapidly lowered to the supine position and the study was terminated. No complications
were encountered during performance of the test, and the induced hypotension and bradycardia always reversed in a few seconds or minutes after resumption of the supine position.
Definitions: Syncope was defined as sudden transient loss of consciousness with inability to maintain postur- al tone and with spontaneous recovery. Presyncope was defined as the complex of premonitory signs and symp- toms of imminent syncope (i.e., severe lightheadedness, severe weakness, transient graying of vision, or hearing loss) with difficulty in maintaining postural tone. A pos- itive response to sublingual nitroglycerin head-up tilt testing was defined as reproduction of the spontaneous syncope in association with hypotension, bradycardia, or both (decrease in systolic blood pressure >50% and de- crease in heart rate >30% of the maximal value observed in the upright position). During the control phase of the test, the occurrence of isolated hypotension was consid- ered sufficient to classify the response as positive. Dur- ing the pharmacologic phase, both hypotension and bradycardia of relatively rapid onset (occurring within 5 minutes) were required (all these 3 criteria were neces- sary) (Figure 1). This definition was derived from our previous experience with intravenous nitroglycerin test- ing16 and was chosen to reduce the number of false-pos- itive results and to be sure that symptoms after nitro- glycerin administration were really due to the triggering of a neural reflex and not to an artificial response because of an excessive drug-induced vasodilatation.
Thus, during the pharmacologic phase, the gradual development of symptoms that were usually minor and different from the spontaneous ones, as a consequence of a progressive and slow (occurring in >5 minutes) de- crease in blood pressure alone, without concomitant bradycardia or with only slight reduction in heart rate
Nitroglycerin 1
Syncope
1
z! 2?
105
88
rB 70 m
:a 2z.p
52
35
18
0
140
2 120 a InA ; I” 100
“0: o- 80 60 0 z 40
20
-- 0 40 42.5 45 47.5 50 52.5 55 57.5
MINUTES FROM ONSET OF TILT
FIGURE 1. Temporal changes in heart rate, systolic blood
ressure (u lack zone
per border of the E P and diastolic blood pressure (lower border of the black zone) in a patient with a positive response to the sublingual nitrog cerin head-up tilt test. Note t3: at syncope occurred at the ninth minute after nitro- glycerin administration coinci-
entally wrth a sudden and marked decrease in heart rate and blood pressure.
268 THE AMERICAN JOURNAL OF CARDIOLOGY@ VOL. 76 AUGUST 1, 1995
TABLE I Results of Head-Up Tilt Testing With and Without Sublingual Nitroglycerin
(~30%) after a very prolonged period of marked hypo- tension, was regarded as a nonspecific result and was called exaggerated response (Figure 2).
Statistical analysis: Statistical analysis was performed by using the chi-square test with Yates’ correction and the Student’s t test for paired and unpaired observations, as appropriate. A p value ~0.05 was considered statisti- cally significant.
RESULTS The results of the sublingual nitroglycerin head-up
tilt test both for patients and control subjects are sum- marized in Table I. During the initial unmedicated phase of the test, 59 patients (25%) had a positive response; 176 (75%) remained asymptomatic and were given nitro- glycerin sublingually. After drug administration, a pos- itive response occurred in another 60 patients (26% of the total population), giving a 51% total positive rate for the test; an exaggerated response was observed in 33 patients (14%) and a negative response in 83 (35%). If we consider only the 176 patients who underwent the pharmacologic phase of the test, the percentages of pos- itive, exaggerated, and negative responses after nitro-
glycerin administration are 34%, 19%, and 47%, respec- tively. Only 1 patient (0.4%) had important side effects (severe headache) after nitroglycerin. Sixteen of the 59 patients (27%) with positive response during the initial 45 minutes of the test and 4 of the 60 patients (7%) who became syncopal after nitroglycerin administration had an asystolic pause of >3 seconds with sinus arrest or third-degree atrioventricular block at the time symptoms developed. The duration of asystolic pause varied from 3 to 32 seconds (mean 13). The mean time to syncope in patients with positive response was 21 4 13 minutes (range 1 to 45) during the control phase and 7 f 8 min- utes (range 3 to 17) after nitroglycerin administration.
The hemodynamic variations observed during sublin- gual nitroglycerin head-up tilt test are listed in Table II.
At baseline, in the supine position, the values of sys- tolic and diastolic blood pressure and heart rate did not differ among patients with positive, exaggerated, and negative responses after nitroglycerin administration. During the drug-free phase of the test, patients with exag- gerated response had a gradual decrease in systolic and diastolic blood pressure (-16% and -6%, respectively) that was significantly greater than that observed in
FIGURE 2. Temporal changes in heart rate, systolic blood
ressure (u per border of the E P lack zone and diastolic blood pressure (lower border of he black zone) in a patient with exag erated response ta the su lmgual 1. nitrog cerin head-up tilt test. Note k at presynco occurred at the 11 r minute after nitroglycerin administra- tion and was preceded by a progressive and slow decrease in blood pressure associated with an increase in heart rate.
ARRHYTHMIAS & CONDUCTION DISTURBANCES/SUBLINGUAL NITROGLYCERIN HEAD-UP TllT TEST 269
TABLE II Changes in Heart Rate and Blood Pressure During Sublingual Nitroglycerin Test in Patients With Positive, Exaggerated, and Negative Responses
Positive Response (n = 60)
P Value*
Exaggerated Response (n = 33)
P Valuet
Negative Response (n = 83)
P Valuet
HR 1 (beats/min) Systolic BP 1 (mm Ha) Diastolic BP l‘(mm &J) HR 2 fbeots/minl Systolic BP 2 (mm Hg) Diastolic BP 2 (mm Hg) HR 3 (beats/min) Systolic BP 3 (mm Hg) Diastolic BP 3 (mm Hg) HR 4 (beats/min) Systolic BP.4 (mm Hg) Diastolic BP 4 (mm Hg)
69* 13 140 * 16
77* 12 86* 19
130 * 17 77* 12
106 LIZ 24 100229
68* 15 52 * 24 46* 10 33 i 8
NS NS NS NS NS NS NS
<o.ooo 1 <0.001 <0.0001
NS NS
70*11 , 148 zt 31
80* 16 84i 10
125 i 29 75* 15.
105 f 21 72 * 21 52 ic 15 92 zt 20 49 * 6 37 f 5
NS NS NS NS NS NS NS
<0.0001 <o.ooo 1
- - -
68* 12 140 * 21
78* 13 80* 16
132 * 23 78* 14
103 f 21 115i25
74* 17 - - -
NS NS NS NS NS NS NS
co.05 NS - - -
*Positive versus exaggerated response; iexaggerated versus negative response; zpositive versus negative response. Values are expressed CIS mean * SD. HR 1 and BP 1 = heart rate and blood pressure at baseline, in the supine position; HR 2 and BP 2 = heart rate and blood pressure at the end of the initial
45 minutes of unmedicated head-up tilt; HR 3 and BP 3 = heart rate and blood pressure at the time of the maximal heart rate value after nitroglycerin odmin- istration; HP 4 and BP 4 = heart rate and blood pressure at the time of test interruption because of syncope or severe symptoms.
patients with a positive response (-7% and O%, p <O.OOl and p ~0.05, respectively) and negative response (-6% and O%, p ~0.01 and p ~0.05, respectively). At the same time, a similar increment in heart rate occurred in the 3 categories of patients (+20%, +25%, and +18%, respec- tively, p = NS). After sublingual nitroglycerin, there was a further progressive decline in systolic and diastolic blood pressure and increment in heart rate in all groups of patients until the appearance of symptoms or com- pletion of the protocol. However, the reduction in sys- tolic and diastolic blood pressure was significantly more pronounced in patients with exaggerated response (-42% and -31%, respectively, vs -23% and -12% in patients with positive response, p ~0.001, and -13% and -5% in patients with negative response, p <O.OOOl). By contrast, the increase in heart rate was of similar extent in the 3 categories of patients (+25%, t-23%, and +29%, p = NS). When symptoms developed, patients with positive re- sponse had a considerable and prompt decrease in blood pressure (-54% for systolic values and -52% for dias- tolic values), whereas patients with an exaggerated re- sponse had a less marked and slower decrease (-32% and -29%, respectively, p ~0.001). Heart rate decreased rapidly and markedly only in patients with a positive response (-51% vs -12%, p cO.0001).
and after nitroglycerin administration. No control sub- ject with positive response had an asystolic pause of >3 seconds (p ~0.0001 in comparison with syncopal pa- tients).
Positive rate and specificity: The positive rate and specificity of the sublingual nitroglycerin head-up tilt test were 51% and 94%, respectively.
DISCUSSION
The mean age of patients with positive response was significantly lower than that of patients with exaggerat- ed or negative responses (48 f 19 vs 56 + 20 and 54 + 20 years, respectively; p ~0.05). Positive and exagger- ated responses prevailed in women (54% and 67%, respectively) and negative responses in men (53%), with differences statistically significant only for exaggerated responses (p cO.05).
Since the introduction of nitroglycerin into clinical practice as a pharmacologic agent for the treatment of angina pectoris, many investigators have described the possible occurrence of syncope in association with hypotension and bradycardia as a complication of the intravenous or sublingual administration of the drug.17-19 Although the exact pathophysiologic mechanism is not completely knovvn, it has been postulated2o that this harmful side effect is due to the triggering of an abnor- mal reflex arising from the heart similar to that respon- sible for a vasovagal reaction. Thus, we have proposed the use of nitroglycerin in conjunction with upright tilt as an alternative tool to the isoproterenol test for the diag- nosis of vasovagal syncope in patients with negative response to baseline head-up tilt.16 Initially, nitroglycerin was administered intravenously for this purpose.16 The results of the intravenous test have recently been report- ed and appear to be satisfactory: positive rate, 52%; specificity, 92%. l6
Only 2 control subjects (6%) had a positive response to the sublingual nitroglycerin head-up tilt test, both after drug administration, with a total positive rate of the test of 6%. An exaggerated response was observed in 5 con- trols (14%) during the pharmacologic phase. The remain- ing 28 subjects (80%) remained asymptomatic before
In this study, a new protocol with sublingual admin- istration of the drug has been evaluated. A significantly higher percentage of positive responses has been ob- served among the 235 patients with syncope of unknown origin than among the 35 asymptomatic control subjects, revealing a positive rate of 51% and a specificity of 94%. The identification rate of patients with vasovagal syn- cope exactly doubled in our study (51% vs 25%) with the addition of sublingual nitroglycerin to head-up tilt.’ These data suggest that the outcomes of intravenous and sublingual nitroglycerin head-up tilt tests are similar.
270 THE AMERICAN JOURNAL OF CARDIOLOGY@ VOL. 76 AUGUST 1, 1995
However, the sublingual test is preferable because it is faster and simpler, and thus more suitable for routine clinical use. It is noteworthy that the positive yield of the initial phase of passive head-up tilt in our patients is significantly lower than that previously observed by many investigators (25% vs 47% as a mean).2-6,8,g This is in accordance with other recent reports21 and probably re- flects a less strict selection of subjects who currently un- dergo head-up tilt testing.
Mechanism of action of nitroglycerin: Regarding the mechanism by which nitroglycerin acts as a provocative agent during tilt testing, it can be hypothesized that, because of its potent vasodilatory effects on the capaci- ty vessels, 22 the drug significantly increases the venous pooling already enhanced by upright posture., As a result there would be an important reduction in venous return, ventricular volume,23 and cardiac output, and a reflex increase in sympathetic tone, with consequent vigorous contraction of the heart around a relatively empty cavi- ty. This is presumed to lead, in predisposed patients, to a paradoxical activation of the ventricular mechanore- ceptors (C-fibers) with inhibitory afferents to cardiovas- cular brainstem centers, which are ultimately responsi- ble for vasodilatation, bradycardia, hypotension, and syncope.24,25
Methodologic aspects and limitations of the study: We used a period of 45 minutes for the initial phase of un- medicated head-up tilt, which is longer than that usual- ly used for the isoproterenol test.‘“12,2~28 However, 45 minutes corresponds to the mean time to syncope ?2 SD reported by Fitzpatrick et al5 for prolonged upright tilt- ing without drug challenge; Kapoor and Bra& sug- gested that such a test is more specific than a short-dura- tion head-up tilt followed by isoproterenol provocation.
We chose a tilting angle of 60” for the sublingual nitroglycerin test because this is the angle generally used for the long-duration unmedicated head-up tilt2-g we per- formed in the first phase of our protocol. It is likely that if we had used a steeper angle (70” to 90”), as is the rule during isoproterenol challenge,10-12,2G28 the positive rate of the sublingual nitroglycerin test would have been higher.2g However, the specificity of the test would prob- ably have decreased at the same time.29
We classified the responses to the sublingual nitro- glycerin test as positive, exaggerated, and negative. We utilized the term “exaggerated response” to define the occurrence, after nitroglycerin administration, of minor or different symptoms as a result of gradually increasing hypotension alone. We regarded this response not as sec- ondary to the triggering of a neural reflex, but rather as the manifestation of an excessive vasodilatation produced by nitroglycerin. The slow development of symptoms and the absence of significant concomitant bradycardia sup- port this hypothesis. We found that the percentage of ex- aggerated responses in our syncopal patients was similar to that in control subjects (14% vs 14%, p = NS). This is in contrast to the percentage of positive responses, which was significantly higher in the patient group (51% vs 6%, p cO.01). This seems to confirm our interpretation of ex- aggerated response as a false-positive or nonspecific re- sult. However, the clinical meaning of the exaggerated
responses is not yet well-defined, and one could regard these responses as a particular type of vasodepressor re- action. If we had included exaggerated responses among positive results, the positive rate and specificity of the sublingual nitroglycerin test would have been 65% and 80%, respectively.
Comparison with other pharmacologic head-up tilt tests: In this study, we did not compare the results of the nitro- glycerin test with those of the isoproterenol test. Such a comparison was performed in our previous study on the intravenous nitroglycerin test16 and showed a superiori- ty of this test over isoproterenol challenge: positive rate of 52% vs 25% with a similar specificity of 92%. How- ever, we cannot exclude the possibility that the results with sublingual nitroglycerin would have been different. We therefore believe that further studies are needed to clarify this point. Meanwhile, it is our opinion that the sublingual nitroglycerin test should be preferred over the isoproterenol test because it is safer and more tolerable. Indeed, in only 1 of our patients (0.4%) was the sublin- gual nitroglycerin test complicated by important side effects (severe headache). By contrast, the reported inci- dence of undesirable side effects during isoproterenol test is quite high (range 16% to 18%).‘!jJ6
Factors associated with positive response: We noted that the mean age of patients with a positive response was significantly lower than that of patients with an exag- gerated or negative response. Also, female sex appeared to be associated with a higher, although not significant- ly different, incidence of positive results. The reason why the sublingual nitroglycerin test is more sensitive in younger patients and in women is unknown.
Conclusions: In conclusion, on the basis of the pres- ent study, the sublingual nitroglycerin test is a fairly sen- sitive and specific means of provoking a vasovagal reac- tion in patients with syncope of an uncertain nature. It yields similar results to the intravenous nitroglycerin test but is more rapid and easier to perform. Thus, we rec- ommend its use in routine clinical practice as a valuable means of diagnosing vasovagal syncope. However, the real usefulness of the sublingual nitroglycerin test com- pared with other head-up tilt tests with pharmacologic provocation (in particular the isoproterenol test), as well as the clinical meaning of the exaggerated responses, needs to be evaluated in future trials.
Acknowledgment: We thank Sakis Themistoclakis, MD, for his assistance in collecting data.
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ARRHYTHMIAS & CONDUCTION DISTURBANCES/SUBLINGUAL NITROGLYCERIN HEAD-UP TllT TEST 271
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