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(Circulation. 1995;92:54-58.)
© 1995 American Heart Association, Inc.

Articles

Provocation of Hypotension During Head-Up Tilt Testing in Subjects With No History of Syncope or Presyncope

Andrea Natale, MD; Masood Akhtar, MD; Mohammad Jazayeri, MD; Anwer Dhala, MD; Zalmen Blanck, MD; Sanjay Deshpande, MD; Anita Krebs, RN; Jasbir S. Sra, MD

From the Electrophysiology Laboratory, Milwaukee Heart Institute of Sinai Samaritan Medical Center and St Luke's Hospital, University of Wisconsin-Milwaukee Clinical Campus, Milwaukee, Wis.

Correspondence to Jasbir S. Sra, MD, 2901 W KK River Pkwy, #470, Milwaukee, WI 53215-3660.

	Abstract

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Background Head-up tilt test is increasingly being used to evaluate patients with syncope. This study was designed to evaluate the specificity of head-up tilt testing using different tilt angles and isoproterenol infusion doses in normal volunteers with no prior history of syncope or presyncope.

Methods and Results One hundred fifty volunteers were randomized to two groups of 75 each. In group 1, subjects were further randomized to have head-up tilt testing at a 60, 70, or 80 degree angle at baseline followed by repeat tilt testing during a low-dose isoproterenol infusion that increased the heart rate by an average of 20%. In group 2, after having a baseline head-up tilt test at a 70 degree angle for a maximum of 20 minutes, subjects were randomized to have a repeat tilt table testing at a 70 degree angle during a low-dose, 3 µg/min, or 5 µg/min isoproterenol infusion. In group 1, syncope or presyncope along with hypotension developed in 2 subjects during the baseline test at 60 and 70 degrees of tilt and in 5 subjects during tilting at 80 degrees. The addition of low-dose isoproterenol reduced the specificity minimally from 92% to 88% at both 60 and 70 degrees of tilt but substantially to 60% at an 80 degree angle. However, 6 of the 10 subjects with a positive test at an 80 degree angle had an abnormal response after 10 minutes of tilt testing. In group 2, using various isoproterenol doses with tilt table testing at a 70 degree angle, low-dose (mean infusion dose, 1.5±0.45 µg/min), 3 µg/min, and 5 µg/min isoproterenol infusions elicited an abnormal response in 1 (4%), 5 (20%), and 14 (56%) of the subjects, respectively. Using multiple logistic regression analysis, head-up tilt testing at an 80 degree angle (P=.01) or during 3 µg/min (P=.02) and 5 µg/min isoproterenol infusion rates (P<.001) was the most significant predictor of an abnormal response.

Conclusions Head-up tilt testing at a 60 or 70 degree angle with or without low-dose isoproterenol infusion provides an adequate specificity. Caution is needed, however, in interpreting the results if the head-up tilt test at 80 degrees is extended beyond 10 minutes or if high doses of isoproterenol are used.

Key Words: hypotension • tilt test • syncope

	Introduction

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Syncope, defined as a transient loss of consciousness, is a common medical problem.^{1 2} It has been recently shown that head-up tilt testing with or without an infusion of isoproterenol can identify patients with syncope in whom hypotension and bradycardia are likely to develop.^{3 4 5 6 7 8 9 10 11 12} Patients with unexplained syncope and positive response during the upright tilt test are known to have "neurocardiogenic syncope,"⁹ previously termed vasovagal syncope.^{3 4 5 6 7 8 9 10 11 12} However, hypotension and bradycardia also can be provoked during upright tilt testing in individuals with no history of syncope or presyncope, and use of isoproterenol as a provocative agent also has been questioned by Kapoor and Brant (see Reference 14). Thus, it is important that, in order to interpret the results correctly, the protocols used during the test are sufficiently specific before subjecting patients to long-term therapy or assessing the efficacy of various therapeutic modalities during double-blind, placebo-controlled trials. Therefore, we designed this study to prospectively compare the specificity of head-up tilt test using different tilt angles and different isoproterenol infusion doses in a large number of normal volunteers with no history of syncope or presyncope.

	Methods

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Population of Subjects
Of the 150 volunteers included in the study, none had a history of syncope or presyncope. The mean (±SD) age of the subjects was 41±15 years (range, 20 to 82); 78 were men and 72 were women. Many published reports have used various protocols, which include testing at baseline, during isoproterenol infusion alone, or head-up tilt testing at baseline followed by isoproterenol infusion.^{3 4 5 6 7 8 9 10 11 12 13} To have a reasonable comparison, however, age and sex distribution of the volunteers was chosen to match as closely as possible the patient populations in the adult literature in which head-up tilt testing was performed at baseline and during isoproterenol infusion in patients with syncope.^{6 7 8} None of the subjects had a history of cardiovascular disease or were taking any medications. Subjects were recruited from hospital medical personnel and through newspaper advertisements. A detailed history, comprehensive physical examination, and 12-lead EGC were obtained in each individual before they were entered into the study. Subjects were randomized to two groups of 75 each to assess various tilt test methods. There were no significant differences in the two groups with regard to age and sex distribution.

Head-Up Tilt Testing
The protocol was approved by the Institutional Review Board of the University of Wisconsin-Milwaukee Clinical Campus. After informed consent was obtained, head-up tilt testing was performed with the subject in a nonsedated, postabsorptive state. Blood pressure was monitored either through an intra-arterial cannula inserted percutaneously into a brachial or radial artery in group 1 subjects or by using a pneumatic cuff in group 2 subjects.

A peripheral venous access for the administration of medications was obtained by introducing a 20-gauge angiocath sheath. Readings from three surface ECG leads (I, II, and V₁), a blood pressure tracing where applicable, and time lines were simultaneously displayed on a multichannel oscilloscope. Hard copies were obtained on photographic paper at a speed of 25 mm/s.

Head-Up Tilt Testing in Group 1
The 75 subjects in this group were randomized to undergo head-up tilt testing at one of the three different tilt angles. Various tilt angles were chosen to systematically look at the effect of increasing orthostatic stress and ß-adrenergic stimulation, as previous studies have used tilt angles varying between 60 to 80 degrees with or without isoproterenol infusion.^{3 4 5 6 7 8 9 10 11} After the heart rate and blood pressure were measured at baseline and after the subject had been in the supine position for at least 15 minutes, the subject was then positioned upright on the tilt table at an angle of 60, 70, or 80 degrees, according to the randomization order, with a footboard used to bear the subject's weight. If syncope or presyncope with hypotension developed during the test, the table was lowered to the supine position; otherwise, tilt table testing was continued for a maximum of 20 minutes, after which the subject was returned to the supine position. To assess the effect of isoproterenol infusion in all subjects, irrespective of the results obtained during the baseline test and after the subject had been in the supine position for 5 minutes, intravenous isoproterenol was infused at a rate of 1 µg/min.

The infusion rate was gradually increased until the average heart rate was increased by at least 20% over baseline. Head-up tilt testing was then repeated at the same angle using the method described above.

Head-Up Tilt Testing in Group 2
The 75 subjects randomized to this group underwent head-up tilt testing at a 70 degree angle at baseline and were subsequently randomized to repeat tilt testing during various isoproterenol doses. The 70 degree angle along with various isoproterenol doses in this group was chosen for the following reasons. First, isoproterenol doses up to 5 µg/min have been used during head-up tilt testing in previous studies.^{12 14} Second, a previous study has shown a high incidence of positive response with tilt testing at an 80 degree angle during an isoproterenol infusion in normal control subjects.¹⁴ Third, the time to a positive test at a 70 or 80 degree angle (usually less than 15 minutes) has been shown to be significantly less than that during head-up tilt testing at a 60 degree angle (usually more than 20 minutes) in patients with syncope.^{5 6 7 8} It was thus hypothesized that if the abnormal responses observed during increasing ß-adrenergic stimulation at 70 degree tilt testing are significant, then the incidence of positive head-up tilt testing is likely to be even higher when performed at an 80 degree angle during isoproterenol infusion. In addition, compared with a 60 degree angle, ß-adrenergic stimulation along with head-up tilt testing at a 70 degree angle may cause at least similar or more abnormal responses.

After the heart rate and blood pressure were measured at baseline and after the subject had been in the supine position for at least 15 minutes, the subject was positioned upright on the tilt table at an angle of 70 degrees. If syncope or presyncope along with hypotension developed, the subject was lowered immediately to the supine position; otherwise, the test was continued for a maximum of 20 minutes, after which the subject was returned to the supine position. Irrespective of the results obtained at baseline, an intravenous isoproterenol infusion was started after the subject had been in the supine position for 5 minutes. Based on the randomization order, the subjects received an isoproterenol infusion either at a dose designed to increase average heart rate by 20% (low dose) or at doses of 3 µg/min or 5 µg/min. Head-up tilt testing was then repeated as described above.

To assess the reproducibility of the test, subjects randomized to undergo tilt table testing with a low dose or 5 µg/min isoproterenol infusion were then crossed over and underwent a repeat head-up tilt test 24 hours later. The head-up tilt testing was performed at a 70 degree angle at baseline, during low-dose isoproterenol infusion, and during 5 µg/min isoproterenol infusion in all subjects.

Definition and Diagnostic Criteria
Syncope was defined as a transient loss of consciousness not compatible with other altered states of consciousness. Presyncope was defined as any of various premonitory signs and symptoms of imminent syncope (for example, severe weakness or lightheadedness).^{2 6} A positive response to tilt testing, alone or in conjunction with an infusion of isoproterenol, was defined as one in which hypotension with or without bradycardia was found to be sufficiently severe to have caused syncope or presyncope.^{6 7 8}

Statistical Methods
The Fisher's exact test was used to determine the statistical significance of the results of tilt tests by using different isoproterenol dose levels and degrees of tilt. An overall analysis for a positive test was made by using the logistic regression model with indicator variables for degrees and dose. Mean changes in heart rate and arterial blood pressure were tested by use of the paired t test. The reproducibility of the results in the crossover study was assessed using the general linear models procedure. A two-tailed value of P<.05 was considered significant. The data were analyzed using the SAS System.¹⁵

	Results

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Effects of Increasing Orthostatic Stress
Among the subjects randomized to undergo head-up tilt testing at a 60, 70, or 80 degree angle, that is, group 1, there were no differences in age, sex distribution, isoproterenol infusion dose, supine baseline heart rate, or mean arterial blood pressure (Table 1). Sixteen subjects developed an abnormal response to head-up tilt testing (Table 2). In these 16 subjects, the mean time before the occurrence of a positive response was 9.7±4.8 minutes (range, 2 to 19). Eight subjects, including 6 during head-up tilt testing at an 80 degree angle, had an abnormal response after 10 minutes.

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of Subjects Undergoing Head-Up Tilt Table Testing at Different Angles

View this table: [in this window] [in a new window]   Table 2. Response to Head-Up Tilt Testing at Different Angles

The changes in mean arterial pressure (mean decline, 46±15 mm Hg; P<.001) and heart rate (mean decline, 33±18 beats per minute; P<.001) from the initial upright position to termination of the test were significant. Three subjects, including 2 tested at an 80 degree angle and 1 at a 70 degree angle at baseline, had cardiac asystole lasting from 12 to 32 seconds. Of the 16 subjects with a positive response, 2 had hypotension and presyncope at a 60 degree angle and 2 had hypotension and syncope during baseline head-up tilt testing at a 70 degree angle. During the infusion of isoproterenol, hypotension and presyncope developed in 1 additional subject during head-up tilt testing at 60 and 70 degree angles. None of the 4 subjects with abnormal responses during baseline testing at 60 or 70 degree angles developed hypotension or bradycardia along with syncope or with presyncope during isoproterenol infusion.

At an 80 degree angle, 10 subjects (40%) developed hypotension along with syncope or presyncope. Three subjects had an abnormal response during baseline head-up tilt testing alone, 5 subjects had an abnormal response during the isoproterenol infusion, and 2 subjects were positive both at baseline and during isoproterenol infusion.

Effects of Increasing ß-Adrenergic Stimulation
Among the 75 subjects randomized to undergo head-up tilt testing at a 70 degree angle during different isoproterenol doses, there were no differences in age, sex distribution, baseline supine heart rate, or mean arterial pressure (Table 3). Twenty-three subjects had abnormal responses to head-up tilt testing (Table 4); of these, 3 subjects had hypotension and presyncope during the baseline test. Hypotension along with syncope or presyncope developed in 1 subject during low-dose isoproterenol infusion, in 5 subjects during a 3 µg/min isoproterenol infusion, and in 14 subjects during a 5 µg/min isoproterenol infusion. None of the 3 subjects with a positive baseline head-up tilt test had an abnormal response during isoproterenol infusion. In the 23 subjects with abnormal responses to head-up tilt testing, the mean time before the occurrence of a positive response was 8.2±5.3 minutes (range, 2 to 18). The changes in mean arterial pressure (mean decline, 36.6±13.4 mm Hg; P<.001) and heart rate (mean decline, 29.4±15 beats per minute; P<.001) from initial upright measurements to that taken upon termination of the test were significant. Almost all patients during 5 µg/min isoproterenol infusion were extremely uncomfortable. The common side effects experienced were warmth, shakiness, palpitations, headache, nausea, and diaphoresis.

View this table: [in this window] [in a new window]   Table 3. Clinical Characteristics of Subjects Undergoing Head-Up Tilt Table Testing at Different Isoproterenol Infusion Rates

View this table: [in this window] [in a new window]   Table 4. Positive Response to Head-Up Tilt Testing at 70 Degrees During Different Isoproterenol Infusion Rates

Specificity of Different Protocols
The specificity of the baseline head-up tilt test was 92% when performed at 60 and 70 degree angles and 80% at an 80 degree angle. These differences were, however, statistically insignificant. The addition of a low-dose isoproterenol infusion reduced the specificity of the test minimally to 88% at 60 and 70 degree angles but substantially to 60% during 80 degree head-up tilt testing. With head-up tilt testing at a 70 degree angle, the specificity of the test during low-dose, 3 µg/min, and 5 µg/min isoproterenol infusion was 96%, 80%, and 44%, respectively. The differences in specificity between 3 and 5 µg/min (P=.02) and low dose and 5 µg/min doses of isoproterenol were highly significant (P<.001).

The positive response to a 5 µg/min isoproterenol infusion dose was highly reproducible. Twelve (86%) of the 14 subjects with an abnormal response during initial head-up tilt testing with a 5 µg/min isoproterenol infusion dose continued to have a positive test when tested 24 hours later, while 48% of the subjects had a positive response when they were crossed over from the low-dose isoproterenol group and tested using a 5 µg/min isoproterenol dose. During repeat tilt testing, only 2 subjects had abnormal response at baseline and during low-dose isoproterenol infusion. Both of these subjects had an abnormal response at baseline and low-dose isoproterenol infusion during initial tilt testing.

Using multiple logistic regression analysis, the most powerful predictors for a positive response during head-up tilt testing were 3 µg/min (P=.02) or 5 µg/min (P<.001) isoproterenol infusion doses and testing at a 70 degree angle and tilt testing at an 80 degree angle during a low-dose isoproterenol infusion (P=.01). Sex distribution or age under 40 or over 40 years did not predict the abnormal response during tilt testing.

	Discussion

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Head-up tilt testing has gained wide acceptance in the diagnosis of neurocardiogenic syncope. Because upright tilt testing at less than a 60 degree angle has been shown to be less sensitive,¹⁴ most laboratories use 60 to 80 degree tilt angles to provoke hypotension and bradycardia.^{3 4 5 6 7 8 9 10 11 12} Differences of opinion, however, remain regarding important factors such as tilt angle, duration of the test, and isoproterenol infusion. The present study provides data in a systematic fashion regarding the specificity of head-up tilt testing at different tilt angles and during various isoproterenol infusion rates in a large number of subjects with no history of syncope or presyncope. The main finding of this study was that the test maintained a high degree of specificity at 60 and 70 degrees of tilt with or without the infusion of low-dose isoproterenol. The specificity of the test was, however, significantly compromised at 80 degree tilt testing along with a low-dose isoproterenol infusion and during head-up tilt testing at 3 or 5 µg/min isoproterenol infusion rates at 70 degree tilt.

There are limited data in the literature on investigations using head-up tilt testing in normal subjects. The incidence of an abnormal response in studies involving a small number of control subjects in which only one protocol was used has ranged from 0% to 65%.^{6 14 16 17 18 19 20} In the study by Almquist et al,⁶ the incidence of a positive response to head-up tilt testing up to 10 minutes in duration at an 80 degree angle was 11%, while Kapoor and Brant¹⁴ reported the incidence of a positive result during upright tilt testing at an 80 degree angle during isoproterenol infusion (mean dose, 1.7 µg/min) as high as 45%. The mean time to a positive response in this study population was 29 minutes, which included 15 minutes of baseline head-up tilt testing. The discrepancy between these two reports can be explained by the different durations used for head-up tilt testing. Careful analysis of our data suggests that if the testing during an 80 degree angle in our subject population was terminated at 10 minutes, the incidence of positive response would have been only 16%, which is comparable to the results of the study of Almquist et al. Although the mean age (24 years) in the study of Kapoor and Brant was less than our study population and the reported series of patients with neurocardiogenic syncope, the positive response between this and our study (45% versus 40%) was comparable when the head-up tilt testing at 80 degrees was extended beyond 10 minutes.

The precise sequence of events leading to tilt-induced hypotension and syncope remains unclear, and several mechanisms including the possible role of Bezold Jarisch reflex in neurocardiogenic syncope have been proposed.^{21 22 23 24 25 26 27} The phenomenon of hypotension and bradycardia can also be seen clinically under circumstances such as fear, anxiety, hemorrhage, and during inferoposterior myocardial infarction or coronary catheterization in patients who may or may not have any previous history of syncope.^{28 29 30} Increasing orthostatic stress by increased peripheral pooling of blood and increased ß-adrenergic stimulation are likely to affect the results of head-up tilt testing. Higher tilt angles and isoproterenol doses up to 5 µg/min have been used to shorten the duration of the test. Data from the present study, however, suggest that after a critical point, increasing orthostatic stress, that is, tilting at an 80 degree angle or increasing ß-adrenergic stimulation, can compromise the specificity of the test. Many studies, especially when the head-up tilt testing was performed at 70 or 80 degrees, have shown that the mean time to positive test was 7 to 14 minutes; some studies, however, have also shown that the mean time to a positive test could be as long as 24 minutes, especially when 60 degree angle is used.^{3 19} Although the mean time to positive tilt in our study was also 8.2 to 9.7 minutes, depending on the protocol used, it is conceivable that the number of false-positives could have increased further if the test was extended beyond 20 minutes. This, in fact, may exaggerate the difference between 80 degree tilt and other angles.

An intriguing phenomenon seen in the present study was that only 2 (17%) of the 12 subjects with a positive test at baseline had an abnormal response during a low-dose isoproterenol infusion. The exact cause for this is unclear. Although reproducibility could account for this disparity, previous studies have shown a high reproducibility of the test when tilt testing was repeatedly performed at the same setting.^{8 16 31} Results of head-up tilt testing during a crossover from a low-dose to a 5 µg/min isoproterenol infusion and vice versa in the present study also showed a high degree of reproducibility of the test in regard to specificity. A complex interplay between ß-adrenergic stimulation, baroreceptor inhibition, and mechanoreceptor stimulation or some other unknown mechanisms could account for this. Further studies will be needed to address this issue. These data, however, suggest that in order to interpret the results correctly in patients with unexplained syncope, head-up tilt testing should be performed at baseline.

Conclusions
Data from the present study suggest that head-up tilt testing at 60 or 70 degree angle at baseline or during low-dose isoproterenol infusion can provide specificity ranging from 92% to 88%. Although results of the head-up tilt test need to be considered in light of the patient's history and other pertinent clinical findings, caution is needed in interpreting the results if head-up tilt testing at 80 degrees is extended beyond 10 minutes or if high doses of isoproterenol infusion rates are used during the test.

Received November 1, 1994; accepted January 10, 1995.

	References

Top Abstract Introduction Methods Results Discussion References

 

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