In a patient who presents with syncope of unknown origin, a thorough history can sometimes provide clues suggesting postural neurally mediated syncope or other forms of neurally mediated syncope, such as carotid sinus syndrome or micturition syncope. In a clinical setting, maneuvers such as head-up tilt table testing or carotid sinus massage are used to reproduce the patient’s symptoms and to produce typical hemodynamic derangements. Such a response to one of these tests has been shown to occur much more frequently in patients who suffer otherwise unexplained syncope than in healthy controls.1–5 The pathophysiology underlying postural neurally mediated syncope is still not fully understood.6,7 One model describes an exaggerated sympathetic reaction to relative hypovolemia countered by a vagal response which leads to the hemodynamic alterations associated with syncope. It would be plausible that in individuals susceptible to this type of reaction, carotid sinus stimulation might also elicit an exaggerated reflex response. However, there are studies that suggest that the autonomic response in patients susceptible to neurally mediated syncope is actually blunted8 or that there are subpopulations with a blunted or with an exaggerated response.9 Some studies have reported differences between patients who faint or have significant hypotension and/or bradycardia on HUT and those who have an exaggerated response to CSM. For example, Brignole et al. found that HUT is more often abnormal in those younger than 65 years while CSM positivity is more frequent in those with cardiovascular disease.10 Combining CSM and HUT may therefore enhance the diagnostic yield when testing patients with syncope of unknown origin.10,11 At the same time, several studies cite a significant overlap for abnormal CSM and HUT results.10–13 That would imply that people who suffer syncope during tilt testing are more likely to have an exaggerated response to CSM and vice versa. Such patients might have a common underlying pathology such as an exaggerated baroreflex response to a variety of stimuli. The studies that reported a concordance between HUT and CSM results mostly addressed a different question and reported this finding as an aside, or they involved few patients9,13 or selected patient populations.11,12 To see whether there is a significant overlap between an exaggerated CSM response and HUT outcome, we retrospectively analyzed the CSM and HUT results of 136 patients who were evaluated for syncope or near-syncope of uncertain origin at our institution and who underwent both tests. Methods Over a two-year period, a total of 1,222 HUT were performed in 880 patients at our institution. Patients were eligible for HUT if they had suffered one or more syncopal events or near-syncopal events not explained by a limited routine examination including a detailed history and physical, a 12-lead ECG, basic laboratory values, and 24-hour telemetry monitoring. Patients were not eligible for HUT if a cause for their complaints was apparent and likely after the above examinations. They were, however, not excluded on the basis of age or comorbidity. There were 136 patients who underwent both HUT and CSM, and they comprise our study population. All these patients were referred for HUT. CSM was performed in addition to the ordered test as a secondary procedure. Written informed consent was obtained from all subjects prior to HUT and CSM and the procedures were explained. The patients were studied while fasting or semi-fasting (last meal > 4 hours past); all studies were performed between 8 am and 6 pm. Bilateral CSM was performed prior to HUT in all patients. In each case, the patient was supine for 5 minutes preceding the test, and blood pressure and heart rate were recorded. Carotid sinus massage was performed with the patient supine by first auscultating over each carotid and ruling out the presence of carotid bruits. Then the left carotid sinus was massaged for 5 seconds while recording an electrocardiographic rhythm strip. Approximately one minute later, right carotid sinus massage was performed in a similar manner. Pauses between 1.6 seconds and 2.9 seconds, a drop in heart rate of at least 30% to less than 50 bpm, or the new onset of atrial fibrillation during CSM were considered indicative of mild carotid sinus sensitivity. Pauses equal to or above 3.0 seconds or symptomatic hypotension were considered indicative or carotid sinus syndrome. Following CSM, each patient was tilted upright to 60 degrees for 30 minutes. Blood pressure was monitored with an automatic cuff sphygmomanometer at baseline and once every minute during tilting. If the result of this tilt table test was negative, the patient was returned to supine position and isoproterenol was infused intravenously at a rate of 0.01–0.04 mg/kg to achieve an increase of 20% above the baseline heart rate. The tilt test was then repeated for up to 30 minutes. Electrocardiographic monitoring was carried out throughout the test. The outcome of HUT was considered abnormal and termed positive if a drop in systolic blood pressure of 20 mmHg (confirmed by manual measurements) was recorded and/or a drop in heart rate below 50/minute was noted, and the patient had symptoms of presyncope or syncope. Comparisons between the means of continuous variables were made using the unpaired, two-tailed t-test. Comparisons between groups (observed vs. expected frequencies for nominal variables) were made using Fisher’s exact test (two-tailed); for more than two conditions, the x2 test was used. A p value below 0.05 was considered significant. Numerical data are expressed as mean ± standard deviation. Results Patient characteristics. The 136 patients included in the analysis were similar to the total group of 880 patients who underwent a first HUT during the study period with regard to age (61 ± 18 vs. 61 ± 20 years); gender (44% female vs. 53% female; p = 0.06); and presenting symptom (71% presenting with syncope in both groups). All 136 patients included in the study underwent testing because of syncope or near-syncope of uncertain origin. Review of their charts revealed that six had symptoms or a history which were suggestive of carotid sinus syndrome: two suffered syncope while turning their body, one had syncope with head movement, one had a cervical mass and suffered recurrent presyncope, and one had a history of carotid sinus hypersensitivity. Patient characteristics are summarized in Table 1. The patients ranged in age from 13 to 89 years (mean, 61 ± 18). Forty-four percent were women. The indication for HUT and CSM was near-syncope in 40 and syncope in 96. Seventy-five subjects had a history of cardiovascular disease, coronary artery disease (CAD) and hypertension (HTN) being the most common diagnoses [27 (20%) and 40 patients (29%), respectively]. Sixty of these patients had a diagnosis consistent with or predisposing to atherosclerotic vascular diseae, including HTN, CAD, cerebrovascular disease, or an abdominal aortic aneurysm. CSM. Carotid sinus syndrome was observed in 18 patients (13%), with pauses of 3–30 seconds in 17 (median, 4 seconds; mean, 6.1 ± 6.6 seconds) and hypotension in one patient (who also had a pacemaker rhythm during CSM). Mild carotid sinus sensitivity was found in 19 patients (14%), with pauses of 1.6 to 2.5 seconds in 16 (median, 2.0 seconds; mean, 2.0 ± 0.3 seconds), bradycardia with or without a junctional rhythm in 2, and CSM-induced atrial fibrillation in one. A normal carotid sinus response was seen in the remaining 99 patients (73%). HUT. HUT was positive in 24 patients (18%) and negative in 112 patients (82%). Of those subjects with a positive HUT, nine experienced vasodepressor syncope, one had cardioinhibitory syncope and 14 had mixed vasodepressor and cardioinhibitory syncope. Presenting symptom. Of the 40 patients who had presented with near-syncope, mild carotid sensitivity was present in 6 (15%) and carotid sinus syndrome in 2 (5%). Thirteen (14%) of the 96 patients with syncope had mild carotid sensitivity and 16 (17%) had carotid sinus syndrome. Thus, patients who presented with syncope were somewhat more likely to have carotid sinus syndrome than those with near-syncope, but this difference did not reach statistical significance (p = 0.15). Twenty (21%) of those presenting with syncope had a positive HUT as compared with 4 (10%) of those with near-syncope (p = 0.15). Of the 6 patients with a history or symptoms suggestive of carotid sinus syndrome, two had carotid sinus syndrome and one (who had a normal carotid sinus response) had a positive HUT. Association of CSM and HUT outcome. Twenty-four patients had a positive HUT, eighteen had carotid sinus syndrome and 19 had mild carotid sensitivity (18%, 13%, and 14% of patients, respectively). There was no significant association between HUT outcome and CSM result (p = 0.3; Table 2). Overall, thirty-eight patients (28%) had a positive result on either HUT or CSM; four (11% of those 38 patients; three percent of all patients) had both carotid sinus syndrome and a positive HUT. The number of patients with one or more abnormal tests increased to 56 (41%) when patients with mild carotid sensitivity were included. Influence of age and gender. Patients with carotid hypersensitivity (mild or frank) were older on average than those with a normal carotid sinus response (mild sensitivity, 72 ± 10 years; carotid sinus syndrome, 66 ± 14 years; normal response, 58 ± 18 years; p for carotid hypersensitivity (mild or frank) vs. normal response = 0.0008). Conversely, the subjects with a positive HUT were slightly younger than those with a negative HUT (53 ± 21 years vs. 62 ± 16 years; p = 0.02). There was no significant association between gender and HUT outcome: twenty-one percent of women had a positive HUT vs. 15% of men (p = 0.36). More men than women had a mildly positive or positive carotid sinus response, but this difference was also not significant (32% of men vs. 20% of women; p = 0.17). Preexisting cardiovascular disease. Subjects with mild or frank carotid sinus hypersensitivity were more likely to have a prior cardiovascular diagnosis (73% vs. 48% with a normal carotid sinus response; p = 0.01). Conversely, patients with a positive HUT were less likely to have preexisting cardiovascular conditions (29% vs. 61% with a negative HUT; p = 0.006). These relationships are depicted in Figure 2. A subgroup of 60 patients who had a diagnosis consistent with or predisposing to atherosclerotic vascular changes (coronary artery disease, hypertension, stroke, transient ischemic attack, or abdominal aortic aneurysm) was compared to the rest of the group as to HUT and CSM outcome (Table 3). These patients had a significantly higher rate or abnormal CSM responses (p = 0.03) and a significantly lower rate of positive HUT (p = 0.01). Discussion In a retrospective analysis of 136 patients who underwent both HUT and CSM for syncope or near-syncope or uncertain origin, we found that there was no significant concordance of HUT and CSM outcomes. An “overlap” (positive HUT and carotid sinus syndrome) was present in only 3% of patients (11% of those with a positive test result). This result is in contrast to the data reported in several previous studies: McIntosh et al. found a 25% overlap between CSM (before and after atropine injection) and HUT in elderly patients.11 Kenny et al. reported syncope during HUT in 3 out of 10 patients with carotid sinus syndrome.13 Morillo et al. elicited a positive HUT in 25% of 80 patients with carotid sinus hypersensitivity as compared with 12% of 16 patients with syncope unrelated to carotid hypersensitivity.5 Brignole et al. studied 35 patients each with sick sinus syndrome and syncope of uncertain origin.12 Both CSM and HUT were positive in 43% of patients with sick sinus syndrome and 20% of those with syncope of uncertain origin. In another study of 100 patients with syncope, the same group studied CSM, eyeball compression and HUT and reporte an overlap between CSM and HUT of 21%.10 It is notable, however, that in the latter two studies, CSM was performed in the upright as well as in the supine position. This manuever has been shown to result in a much higher rate of bradycardia and/or hypotensive responses to CSM.5,14–16 The present study assessed only for a cardioinhibitory or symptomatically hypotensive response to CSM performed with the patient supine. It may be significant that under these conditions there was minimal overlap between HUT and CSM outcomes because it could imply different pathophysiological mechanisms underlying cardioinhibitory and vasodepressor CSS in the supine and upright position. The studies using both CSM and HUT cite an overall positivity of either HUT or CSM or both of 68–92%. This is in contrast to the lower yield observed in the present study (CSM positive in 13%, HUT positive in 18%, either one positive in 28%). Again, this might be due to the experimental design; in addition to performing CSM supine only, we also limited the time of the baseline HUT to 30 minutes. Moreover, our overall HUT positivity was low at 18% of all patients. We did include patients with near-syncope, who are known to have a lower positive HUT rate (10% in our study) and are therefore often excluded from studies involving HUT. Also, whereas some of the cited studies involved patients referred to a “syncope clinic”11 or with prior diagnoses of sick sinus syndrome,12 our patient group consisted of unselected patients with syncope or near-syncope of uncertain origin. A rather large proportion of our group had prior cardiovascular diagnoses, which would be expected to reduce the “yield” of HUT since patients with organic cardiovascular disease are less likely to have a positive HUT.10,17 The relationships we observed between HUT or CSM results on one hand and age and cardiovascular disease on the other are consistent with prior experience. It has been shown that carotid sinus syndrome is frequent in elderly patients with recurrent fals or syncope,14–16,18,19 while vasovagal syncope occurs in people of all age groups. A positive HUT is more frequently elicited in younger patients,15,20–22 and less frequently elicited in those with cardiovascular disease.10,17 In a recent retrospective study of patients presenting to a tertiary care facility with syncope or presyncope, the mean age of patients with carotid sinus syndrome was 76 years, while patients diagnosed with vasovagal syncope had a mean age of 35 years.23 These observations would not only appear to validate our results to some extent, but also help to explain why CSM results and HUT outcome could indeed be expected to be independent of each other. There is still considerable uncertainty about the pathophysiology of neurally mediated syncope. In particular, it is uncertain from animal and human studies whether it is initiated by an exaggerated or a blunted reflex sympathetic response. A study by Wahba et al. found that in a subgroup of patients, a blunted baroreflex response (as determined by carotid baroreceptor stimulation) coincided with a reduced cardiac output during HUT, while in another subgroup there was an exaggerated baroreflex response which coincided with syncope during HUT.9 While that study had an unusually low rate of syncope during the initial 20-minute tilt (2 out of 67), it nevertheless raises the possibility that combining HUT and CSM may identify subgroups of patients with different types of abnormal hemodynamic reactions potentially responsible for their syncopal events, which in turn might influence therapy. It would appear that the few patients who had both an abnormal CSM response and an abnormal HUT outcome in our study would correspond to that study’s patient subgroup with an exaggerated baroreflex response and syncope on HUT. Our study is limited, because it is a retrospective analysis. There is a potential selection bias since the reason for performing CSM along with HUT in these 136 patients was not documented. However, if patients with a history consistent with carotid sinus sensitivity were indeed more likely to undergo CSM along with HUT this would be expected to increase the overall rate of abnormal CSM, but should not affect the rate of overlap between HUT and CSM outcomes. In fact, our observed rate of abnormal CSM was 27% (carotid sinus syndrome in 14%, carotid sinus sensitivity in 13%), which is within the range reported in the literature for similar patient populations.15,18,19 We are currently planning a prospective study which will be designed to address some questions raised by this retrospective analysis: Is there a particular subgroup of patients that is susceptible to both carotid sinus syndrome and postural neurally mediated syncope? Is there a difference between these patients and those in whom only one of the studies (HUT or CSM) is abnormal? Which subpopulation of syncope patients is identified by using carotid sinus massage in the upright position?
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