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Carotid sinus hypersensitivity and syncope
Carotid Sinus Hypersensitivity and Syncope
Hyperactivity of the carotid sinus reflex is common in older men. However, an unequivocal diagnosis of carotid sinus syncope is difficult to establish because the symptoms are nonspecific, and both hyperactivity of the carotid sinus reflex and syncope are common. Twenty-one men were evaluated for episodes of lightheadedness or syncope, or both, associated with a hypersensitive carotfd sinus reflex. Seventeen patients had the cardioinhibitory type, two the vasodepressor type and two both the cardioinhibitory and vasodepressor types. Patients with the cardioinhibitory type benefited from the insertion of a permanent pacemaker if they had multiple episodes of syncope. A history of syncope associated wtth some event capable of stimulating the carotid sinus was also helpful in selecting patients for pacemaker treatment. The combination of the cardioinhibttory and vasodepressor types may be missed unless carotid sinus stimulation is repeated after the administration of atropine. The results of electrophysiologic studies in 17 patients with the cardioinhibitory type suggest that intrinsic sinus nodal dysfunction is not the major cause for asystole after carotid sinus stimulation.
PAUL F. WALTER, MD, FACC I. SYLVIA CRAWLEY, MD EDWARD R. DORNEY, MD Atlanta, Georgia
From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, and the Medical Services of the Veterans Administration Hospital and Emory University Hospital, Atlanta, Georgia. Manuscript received February 8. 1978; revised manuscript received April 18, 1978, accepted April 19, 1978. Address for reprints: Paul F. Walter, MD, Cardiology Section of the Medical Service, Veterans Administration Hospital, 1870 Clairmont Road, Decatur, Georgia 30033.
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The carotid sinus has an important role in the normal reflex regulation of heart rate and peripheral vascular tone. An increase in intrasinusal tension produces a slowing of the heart rate and a decrease in systemic arterial blood pres9ure.l Mechanical stimulation of the carotid sinus in normal subjects results in a mild slowing of the heart rate and an insignificant decrease in arterial blood pressure.2 Hyperactivity of the carotid sinus has been recognized and is associated with an exaggeration of the normal response. In some persons the hemodynamic response to carotid stimulation is so pronounced that clinical symptoms of syncope and profound hypotension result. The hyperactive carotid sinus reflex is found in approximately one third of older men with coronary atherosclerotic and hypertensive heart disease.s-5 Syncope or a transient clouding of consciousness without syncope is a common symptom in these patients. When spontaneous syncope and a hyperactive carotid sinus reflex coexist, it is tempting to assume that the hyperactive reflex is the cause of syncope. However, its presence may be coincidental because most patients with a hyperactive carotid sinus reflex are asymptomatic.3T4 It may be difficult to know whether the hyperactive reflex is responsible for the symptoms. There is a paucity of published information about the selection of patients for therapy directed toward the hyperactive reflex. Therefore, the present study was undertaken for the following purposes: (1) to examine the clinical symptoms and response to treatment of patients with hyperactive carotid sinus reflex and syncope or near syncope, in an attempt to improve the accuracy of diagnosis; and (2) to assess sinoatrial nodal and atrioventricular (A-V) nodal function in these patients with atria1 pacing and administration of intravenous atropine.
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nodal function were discontinued stimulation.
Patients: From 1971 to 1976 patients seen by the Cardiology Services at the Atlanta Veterans Administration Hospital and Emory University Hospital for evaluation of syncope or near syncope of unknown cause were tested with external carotid sinus stimulation unless they had cerebral vascular disease or other contraindications to this procedure. Twenty-one men were considered to have hypertensive carotid sinus. The patients were considered to have syncope of unknown cause if the history, physical examination, resting electrocardiogram, neurologic consultation or, in 71 percent of cases, continuous 24 hour ambulatory electrocardiographic monitoring did not explain the symptoms. Eight of the nine patients with cardioinhibitory carotid sinus hypersensitivity experiencing only dizziness (Patients 10 to 18, Table I) had 24 hour ambulatory electrocardiographic monitoring. Digitalis, propranolol and other drugs known to affect sinoatrial
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1 week before carotid sinus
Carotid sinus stimulation: This was performed initially with the patient supine and was repeated with the patient sitting and standing when vasodepressor syncope was suspected. The carotid sinus was massaged gently for approximately 5 seconds, first on one side and then on the other, while an electrocardiogram was recorded and blood pressure monitored. If there was no response, manual pressure was increased for an additional 5 seconds. Cardioinhibitory carotid sinus hypersensitivity was defined as ventricular asystole for more than 3 seconds during carotid sinus stimulation. This definition was proposed by Franke2 and is accepted by others.3 The vasodepressor type of carotid sinus hypersensitivity was considered to exist when there was a decrease in systolic blood pressure of 50 mm Hg or greater with no associated cardiac slowing, or when the decrease in systolic blood pressure was
TABLE I Clinical Features of 21 Patients Case no.
Age (yr)
We
of CSH
Symptoms; Inciting Events
Associated Disease
Multiple syncope: micturition Multiple syncope
CASHD
LAD
CASHD, DM
ST-T
Multiple syncope; shaving Multiple syncope; sneezing, head turning Multiple syncope; shaving Multiple syncope
CASHD, SAH
LAD
66
Cl
63
Cl
47
Cl
50
Cl
5
63
Cl
6
57
Cl
7
63
Cl
6
47
Cl
9
51
10
65
Cl, VD Cl
Multiple syncope; looking up Multiple syncope; shavina Multiple-syncope; neck pressure Dizziness
11
47
Cl
Dizziness
12
75
Cl
13
60
Cl
14
a4
ci
15
54
Cl
16
62
Cl
Dizziness
17
68
Cl
18
76
Cl
Dizziness; head turning Dizziness
19
64
VD
20
76
Cl, VD
21
59
VD
CSS (set)
ECG
WNL
CASHD
IMI
Hyperthyroid treatment CASHD
lo A-V block LVH
CASHD, SAH
IMI
CASHD
IMI
CASHD
IMI
CASHD, SAH
IMI
CASHD
LAD
Dizziness
CASHD, SAH
IMI
Postural collapse; no syncope Fading out; no syncope
SAH
LVH
CASHD, DM
IMI
CASHD, DM, SAH CASHD, SAH
IMI, LVH LBBB
DM
WNL
Dizziness; neck extension Dizziness with exercise Multiple syncope; head turning; tight collar
No syncope or dizziness (8) No syncope or dizziness (24) No syncope or dizziness (45) No syncope or dizziness (41)
Pacemaker
L,6 asystole R,3.8 asystole R,3.4 asystole L.6 asystole R,3.6 asystole L,3.7 asystole R.3.3 asystole L.3.7 CHB
Pacemaker
R,5.4 asystole L.5.4 asystole L.6.1 asystole
..
No syncope (39)
...
No syncope (12)
.
No syncope, transient confusion, normal pulse, BP (48) No syncope (50)
...
Lost to follow-up
WNL
Mitral regurgitation
lo A-V block
R”s’ &ystole
Aortic stenosis
WNL
Decrease in BP
’
Clinical Observation (mo.)
R,4 asystole L.3.1 asystole R,3.5 asystole R.3.1 asystole
R.6 asystole R.6 asystole R,4 asystole Decrease in
SAH
Treatment
Pacemaker Pacemaker Pacemaker
Pacemaker Pacemaker Pacemaker Pacemaker
... .
No syncope, rare dizziness (7) No syncope or dizziness (27) No syncope, rare dizziness (26) No syncope or dizziness (12) Syncope (1 episode), BP decrease with CSS (5) Dizziness and visual blurring, VBI (57) No syncope (24) Dizziness, VBI (2)
Lost to follow-up Stop all medication Pacemaker, mineralocorticoid Pacemaker, irradiation
Episodes less frequent (12) Orthostatic dizziness controlled by mineralocorticoid (21) No syncope for 6 1 mo postirradiation (89)
A-V = atrioventricular; BP = blood pressure; CASED = coronary atherosclerotic heart disease; CHB = complete heart block; Cl = cardioinhlbitory; CSH = carotid sinus hypersensitivity: CSS = carotid sinus stimulation; DM = diabetes mellitus; IMI = inferior myocardial infarction; L = left; LAD = left axis deviation; LBBB = left bundle branch block; LVH = left ventricular hypertropy; R 7 right; SAH = systemic arterial hypertension: ST-T = ST-T wave change; VBI = vertebral basilar arterial Insufficiency: VD = vasodepressor; WNL = within normal limits.
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greaterthan 30 mm Hg and the patient’s symptoms were reproduced.2 Electrophysiologic study: This was performed in 17 patients with cardioinhibitory carotid sinus hypersensitivity. Informed consent was obtained. The patients were studied in the resting nonsedated state. At the time of study, all cardioactive drugs had been discontinued for at least 1 week. A bipolar electrocatheter was passed under fluoroscopic control by way of an antecubital vein into the right atrium and positioned so that the electrodes were at the junction of the right atrium and superior vena cava. Atria1 pacing was begun at a rate of 10 beats/min faster than the spontaneous sinus rate and was increased every 2 minutes by increments of 10 beats/min until a rate of 150 beats/min was achieved. His bundle electrograms were obtained with the technique of Sherlag et a1.6in six patients. After the studies, 1 mg of atropine sulfate was administered intravenously in 14 patients, and carotid sinus stimulation was repeated in the same manner. At the rate of maximal suppression, the sinus nodal recovery time was measured from the last atria1 paced beat to the following sinus beat. Secondary pauses after the termination of rapid atria1 pacing were measured if these pauses exceeded the length of the first escape cycle (one patient). The corrected sinus recovery time was obtained by subtracting the spontaneous sinus cycle length before pacing (average 10 cycles) from the sinus nodal recovery time. The corrected sinus recovery time was considered abnormal if the interval exceeded 525 msec.7 Atrioventricular (A-V) nodal conduction was considered abnormal if second degree A-V block occurred at pacing rates of less than 130 beats/min.s
on backing up in a motor vehicle, local pressure on the neck, micturition or sneezing suggested possible precipitating factors. These possible causal factors preceded only the minority of episodes, and in some instances the history of these events was obtained only after repeated questioning. A history of a precipitating event was not obtained in two patients who could not remember events prior to syncope. Three patients had syncope while driving. One of these patients had several serious accidents while backing up his truck. Two patients had postsyncopal chest pain typical of myocardial ischemia. One patient had a marked increase in frequency of syncope while taking propranolol. The duration of symptoms before the demonstration of carotid sinus hypersensitivity in these nine patients was 1 to 46 months (mean 17 months). Three patients were followed up for 8,26 and 48 months before pacemaker implantation. Tincture of belladonna was tried in all three but was beneficial only temporarily. Serious side effects, including visual blurring and urinary retention, necessitated stopping the drug or reducing the dose to a level that no longer prevented symptoms. During the observation period before pacemaker insertion, two patients were asymptomatic for 16 and 37 months, respectively, but both had later recurrence of multiple episodes of syncope.
Results
5 to 45 months (mean 22) since pacemaker implantation. Syncope has not recurred in eight of the nine patients. Patient 9 had a single episode of syncope while eating breakfast 4 months after pacemaker insertion. Evaluation at that time showed the pacemaker to be functioning normally. The systemic arterial blood pressure was 120/82 mm Hg in the sitting position, but decreased to 80/70 mm Hg with gentle right carotid stimulation.During stimulationthe pacemaker rate was unaltered at 70 beats/min. The patient noted transient dizzinesscoincident with the decrease in blood pressure. He appears to have both cardioinhibitory and vasodepressor hypersensitivity and, if his symptoms continue, further therapy will be necessary. Although syncope has not recurred since pacemaker insertion,two of these patients have occasional episodes of lightheadedness while standing. Orthostatic hypotension appears to be the cause of symptoms in one patient and the cause is unknown in the other.
Clinical features: The 21 men evaluated for episodes of lightheadedness or syncope associated with carotid sinus hypersensitivity ranged in age from 47 to 84 years (mean 62) (Table I). Seventeen patients had the cardioinhibitory type of hypersensitivecarotid sinus reflex, two the vasodepressor form and two both the cardioinhibitory and vasodepressor types. Most of the 21 patients had heart disease; 14 had coronary atherosclerotic heart disease, diagnosed from a history of angina pectoris (14 patients), prior myocardial infarction (9 patients) or coronary arteriography (4 patients). Three patients had had coronary bypass surgery. Only two men had no clinical evidence of associated organic heart disease, but neither had had cardiac catheterization or coronary arteriography. Electrocardiographic evidence of prior inferior myocardial infarction was found in 8 of the 14 patients with coronary atherosclerotic heart disease. No patient had documented spontaneous sinoatrial block. The one patient with paroxysmal atrial tachyarrhythmia had been treated for hyperthyroidism 24 years earlier but was euthyroid at the time of examination. Cardioinhibitory type with syncope: Patients 1 to 9 (Table I) with the cardioinhibitory type each had had five or more episodes of syncope and also numerous episodes of near syncope. Their symptoms occurred when they were sitting or standing and never while recumbent. Seven of these nine patients recalled some event that may have been important in precipitating syncope. A history of hyperextension of the neck when shaving, looking at the sky, head turning or head turning
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Patients 1 to 9 were treated with a demand cardiac pacemaker: These patients have been followed up for
Three of the nine patients had significant complications related to the insertion of a permanent cardiac pacemaker. One patient had a perioperative subendo-
cardial myocardial infarction, one had the postpericardiotomy syndrome and required hospitalization for treatment of a large pericardial effusion and one had a perioperative myocardial infarction when the pacemaker was implanted at the time of coronary bypass surgery. Cardioinhibitory type without syncope: Patients 10 to 18 (Table I) did not have syncope (except for a single episode in one man) but had a spectrum of complaints involving transient clouding of consciousness.
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Unlike most of the patients requiring pacemaker therapy, only one of these nine patients could recall a precipitating event capable of stimulating the carotid sinus. Seven of these’nine patients have been followed up for an average of 33 months, and none have experienced syncopal episodes. During the follow-up period a neurologic consultant diagnosed vertebral basilar arterial insufficiency in addition to carotid sinus sensitivity in two patients; the symptoms typical of the insufficiency were not apparent from the initial evaluation. Five patients have noted a decrease or disappearance of their symptoms, for which no satisfactory explanation was found. Vasodepressor or mixed type: Patients 19,20 and 21 have vasodepressor or both vasodepressor and cardioinhibitory carotid hypersensitivity; they will be discussed individually. Patient 19: For the preceding 5 years, this 64 year old man had experienced dizziness without complete loss of consciousness when he extended his neck and lifted his arms to place articles on shelves in a warehouse; At the time of the initial examination, he was taking hydralazine, 40 n&day, for arterial hypertension. The maximal pause ever recorded on his electrocardiogram during carotid sinus stimulation was 1.4 seconds. The recumbent blood pressure was 140/80 mm Hg and decreased to 125/70 mm Hg on standing. During right carotid sinus stimulation, the blood pressure decreased to 80160 mm Hg during sitting and 70150during standing, and the patient’s spontaneous symptoms were reproduced. On repeat testing after discontinuation of hydralazine, blood pressure was 150/82 mm Hg while he was recumbent, 130/80 during standing and 98180during standing with right carotid sinus stimulation. The patient had no symptoms when blood pressure was 98/80 mm Hg. During the past year the patient continued to have symptoms at work, but they occurred less frequently. In the future more definitive therapy may be needed. The reflex decrease in systolic blood pressure did not exceed 50 mm Hg when all medications were discontinued and therefore did not meet the criteria proposed by Franke2; however, the vasodepressor response to carotid stimulation probably played a major role in the genesis of this patient’s symptoms. Patient 20: This 76 year old man with both oardioinhibitory and vssodepressor carotid sinus hypersensitivitywas first seen because of three episodes of dizziness with near syncope during exercise. The blood pressure was 150/70 mm Hg with the patient recumbent and 140170while he was sitting. Right carotid sinus stimulation produced a 6 second,peri,od.ofasystole. A permanent demand pacemaker was inserted. One month later, the patient complained of dizziness while walking. Blood pressure was 120/80 mm Hg in the recumbent and standing positions, respectively. Right carotid sinus stimulation performed with the patient seated resulted in a decrease in blood pressure to 80/60 mm Hg with a pacemaker-driven heart rate of 71 beats/min. The patient’s symptoms of dizziness were duplicated during right carotid sinus stimulation. He was given fludrocortisone (FlorineF) acetate, 0.1 mg/day, and has been free of dizziness for 1 year, except for a few weeks when the medication was inadvertently discontinued. The fludrocortisone acetate increased the blood pressure to 160/100 and 150/100 mm Hg in the recumbent and standing
position, respectively. Patient 21: This 59 year old school teacher experienced
syncope when he turned his head to look at the back of his classroom. He had stopped wearing neckties because he as-
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sociated wearing a tight collar with spells of dizziness. A permanent demand pacemaker had been inserted 9 months earlier because of three syncopal attacks that were assumed to be secondary to a bradyarrhythmia. Asystole had not been documented, however, and carotid sinus stimulation was not performed before the pacemaker insertion. The pacemaker was found to be functioning normally. Aortic valve stenosis of mild to moderate severity was detected. Bilateral carotid arteriograms were normal. Blood pressure was 130/80 mm Hg in the standing position. During right carotid sinus stimulation Korotkoff sounds could not be heard, and presyncopal symptoms developed. The patient was advised not to wear tight collars or turn his head abruptly, but syncopal episodes continued, some associated with singing or head turning. Radiation therapy to a tissue dose of 900 roentgens was administered to both the right and the left carotid sinus. One year after the radiation therapy, the patient’s symptoms recurred. Syncope was induced by head turning but not by exercise. Right carotid stimulation performed with the patient seated produced a decrease in systolic blood pressure from 130 to 82 mm Hg, and the patient became dizzy. There was no change in systolic blood pressure during left carotid stimulation. The right carotid sinus was again radiated, with a tissue dose of 1,200 roentgens yielding a total dose to the right carotid sinus of 2,100 roentgens. Over the ensuing 5 years, the patient has had no syncope or near syncope, and right or left carotid sinus stimulation does not alter blood pressure. Two years after the second course of radiation therapy, the patient had congestive heart failure due to aortic stenosis. Cardiac catheterization confirmed the presence of severe aortic stenosis and demonstrated normal coronary arteries. The stenotic aortic valve was replaced. Although the presence of aortic stenosis surely decreased the patient’s ability to compensate for decrease in peripheral arterial resistance induced by the carotid sinus reflex, the valve lesion was probably not the major cause of syncope because: (1) syncope was incited by head turning and carotid sinus stimulation rather than by exercise, and (2) the symptoms were abolished by the carotid sinus radiation a full 2 years before the replacement of the stenotic aortic valve.
Electrophysiologic studies: In the 17 patients with cardioinhibitory hypersensitive carotid sinus reflex, the corrected sinus nodal recovery time was less than 525 msec in 14 patients and greater than 525 msec in 3 patients (Table II). The rate of atrial pacing that produced maximal sinoatrial nodal suppression varied from 76 to 150 beats/min. Of the eight patients treated successfully with pacemakers who consented to be studied, seven had a normal and one a prolonged corrected sinus nodal recovery time. The single patient with prolonged recovery time had sinus bradycardia and paroxysmal atria1 fibrillation and flutter. Atrioventricular Wenckebach periods developed at a paced atria1 rate greater than 130 beatsfmin in 13 patients and less than 130 beats/min in 3. After the administration of 1 mg of atropine, 1:l A-V conduction was present at a pacing rate of 140 beats/min or less in the later three patients. His bundle recordings were obtained in six patients. The H-V intervals were 55 msec or less, and the A-H intervals ranged from 65 to 90 msec. The effect of 1 mg of atropine on corrected sinus nodal recovery time was studied in two of the three patients with prolonged recovery time. The recovery time was normal in one patient and could not be determined in the second patient
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TABLE II Results of Physiologic Studies
Case no.
Resting Sinus Rate (beats/min)
Sinus Nodal Reovery Time (msec)
Connected Sinus Recovery Time (msec)
El 87 80
920 880 1090 1280
11: 190 280
: 7 8
:: 57 81
1900 1040 1550 860
850 290 490 120
10
58 76 78
1580 1040 1180 1850 1150
530 250 410 780 150
2530 (beat #2) 1130 1150
1460
: 3 4
::
15 16
80 77
Paced Rate at Maximal Suppression (beats/min)
380 370
130 150 123 120
Sinus Rate Before Atropine (beatslmin)
77 58
98 79
>130 >150 >150 >130
:: 70 79
88 58 75 88
>140 >130 105 >I50
60
114
ss 58 75
ibs 100 88
ii
143 1:: 97. 156 76 105 90 148 138
Rate of A-V Wenckebach Conduction (beats/min)
Heart Rate After Atropine (beatsjmin)
iib
X39: >140 >140 138
(junctional) 144 133
76 80
92 75 liunctionall
>145
.
’ ::
:8
1240 1080
240 330
.80.
107 143
. 9ii
>143 107
A-V = atrioventricular.
because the postpacing pause was terminated by an A-V junctional beat. Ah-opine (1 mg) was given to 14 patients. The postatropine pulse rate was less than 90 beats/min in seven patients (five with sinus rhythm and two with A-V junctional rhythm), and in the other seven patients the sinus rate was 90 beats/min or greater. Discussion Cardioinhlbitory
Type
Precipitating causes of syncope: Our results in patients with the cardioinhibitory type of carotid sinus hypersensitivity suggest that the patient’s history may be of value in selecting candidates for aggressive therapy. All of our patients whose syncope was abolished by a cardiac pacemaker had multiple syncopal episodes and many additional episodes of near syncope. These symptoms always occurred when the patient was standing or seated. Most patients could recall a precipitating event associated with episodes of syncope, although the majority of syncopal episodes were not initiated by a trigger mechanism. A few patients were unable to give a hi&toryof a precipitating event because they were unable to remember events before the episode. Most of the factors that produced syncope were maneuvers inducing direct pressure or tension on the carotid sinus. It should be noted that head turning or neck extension may produce, in addition to carotid sinus stimulation, mechanical impairment of blood flow through the vertebral arteries.g Activities other than those that produce extravascular stimulation of the carotid sinus region can induce clinical symptoms in certain predisposed persons. In some patients coughing, sneezing and straining at stool have induced sponta-
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neous syncope.4~10 Syncope associated with micturition and intense sneezing was noted in our series. Reproducibility of symptoms by carotid sinus stimulation: The need to reproduce the exact symp-
toms with carotid sinus massage before instituting treatment is controversial.3J0J1In most of our patients we were unable to reproduce an identical symptom complex with carotid sinus stimulation. All patients noted dizziness during the period of asystole; however, a complete loss of consciousness occurred in only one patient, probably because carotid sinus stimulationwas performed with the patient recumbent and was stopped when a pause was noted in the electrocardiogram. The additional information that might be obtained by having the patient sit or stand during manual stimulation of the carotid sinus or by continuing stimulation until syncope occurs, may not justify the risk of inducing seriouscerebral or cardiac ischemia.In addition, in some patients with no spontaneous symptoms the carotid sinus may be sensitive and massage may precipitate unconsciousness. Natural history: Little is known about the natural history of the cardioinhibitory form of hypersensitivity. Because Patients 1 to 9 had had symptoms an average of 17 months before examination and three patients were followed up before pacemaker insertion, we observed the clinical course of these patients for a con-
siderable period of time. In general, the frequency of spontaneous syncope seemed to wax and wane, and some patients were free of symptoms for more than a year. We were unable to detect any factors such as variation in the severity of angina pectoris or hypertension to account for the variability in spontaneous attacks. However, syncope did recur and no patient had a permanent resolution of his symptoms without defi-
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nite treatment. During symptom-free periods, the response to carotid sinus stimulation was sometimes normal. Fluctuation in carotid sinus sensitivity has been noted by others.3J0 Patients without syncope: In the patients with episodes of clouding of consciousness rather than syncope, a history of precipitating factors was rarely obtained on the initial or follow-up visits. In seven of the nine patients followed up for an average of 33 months syncope did not develop. Follow-up examination, including a repeat history, supine and standing blood pressure measurements and treadmill exercise testing, was useful in establishing a diagnosis in a few patients. Occasionally a patient’s symptoms disappeared spontaneously, although in others they continued but defied explanation. Hypersensitivity of the carotid sinus reflex may have contributed to symptoms in these patients without true syncope, but it was probably not a major factor. Vasodepressor or Mixed Type The effects of carotid sinus stimulation on the heart and the peripheral vasculature appear to be independent of each other.12 Atropine abolishes slowing of the heart rate but does not prevent a decrease in systemic The decrease in blood pressure blood pressure. 1~*2~13 results from inhibition of sympathetic vasoconstrictor nerves and possibly activation of cholinergic sympathetic vasodilator fibers.l Epinephrine administered parenterally may prevent the hypotension.3 The clinical symptoms of the vasodepressor type are the same as those occurring in the cardioinhibitory form, but the episodes may be extended in the vasodepressor form because the decrease in blood pressure generally lasts longer than the bradycardia.‘J2 Patients having vasodepressor or both cardioinhibitory and vasodepressor hypersensitivity are especially challenging. Although one reviewi of the hyperactive carotid sinus reflex states that various reflex types often occur in the mixed form, it is difficult to find published examples of such patients. Two patients in our group appear to demonstrate both vasodepressor and cardioinhibitory types. The definition for the vasodepressor type of hyperactive reflex proposed by Franke2 is a decrease in systolic blood pressure of 50 mm Hg or greater. The systolic blood pressure did not always decrease 50 mm Hg or more in our patients with the vasodepressor type, but symptoms were reproduced in all patients. The response may have been blunted because blood pressure was determined in the sitting position in two patients and carotid stimulation was terminated on the appearance of symptoms. However, it appears that vasodepressor hypersensitive carotid sinus reflex was important in the genesis of symptoms in our patients. Diagnosis of vasodepressor type in presence of cardioinhibitory type: It is distressing to find patients who continue to have syncope or near syncope after pacemaker treatment for cardioinhibitory carotid sinus hypersensitivity. It is possible that the carotid hypersensitivity and syncope are unrelated and that the Cal-se
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of the syncope has been missed. A second possibility is that the patient has both the cardioinhibitory and vasodepressor types of carotid hypersensitivity and that, despite the prevention of bradycardia by the pacemaker, the reflex decrease in blood pressure continues to produce symptoms. This combination appears with sufficient frequency to warrant screening for the vasodepressor type in all patients with the cardioinhibitory form. If carotid sinus stimulation provokes cardiac asystole for longer than 3 seconds, 1 mg of atropine should be given intravenously, and the carotid sinus stimulation should be repeated within 5 minutes with the patient seated. If retesting results in a decrease in blood pressure despite the maintenance of a normal heart rate, the patient may be assumed to have vasodepressor as well as cardioinhibitory carotid sinus hypersensitivity. Treatment Indications for treatment: A hyperactive carotid sinus reflex that does not cause symptoms requires no treatment. The question of therapy occurs when a patiept has repeated episodes of syncope or near syncope, and the common causes of syncope have been excluded. If the patient is taking any drug that affects cardiac pacemaker activity or the capacitance or resistance vessels, therapeutic decisions should be deferred and carotid sinus stimulation repeated when the effects of the drug have dissipated. Digitalis was demonstrated to increase carotid sinus neural discharge for a given change in carotid sinus pressure.14 We saw one patient, not included in this report, who had syncope and a 3.4 second sinus pause with carotid sinus stimulation only while taking propranolol. The hyperactive carotid reflex and symptoms of syncope disappeared when propran0101was discontinued. Drugs that decrease intravascular blood volume or peripheral arterial resistance or that increase venous capacitance may enhance the hypotensive response to carotid stimulation in a patient with the vasodepressor type of hyperactive carotid sinus reflex. Patients with cardioinhibitory hypersensitivity who have repeated spontaneous episodes of syncope should be treated. If syncope is precipitated by a maneuver that produces mechanical stimulation of carotid arteries or by a vagal reflex activated from some other site, a reflexly induced cardiac asystole is probably responsible for the symptoms. Observations in several of our patients suggest that spontaneous syncope may disappear for months or even a year but often recurs later. The long-term follow-up of more patients is necessary to determine whether these findings represent the natural history of cardioinhibitory hypersensitivity. The risk of syncope while driving a vehicle or working in certain situations usually necessitates treatment whenever the diagnosis is fairly certain. Patients who have episodes of clouding of consciousness without a known inciting event can, according to our experience, be followed up without therapy. Cardiac pacemaker imprantation: The preferred treatment for cardioinhibitory induced syncope is im-
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plantation of a demand cardiac pacemaker. Pacemaker treatment is highly successful, and the results are superior to those reported in any other form of theraPY.~JOJ~J~J” Only about two thirds of patients are free of symptoms after radiation therapy or surgical denervation of the carotid sinus.‘J6 Large doses of anticholinergic drugs are often poorly tolerated and may not abolish symptoms.‘5 Treatment of vasodepressor or mixed types: The best treatment for vasodepressor or mixed vasodepressor and cardioinhibitory carotid hypersensitivity remains to be established. Some milder cases of the vasodepressor form may respond to simple measures, such as increasing blood volume with mineralocorticoids. Severe vasodepressor or mixed vasodepressor cardioinhibitory may require treatment with either radiation therapy or surgical denervation of the carotid sinus. In one of our patients, a total tissue dose of 2,100 roentgens was required to abolish the reflex decrease in blood pressure. This dose is substantially higher than that recommended previously.16 Carotid sinus denervation with periarterial stripping or the use of electrical nerve stimulation to facilitate the search for sensitive areas on the carotid sinus and surrounding nerves may improve the results of surgical therapy.17J8 Electrophysiology
Some authors1gp20 consider carotid sinus hypersensitivity to be part of the “sick sinus node” syndrome. Our results and those of othersll suggest that carotid sinus hypersensitivity and sick sinus syndrome are separable entities but that both may occur in the same patient. In contrast to patients with the sick sinus syndrome, only one of our patients had paroxysmal atria1 tachyarrhythmia alternating with sinus bradycardia (bradycardia-tachycardia syndrome), and no patient had electrocardiographic documentation of type I or II sinoatrial block. Sinus nodal function: Only 3 of our 17 patients (18 percent) with the cardioinhibitory type of hypersensitivity had a corrected sinus nodal recovery time greater than 525 msec. One of these three patients had abnormal prolongation of a cycle after, the first postpacing cycle. Although electrophysiologic testing of sinus nodal function by atria1 pacing with determination of corrected sinus nodal recovery time is not a definitive test for separating normal from abnormal sinus nodal function, the incidence rate (18 percent) in our patients of a prolonged corrected sinus nodal recovery time or secondary postpacing pauses was considerably less than the rate reported in patients with symptomatic sinus
nodal dysfunction .21y22Rosen et a1.8 reported a high incidence rate of A-V conduction defects in patients with sinus nodal dysfunction. Atrioventricular conduction appeared normal in 81 percent of our patients. The results of sinus nodal recovery time in our patients were of little value in selecting patients for pacemaker therapy. Pathophysiology: The pathophysiology of cardioinhibitory hypersensitivity and the site from which it arises are unknown. The carotid sinus receptors or reflex afferents, the autonomic centers of the brain stem and the efferent limb of the reflex arc have all been proposed as sites of hypersensitivity.3-5J2,23 A combination of abnormalities at multiple sites is also possible. Changes in the efferent limb of the reflex have received the greatest attention because a hypersensitive carotid sinus reflex is commonly associated with organic heart disease. The cardioinhibitory response to carotid sinus stimulation was demonstrated to increase in experimental animals by myocardial hypoxia and chronically studied unilateral vagotomy.5124 Chronically, vagotomy may increase sensitivity to acetylcholine because of degeneration of postganglionic fibers.24 Events in the heart that account for prolonged asystole have not been determined. Our data suggest
that a disorder of sinus nodal automaticity or sinoatrial conduction is not the major reason for asystole. The corrected sinus nodal recovery time was normal in 82 percent of the patients with the cardioinhibitory type of carotid sinus hypersensitivity in our series and in that reported on by Hartzler and Maloney.li Increased vagal tone is a more likely explanation, with several possible mechanisms in effect: (1) a high
level of resting vagal tone, (2) hyperresponsiveness to acetylcholine, (3) excessive release of acetylcholine, and (4) inadequate cholinesterase activity. A high level of resting vagal tone seems unlikely because atropine did not produce an excessive increase in pulse rate. The heart rate remained less than 90 beats/min in 50 percent of our tested patients. Hyperresponsiveness to acetylcholine is another possibility.25 The release of acetylcholine induced by electrical stimulation during rapid atria1 pacing plays a major role in overdrive suppression of atria1 pacemakers. 26 If the sinus node were hyperresponsive to acetylcholine, rapid atria1 pacing might produce a prolonged pause. However, the fact that sinus nodal recovery times were normal in 14 of our 17 patients (82 percent) may invalidate this proposed mechanism. Other suggested explanations for prolonged asystole are an excessive release of acetylcholine or inadequate cholinesterase activity after carotid sinus stimulation.25
References 1. Thomas JE: Diseases of the carotid sinus-syncope. In Handbook of Clinical Neurology, Vol II, chap 19 (Vinken PJ. Bruyn GW, ed). Amsterdam, North-Holland Publishing, 1972, p 532 2. Franke H: Uber das Karotissinus-Syndrom und den sogenannf :n hyperaktiven Karotissinus-Reflex. Stuttgart, Friedrich-K wl
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Schattauer-Verlag, 1963, p 149 3. Thomas JE: Hyperactive carotid sinus reflex and carotid sinus syncope. Mayo Clin Proc 44~127-139, 1969 4. Nathanson MH: Hyperactive cardioinhibitory carotid sinus reflex. Arch Intern Med 77:491-503, 1946
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5. Slgler LH: The cardioinhibitory carotid sinus reflex. Am J Cardiol 12:175-183, 1983 8. Scherlag BJ, Lau SH, HeKant RH, et al: Catheter technique for recording His bundle activity in man. Circulation 39:13-18, 1989 7. Narula OS, Samet P, Javkr RP: Significance of sinus-node recovery time. Circulation 45:140-158, 1972 8. Rosen KM, Loeb MS, Slnno MZ, et al: Cardiac conduction in patients with symptomatic sinus node disease. Circulation. 43: 838-844, 1971 9. Hutchlnson EC, Yates PO: The cervical portion of the vertebral artery: a clinico-pathological study. Brain 79:319-331, 1958 10. Pereta M, Gereln AN, Mfya@f&hna RR Permanent demand pacing for hypersensitive carotid sinus syndrome. J Can Med Assoc 108:1131-1134, 1973 11. Hartzler CO, Maloney JE: Cardioinhibitory carotid sinus hypersensitivity. Arch Intern Med 137:727-731, 1977 12. Lown B, Levlne SA: The carotid sinus. Circulation 23:788-789, 1981 13. Heron JR, Anderson EG, Noble IM: Cardiac abnormalities associated with carotid-sinus syndrome. Lancet 2:214-218, 1985 14. Guest JA, Gllffs RA: Effect of digitalis on carotii sinus baroreceptor activity. Circ Res 35~247-255, 1974 15. Voss DM. Margnfn GE: Demand pacing and carotid sinus syncope. Am Heart J 79:544-547.1970 16. Greefey HP, Smedal MI, Most W: The treatment of the carotid sinus syndrome by irradiation. N Engl J Med 252:91-94, 1955
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17. Cohen FL, Fruehan CT, King RB: Carotid sinus syndrome. Report of five cases and review of the literature. J Neurosurg 45:78-84, 1976 18. Gardnar RS, Magovern GJ, Park SB, et al: Carotii sinus syndrome: new surgical considerations. Vast Surg 9:204-210, 1975 19. Mandel WJ, Hayakawa H, Alfen HN, et ai: Assessment of sinus node function in patients with the sick sinus syndrome. Circulation 46:761-769, 1972 20. Goldreyer BN: Sinus node dysfunction-a physiologic consideration of arrhythmias involving the sinus node. Cardiovasc Clin 6: 179-198.1974 21. Gupta PK, Lkhsleln E, Chadda KD, et al: Appraisal of sinus nodal recovery time in patients with sick sinus syndrome. Am J Cardiol 34~265-270, 1974 22. BendKl DG, Strauss HC, Schelnman MM, et al: Analysis of secondary pauses following termination of rapid atrial pacing in man. Circulation 54:436-441, 1976 23. Scott JC, Reed EA: Comparison of unilateral with bilateral stimulation of the carotid sinus cardioinhibitory reflex. Am J Physiol 181:27-29.1955 24. Reed EA, Scott JC: Factors influencing the carotid sinus cardioinhibitory reflex. Am J Physiol 181:21-26. 1955 25. Dlghton DH:Sinus bradycardia. Autonomic influence and clinical assessment. Br Heart J 36:791-797, 1974 26. Vassale M: The relationship among cardiac pacemakers. Circ Res 41:269-277, 1977
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Hyperactivity of the carotid sinus reflex is common in older men. However, an unequivocal diagnosis of carotid sinus syncope is difficult to establish because the symptoms are nonspecific, and both hyperactivity of the carotid sinus reflex and syncope are common. Twenty-one men were evaluated for episodes of lightheadedness or syncope, or both, associated with a hypersensitive carotfd sinus reflex. Seventeen patients had the cardioinhibitory type, two the vasodepressor type and two both the cardioinhibitory and vasodepressor types. Patients with the cardioinhibitory type benefited from the insertion of a permanent pacemaker if they had multiple episodes of syncope. A history of syncope associated wtth some event capable of stimulating the carotid sinus was also helpful in selecting patients for pacemaker treatment. The combination of the cardioinhibttory and vasodepressor types may be missed unless carotid sinus stimulation is repeated after the administration of atropine. The results of electrophysiologic studies in 17 patients with the cardioinhibitory type suggest that intrinsic sinus nodal dysfunction is not the major cause for asystole after carotid sinus stimulation.
PAUL F. WALTER, MD, FACC I. SYLVIA CRAWLEY, MD EDWARD R. DORNEY, MD Atlanta, Georgia
From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, and the Medical Services of the Veterans Administration Hospital and Emory University Hospital, Atlanta, Georgia. Manuscript received February 8. 1978; revised manuscript received April 18, 1978, accepted April 19, 1978. Address for reprints: Paul F. Walter, MD, Cardiology Section of the Medical Service, Veterans Administration Hospital, 1870 Clairmont Road, Decatur, Georgia 30033.
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The carotid sinus has an important role in the normal reflex regulation of heart rate and peripheral vascular tone. An increase in intrasinusal tension produces a slowing of the heart rate and a decrease in systemic arterial blood pres9ure.l Mechanical stimulation of the carotid sinus in normal subjects results in a mild slowing of the heart rate and an insignificant decrease in arterial blood pressure.2 Hyperactivity of the carotid sinus has been recognized and is associated with an exaggeration of the normal response. In some persons the hemodynamic response to carotid stimulation is so pronounced that clinical symptoms of syncope and profound hypotension result. The hyperactive carotid sinus reflex is found in approximately one third of older men with coronary atherosclerotic and hypertensive heart disease.s-5 Syncope or a transient clouding of consciousness without syncope is a common symptom in these patients. When spontaneous syncope and a hyperactive carotid sinus reflex coexist, it is tempting to assume that the hyperactive reflex is the cause of syncope. However, its presence may be coincidental because most patients with a hyperactive carotid sinus reflex are asymptomatic.3T4 It may be difficult to know whether the hyperactive reflex is responsible for the symptoms. There is a paucity of published information about the selection of patients for therapy directed toward the hyperactive reflex. Therefore, the present study was undertaken for the following purposes: (1) to examine the clinical symptoms and response to treatment of patients with hyperactive carotid sinus reflex and syncope or near syncope, in an attempt to improve the accuracy of diagnosis; and (2) to assess sinoatrial nodal and atrioventricular (A-V) nodal function in these patients with atria1 pacing and administration of intravenous atropine.
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nodal function were discontinued stimulation.
Patients: From 1971 to 1976 patients seen by the Cardiology Services at the Atlanta Veterans Administration Hospital and Emory University Hospital for evaluation of syncope or near syncope of unknown cause were tested with external carotid sinus stimulation unless they had cerebral vascular disease or other contraindications to this procedure. Twenty-one men were considered to have hypertensive carotid sinus. The patients were considered to have syncope of unknown cause if the history, physical examination, resting electrocardiogram, neurologic consultation or, in 71 percent of cases, continuous 24 hour ambulatory electrocardiographic monitoring did not explain the symptoms. Eight of the nine patients with cardioinhibitory carotid sinus hypersensitivity experiencing only dizziness (Patients 10 to 18, Table I) had 24 hour ambulatory electrocardiographic monitoring. Digitalis, propranolol and other drugs known to affect sinoatrial
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1 week before carotid sinus
Carotid sinus stimulation: This was performed initially with the patient supine and was repeated with the patient sitting and standing when vasodepressor syncope was suspected. The carotid sinus was massaged gently for approximately 5 seconds, first on one side and then on the other, while an electrocardiogram was recorded and blood pressure monitored. If there was no response, manual pressure was increased for an additional 5 seconds. Cardioinhibitory carotid sinus hypersensitivity was defined as ventricular asystole for more than 3 seconds during carotid sinus stimulation. This definition was proposed by Franke2 and is accepted by others.3 The vasodepressor type of carotid sinus hypersensitivity was considered to exist when there was a decrease in systolic blood pressure of 50 mm Hg or greater with no associated cardiac slowing, or when the decrease in systolic blood pressure was
TABLE I Clinical Features of 21 Patients Case no.
Age (yr)
We
of CSH
Symptoms; Inciting Events
Associated Disease
Multiple syncope: micturition Multiple syncope
CASHD
LAD
CASHD, DM
ST-T
Multiple syncope; shaving Multiple syncope; sneezing, head turning Multiple syncope; shaving Multiple syncope
CASHD, SAH
LAD
66
Cl
63
Cl
47
Cl
50
Cl
5
63
Cl
6
57
Cl
7
63
Cl
6
47
Cl
9
51
10
65
Cl, VD Cl
Multiple syncope; looking up Multiple syncope; shavina Multiple-syncope; neck pressure Dizziness
11
47
Cl
Dizziness
12
75
Cl
13
60
Cl
14
a4
ci
15
54
Cl
16
62
Cl
Dizziness
17
68
Cl
18
76
Cl
Dizziness; head turning Dizziness
19
64
VD
20
76
Cl, VD
21
59
VD
CSS (set)
ECG
WNL
CASHD
IMI
Hyperthyroid treatment CASHD
lo A-V block LVH
CASHD, SAH
IMI
CASHD
IMI
CASHD
IMI
CASHD, SAH
IMI
CASHD
LAD
Dizziness
CASHD, SAH
IMI
Postural collapse; no syncope Fading out; no syncope
SAH
LVH
CASHD, DM
IMI
CASHD, DM, SAH CASHD, SAH
IMI, LVH LBBB
DM
WNL
Dizziness; neck extension Dizziness with exercise Multiple syncope; head turning; tight collar
No syncope or dizziness (8) No syncope or dizziness (24) No syncope or dizziness (45) No syncope or dizziness (41)
Pacemaker
L,6 asystole R,3.8 asystole R,3.4 asystole L.6 asystole R,3.6 asystole L,3.7 asystole R.3.3 asystole L.3.7 CHB
Pacemaker
R,5.4 asystole L.5.4 asystole L.6.1 asystole
..
No syncope (39)
...
No syncope (12)
.
No syncope, transient confusion, normal pulse, BP (48) No syncope (50)
...
Lost to follow-up
WNL
Mitral regurgitation
lo A-V block
R”s’ &ystole
Aortic stenosis
WNL
Decrease in BP
’
Clinical Observation (mo.)
R,4 asystole L.3.1 asystole R,3.5 asystole R.3.1 asystole
R.6 asystole R.6 asystole R,4 asystole Decrease in
SAH
Treatment
Pacemaker Pacemaker Pacemaker
Pacemaker Pacemaker Pacemaker Pacemaker
... .
No syncope, rare dizziness (7) No syncope or dizziness (27) No syncope, rare dizziness (26) No syncope or dizziness (12) Syncope (1 episode), BP decrease with CSS (5) Dizziness and visual blurring, VBI (57) No syncope (24) Dizziness, VBI (2)
Lost to follow-up Stop all medication Pacemaker, mineralocorticoid Pacemaker, irradiation
Episodes less frequent (12) Orthostatic dizziness controlled by mineralocorticoid (21) No syncope for 6 1 mo postirradiation (89)
A-V = atrioventricular; BP = blood pressure; CASED = coronary atherosclerotic heart disease; CHB = complete heart block; Cl = cardioinhlbitory; CSH = carotid sinus hypersensitivity: CSS = carotid sinus stimulation; DM = diabetes mellitus; IMI = inferior myocardial infarction; L = left; LAD = left axis deviation; LBBB = left bundle branch block; LVH = left ventricular hypertropy; R 7 right; SAH = systemic arterial hypertension: ST-T = ST-T wave change; VBI = vertebral basilar arterial Insufficiency: VD = vasodepressor; WNL = within normal limits.
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greaterthan 30 mm Hg and the patient’s symptoms were reproduced.2 Electrophysiologic study: This was performed in 17 patients with cardioinhibitory carotid sinus hypersensitivity. Informed consent was obtained. The patients were studied in the resting nonsedated state. At the time of study, all cardioactive drugs had been discontinued for at least 1 week. A bipolar electrocatheter was passed under fluoroscopic control by way of an antecubital vein into the right atrium and positioned so that the electrodes were at the junction of the right atrium and superior vena cava. Atria1 pacing was begun at a rate of 10 beats/min faster than the spontaneous sinus rate and was increased every 2 minutes by increments of 10 beats/min until a rate of 150 beats/min was achieved. His bundle electrograms were obtained with the technique of Sherlag et a1.6in six patients. After the studies, 1 mg of atropine sulfate was administered intravenously in 14 patients, and carotid sinus stimulation was repeated in the same manner. At the rate of maximal suppression, the sinus nodal recovery time was measured from the last atria1 paced beat to the following sinus beat. Secondary pauses after the termination of rapid atria1 pacing were measured if these pauses exceeded the length of the first escape cycle (one patient). The corrected sinus recovery time was obtained by subtracting the spontaneous sinus cycle length before pacing (average 10 cycles) from the sinus nodal recovery time. The corrected sinus recovery time was considered abnormal if the interval exceeded 525 msec.7 Atrioventricular (A-V) nodal conduction was considered abnormal if second degree A-V block occurred at pacing rates of less than 130 beats/min.s
on backing up in a motor vehicle, local pressure on the neck, micturition or sneezing suggested possible precipitating factors. These possible causal factors preceded only the minority of episodes, and in some instances the history of these events was obtained only after repeated questioning. A history of a precipitating event was not obtained in two patients who could not remember events prior to syncope. Three patients had syncope while driving. One of these patients had several serious accidents while backing up his truck. Two patients had postsyncopal chest pain typical of myocardial ischemia. One patient had a marked increase in frequency of syncope while taking propranolol. The duration of symptoms before the demonstration of carotid sinus hypersensitivity in these nine patients was 1 to 46 months (mean 17 months). Three patients were followed up for 8,26 and 48 months before pacemaker implantation. Tincture of belladonna was tried in all three but was beneficial only temporarily. Serious side effects, including visual blurring and urinary retention, necessitated stopping the drug or reducing the dose to a level that no longer prevented symptoms. During the observation period before pacemaker insertion, two patients were asymptomatic for 16 and 37 months, respectively, but both had later recurrence of multiple episodes of syncope.
Results
5 to 45 months (mean 22) since pacemaker implantation. Syncope has not recurred in eight of the nine patients. Patient 9 had a single episode of syncope while eating breakfast 4 months after pacemaker insertion. Evaluation at that time showed the pacemaker to be functioning normally. The systemic arterial blood pressure was 120/82 mm Hg in the sitting position, but decreased to 80/70 mm Hg with gentle right carotid stimulation.During stimulationthe pacemaker rate was unaltered at 70 beats/min. The patient noted transient dizzinesscoincident with the decrease in blood pressure. He appears to have both cardioinhibitory and vasodepressor hypersensitivity and, if his symptoms continue, further therapy will be necessary. Although syncope has not recurred since pacemaker insertion,two of these patients have occasional episodes of lightheadedness while standing. Orthostatic hypotension appears to be the cause of symptoms in one patient and the cause is unknown in the other.
Clinical features: The 21 men evaluated for episodes of lightheadedness or syncope associated with carotid sinus hypersensitivity ranged in age from 47 to 84 years (mean 62) (Table I). Seventeen patients had the cardioinhibitory type of hypersensitivecarotid sinus reflex, two the vasodepressor form and two both the cardioinhibitory and vasodepressor types. Most of the 21 patients had heart disease; 14 had coronary atherosclerotic heart disease, diagnosed from a history of angina pectoris (14 patients), prior myocardial infarction (9 patients) or coronary arteriography (4 patients). Three patients had had coronary bypass surgery. Only two men had no clinical evidence of associated organic heart disease, but neither had had cardiac catheterization or coronary arteriography. Electrocardiographic evidence of prior inferior myocardial infarction was found in 8 of the 14 patients with coronary atherosclerotic heart disease. No patient had documented spontaneous sinoatrial block. The one patient with paroxysmal atrial tachyarrhythmia had been treated for hyperthyroidism 24 years earlier but was euthyroid at the time of examination. Cardioinhibitory type with syncope: Patients 1 to 9 (Table I) with the cardioinhibitory type each had had five or more episodes of syncope and also numerous episodes of near syncope. Their symptoms occurred when they were sitting or standing and never while recumbent. Seven of these nine patients recalled some event that may have been important in precipitating syncope. A history of hyperextension of the neck when shaving, looking at the sky, head turning or head turning
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Patients 1 to 9 were treated with a demand cardiac pacemaker: These patients have been followed up for
Three of the nine patients had significant complications related to the insertion of a permanent cardiac pacemaker. One patient had a perioperative subendo-
cardial myocardial infarction, one had the postpericardiotomy syndrome and required hospitalization for treatment of a large pericardial effusion and one had a perioperative myocardial infarction when the pacemaker was implanted at the time of coronary bypass surgery. Cardioinhibitory type without syncope: Patients 10 to 18 (Table I) did not have syncope (except for a single episode in one man) but had a spectrum of complaints involving transient clouding of consciousness.
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Unlike most of the patients requiring pacemaker therapy, only one of these nine patients could recall a precipitating event capable of stimulating the carotid sinus. Seven of these’nine patients have been followed up for an average of 33 months, and none have experienced syncopal episodes. During the follow-up period a neurologic consultant diagnosed vertebral basilar arterial insufficiency in addition to carotid sinus sensitivity in two patients; the symptoms typical of the insufficiency were not apparent from the initial evaluation. Five patients have noted a decrease or disappearance of their symptoms, for which no satisfactory explanation was found. Vasodepressor or mixed type: Patients 19,20 and 21 have vasodepressor or both vasodepressor and cardioinhibitory carotid hypersensitivity; they will be discussed individually. Patient 19: For the preceding 5 years, this 64 year old man had experienced dizziness without complete loss of consciousness when he extended his neck and lifted his arms to place articles on shelves in a warehouse; At the time of the initial examination, he was taking hydralazine, 40 n&day, for arterial hypertension. The maximal pause ever recorded on his electrocardiogram during carotid sinus stimulation was 1.4 seconds. The recumbent blood pressure was 140/80 mm Hg and decreased to 125/70 mm Hg on standing. During right carotid sinus stimulation, the blood pressure decreased to 80160 mm Hg during sitting and 70150during standing, and the patient’s spontaneous symptoms were reproduced. On repeat testing after discontinuation of hydralazine, blood pressure was 150/82 mm Hg while he was recumbent, 130/80 during standing and 98180during standing with right carotid sinus stimulation. The patient had no symptoms when blood pressure was 98/80 mm Hg. During the past year the patient continued to have symptoms at work, but they occurred less frequently. In the future more definitive therapy may be needed. The reflex decrease in systolic blood pressure did not exceed 50 mm Hg when all medications were discontinued and therefore did not meet the criteria proposed by Franke2; however, the vasodepressor response to carotid stimulation probably played a major role in the genesis of this patient’s symptoms. Patient 20: This 76 year old man with both oardioinhibitory and vssodepressor carotid sinus hypersensitivitywas first seen because of three episodes of dizziness with near syncope during exercise. The blood pressure was 150/70 mm Hg with the patient recumbent and 140170while he was sitting. Right carotid sinus stimulation produced a 6 second,peri,od.ofasystole. A permanent demand pacemaker was inserted. One month later, the patient complained of dizziness while walking. Blood pressure was 120/80 mm Hg in the recumbent and standing positions, respectively. Right carotid sinus stimulation performed with the patient seated resulted in a decrease in blood pressure to 80/60 mm Hg with a pacemaker-driven heart rate of 71 beats/min. The patient’s symptoms of dizziness were duplicated during right carotid sinus stimulation. He was given fludrocortisone (FlorineF) acetate, 0.1 mg/day, and has been free of dizziness for 1 year, except for a few weeks when the medication was inadvertently discontinued. The fludrocortisone acetate increased the blood pressure to 160/100 and 150/100 mm Hg in the recumbent and standing
position, respectively. Patient 21: This 59 year old school teacher experienced
syncope when he turned his head to look at the back of his classroom. He had stopped wearing neckties because he as-
&pbnbu
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sociated wearing a tight collar with spells of dizziness. A permanent demand pacemaker had been inserted 9 months earlier because of three syncopal attacks that were assumed to be secondary to a bradyarrhythmia. Asystole had not been documented, however, and carotid sinus stimulation was not performed before the pacemaker insertion. The pacemaker was found to be functioning normally. Aortic valve stenosis of mild to moderate severity was detected. Bilateral carotid arteriograms were normal. Blood pressure was 130/80 mm Hg in the standing position. During right carotid sinus stimulation Korotkoff sounds could not be heard, and presyncopal symptoms developed. The patient was advised not to wear tight collars or turn his head abruptly, but syncopal episodes continued, some associated with singing or head turning. Radiation therapy to a tissue dose of 900 roentgens was administered to both the right and the left carotid sinus. One year after the radiation therapy, the patient’s symptoms recurred. Syncope was induced by head turning but not by exercise. Right carotid stimulation performed with the patient seated produced a decrease in systolic blood pressure from 130 to 82 mm Hg, and the patient became dizzy. There was no change in systolic blood pressure during left carotid stimulation. The right carotid sinus was again radiated, with a tissue dose of 1,200 roentgens yielding a total dose to the right carotid sinus of 2,100 roentgens. Over the ensuing 5 years, the patient has had no syncope or near syncope, and right or left carotid sinus stimulation does not alter blood pressure. Two years after the second course of radiation therapy, the patient had congestive heart failure due to aortic stenosis. Cardiac catheterization confirmed the presence of severe aortic stenosis and demonstrated normal coronary arteries. The stenotic aortic valve was replaced. Although the presence of aortic stenosis surely decreased the patient’s ability to compensate for decrease in peripheral arterial resistance induced by the carotid sinus reflex, the valve lesion was probably not the major cause of syncope because: (1) syncope was incited by head turning and carotid sinus stimulation rather than by exercise, and (2) the symptoms were abolished by the carotid sinus radiation a full 2 years before the replacement of the stenotic aortic valve.
Electrophysiologic studies: In the 17 patients with cardioinhibitory hypersensitive carotid sinus reflex, the corrected sinus nodal recovery time was less than 525 msec in 14 patients and greater than 525 msec in 3 patients (Table II). The rate of atrial pacing that produced maximal sinoatrial nodal suppression varied from 76 to 150 beats/min. Of the eight patients treated successfully with pacemakers who consented to be studied, seven had a normal and one a prolonged corrected sinus nodal recovery time. The single patient with prolonged recovery time had sinus bradycardia and paroxysmal atria1 fibrillation and flutter. Atrioventricular Wenckebach periods developed at a paced atria1 rate greater than 130 beatsfmin in 13 patients and less than 130 beats/min in 3. After the administration of 1 mg of atropine, 1:l A-V conduction was present at a pacing rate of 140 beats/min or less in the later three patients. His bundle recordings were obtained in six patients. The H-V intervals were 55 msec or less, and the A-H intervals ranged from 65 to 90 msec. The effect of 1 mg of atropine on corrected sinus nodal recovery time was studied in two of the three patients with prolonged recovery time. The recovery time was normal in one patient and could not be determined in the second patient
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TABLE II Results of Physiologic Studies
Case no.
Resting Sinus Rate (beats/min)
Sinus Nodal Reovery Time (msec)
Connected Sinus Recovery Time (msec)
El 87 80
920 880 1090 1280
11: 190 280
: 7 8
:: 57 81
1900 1040 1550 860
850 290 490 120
10
58 76 78
1580 1040 1180 1850 1150
530 250 410 780 150
2530 (beat #2) 1130 1150
1460
: 3 4
::
15 16
80 77
Paced Rate at Maximal Suppression (beats/min)
380 370
130 150 123 120
Sinus Rate Before Atropine (beatslmin)
77 58
98 79
>130 >150 >150 >130
:: 70 79
88 58 75 88
>140 >130 105 >I50
60
114
ss 58 75
ibs 100 88
ii
143 1:: 97. 156 76 105 90 148 138
Rate of A-V Wenckebach Conduction (beats/min)
Heart Rate After Atropine (beatsjmin)
iib
X39: >140 >140 138
(junctional) 144 133
76 80
92 75 liunctionall
>145
.
’ ::
:8
1240 1080
240 330
.80.
107 143
. 9ii
>143 107
A-V = atrioventricular.
because the postpacing pause was terminated by an A-V junctional beat. Ah-opine (1 mg) was given to 14 patients. The postatropine pulse rate was less than 90 beats/min in seven patients (five with sinus rhythm and two with A-V junctional rhythm), and in the other seven patients the sinus rate was 90 beats/min or greater. Discussion Cardioinhlbitory
Type
Precipitating causes of syncope: Our results in patients with the cardioinhibitory type of carotid sinus hypersensitivity suggest that the patient’s history may be of value in selecting candidates for aggressive therapy. All of our patients whose syncope was abolished by a cardiac pacemaker had multiple syncopal episodes and many additional episodes of near syncope. These symptoms always occurred when the patient was standing or seated. Most patients could recall a precipitating event associated with episodes of syncope, although the majority of syncopal episodes were not initiated by a trigger mechanism. A few patients were unable to give a hi&toryof a precipitating event because they were unable to remember events before the episode. Most of the factors that produced syncope were maneuvers inducing direct pressure or tension on the carotid sinus. It should be noted that head turning or neck extension may produce, in addition to carotid sinus stimulation, mechanical impairment of blood flow through the vertebral arteries.g Activities other than those that produce extravascular stimulation of the carotid sinus region can induce clinical symptoms in certain predisposed persons. In some patients coughing, sneezing and straining at stool have induced sponta-
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neous syncope.4~10 Syncope associated with micturition and intense sneezing was noted in our series. Reproducibility of symptoms by carotid sinus stimulation: The need to reproduce the exact symp-
toms with carotid sinus massage before instituting treatment is controversial.3J0J1In most of our patients we were unable to reproduce an identical symptom complex with carotid sinus stimulation. All patients noted dizziness during the period of asystole; however, a complete loss of consciousness occurred in only one patient, probably because carotid sinus stimulationwas performed with the patient recumbent and was stopped when a pause was noted in the electrocardiogram. The additional information that might be obtained by having the patient sit or stand during manual stimulation of the carotid sinus or by continuing stimulation until syncope occurs, may not justify the risk of inducing seriouscerebral or cardiac ischemia.In addition, in some patients with no spontaneous symptoms the carotid sinus may be sensitive and massage may precipitate unconsciousness. Natural history: Little is known about the natural history of the cardioinhibitory form of hypersensitivity. Because Patients 1 to 9 had had symptoms an average of 17 months before examination and three patients were followed up before pacemaker insertion, we observed the clinical course of these patients for a con-
siderable period of time. In general, the frequency of spontaneous syncope seemed to wax and wane, and some patients were free of symptoms for more than a year. We were unable to detect any factors such as variation in the severity of angina pectoris or hypertension to account for the variability in spontaneous attacks. However, syncope did recur and no patient had a permanent resolution of his symptoms without defi-
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nite treatment. During symptom-free periods, the response to carotid sinus stimulation was sometimes normal. Fluctuation in carotid sinus sensitivity has been noted by others.3J0 Patients without syncope: In the patients with episodes of clouding of consciousness rather than syncope, a history of precipitating factors was rarely obtained on the initial or follow-up visits. In seven of the nine patients followed up for an average of 33 months syncope did not develop. Follow-up examination, including a repeat history, supine and standing blood pressure measurements and treadmill exercise testing, was useful in establishing a diagnosis in a few patients. Occasionally a patient’s symptoms disappeared spontaneously, although in others they continued but defied explanation. Hypersensitivity of the carotid sinus reflex may have contributed to symptoms in these patients without true syncope, but it was probably not a major factor. Vasodepressor or Mixed Type The effects of carotid sinus stimulation on the heart and the peripheral vasculature appear to be independent of each other.12 Atropine abolishes slowing of the heart rate but does not prevent a decrease in systemic The decrease in blood pressure blood pressure. 1~*2~13 results from inhibition of sympathetic vasoconstrictor nerves and possibly activation of cholinergic sympathetic vasodilator fibers.l Epinephrine administered parenterally may prevent the hypotension.3 The clinical symptoms of the vasodepressor type are the same as those occurring in the cardioinhibitory form, but the episodes may be extended in the vasodepressor form because the decrease in blood pressure generally lasts longer than the bradycardia.‘J2 Patients having vasodepressor or both cardioinhibitory and vasodepressor hypersensitivity are especially challenging. Although one reviewi of the hyperactive carotid sinus reflex states that various reflex types often occur in the mixed form, it is difficult to find published examples of such patients. Two patients in our group appear to demonstrate both vasodepressor and cardioinhibitory types. The definition for the vasodepressor type of hyperactive reflex proposed by Franke2 is a decrease in systolic blood pressure of 50 mm Hg or greater. The systolic blood pressure did not always decrease 50 mm Hg or more in our patients with the vasodepressor type, but symptoms were reproduced in all patients. The response may have been blunted because blood pressure was determined in the sitting position in two patients and carotid stimulation was terminated on the appearance of symptoms. However, it appears that vasodepressor hypersensitive carotid sinus reflex was important in the genesis of symptoms in our patients. Diagnosis of vasodepressor type in presence of cardioinhibitory type: It is distressing to find patients who continue to have syncope or near syncope after pacemaker treatment for cardioinhibitory carotid sinus hypersensitivity. It is possible that the carotid hypersensitivity and syncope are unrelated and that the Cal-se
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of the syncope has been missed. A second possibility is that the patient has both the cardioinhibitory and vasodepressor types of carotid hypersensitivity and that, despite the prevention of bradycardia by the pacemaker, the reflex decrease in blood pressure continues to produce symptoms. This combination appears with sufficient frequency to warrant screening for the vasodepressor type in all patients with the cardioinhibitory form. If carotid sinus stimulation provokes cardiac asystole for longer than 3 seconds, 1 mg of atropine should be given intravenously, and the carotid sinus stimulation should be repeated within 5 minutes with the patient seated. If retesting results in a decrease in blood pressure despite the maintenance of a normal heart rate, the patient may be assumed to have vasodepressor as well as cardioinhibitory carotid sinus hypersensitivity. Treatment Indications for treatment: A hyperactive carotid sinus reflex that does not cause symptoms requires no treatment. The question of therapy occurs when a patiept has repeated episodes of syncope or near syncope, and the common causes of syncope have been excluded. If the patient is taking any drug that affects cardiac pacemaker activity or the capacitance or resistance vessels, therapeutic decisions should be deferred and carotid sinus stimulation repeated when the effects of the drug have dissipated. Digitalis was demonstrated to increase carotid sinus neural discharge for a given change in carotid sinus pressure.14 We saw one patient, not included in this report, who had syncope and a 3.4 second sinus pause with carotid sinus stimulation only while taking propranolol. The hyperactive carotid reflex and symptoms of syncope disappeared when propran0101was discontinued. Drugs that decrease intravascular blood volume or peripheral arterial resistance or that increase venous capacitance may enhance the hypotensive response to carotid stimulation in a patient with the vasodepressor type of hyperactive carotid sinus reflex. Patients with cardioinhibitory hypersensitivity who have repeated spontaneous episodes of syncope should be treated. If syncope is precipitated by a maneuver that produces mechanical stimulation of carotid arteries or by a vagal reflex activated from some other site, a reflexly induced cardiac asystole is probably responsible for the symptoms. Observations in several of our patients suggest that spontaneous syncope may disappear for months or even a year but often recurs later. The long-term follow-up of more patients is necessary to determine whether these findings represent the natural history of cardioinhibitory hypersensitivity. The risk of syncope while driving a vehicle or working in certain situations usually necessitates treatment whenever the diagnosis is fairly certain. Patients who have episodes of clouding of consciousness without a known inciting event can, according to our experience, be followed up without therapy. Cardiac pacemaker imprantation: The preferred treatment for cardioinhibitory induced syncope is im-
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plantation of a demand cardiac pacemaker. Pacemaker treatment is highly successful, and the results are superior to those reported in any other form of theraPY.~JOJ~J~J” Only about two thirds of patients are free of symptoms after radiation therapy or surgical denervation of the carotid sinus.‘J6 Large doses of anticholinergic drugs are often poorly tolerated and may not abolish symptoms.‘5 Treatment of vasodepressor or mixed types: The best treatment for vasodepressor or mixed vasodepressor and cardioinhibitory carotid hypersensitivity remains to be established. Some milder cases of the vasodepressor form may respond to simple measures, such as increasing blood volume with mineralocorticoids. Severe vasodepressor or mixed vasodepressor cardioinhibitory may require treatment with either radiation therapy or surgical denervation of the carotid sinus. In one of our patients, a total tissue dose of 2,100 roentgens was required to abolish the reflex decrease in blood pressure. This dose is substantially higher than that recommended previously.16 Carotid sinus denervation with periarterial stripping or the use of electrical nerve stimulation to facilitate the search for sensitive areas on the carotid sinus and surrounding nerves may improve the results of surgical therapy.17J8 Electrophysiology
Some authors1gp20 consider carotid sinus hypersensitivity to be part of the “sick sinus node” syndrome. Our results and those of othersll suggest that carotid sinus hypersensitivity and sick sinus syndrome are separable entities but that both may occur in the same patient. In contrast to patients with the sick sinus syndrome, only one of our patients had paroxysmal atria1 tachyarrhythmia alternating with sinus bradycardia (bradycardia-tachycardia syndrome), and no patient had electrocardiographic documentation of type I or II sinoatrial block. Sinus nodal function: Only 3 of our 17 patients (18 percent) with the cardioinhibitory type of hypersensitivity had a corrected sinus nodal recovery time greater than 525 msec. One of these three patients had abnormal prolongation of a cycle after, the first postpacing cycle. Although electrophysiologic testing of sinus nodal function by atria1 pacing with determination of corrected sinus nodal recovery time is not a definitive test for separating normal from abnormal sinus nodal function, the incidence rate (18 percent) in our patients of a prolonged corrected sinus nodal recovery time or secondary postpacing pauses was considerably less than the rate reported in patients with symptomatic sinus
nodal dysfunction .21y22Rosen et a1.8 reported a high incidence rate of A-V conduction defects in patients with sinus nodal dysfunction. Atrioventricular conduction appeared normal in 81 percent of our patients. The results of sinus nodal recovery time in our patients were of little value in selecting patients for pacemaker therapy. Pathophysiology: The pathophysiology of cardioinhibitory hypersensitivity and the site from which it arises are unknown. The carotid sinus receptors or reflex afferents, the autonomic centers of the brain stem and the efferent limb of the reflex arc have all been proposed as sites of hypersensitivity.3-5J2,23 A combination of abnormalities at multiple sites is also possible. Changes in the efferent limb of the reflex have received the greatest attention because a hypersensitive carotid sinus reflex is commonly associated with organic heart disease. The cardioinhibitory response to carotid sinus stimulation was demonstrated to increase in experimental animals by myocardial hypoxia and chronically studied unilateral vagotomy.5124 Chronically, vagotomy may increase sensitivity to acetylcholine because of degeneration of postganglionic fibers.24 Events in the heart that account for prolonged asystole have not been determined. Our data suggest
that a disorder of sinus nodal automaticity or sinoatrial conduction is not the major reason for asystole. The corrected sinus nodal recovery time was normal in 82 percent of the patients with the cardioinhibitory type of carotid sinus hypersensitivity in our series and in that reported on by Hartzler and Maloney.li Increased vagal tone is a more likely explanation, with several possible mechanisms in effect: (1) a high
level of resting vagal tone, (2) hyperresponsiveness to acetylcholine, (3) excessive release of acetylcholine, and (4) inadequate cholinesterase activity. A high level of resting vagal tone seems unlikely because atropine did not produce an excessive increase in pulse rate. The heart rate remained less than 90 beats/min in 50 percent of our tested patients. Hyperresponsiveness to acetylcholine is another possibility.25 The release of acetylcholine induced by electrical stimulation during rapid atria1 pacing plays a major role in overdrive suppression of atria1 pacemakers. 26 If the sinus node were hyperresponsive to acetylcholine, rapid atria1 pacing might produce a prolonged pause. However, the fact that sinus nodal recovery times were normal in 14 of our 17 patients (82 percent) may invalidate this proposed mechanism. Other suggested explanations for prolonged asystole are an excessive release of acetylcholine or inadequate cholinesterase activity after carotid sinus stimulation.25
References 1. Thomas JE: Diseases of the carotid sinus-syncope. In Handbook of Clinical Neurology, Vol II, chap 19 (Vinken PJ. Bruyn GW, ed). Amsterdam, North-Holland Publishing, 1972, p 532 2. Franke H: Uber das Karotissinus-Syndrom und den sogenannf :n hyperaktiven Karotissinus-Reflex. Stuttgart, Friedrich-K wl
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Schattauer-Verlag, 1963, p 149 3. Thomas JE: Hyperactive carotid sinus reflex and carotid sinus syncope. Mayo Clin Proc 44~127-139, 1969 4. Nathanson MH: Hyperactive cardioinhibitory carotid sinus reflex. Arch Intern Med 77:491-503, 1946
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5. Slgler LH: The cardioinhibitory carotid sinus reflex. Am J Cardiol 12:175-183, 1983 8. Scherlag BJ, Lau SH, HeKant RH, et al: Catheter technique for recording His bundle activity in man. Circulation 39:13-18, 1989 7. Narula OS, Samet P, Javkr RP: Significance of sinus-node recovery time. Circulation 45:140-158, 1972 8. Rosen KM, Loeb MS, Slnno MZ, et al: Cardiac conduction in patients with symptomatic sinus node disease. Circulation. 43: 838-844, 1971 9. Hutchlnson EC, Yates PO: The cervical portion of the vertebral artery: a clinico-pathological study. Brain 79:319-331, 1958 10. Pereta M, Gereln AN, Mfya@f&hna RR Permanent demand pacing for hypersensitive carotid sinus syndrome. J Can Med Assoc 108:1131-1134, 1973 11. Hartzler CO, Maloney JE: Cardioinhibitory carotid sinus hypersensitivity. Arch Intern Med 137:727-731, 1977 12. Lown B, Levlne SA: The carotid sinus. Circulation 23:788-789, 1981 13. Heron JR, Anderson EG, Noble IM: Cardiac abnormalities associated with carotid-sinus syndrome. Lancet 2:214-218, 1985 14. Guest JA, Gllffs RA: Effect of digitalis on carotii sinus baroreceptor activity. Circ Res 35~247-255, 1974 15. Voss DM. Margnfn GE: Demand pacing and carotid sinus syncope. Am Heart J 79:544-547.1970 16. Greefey HP, Smedal MI, Most W: The treatment of the carotid sinus syndrome by irradiation. N Engl J Med 252:91-94, 1955
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17. Cohen FL, Fruehan CT, King RB: Carotid sinus syndrome. Report of five cases and review of the literature. J Neurosurg 45:78-84, 1976 18. Gardnar RS, Magovern GJ, Park SB, et al: Carotii sinus syndrome: new surgical considerations. Vast Surg 9:204-210, 1975 19. Mandel WJ, Hayakawa H, Alfen HN, et ai: Assessment of sinus node function in patients with the sick sinus syndrome. Circulation 46:761-769, 1972 20. Goldreyer BN: Sinus node dysfunction-a physiologic consideration of arrhythmias involving the sinus node. Cardiovasc Clin 6: 179-198.1974 21. Gupta PK, Lkhsleln E, Chadda KD, et al: Appraisal of sinus nodal recovery time in patients with sick sinus syndrome. Am J Cardiol 34~265-270, 1974 22. BendKl DG, Strauss HC, Schelnman MM, et al: Analysis of secondary pauses following termination of rapid atrial pacing in man. Circulation 54:436-441, 1976 23. Scott JC, Reed EA: Comparison of unilateral with bilateral stimulation of the carotid sinus cardioinhibitory reflex. Am J Physiol 181:27-29.1955 24. Reed EA, Scott JC: Factors influencing the carotid sinus cardioinhibitory reflex. Am J Physiol 181:21-26. 1955 25. Dlghton DH:Sinus bradycardia. Autonomic influence and clinical assessment. Br Heart J 36:791-797, 1974 26. Vassale M: The relationship among cardiac pacemakers. Circ Res 41:269-277, 1977
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