Permanent cardiac pacing for neurocardiogenic syncope

Abstract

Vasovagal syncope is not a benign condition in the elderly population. In patients not responsive to conservative therapy and whose abrupt faints are associated with serious injuries and seriously affected quality of life, pacemaker therapy was suggested. However, the usefulness of cardiac pacing for the prevention of recurrences of vasovagal syncope remains controversial because of the dominant role of the vasodepressor component during the episode. In the Medical Center Alkmaar, the Head-Up Tilt Test (HUTT) has been used since 1996 during the work-up of patients who present with vasovagal syncope. The HUTT showed a dominant cardioinhibitory response in 4.5% of our patients; in elderly patients with vasovagal syncope without prodromal symptoms and refractory on conservative therapy, pacemaker therapy was very effective in preventing syncope during long-term follow-up. (Neth Heart J 2008;16(Suppl1):S15-S19.)

Neurocardiogenic syncope is the most common cause of transient loss of consciousness; other terms that have been used for this condition include vasovagal reflex syncope, vasovagal faint as well as neurally mediated syncope. In this article we will use the term vasovagal syncope.

Roughly 40% of people faint at least once in their life with a first peak in teenagers and a second peak in subjects older than 70 years.¹ This self-limited loss of consciousness is due to a transient global cerebral hypo-perfusion, usually provoked by prolonged standing triggering a reduction of the central blood volume because of pooling in the lower body veins.² The vasovagal reflex also occurs as a secondary response to a wide variety of stimuli such as compression of the carotid sinus and manoeuvres that impair venous return, for example cough, micturation and defecation. Many emotional factors such as pain and unpleasant auditory, olfactory or optical stimuli can bring about the same inappropriate cerebral-mediated afferent reflex in susceptible people. The types of environments in which syncopes are more common are often hot, crowded and emotionally upsetting. Typical warning symptoms are a hot/cold feeling, sweating or clammy sensation and nausea, which may alert most individuals to recognise an impending episode and thereby avert the faint. In the elderly population these warning symptoms are much less clear; the provocative factors are also different. Moreover, the adverse effects of multiple medications, especially antihypertensives, diuretics and antidepressants, are common causes of syncope in older patients.³

In most individuals who are susceptible to reflex syncope the episodes are sporadic by nature; however, in a small percentage of the population vasovagal syncope presents as a chronic and recurrent disorder with a significant impact on quality of life. These patients may suffer from recurrent syncopal or presyncopal attacks once a year to weekly or even daily.⁴

Once the diagnosis is made, it may be sufficient in most patients to provide counselling to avoid provocative situations and to increase water and salt intake. Krediet et al. showed that crossing legs combined with tensing of muscles at the onset of prodromal symptoms can abort or delay impending faints in subjects prone to vasovagal reactions.⁵

In the management of vasovagal syncope, drugs have a limited role and must be combined with physical manoeuvres, and salt and fluid intake.

In patients not responsive to conservative therapy – usually elderly patients with recurrent episodes with few or no prodromal symptoms whose abrupt faints are associated with serious injuries and a significantly affected quality of life – pacemaker implantation was an option. Patients for pacemaker therapy were selected on the basis of the haemodynamic response during a tilt table induced vasovagal syncope. While bradycardia and vasodilation typically occur together, one component may predominate. For instance, marked bradycardia or asystole may be the primary response in some patients, with hypotension as secondary response to the severe drop in heart rate. In these tilt-selected patients, small non-randomised and randomised trials showed a marked improvement in quality of life and a significant decline in the number of faints after pacemaker implantation. A large prospective randomised trial, the North American Vasovagal Pacemaker Study, confirmed these observations; however, in this study the patients were randomised to pacemaker or no pacemaker implant.⁶ Later studies of patients who all had pacemaker implants but were randomised to the pacemaker programmed to on or off were not convincing regarding any benefit.⁷

In the Medical Center Alkmaar, pacemaker therapy followed by counselling has been used since 1996 in carefully selected patients with severe symptoms who are not responsive to drug treatment and who show a cardioinhibitor response during the tilt-table test.

We explored the long-term follow-up of tilt-positive vasovagal patients and compared the effect of conservative treatment and cardiac pacing to prevent further occurrence of syncope.

Methods

The diagnosis of vasovagal syncope was based on the exclusion of all possible causes of syncope by means of a systematic workup.^8,9 Particularly in the elderly population, the diagnosis can be difficult; histories may be inaccurate or unreliable and the situation is often complicated by comorbidity and polypharmacy. The three key questions in the initial evaluation are: 1: Is loss of consciousness attributable to syncope, 2: Is heart disease present or absent, 3: Are there important clues in the history that suggest the diagnosis? In the initial evaluation of the patient, accurate medical history taking and recording of witness reports are crucial in every case. The 12-lead ECG and echocardiogram are included. In many cases no further evaluation is needed and the patient is reassured and sent home with an appointment for a follow-up visit to the syncope clinic for counselling about the condition and preventive measures that can be taken. In less clear cases and patients with recurrent symptoms, especially in the absence of prodrominal symptoms, head-up tilt testing was performed and implantable loop recorders were used. The tilt test protocol recommended by the European Society of Cardiology (ESC)⁹ with a tilt angle of 60% was used with continuous beat-to-beat ECG and finger arterial blood pressure recording. If the passive phase of 20 minutes is negative, a drug challenge is given with 0.4 mg sublingual nitroglycerin for an additional 20 minutes. During supine and tilt testing, sinus carotid massage is performed. The end-point of the test is defined as induction of syncope or completion of the planned duration of tilt including drug provocation. The test is regarded positive when syncope occurs, particularly when the patient recognises the symptoms. The details of haemodynamic response are classified according the VASIS classification, which was first proposed in 1992 and modified in 2000 (table 1).⁹ Patients with a type 2B (cardioinhibitory) HUTT response were regarded as potential responders to pacemaker therapy. Type 2B (cardioinhibitory) response is defined as an initial increase in heart rate followed by a drop in the ventricular rate <40 beats/min for >10 seconds or an asystole occurring for >3 seconds with blood pressure rising initially and only falling to hypotensive levels <80 mmHg systolic at or after the onset of a rapid and severe drop in heart rate (figure 1).

Table 1.

Classification of positive responses to tilt testing, according to the Vasovagal Syncope International Study (VASIS ).

Type 1, Mixed

Heart rate falls at the time of syncope but the ventricular rate does not drop below 40 beats/min or drops to less than 40 beats/min for less than 10 sec with or without asystole of less than 3 sec. Blood pressure falls before the heart rate falls

Type 2A, Cardioinhibition without asystole >3 sec

Heart rate falls to a ventricular rate below 40 beats/min for more than 10 sec but asystole of more than 3 sec does not occur.

Blood pressure falls before the heart rate falls

Type 2B, Cardioinhibition with asystole >3 sec

Asystole occurs for more than 3 sec. Fall in blood pressure coincides with or occurs before the drop in heart rate

Type 3, Vasodepressor

Heart rate does not fall more than 10% from its peak at the time of syncope

Exception 1, Chronotropic incompetence

No rise in heart rate during tilt testing (i.e. less than 10% from the pre-tilt rate)

Exception 2, Excessive heart rate rise

An excessive rise in heart rate both at the onset of the upright position and throughout its duration before syncope (i.e. greater than 130 beats/min)

Figure 1.

Haemodynamic responses according the VASIS classification. Type 1=mixed response, type 2A and 2B=cardioinhibitory responses, type 3=vasodepressive response

Between 1996 and 2000, pacemakers were implanted in 25 tilt-positive VASIS 1 and 3 patients not responding to fludrocortisone and/or midodrine; all these patient had typical heart rate and blood pressure fluctuations 1 to 5 minutes before syncope. It was postulated that these variations were due to a compensatory increase in sympathetic tone induced by diminished venous backflow, and dual chamber pacemakers with sensors responsive to the effect of sympathetic activity should be able to respond early in the vasovagal syncope.

Results

Between 1996 and 2008, 528 patients, 315 (59.7%) male, 213 (40.3%) female, underwent tilt testing; 246 (46.6%) patients had a positive test and in 208 (39.4%) we found a mixed or vasodepressor response (VASIS 1 and 3) in 38 (7.2%) patients a cardioinhibitory response type 2A in 17 and 2B (3.2%) in patients. In nine (1.7%) patients a hypersensitive sinus carotid syndrome was diagnosed with documented bradycardia and recognition of symptoms on carotid sinus massage. Cardiac pacing was beneficial in all nine patients, one patient still had dizzy spells, but without fainting.

Of the vasovagal (VASIS) 2B group, ten patients (mean age 34.6±9.6 years, 8 male, 2 female, mean of 3 syncopal episodes before HUTT), all had asystole during HUTT, varying from 5 to 24 seconds, mean 14.1±8.8. All showed prodromal symptoms during tilting and recognised their symptoms. A conservative treatment was applied in these patients consisting of education, increased water and salt intake and counter pressure manoeuvres. After a mean follow-up of 55.9±30.4 months, four of these ten patients suffered a single new syncope and in one patient two new syncopes occurred. This outcome obviously differed from the number of syncopal episodes (n=30 for the whole group) in the six months before HUTT.

The other 11 patients with VASIS 2B (mean age 62.3±14.8 years, 10 male, one female, mean of 1.8 syncopal episodes before HUTT) all had asystole during HUTT, varying from 5 to 26 seconds, mean 9.8±6.9. All patients experienced serious injuries because of a sudden fall and their quality of life was strongly diminished. All patients received a DDDR pacemaker with a programmable rate drop response feature. After a mean follow-up of 59.9±26.3 months, no syncopes occurred in contrast to the 20 attacks emerging in the whole group before HUTT. In the paced group, one patient died from a non-cardiac cause.

In the 25 patients (aged 72.2±6.4 years) who failed to respond to pharmacological therapy and who had a positive vasodepressive tilt response (VASIS 1 and 3), permanent pacing seemed the last available solution; during a follow-up of 118.2±32.9 months syncopal attacks recurred in 21 patients, but 11 patients improved significantly and remained free from falling during syncope.

Discussion

Underlying cardiac disease, not vasovagal syncope, predicted mortality in several studies.¹⁰ Since vasovagal syncope does not carry a direct risk of mortality, the treatment is primarily directed toward the prevention of both the recurrence of symptoms and associated injuries. In the younger population, reassurance combined with explanation of the trigger mechanisms, the prodromal signs and the preventive measures will be sufficient in most cases. In patients suffering persistent posture-related vasovagal syncope, attacks can be delayed or even prevented by leg crossing and muscle tensing.^5,9 The role of medical treatment in patients with vasovagal syncope is minor and must be combined with physical manoeuvres, and fluid and salt intake. The usefulness of cardiac pacing for the prevention of recurrences of vasovagal syncope remains controversial because of the dominant role of the vasodepressor component in comparison with the cardioinhibitory component (marked bradycardia or asystole).

In our patient population in whom a vasovagal syncope was suspected, the diagnosis was supported by a positive tilt table test in only 47% of the cases. The assumption that fainting is a female problem was certainly not true in our series; almost 60% of tilt table testing was performed in males. Ganzeboom et al.¹ found no striking differences between males and females; however, young females are more likely to faint but the peak of late-onset vasovagal syncope between ages 40 and 60 years is particularly seen in men.

Almost 95% of the positive tests showed a vasodepressive response not suitable for pacing; in half of the remaining 5%, pacemakers were implanted. In 25 elderly patients (aged 72.2±6.4 years) who failed to respond to pharmacological therapy and with a positive vasodepressive tilt response (VASIS 1 and 3) permanent pacing seemed to be the last available solution; during a follow-up of 118.2±32.9 months syncopal attacks recurred in 21 patients; however, 11 improved significantly and remained free from falling during syncope. Unfortunately, we were not able to predict the responders to pacemaker therapy and in 1999 we started an outpatient clinic for intensive follow-up and counselling of severely symptomatic vasodepressive patients. The patients were advised to greatly increase their fluid intake and were taught how to apply physical counterpressure. This approach was so successful in preventing syncope that we stopped implanting pacemakers in vasodepressive syncope.

Only cardioinhibitory patients who were suitable for cardiac pacing on the basis of tilt table testing and did not respond to conservative therapy, received pacemaker implants; see data above. The patients who responded to conservative management were much younger, they experienced prodrominal symptoms, but the asystolic periods during tilt were longer. Likely, the vagal-induced reflex bradycardia in young people is more pronounced. In the older pacemaker group there is a greater coincidence of hypertension; hypertension impairs baroreflex sensitivity and restricts ventricular filling and, paradoxically, increases the risk of episodic hypotension.³ In our 11 patients with cardioinhibitory response on tilt table testing, pacemaker implantation was very effective in the treatment of syncope; syncope did not recur in any of these patients during a follow-up of many years. In our paced patients, two had syncope during sleep. They gave a history of waking up with abdominal discomfort, nausea followed by loss of consciousness. Both patients were observed on telemetry and showed an asystole of more than 25 seconds during the attack. Nurses rushed to the bed and found the patients profusely sweating. After regaining consciousness the patients felt weak and bradycardia and a low blood pressure were measured. This new entity was defined as ‘sleep syncope’ and has been recently described.¹¹ After pacemaker implant our patients were free of symptoms.

Several small non-randomised studies have evaluated the efficiency of pacemakers in the prevention of vasovagal syncope and found that pacing looked better than no therapy or medication. The initial randomised trials showing favourable results for pacing⁶ did not include the implantation of a pacemaker in the control group, a potential for a ‘placebo effect’ due to the psychological benefit from receiving a device can not be ruled out.

A later randomised trial comparing DDD pacing with rate drop response (RDR) with a sensing without pacing mode (ODO) showed a nonsignificant relative risk reduction in the recurrence rate of syncope with the use of the DDD-RDR mode.⁷

However, not all the randomised studies were based on tilt table information; in the VPS I and II studies the VASIS classification was not even used. The predictive value of the tilt table test has been questioned.^9,12 Recent studies combining tilt table testing haemo-dynamics with information gathered from implanted loop recorders showed that syncope patterns on tilt table testing may not be the same as those during spontaneous attacks.⁹

The ISSUE 2 Registry¹² established the utility of an implanted loop recorder (ILR) in the diagnosis of syncope in patients without significant electrocardio-graphic or cardiac abnormalities who presumably had vasovagal syncope. The patients underwent tilt testing; however, the pacemaker therapy was based on ILR diagnosis of recurrent suspected cardioinhibitory vasovagal syncope. The one-year recurrence rate among the 53 patients receiving an ILR-specific therapy was 10% compared with 41% in the patients without specific therapy; patients undergoing pacing therapy had the largest reduction.

This trial formed the basis for the ISSUE III study, an international study with Dutch centres participating, in which enrolment started in September 2007. Patients who show asystole longer than 5 seconds during a ‘real life’ attack recorded by the ILR will be randomised. All patients will receive a dual-chamber pacemaker; half will be randomised to the ODO mode (no pacing) and the other half to the active DDD-RDR mode. ISSUE III inclusion stops at the end of this year, and the results are eagerly awaited in 2009. The results of the ISSUE III will probably determine the future role of cardiac pacing in patients severely affected by vasovagal syncope.

In carotid sinus syndrome the role of pacing is considered to be established,^13,14 because in most patients there is a marked cardioinhibitory component of the hypotension. In the recent ACC/AHA/ESC guidelines for permanent pacing,¹⁴ recurrent syncope caused by carotid sinus pressure with a ventricular asystole of more than 3 seconds in the absence of any cardioactive medication is a class I indication, level of evidence B. Following the same guidelines, recurrent syncope without clear provocative events and with hypersensitive cardioinhibitory response is a class 2A indication, level of evidence C. Supine and upright carotid sinus massage will achieve the diagnosis. In up to a third of older patients, a diagnostic cardioinhibitory response is only present when the patient is upright. The reflex sensitivity changes with postural change.⁹ Dual chamber pacing is the preferable pacing mode to cope with the vasodepressor part of the reflex. In current clinical practice the importance of carotid sinus syndrome as a potential cause of syncope in older persons is likely underestimated. Probably many class 2A indications are not recognised. Spontaneous carotid sinus syndrome is rare; however, a positive response occurs in 26 to 60% of patients affected by unexplained syncope .^9,13,14

Conclusion

Vasovagal syncope is not a benign condition in the elderly population. Pacemaker therapy is as yet not an evidence-based treatment. However, in our series pacemaker therapy could be very effective in preventing syncope in highly selected patients. In the Medical Center Alkmaar we adopted a strategy based on diagnostic information from early ILR implant with therapy delayed until documentation of syncope. This approach seems to be safe and provides effective therapy in patients with vasovagal syncope. The results of the ISSUE III study are awaited. In younger patients, counselling on the triggering factors and preventive measures will reduce their symptoms, and medication or pacing will seldom be needed. The role of pacing in carotid sinus syndrome has already been established.