26 Syncope

Syncope is a transient loss of consciousness due to global cerebral hypoperfusion characterized by rapid onset, short duration, and spontaneous complete recovery. The starting point for evaluation of syncope is the ‘initial evaluation’, which consists of history, physical examination, standard electrocardiogram and (if appropriate) echocardiogram, orthostatic challenge, and carotid sinus massage. The initial evaluation has two objectives: to assess the specific risk for the patient (death, severe adverse events, or recurrence of syncope) and to identify the specific cause of the faint in order to address an effective mechanism-specific treatment.

Differentiating true syncope from other ‘non-syncopal’ conditions associated with real or apparent transient loss of consciousness is generally the first diagnostic challenge and influences the subsequent diagnostic strategy. Patients at high short-term risk require immediate hospitalization or early intensive evaluation. Others should be evaluated mostly as out-patients or day cases, and preferably referred to a specialized syncope facility (so-called ‘syncope unit’) if available. In the less severe forms, no further investigation is usually necessary and patients can be educated and reassured on the benign nature of their symptom.

The strategy of evaluation varies according to the severity and frequency of the episodes and to the presence or absence of heart disease. In general, the absence of suspected or certain heart disease excludes a cardiac cause of syncope. Conversely, the presence of heart disease at the initial evaluation is a strong predictor of a cardiac cause of syncope, but its specificity is low because about half of patients with heart disease have a non-cardiac cause of syncope. Determining the mechanism of syncope is a prerequisite to developing an effective mechanism-specific treatment. Most patients with syncope require only reassurance and education regarding the nature of the disease and the avoidance of triggering events.

Syncope is a transient loss of consciousness due to global cerebral hypoperfusion characterized by rapid onset, short duration, and spontaneous complete recovery. This definition of syncope differs from others in including the cause of unconsciousness, i.e. transient global cerebral hypoperfusion. Without that addition, the definition of ‘syncope’ becomes wide enough to include disorders such as epileptic seizures and concussion; in fact, the definition then becomes that of ‘transient loss of consciousness’ (T-LOC), a term purposely meant to encompass all disorders with several similar presenting features. T-LOC is divided into traumatic and non-traumatic forms. Concussion causes LOC by definition; as the presence of a trauma is usually clear there is limited chance of diagnostic confusion. Non-traumatic T-LOC is divided into syncope, epileptic seizures, functional T-LOC, and rare miscellaneous causes ( Fig. 26.1).

Syncope is a symptom, not a disease (neither is it a ‘diagnosis’), and the mechanism has to be identified to allow a nosological diagnosis to be made. In some forms of syncope there

may be a premonitory period in which various symptoms (e.g. light-headedness, nausea, sweating, weakness, and visual disturbances) offer warning of an impending syncopal event. Often, however, loss of consciousness occurs without warning. An accurate estimate of the duration of syncope episodes is rarely obtained. However, typical syncopal episodes are brief. Complete loss of consciousness in vasovagal syncope is usually no longer than 20s in duration. However, rarely syncope duration may be longer, even lasting for several minutes. In such cases, the differential diagnosis between syncope and other causes of loss of consciousness can be difficult. Recovery from syncope is usually accompanied by almost immediate restoration of appropriate behaviour and orientation. Retrograde amnesia, although believed to be uncommon, may be more frequent than previously thought, particularly in older individuals. Sometimes the post-recovery period may be marked by fatigue [1, 2].

‘Presyncope’ or ‘near-syncope’ is used often to describe a state that resembles the premonitory phase of syncope but which is not followed by loss of consciousness; doubts may remain whether the mechanisms involved are the same as in syncope. The term ‘presyncopal’ is used to indicate signs and symptoms that occur before unconsciousness in syncope, so its meaning is more literal and it is a synonymous of ‘warning’ and ‘prodromal’.

Syncope is extremely frequent in the general population and probably >50% of the general population complains of an episode of T-LOC of suspected syncopal nature during life. Approximately 30–40% of young adults experience at least one episode of T-LOC with a peak between the ages of 10–30 years. T-LOC also becomes increasingly frequent over the age of 60. In the Framingham study [3], the 10-year cumulative incidence of syncope was 6%. However, the incidence was not constant, but increased rapidly starting at the age of 70 years. The 10-year cumulative incidence of syncope was 11% for both men and women at age 70–79, and 17% and 19% respectively for men and women at age ≥80. In brief, there is a very high prevalence of first faints in patients in the age group between 10–30 years; first faint is uncommon in middle aged adults; there appears to be a peak above the age of 65 years [4, 5] ( Fig. 26.2). However, only a small fraction of these subjects present in a clinical setting and an even smaller proportion deserve some specialized evaluation [6] ( Fig. 26.3).

Table 26.1 provides a pathophysiological classification of the principal known causes of syncope. Several disorders may resemble syncope in two different ways. In some, consciousness is truly lost, but the mechanism is different from cerebral hypoperfusion. Examples are epilepsy, several metabolic disorders (including hypoxia and hypoglycaemia), and intoxications. In several other disorders, consciousness is only apparently lost; this is the case in ‘psychogenic pseudo-syncope’, cataplexy, and drop attacks. In psychogenic pseudo-syncope, patients may pretend to be unconscious when they are not. This condition can be seen in the context of factitious disorders, malingering, and conversion. Finally, some patients may voluntarily trigger true syncope in themselves to attract attention, as a game, or to obtain some other advantage. Table 26.2 lists the most common conditions misdiagnosed as the cause of syncope. A differentiation such as this is important because the clinician is usually confronted with patients with sudden loss of consciousness (real or apparent) which may be due to

causes not associated with decreased cerebral blood flow, such as seizure and/or conversion reaction.

Syncope classification ( Table 26.1) emphasises large groups of disorders with a common presentation associated with different risk profiles. A distinction along pathophysiological lines centres on a fall in systemic blood pressure as the basis for syncope. Systemic blood pressure is the product of cardiac output and total peripheral vascular resistance and a dysfunction of either can cause syncope, but a combination of both mechanisms is often present, even if their relative contributions vary considerably. Fig. 26.4 shows the pathophysiological underpinning of the classification with low blood pressure at the centre, and low peripheral resistance and low cardiac output next to it. A low peripheral resistance can be due to inappropriate reflex activity in the next ring, known as the vasodepressor type of reflex syncope in the outer ring. Other causes of a low peripheral resistance are functional and structural impairments of the autonomic nervous system with drug-induced, primary, and secondary autonomic failure in the outer ring. The causes of low cardiac output are threefold; the first is a reflex causing bradycardia known as cardioinhibitory type of reflex syncope. The second is purely cardiac, due to arrhythmia, structural cardiac diseases, or to pulmonary embolism. The third is inadequate venous return, due to volume depletion or venous pooling. Note that the possible mixture of causes is most apparent in reflex syncope. The main groups of the classification are shown outside the ring system; for reflex syncope and orthostatic hypotension, they span the two main pathophysiological categories.

A decrease of blood flow below critical levels causes loss of consciousness and of voluntary motor control, at a time when the electroencephalogram (EEG) shows slowing. Prolonged hypoperfusion causes flattening of the EEG. In children with vagally mediated asystole, induced by eyeball pressure, EEG flattening occurs only after a minimum duration of asystole of 9s. It then lasted longer as asystole lasted longer [7]. Experience from tilt testing showed that a decrease in systolic blood pressure to 40–60mmHg is associated with syncope [8]. The integrity of a number of control mechanisms is crucial to maintain sufficient arterial pressure and cerebral perfusion including: arterial baroreceptor-induced adjustments of heart rate, cardiac contractility, and systemic vascular resistance, which modulate circulatory dynamics with arterial pressure as the controlled variable; renin–angiotensin and vasopressin vasoconstriction; renal–body-fluid pressure control system; cerebrovascular ‘autoregulatory’ capability, which permits cerebral blood flow to be maintained over a relatively wide range of arterial pressures.

Reflex syncope traditionally refers to a heterogeneous group of conditions in which cardiovascular reflexes that are normally useful in controlling the circulation become overactive, resulting in vasodilatation and bradycardia and thereby in a fall of arterial blood pressure and cerebral perfusion. A prerequisite for reflex syncope is therefore that the autonomic nervous system is intact. The term ‘vasodepressor type’ is commonly used if vasodilatation predominates. ‘Cardioinhibitory’ is used when bradycardia or asystole predominate and ‘mixed’ is used if both mechanisms come into play.

Reflex syncope may also be classified based on its trigger, i.e. the afferent pathway. The triggering situations vary considerably in and between individual patients. Knowing the various triggers is clinically important, as recognizing them may be instrumental in diagnosing syncope. ‘Vasovagal syncope’, also known as the ‘common faint’, is mediated by emotion (fear, pain, emotional distress, instrumentation, blood phobia) or by orthostatic stress. It is usually preceded by prodromal symptoms of ‘autonomic activation’ (sweating, pallor, nausea). ‘Situational’ syncope traditionally referred to reflex syncope associated with some specific circumstances (e.g. micturition, coughing, defecating, etc.), but there is no cause or need to set one set of triggers apart from others. ‘Carotid sinus syncope’ deserves special mention: in its rare ‘spontaneous’ form it is triggered by accidental mechanical manipulation of the carotid sinuses. This should be distinguished from ‘carotid sinus hypersensitivity’, which refers to a response to carotid sinus massage as a diagnostic test, and which is linked to apparently spontaneous syncope in the elderly: carotid sinus syndrome.

Reflex syncope may occur with uncertain or even apparently absent triggers. The diagnosis then rests less squarely on history taking alone, and more on the exclusion of other causes of syncope (absence of structural heart disease) and on reproducing similar complaints with tilt testing or through carotid sinus massage, (i.e. ‘induced carotid sinus syndrome’). Such less clear presentations overlap with clear-cut occurrences within patients; together with the observation that syncope may be precipitated by different afferent pathways in the same subjects, this supports the concept that reflex syncope represents a tendency to respond in the central or efferent pathways rather than in an abnormality of afferent pathways.

Nonetheless, the classical form of emotional vasovagal syncope, which usually starts in young subjects as an isolated manifestation, should be distinguished from forms, frequently with a non-classical presentation, which start in old age and are often associated with cardiovascular or neurological disorders, and other disturbances such as orthostatic or postprandial hypotension. In these latter subjects, reflex syncope appears as an expression of a pathologic process, mainly related to an impairment of the autonomic nervous system to activate compensatory reflexes, so there is an overlap with autonomic failure. A comparison with other conditions causing syncope in the standing position is presented in Table 26.3.

‘Orthostatic intolerance syndrome’ refers to symptoms and signs in the upright position due to a circulatory abnormality. Syncope is one symptom, and others are dizziness/light-headedness; visual disturbances (including blurring, enhanced brightness, and tunnel vision); hearing disturbances (including impaired hearing, crackles, and tinnitus); pain in the neck (occipital/paracervical and shoulder region); low back pain or precordial pain; weakness, fatigue, lethargy; palpitations and sweating [9]. Orthostatic intolerance syndromes include all the forms of orthostatic hypotension (see list) and also those forms of reflex syncope in which orthostatic stress is the main trigger. Since they have in common the same final mechanism, they also share similar therapies. The change in position may involve lying to sitting or standing as well as sitting to standing; note that it is the upright position that is important, not the change per se.

It is of direct clinical relevance to make a distinction between three main types of orthostatic hypotension ( Table 26.3):

Cardiac arrhythmias can cause a decrease in cardiac output, which usually occurs irrespectively of circulatory demands. Nonetheless, syncope is often multifactorial in arrhythmias, including type of arrhythmia (atrial or ventricular), heart rate, the status of left ventricular function, posture, and the adequacy of vascular compensation (see Chapters 27, 28, and 30). The latter include baroreceptorial neural reflexes as well as responses to orthostatic hypotension induced by the arrhythmia. Regardless of such contributing effects, an intrinsic cardiac arrhythmia is the primary cause of syncope, determining clinical decisions. The different clinical presentation helps to differentiate cardiac from reflex and orthostatic syncopes (see Identifying the mechanism of T-LOC: the diagnostic strategy based on the initial evaluation, p.965).

Structural heart disease can cause syncope when circulatory demands outweigh the impaired ability of the heart to increase its output. Nonetheless, in several cases, syncope is not solely the result of restricted cardiac output, but may be in part due to an inappropriate reflex or orthostatic hypotension. The importance of appropriately recognizing the heart as the cause of the problem justifies the oversimplification.

There are two main reasons for evaluating a patient with T-LOC: one is to identify the specific cause of the faint in order to address an effective mechanism-specific treatment strategy; the other is to identify the specific risk for the patient (either death, severe adverse events, or recurrence of syncope). The prognosis, i.e. the risk of future adverse clinical events to which the patient is subjected, is either directly related to the faint or more generally related to the underlying disease, of which syncope is only an ominous finding or one of the clinical manifestations. Physicians should be aware not to confound the prognostic significance of syncope with that of the underlying disease. The treatment of syncope frequently differs from the treatment of the underlying disease. Therapy should be aimed either to eliminate the cause of syncope or to cure the underlying disease which predisposes to syncope. Therapeutical decisions of both situations greatly depend on the estimation of the relative prognostic significance that physicians attribute to syncope and to underlying disease.

With regard to the prognosis (i.e. risk stratification) associated with syncope, two important elements should be considered: 1) risk of death and life-threatening events and 2) risk of syncopal recurrence.

Structural heart disease is a major risk factor for sudden death and overall mortality in patients with syncope. Conversely, young patients without structural heart disease and patients affected by neurally mediated syncope or orthostatic hypotension have an excellent prognosis with respect to mortality. Life-threatening diseases (e.g. acute coronary event, pulmonary embolism, acute heart failure) are suspected by non-invasive initial assessment, the presence of signs and symptoms such as chest pain or dyspnoea in addition to syncope suggesting those conditions. These situations require prompt and targeted confirmatory testing which should be done urgently. Most of the deaths and many detrimental outcomes seemed to be related to the severity of the underlying disease rather than to syncope per se. Life-threatening diseases may also include severe arrhythmias (e.g. third-degree atrioventricular (AV) block or ventricular tachyarrhythmias). Several clinical factors able to predict outcome have been identified in some prospective population studies involving a validation cohort ( Table 26.4).

Few studies have directly evaluated the short-term risk (within a few days). In the San Francisco Syncope Rule [18], an abnormal electrocardiogram (ECG) result (defined as new changes or non-sinus rhythm), shortness of breath, systolic blood pressure ≤90mmHg, haematocrit ≤30%, and congestive heart failure (by history or examination) predicted the likelihood of serious adverse event within 7 days of Emergency Department (ED) evaluation (defined as death, myocardial infarction, arrhythmia, pulmonary embolism, stroke, subarachnoid haemorrhage, significant haemorrhage, or any condition causing a return ED visit and hospitalization for a related event) with a sensitivity of 98% and a specificity of 56%. However, these results could be only partially confirmed by three other external validation studies [19–21] which showed a high rate of false positive and false negative results ( Table 26.4). The risk of life-threatening conditions in the next few days following referral is obviously the main reason for immediate hospital admission and exhaustive evaluation.

More studies have evaluated the long-term (1-year or more) risk ( Table 26.4). In the pivotal study of Martin et al. [22], an abnormal ECG (defined as rhythm abnormalities, conduction disorders, hypertrophy, old myocardial infarction, and AV block), history of ventricular arrhythmia, history of congestive heart failure, or age more than 45 years were found to be predictors of severe arrhythmias (sustained ventricular tachycardia, symptomatic supraventricular tachycardia, pauses >3s, AV block, pacemaker malfunction) or 1-year mortality. The event rate (clinically significant arrhythmia or arrhythmic death) at 1 year ranged from 0% for those with none of the four risk factors to 27% for those with three or four risk factors. In the OESIL study [23], 1-year predictors of mortality were found to be age >65 years, history of cardiovascular diseases, lack of prodromes, and abnormal ECG (defined as rhythm abnormalities, conduction disorders, hypertrophy, old myocardial infarction, possible acute ischaemia, and AV block) In the OESIL risk score the mortality within 1 year increased progressively from 0% for no factor, to 57.1% for four factors. The EGSYS score [24], although specifically designed to identify cardiac syncope, was also proved to be able to predict a 2-year mortality of 21% in those with a score ≥3 compared with 2% in those with a score <3. In the STePS study [25], the long-term severe outcome was correlated with an age >65 years, history of neoplasms, cerebrovascular diseases, structural heart diseases, and ventricular arrhythmias. This finding is likely to reflect the importance of comorbidities, as suggested by long-term risk factors such as cardiac and cerebrovascular diseases and neoplasms.

In summary, age, an abnormal ECG, a history of cardiovascular disease, especially ventricular arrhythmia, heart failure, syncope occurring without prodrome or during effort or supine, were found to be predictors of arrhythmia and/or 1-year mortality. Risk stratification tools have been developed from these data. Again, similar to the short-term events, most of the deaths and of serious outcomes seemed to be correlated to the severity of the underlying disease rather than to syncope per se. High-risk patients need to be followed closely; optimal therapy and management must be provided. However, the presumption that an immediate in-hospital evaluation improves a patient’s long-term clinical outcome has never been demonstrated and alternative strategies could be considered.

In population studies, approximately one-third of patients have recurrences of syncope at 3 years of follow-up. Number of episodes of syncope during life and their frequency are the strongest predictors of recurrence. In ‘low-risk’ patients with uncertain diagnosis (see Management according to risk stratification, p.964), a history of fewer than three syncopes yields a probability of recurrence of syncope of 20% during the next 2 years, whereas a history of three syncopes yields a probability of recurrence of syncope of 42% during the same period ( Table 26.5). A psychiatric diagnosis and age <45 years are also associated with higher rates of syncopal recurrence. Conversely, sex, tilt-test response, severity of presentation, and presence or absence of structural heart disease have minimal or absent predictive value.

Major morbidity such as fractures and motor vehicle accidents were reported in 6% of patients and minor injury such as laceration and bruises in 29%. In patients presenting to an ED minor trauma were reported in 29.1% and major trauma in 4.7% of cases; the highest prevalence (43%) was observed in elderly patients with carotid sinus hypersensitivity [26]. Recurrent syncope is associated with fractures and soft-tissue injury in 12% of patients. The risk of events (i.e. trauma) is higher if syncope recurrence is unpredictable and in the absence of prodromes [25].

In general, the risk related to recurrence of syncope is higher (and it generally calls for precise diagnosis and specific treatment) in the following settings:

The management flow-chart of the European Society of Cardiology (ESC) Guidelines on Syncope is reported in Fig. 26.5. According to the 2009 Guidelines on Syncope of the ESC, the patients at high short-term risk who require immediate hospitalization or early intensive evaluation can be identified after the initial evaluation ( Table 26.6). In particular:

If, at the end of the intensive evaluation, the work-up is negative (i.e. not persistent severe co-morbidities and no diagnosis of the cause of syncope) the patient can be evaluated as those at low risk.

When the high-risk features are absent or, if present, the subsequent work-up is negative, the risk of life-threatening events is low and the evaluation is aimed at prevention of syncopal recurrences. The patients who have a severe presentation of syncope (because of high risk of trauma or high frequency of episodes) which can benefit from a mechanism-specific therapy should be evaluated mostly as out-patients or day cases preferably referred to a specialized syncope facility (so-called ‘syncope unit’) if available.

Knowledge of what occurs during a spontaneous event is ideally the gold standard for evaluation. An electrocardiographic documentation of a spontaneous syncope can be achieved by in-hospital telemetry, ambulatory Holter, external (ELRs) and implantable loop recorders (ILRs). Since the diagnostic yield depends on the duration of the monitoring period, ILR is by far the most powerful and useful tool among them. However, in-hospital telemetry (or Holter monitoring, see Chapter 2) has been shown to be useful when applied in selected patients referred in urgency for syncope because the probability of documenting a relapse in the ‘hot phase’ of the disease is high in this setting [27, 28] and ELRs are of some utility in patients with recurrent syncopes with an inter-symptom interval ≤4 weeks. Two recent randomized controlled trials showed that an early ILR strategy was safe and had a higher diagnostic yield than laboratory test strategy [29, 30]. In the less severe forms, no further investigation is usually necessary and patients can be educated and reassured on the benign nature of their symptom.

The initial evaluation of a patient presenting with T-LOC consists of careful history, physical examination including orthostatic blood pressure measurements, and 12-lead ECG ( Chapter 2). In patients with suspected heart disease, echocardiography is recommended as first evaluation step. In older patients without suspicion of heart or neurological disease and recurrent syncope, carotid sinus massages is recommended as first evaluation step. When loss of consciousness is related to standing position, orthostatic challenge (lying-to-standing orthostatic test and/or head-up tilt test) is recommended as first evaluation test ( Table 26.7).

Three key questions should be addressed during the initial evaluation:

The initial evaluation may lead to certain or uncertain diagnosis ( Fig. 26.5).

Initial evaluation may lead to a certain diagnosis based on symptoms, physical signs, or ECG findings. Under such circumstances, no further evaluation may be needed and treatment, if any, can be planned. The results of the initial evaluation are most often diagnostic of the cause of syncope in the following situations:

However, it is important to bear in mind that syncope is often multifactorial; this is especially true in older individuals. Thus, careful consideration should be given to multiple, potentially interacting factors (e.g. diuretics in older patients already susceptible to orthostatic hypotension and myocardial ischaemia in the setting of moderate aortic stenosis).

Commonly, the initial evaluation leads to a suspected diagnosis when one or more of the features listed in Tables 26.8 and 26.9 are present. The patients with an EGSYS score >4 ( Table 26.4) yielded a 77% predictive value having an established diagnosis of cardiac syncope. The patients with an EGSYS score <3 yielded a 98% predictive negative value for cardiac syncope and low risk of death (24).

The presence of suspected or certain heart disease is associated with a higher risk of arrhythmias and mortality. In these patients, cardiac evaluation (echocardiography, stress testing, electrophysiological study, and prolonged ECG monitoring including loop recorder) is recommended. If cardiac evaluation does not show evidence of arrhythmia as a cause of syncope, evaluation for neurally mediated syndromes is recommended only in those with recurrent or severe syncope. It includes tilt testing, carotid sinus massage, and ECG monitoring, and often further necessitates implantation of an ILR. The majority of patients with single or rare episodes in this setting have a high likelihood of neurally mediated syncope, and tests for confirmation are usually not necessary.

Neurologic disease may cause T-LOC (e.g. certain seizures), but is almost never the cause of syncope. Thus, neurologic testing may be needed to distinguish seizures from syncope in some patients, but these should not be considered as essential elements in the evaluation of the basis of true syncope. The possible contribution of electroencephalography (EEG), computed tomography (CT) and magnetic resonance imaging (MRI) of the brain is to disclose abnormalities due to epilepsy; there are no specific EEG findings for any loss of consciousness other than epilepsy. Accordingly, several studies conclusively showed that EEG monitoring was of little use in unselected patients with syncope. Thus, EEG is not recommended for patients in whom syncope is the most likely cause for a T-LOC. Carotid TIAs are not accompanied by loss of consciousness. Therefore, carotid Doppler ultrasonography is not required in patients with syncope ( Table 26.10).

If the cause of syncope is undetermined once the evaluation is completed, reappraisal of the work-up is needed because subtle findings or new historical information may change the strategy. Reappraisal may consist of obtaining additional details of history and re-examining the patient, placement of an ILR if not previously undertaken, as well as review of the entire work-up. If new clues to possible cardiac or neurological disease are yielded, further cardiac and neurological assessment are recommended. In these circumstances, consultation with appropriate specialists may be useful. Psychiatric assessment is recommended in patients with frequent recurrent syncope who have multiple other somatic complaints and in whom initial evaluation raises concerns about stress, anxiety, and possible other psychiatric disorders. If no diagnosis can be established at the end of the complete work-up as described here, the syncope is termed unexplained.

Echocardiography ( Chapter 4) is diagnostic of the cause of syncope in the presence of severe aortic stenosis and atrial myxoma. This investigation also provides information about the type and severity of underlying heart disease. If moderate-to-severe structural heart disease is found, evaluation is directed towards a cardiac cause of syncope, whereas in the presence of minor abnormalities the probability of cardiac cause of syncope is low and the evaluation proceeds as in patients without structural heart disease.

Carotid sinus syndrome is diagnosed in patients who have an abnormal response to carotid sinus massage (carotid sinus hypersensitivity) and an otherwise negative work-up for syncope. Carotid sinuses (alternatively right and left) are firmly massaged for 5–10s. The site for massage is the anterior margin of the sternocleomastoid muscle at the level of the cricoid cartilage. Both a cardioinhibitory reflex and a vasodepressor reflex are usually evoked with the massage (mixed form) but their relative contribution varies. A correct determination of the vasodepressor component of the reflex is of practical importance for the choice of pacing therapy, which is more effective in dominant cardioinhibitory forms ( Fig. 26.7). A positive response is defined as a ventricular pause >3s and/or a fall in systolic blood pressure >50mmHg. However, abnormal responses are frequently observed in patients without syncope [32]. The specificity of the test increases if reproduction of spontaneous syncope during carotid massage is a requisite for positivity of the test [33, 34]. The syndrome is misdiagnosed in half of the cases if the massage is not performed in the upright position [33, 35]. There is a relationship between carotid sinus hypersensitivity and spontaneous, otherwise unexplained, syncope [36, 37]. Carotid sinus syndrome is a frequent cause of syncope, especially in elderly men, ranging from 4% in patients aged <40 years to 41% in patients >80 years. In a large population of 1719 consecutive patients with syncope uncertain after the initial evaluation (mean age 66 ± 17 years), carotid sinus hypersensitivity was found in 56% and syncope was reproduced in 26% of cases [33]. The response was cardioinhibitory in 46% of patients, mixed in 40%, and vasodepressor in 14%. The main complication of carotid sinus massage is neurological, i.e. TIA and stroke, its incidence ranging in three studies between 0.17–0.45% [33, 38, 39]. If there is a risk of stroke ( Chapter 15) due to carotid artery disease, massage should be avoided. Therefore, carotid sinus massage is recommended in patients over the age of 40 years with syncope of unknown aetiology after the initial evaluation.

On changing from supine to erect posture, there is a large gravitational shift of blood from the chest to the venous capacitance system below the diaphragm. Failure of compensatory reflexes to orthostatic stress causes the clinical features of the syndrome of orthostatic intolerance listed in Table 26.3. Two orthostatic challenges [12] are widely applied in practice to diagnose the forms of orthostatic hypotension and the form of vasovagal syncope triggered by prolonged standing syndrome of orthostatic intolerance: the lying-to-standing test and the head-up tilt test. Tests involving simulated orthostatic stress by applying lower body negative pressure are mainly used in research settings.

The anaeroid sphygmomanometer is used for routine clinical testing because of its reliability and simplicity. This is the standard method to which other non-invasive devices of blood pressure measurement are validated. Automatic arm-cuff devices, as they are programmed to repeat and confirm measurements when discrepant values are recorded, are at a disadvantage in following the rapidly dropping blood pressure during orthostatic hypotension and are discouraged. Beat-to-beat non-invasive blood pressure measurement is widely used in research and tilt laboratories and is recommended when tilt testing is performed. The most favoured devices are those which utilize the method of Penaz to record the arterial waveform indirectly from a finger. Studies on its accuracy have suggested little systematic bias versus intra-arterial pressure but substantial variability. In combined data from 20 published studies [40] the average systolic bias was 2.2 ± 12.4mmHg. Heart rate recording is integral to orthostatic challenge and is indispensable to the differentiation between certain clinical syndromes.

A marked day-to-day variability of postural response is well documented with both lying-to-standing test and tilt testing. In one study the day-to-day reproducibility of classic orthostatic hypotension in the elderly was only 67% [41]. The reproducibility of tilt testing has been widely studied. The overall reproducibility of an initial negative response (85–94%) is higher than the reproducibility of an initial positive response (31–92%) [42–44]. Data from controlled trials showed that approximately 50% of patients with a baseline positive tilt test became negative when the test was repeated with placebo [45]. Moreover, postural responses show diurnal (worse in the morning) and seasonal (worse during summer) variability. In addition, in patients with postprandial hypotension, the effect is almost immediately apparent after a meal and reaches a nadir within 30–60min [12].

A single postural orthostatic test is sufficient for diagnosis. As orthostatic intolerance is poorly reproducible, it has been shown that several measurements may be required, on several occasions, to detect it.

A frequently utilized protocol is the short, bedside orthostatic test: the patient’s blood pressure is measured after a few minutes of rest in the supine position; the patient arises and the measurements are then repeated while they stand motionless for 3min with the cuffed arm supported at heart level. The advantages are that it corresponds to real-life situations, is simple to perform, its instruments are generally available, and it requires minimal patient cooperation. Initial and classical forms of orthostatic hypotension are usually diagnosed by this method.

The widely accepted protocols [46–53] consist of:

Experience from tilt testing [54, 55] showed that the vasovagal reaction lasts roughly ≤3min before loss of consciousness. A decrease in systolic blood pressure to ≤90mmHg is associated with symptoms of impending syncope reproducing the patient’s previous experience, and ≤60mmHg is associated with syncope. Prodromal symptoms are present in virtually all cases of tilt-induced vasovagal syncope, which occurs, on average, 1min after the onset of prodromal symptoms. During the prodromal phase, blood pressure falls markedly; this fall frequently precedes the decrease in heart rate, which may be absent at least at the beginning of this phase. During the syncopal phase, a cardioinhibitory reflex of variable severity (ranging from slight heart rate decrease up to prolonged asystole) is frequent and contributes to the loss of consciousness ( Fig. 26.8). Delayed (progressive) orthostatic hypotension is usually diagnosed by tilt testing but not by lying-to-standing test ( Fig. 26.9).

In patients without structural heart disease, tilt testing can be considered diagnostic, and no further tests are needed when syncope is reproduced. In patients with structural heart disease, arrhythmias or other cardiac causes should be excluded prior to considering positive tilt test results. The clinical meaning of abnormal responses other than induction of syncope is unclear.

It should be kept in mind, however, that the relationship between symptoms occurring during an orthostatic test, essentially representative of a laboratory phenomenon, and symptoms occurring in a patient’s natural ambience is not always clear [56]. The mechanism of tilt-induced syncope was frequently different from that of the spontaneous syncope recorded with the ILR in some studies [57, 58]. These data show, in addition to those of weak reproducibility, that the use of tilt testing for assessing the effectiveness of different treatments has important limitations.

In general, ECG monitoring ( Chapter 2) is indicated only when there is a high pre-test probability of identifying an arrhythmia responsible for syncope. These conditions are listed in Tables 26.8 and 26.9. ECG monitoring is diagnostic when a correlation between syncope and electrocardiographic abnormality (brady- or tachyarrhythmia) is detected. Conversely, ECG monitoring excludes an arrhythmic cause when there is a correlation between syncope and no rhythm variation. Presyncope may not be an accurate surrogate for syncope in establishing a diagnosis and, therefore, therapy should not be guided by presyncopal findings. In the absence of such correlations, additional testing is recommended with the possible exception of a ventricular pause >3s or periods of Mobitz II or third-degree AV block (with possible exceptions for young trained persons, sleeping conditions, or medicated patients), or rapid prolonged (i.e. ≥160bpm for >32 beats) paroxysmal atrial or ventricular tachyarrhythmias are detected.

In-hospital monitoring (in bed or telemetric) is warranted only when the patient has important structural heart disease and is at high risk of life-threatening arrhythmias. A few days of ECG monitoring may be of value, especially if the monitoring is applied immediately after syncope [27, 28].

The vast majority of patients have a syncope-free interval measured in weeks, months, or years, and therefore symptom-ECG correlation can rarely be achieved with Holter monitoring. In an overview of the results of eight studies of ambulatory monitoring in syncope, only 4% of patients (range between 1–20%) had correlation of symptoms with arrhythmia. The true yield of conventional ECG monitoring in syncope may be as low as 1–2% in an unselected population. Therefore, Holter monitoring is indicated only in patients who have very frequent syncopes or presyncope. Holter monitoring may also be useful in patients who have the clinical or ECG features suggesting an arrhythmic syncope in order to guide subsequent examinations (i.e. electrophysiological study).

The ELR appears to have its greatest role in motivated patients with frequent (pre)syncopes where spontaneous symptoms are likely to recur within 4–6 weeks. This time frame is usually the maximum with which a patient can comply. Since true syncope usually recurs unpredictably over months or years, the indications for an ELR are limited to a few selected patients with high probability of recurrence. In a study [59], the ELR yielded a low diagnostic value in patients with 3 ± 4 syncopal episodes (>2) during the previous 6 months, no overt heart disease, and negative tilt test. ELRs proved to be more useful when frequent presyncopal symptoms were considered in addition to true syncopal episodes and less specific positivity criteria are used, mainly in order to exclude an arrhythmic cause of symptoms. For example, in COLAPS trial [60], an ECG-symptom correlation was found in 44/78 patients (56%), but an arrhythmia was identified in only one patient whereas it could be excluded in the other 43. In a multicentre study [61], a symptom-arrhythmia correlation was found in 15% and symptom-absence of arrhythmia correlation was found in another 25% of 51 patients. With the new auto-triggered devices, many asymptomatic tachyarrhythmias are usually recorded [61]. It should be stressed that, in the absence of a study of correlation with syncopal events, their positive predictive value is unknown, and monitoring should be

continued until diagnosis is confirmed by symptom documentation whenever possible.

Patients with infrequent syncopes are unlikely to be diagnosed by the above systems. In such circumstances, consideration should be given to ILRs ( Fig. 26.10). Pooled data from nine studies [57, 62–69] for a total of 506 patients with unexplained syncope at the end of a complete conventional investigation show that a correlation between syncope and ECG was found in 176 patients (35%); of these 56% had asystole (or bradycardia in few cases) at the time of the recorded event, 11% had tachycardia, and 33% had no arrhythmia ( Fig. 26.11). ILRs proved to be particularly useful in patients with bundle branch block and negative electrophysiological study to confirm or exclude the suspicion of a paroxysmal AV block and guide subsequent specific therapy, i.e. pacemaker implantation [65]. The diagnostic yield was higher in the older patients. In one study [70], the patients >65 years had a 2.7 times higher syncope recurrence rate (56% vs. 32%) than those <65 years and were 3.1 times more likely to have an arrhythmia at time of syncope (44% vs. 20%). An increased incidence of bradycardia with advancing age was also noted by Krahn et al. [71]. On the contrary, the diagnostic yield was similar in patients with and without structural heart diseases (including abnormal ECG) [72]. Two randomized trials [29, 30] showed that an early ILR implantation in low risk patients (as defined elsewhere) is safe and yields a higher diagnostic value than conventional investigations. Finally, the ILR implantation in an early phase of the diagnostic work-up was proven to be useful in patients at low risk with suspected neurally mediated syncope in order to understand the exact mechanism and to guide specific therapy [70].

Therefore, when the mechanism of syncope remains unclear after full evaluation, an ILR is indicated in patients who have clinical or ECG features suggesting arrhythmic syncope ( Tables 26.8 and 26.9). An ILR may also be indicated in an initial phase of the work-up instead of the completion of conventional investigations. This is particularly the case for patients with recurrent syncope of uncertain origin who have a likely recurrence within battery longevity of the device (i.e. three or more syncopal episodes during the last 2 years) and absence of high-risk criteria which require immediate hospitalization or intensive evaluation (i.e. those listed in Table 26.6).

An ILR may also be indicated to confirm suspected bradycardia before embarking on cardiac pacing in patients with suspected or certain neurally mediated syncope presenting with frequent or traumatic syncopal episodes [73]. Finally, an ILR may be indicated in selected ‘difficult’ cases of patients with T-LOC of uncertain syncopal origin in order to definitely exclude an arrhythmic mechanism [74].

Because of the heterogeneity of findings and the wide variety of rhythm disturbances recorded with ILR at the time of syncope, the ISSUE investigators have proposed a classification that aims to group the observations into homogeneous patterns in order to define an acceptable standard useful for future studies and clinical practice ( Table 26.11) [75]. Type 1 (asystole) was the most frequent finding which was observed in 63% of patients; type 2 (bradycardia) was observed in 5% of patients; type 3 (no or slight rhythm variations was observed in 18% of patients; and type 4 (tachycardia) was observed in 14% of patients. This classification has become widely used and validated by others [74, 76, 77]. The ISSUE classification has some pathophysiological implications which are helpful to distinguish different types of arrhythmic syncope and have potential different diagnostic, therapeutic and prognostic implications. In types 1A, 1B, and 2 the findings of progressive sinus bradycardia, most often followed by ventricular asystole due to sinus arrest, or progressive tachycardia followed by progressive bradycardia and, eventually, ventricular asystole due to sinus arrest suggest that the syncope is probably neurally-mediated ( Fig. 26.12). In type 1C, the finding of prolonged asystolic pauses due to sudden-onset paroxysmal AV block with concomitant increase in sinus rate suggests another mechanism, namely intrinsic disease of the His-Purkinje system as observed in Stokes–Adam attacks ( Fig. 26.13). In types 4B, 4C, and 4D a primary cardiac arrhythmia is typically responsible for syncope. In the other types (3 and 4A), in which no arrhythmia is detected, the exact nature of syncope remains uncertain because of the lack of contemporary recording of blood pressure; however, the finding of progressive heart rate increase and/or decrease at the time of syncope suggests a (primary or secondary) activation of the cardiovascular system and a possible hypotensive mechanism.

Since prolonged asystole is the most frequent finding at the time of syncope recurrence, cardiac pacing was the specific therapy most used in ILR populations ranging from 12% in patients with neurally mediated syncope [73] to 44% in patients with bundle branch block [65]. ICD and catheter ablation were also consistently used in about 1% of the patients. Few data are available on the subsequent outcome of the patients treated with pacing. Cardiac pacing was very effective in reducing syncopal recurrences, especially in patients with type 1C pattern [76]. However, syncope still recurred in 12% (range 3–18%) of the patients during the long-term follow-up (2–3.6 years), especially in those patients more likely to be affected by neurally mediated syncope (type 1A or 1B), probably accounting for the coexistence of some vasodepressor reflex which cannot be overcome by pacing [70, 73, 76]. In patients with neurally mediated syncope [73] the 1-year burden of syncope decreased from 0.83 ± 1.57 episodes per patient/year in the control group of patients without any ILR-guided specific therapy to 0.05 ± 0.15 episodes per patient/year in the patients treated with a pacemaker (87% relative risk reduction, p = 0.001).

The diagnostic efficiency of the invasive electrophysiological study is not only highly dependent on the degree of suspicion of the abnormality (pre-test probability) but also on the protocol ( Table 26.12) and the criteria used for diagnosing clinically significant abnormalities. Positive results at electrophysiological study occur almost exclusively in patients with overt heart disease or conduction defects. It must be emphasized that normal electrophysiological findings cannot completely exclude an arrhythmic cause of syncope. When an arrhythmia is likely, further evaluations (e.g. loop recording) are recommended. Finally, depending on the clinical context, even apparently abnormal electrophysiological findings (e.g. relatively long HV interval, inducible ventricular fibrillation with aggressive stimulation) may not be diagnostic of the cause of syncope [78–80].

There are four areas of particular pertinence to electrophysiological testing in syncope patients: suspected sinus node disease ( Chapter 27), bundle branch block (impending high-degree AV block) ( Chapter 27),

suspected supraventricular tachycardia ( Chapter 28), and suspected ventricular tachycardia ( Chapter 30).

The pre-test probability of a transient symptomatic bradycardia as the cause of syncope is relatively high when there is asymptomatic sinus bradycardia (<50bpm) or sinus pauses in the absence of negatively chronotropic medications. Sinus node dysfunction can be demonstrated by abnormal beat-to-beat variability and chronotropic incompetence, and by a prolonged sinus node recovery time. The prognostic value of a prolonged sinus node recovery time is largely unknown. It is widely accepted that, in presence of an SNRT >2s or corrected SNRT >1s, sinus node dysfunction may be the cause of syncope [81, 82].

In patients with syncope and bifascicular block, an electrophysiological study is diagnostic and, usually, no additional tests are required when the baseline HV interval is ≥100ms, second- or third-degree His–Purkinje block is demonstrated during incremental atrial pacing, or high-degree His–Purkinje block is provoked by intravenous administration of ajmaline (1mg/kg), procainamide (10mg/kg), or disopyramide (2mg/kg). An electrophysiological study is highly sensitive (>80%) in identifying patients with intermittent or impending high-degree AV block, but, when negative, it cannot rule out paroxysmal AV block as the cause of syncope [83–89].

This block is the likely cause of syncope in most cases but not of the high mortality rate observed in these patients, which is mainly related to underlying structural heart disease and ventricular tachyarrhythmias. Unfortunately, ventricular programmed stimulation does not seem to be able correctly to identify these patients, and the finding of inducible ventricular arrhythmia should therefore be interpreted with caution [90].

Supraventricular tachycardia ( Chapter 28) presenting as syncope without accompanying palpitations is probably a rare event. The induction of rapid supraventricular arrhythmia that reproduces hypotensive or spontaneous symptoms is usually considered diagnostic. The combination of supraventricular tachycardia and orthostasis may be responsible for syncope.

The outcome largely depends on the clinical features of the patients. Inducibility of sustained monomorphic ventricular tachycardia ( Chapter 30) and/or very depressed systolic function are the two strongest predictors of life-threatening arrhythmic cause of syncope; conversely, their absence suggests a more favourable outcome.

Electrophysiological study with programmed electrical stimulation is an effective diagnostic test in patients with coronary artery disease, markedly depressed cardiac function, and unexplained syncope [91, 92]. For example, in the ESVEM trial [93], syncope associated with induced ventricular tachycardia at electrophysiological testing indicated high risk of death, similar to that of patients with documented spontaneous ventricular tachyarrhythmias. On the contrary, the induction of polymorphic ventricular tachycardia and ventricular fibrillation has low specificity and is of no value in risk stratification and therapeutical decisions [94].

Programmed ventricular stimulation has a low predictive value in patients with non-ischaemic dilated cardiomyopathy [95].

Exercise testing ( Chapter 2 and 25) should be performed in patients who have experienced episodes of syncope during or shortly after exertion.

The following two situations should be separately considered. Syncope occurring during exercise in the presence of structural heart disease is likely to have a cardiac cause. Tachycardia-related (phase 3), exercise-induced, second- and third-degree AV block has been shown to be invariably located in the His–Purkinje system and is an ominous finding of progression to chronic AV block. The resting ECG frequently shows an intraventricular conduction abnormality [96]. In the absence of structural heart disease, syncope occurring during exercise may be a manifestation of an exaggerated reflex vasodilatation [97]. By contrast, postexertional syncope is almost invariably due to autonomic failure or to a neurally mediated mechanism [98]. Syncope in athletes may be an important problem ( Chapter 32). However, in the absence of structural heart disease, syncope occurring during or immediately after exercise in athletes is a benign condition, with a good long-term outcome. The likely final diagnosis is neurally mediated [97].

In patients with syncope suspected to be due, directly or indirectly, to myocardial ischaemia, coronary angiography ( Chapter 8) is recommended in order to confirm the diagnosis. However, angiography alone is rarely diagnostic of the cause of syncope.

The test requires the rapid (<2s) injection of a 20-mg bolus of ATP (adenosine triphosphate) during electrocardiographic monitoring. The induction of AV block with ventricular asystole lasting >6s, or the induction of an AV block lasting >10s, are considered abnormal. ATP testing produced an abnormal response in patients with syncope of unknown origin (especially elderly female patients without structural heart disease), but not in controls, thus suggesting that paroxysmal AV block could be the cause of unexplained syncope [99–101]. Unfortunately, some recent studies showed no correlation between AV block induced with ATP test and the electrocardiographic findings (documented by means of implantable loop recorder) during spontaneous syncope [58, 77, 102]. Thus, the low predictive value of the test excludes any potential utility in selecting patients for cardiac pacing. The role of endogenus adenosine release in triggering some forms of syncope due to otherwise unexplained paroxysmal AV block (the so-called ‘adenosine-sensitive AV block’) still remains under investigation.

Neurological disease may cause transient loss of consciousness (e.g. certain seizures), but is almost never the cause of syncope. Thus, neurological testing may be needed to distinguish seizures from syncope in some patients, but these should not be considered as essential elements in the evaluation of the basis of true syncope. The possible contribution of an EEG, CT, and MRI of the brain is to disclose abnormalities due to epilepsy; there are no specific EEG findings for any loss of consciousness other than epilepsy. Accordingly, several studies conclusively showed that EEG monitoring was of little use in unselected patients with syncope. Thus, EEG is not recommended for patients in whom syncope is the most likely cause of transient loss of consciousness [103–107].

Carotid TIAs are not accompanied by loss of consciousness. Therefore, carotid Doppler ultrasonography is not required in patients with syncope.

Table 26.13 shows the comparative prevalence of the causes of syncope as determined by pooling data from six older population studies [108–113] performed in the 1980s (total 1499 patients) with that of four more recent population-based studies [31, 114–116] performed in the 2000s (total 1640 patients) and with that of the EGSYS study [27], which was a prospective systematic evaluation aimed at assessing the management of syncope on strict adherence to the Guidelines on Syncope of the ESC. Although difficult to reproduce in actual practice, the results of the EGSYS study probably assess the current standard for the management of syncope.

Reflex (neurally mediated) and orthostatic hypotension were the most frequent causes of T-LOC and their frequency increased in recent years, probably owing to a better knowledge of diagnostic criteria and to a more extensive use of carotid sinus massage and tilt testing. Cardiac syncope was the next most frequent cause of T-LOC and its frequency remained stable over the years. The proportion of T-LOC of suspected syncopal

nature (neurological and psychiatric) at the initial evaluation was not very high and decreased slightly over time. The proportion of unexplained syncope dramatically decreased.

In general, the initial evaluation established a diagnosis in about 50% of cases in all studies. Apart from the initial evaluation, in the EGSYS study [27] a mean of 1.9 ± 1.1 appropriate tests per patient was necessary for diagnosis. The rate of appropriate indications and the diagnostic value of the most frequently used tests are reported in Table 26.14. Hospitalization was appropriate in 25% of patients, but it was required for other reasons in a further 13% of cases. The median in-hospital stay was 5.5 days.

There are two main reasons for treatment of a patient with syncope; one is to prevent recurrence by an effective mechanism-specific treatment strategy, the other is to apply an effective treatment of the underlying disease which could cause severe events unrelated to syncopal recurrence. Physicians should be aware not to confound therapy for prevention of syncopal recurrences from that of the underlying disease.

In most patients at high short- and long-term risk of death (see Assessing the risk), a disease-specific treatment is warranted in order to reduce the risk of death and of life-threatening events even if the mechanism of syncope is still unknown at the end of a complete work-up.

In particular, the following conditions are to be considered:

It is important to bear in mind, however, that even if an effective specific treatment of the underlying disease is found, patients may remain at risk of syncopal recurrences. For example, ICD-treated patient may remain at risk for fainting because only the sudden-death risk is being addressed and not the cause of syncope. An analysis of the SCD-HeFT trial [120] has shown that ICD did not protect patients against syncope recurrence compared with those treated with amiodarone or placebo. This implies the need of a precise identification of the mechanism of syncope and their specific treatment.

Syncope due to documented cardiac arrhythmias must receive treatment appropriate to the cause in all patients. Cardiac pacing, ICDs, and catheter ablation are the usual treatments of syncope due to cardiac arrhythmias, depending on the mechanism of syncope.

In general, cardiac pacemaker therapy ( Chapter 27) is indicated and has proved highly effective in patients with sinus node dysfunction when bradyarrhythmia has been demonstrated to account for syncope or by means of ECG documentation (see Electrocardiographic monitoring) or as consequence of abnormal sinus node recovery time (see Electrophysiological testing) [130–134]. Although formal randomized controlled trials have not been performed, it is clear from several observational studies that pacing is able to improve survival in patients with heart block as well as prevent syncopal recurrences [135, 136]. A logical inference, but not proven, is that pacing may also be life saving in patients with bundle branch block and syncope in whom the mechanism of the faint is suspected to be an intermittent AV block (see Electrophysiological testing) [84].

Owing to its curative effect, catheter ablation (see Chapter 28 and 29) is the first-choice therapy for the most common forms of atrial arrhythmias causing syncope. The efficacy of conventional antiarrhythmic drugs when atrial arrhythmia is presenting with syncope is not satisfactory.

Iatrogenic atrial and ventricular arrhythmias are cured by eliminating the underlying responsible causes.

ICDs are the therapy of choice in patients with structural heart disease in whom ventricular tachycardia and ventricular fibrillation ( Chapter 30) has been demonstrated to account for syncope or by means of ECG documentation (see Electrocardiographic monitoring) or as consequence of their induction by means of ventricular premature stimulation (see Electrophysiological testing). Several non-randomized studies have evaluated the utility of ICDs in highly selected patients with severe ischaemic and non-ischaemic cardiomyopathy and undocumented syncope suspected to be due to ventricular tachyarrhythmia: in general a high rate of appropriate shocks was observed which suggested a potential benefit in regard of survival [137–144]. Table 26.15 provides commonly accepted indications for ICD therapy for the prevention of sudden death in patients with syncope. Catheter ablation is warranted in patients without structural heart disease. On the contrary, the efficacy of conventional antiarrhythmics is not satisfactory.

Treatment is best directed at amelioration of the specific structural lesion or its consequences.

Patients who seek medical advice after having experienced a vasovagal faint require reassurance and education regarding the nature of the disease and the avoidance of triggering events. In general, education and reassurance are sufficient for most patients. Modification or discontinuation of hypotensive drug treatment for concomitant conditions is another first-line measure for the prevention of syncope recurrence [145]. Treatment is not necessary for patients who have sustained a single or rare episode and are not having syncope in a high-risk setting. Additional treatment may be necessary in high-risk or high-frequency settings (see Risk of syncopal recurrence).

Non-pharmacological ‘physical’ treatments are emerging as a new front-line treatment of vasovagal syncope. Two recent clinical trials [146, 147] have shown that isometric counter-pressure manoeuvres of the legs (leg crossing), or of the arms (hand grip and arm tensing), are able to induce a significant blood pressure increase during the phase of impending vasovagal syncope that allows the patient to avoid or delay losing consciousness in most cases ( Fig. 26.14). The results have been confirmed in a randomized multicentre prospective trial [148] which assessed the effectiveness of physical counter-pressure manoeuvres in daily life in 223 patients, aged 38 ± 15 years, with recurrent vasovagal syncope and recognizable prodromal (i.e. warning) symptoms: 117 patients were randomized to standardized conventional therapy alone, and 106 patients received conventional therapy plus training in counter-pressure manoeuvre. The median yearly syncope burden during follow-up was significantly lower in the group trained in physical counter-pressure manoeuvre (PCM) than in the control group (p <0.004); overall 51% of the patients with conventional treatment and 32% of the patients trained in PCM experienced a syncopal recurrence (p <0.005). Actuarial recurrence-free survival was better in the treatment group (log-rank p <0.018), resulting in a relative risk reduction of 39% (95% confidence interval, 11–53%). No adverse events were reported.

In highly motivated young patients with recurrent vasovagal symptoms triggered by orthostatic stress, the prescription of progressively prolonged periods of enforced upright posture (so-called ‘tilt training’) may reduce syncope recurrence [149–151]. However, this treatment is hampered by the low compliance of patients in continuing the training programme for a long period and two randomized controlled trials failed to confirm short-term effectiveness of tilt training in reducing the positive response rate of the tilt test [152–155].

Many drugs have been used in the treatment of vasovagal syncope (beta-blockers, disopyramide, scopolamine, clonidine, theophylline, fludrocortisone, ephedrine, etilefrine, midodrine, serotonin reuptake inhibitors, etc.). In general, although the results have been satisfactory in uncontrolled trials or short-term controlled trials, long-term placebo-controlled prospective trials have failed to show any benefit of the active drug over placebo. Beta-adrenergic blocking drugs have failed to be effective in five of six long-term follow-up controlled studies [156–161]. Vasoconstrictor drugs are potentially more effective in orthostatic hypotension caused by autonomic dysfunction than in the neurally mediated syncope [162–164]. However, etilefrine proved to be ineffective in a large randomized double-blind trial [45]. To date, there are insufficient data to support the use of any other pharmacological therapy for vasovagal syncope.

Pacing for vasovagal syncope has been the subject of five major multicentre randomized controlled trials which gave contrasting results [165–169]; in all the patient the pre-implant selection was based on tilt-testing response. Adding together the results of the five trials, 318 patients were evaluated; syncope recurred in 21% of the paced patients and in 44% of unpaced patients (p <0.001). The sub-optimal results are not surprising if we consider that pacing may affect the cardioinhibitory component of the vasovagal reflex, but will have no effect on the vasodepressor component, which is often dominant. The ISSUE 2 study [27] hypothesized that spontaneous asystole and not tilt test results should form the basis for patient selection for pacemaker therapy. This study followed 392 patients with presumed vasovagal syncope with an ILR. Of the 102 patients with a symptom-rhythm correlation, 53 underwent loop recorder guided therapy, predominantly pacing for asystole. These patients experienced a striking reduction in recurrence of syncope compared with non-loop recorder guided therapy (10% vs. 41%, p = 0.002). In summary, pacing plays a minimal role in therapy for vasovagal syncope, unless spontaneous bradycardia is detected during prolonged monitoring.

Cardiac pacing appears to be beneficial in carotid sinus syndrome [170–173] and, although only two relatively small randomized controlled trials have been undertaken, pacing is acknowledged to be the treatment of choice when bradycardia has been documented [32, 174]. Single-chamber atrial pacing is not appropriate for carotid sinus syndrome and dual-chamber pacing is generally preferred over single-chamber ventricular pacing [175, 176].

Although there is a range of aetiologies that lead to orthostatic intolerance (see Table 26.3), the global strategy aims to counteract the orthostatic stress which is the common denominator leading to symptoms. Since they have the same final mechanism in common, they also share similar therapies. Contrary to reflex syncope in which syncope and pre-syncope are largely the prevalent symptoms, the syndromes of orthostatic intolerance are characterized by frequent non-syncopal posture-related symptoms (dizziness, fatigue, weakness, palpitations, hearing disturbances, etc.) and syncope occurs less frequently. The goal of therapy is primarily prevention of recurrence and associated injuries, and improvement in quality of life.

In general, initial treatment comprises education regarding awareness and possible avoidance of triggers (e.g. hot crowded environments, volume depletion), early recognition of premonitory symptoms, and performing manoeuvres to abort the episode (e.g. supine posture, PCMs as described in Reflex syncope). Drug-induced autonomic failure is probably the most frequent cause of orthostatic hypotension. The principal treatment strategy is elimination of the offending agents, mainly diuretics and vasodilators. Alcohol is also commonly associated with orthostatic intolerance.

Additional treatment principles, used alone or in combination, are appropriate for consideration on an individual patient basis: