Guidelines for the diagnosis and management
of syncope (version 2009)
The Task Force for the Diagnosis and Management of Syncope of the
European Society of Cardiology (ESC)
Developed in collaboration with, European Heart Rhythm Association (EHRA)1,
Heart Failure Association (HFA)2, and Heart Rhythm Society (HRS)3
Endorsed by the following societies, European Society of Emergency Medicine (EuSEM)4, European Federation of
Internal Medicine (EFIM)5, European Union Geriatric Medicine Society (EUGMS)6, American Geriatrics Society
(AGS), European Neurological Society (ENS)7, European Federation of Autonomic Societies (EFAS)8, American
Autonomic Society (AAS)9
Authors/Task Force Members, Angel Moya (Chairperson) (Spain)*, Richard Sutton (Co-Chairperson) (UK)*,
Fabrizio Ammirati (Italy), Jean-Jacques Blanc (France), Michele Brignole1(Italy), Johannes B. Dahm (Germany),
Jean-Claude Deharo (France), Jacek Gajek (Poland), Knut Gjesdal2(Norway), Andrew Krahn3(Canada),
Martial Massin (Belgium), Mauro Pepi (Italy), Thomas Pezawas (Austria), Ricardo Ruiz Granell (Spain),
Francois Sarasin4(Switzerland), Andrea Ungar6(Italy), J. Gert van Dijk7(The Netherlands), Edmond P. Walma
(The Netherlands), Wouter Wieling (The Netherlands)
External Contributors, Haruhiko Abe (Japan), David G. Benditt (USA), Wyatt W. Decker (USA), Blair P. Grubb
(USA), Horacio Kaufmann9(USA), Carlos Morillo (Canada), Brian Olshansky (USA), Steve W. Parry (UK),
Robert Sheldon (Canada), Win K. Shen (USA)
ESC Committee for Practice Guidelines (CPG), Alec Vahanian (Chairperson) (France), Angelo Auricchio
(Switzerland), Jeroen Bax (The Netherlands), Claudio Ceconi (Italy), Veronica Dean (France), Gerasimos Filippatos
(Greece), Christian Funck-Brentano (France), Richard Hobbs (UK), Peter Kearney (Ireland), Theresa McDonagh
(UK), Keith McGregor (France), Bogdan A. Popescu (Romania), Zeljko Reiner (Croatia), Udo Sechtem (Germany),
Per Anton Sirnes (Norway), Michal Tendera (Poland), Panos Vardas (Greece), Petr Widimsky (Czech Republic)
Document Reviewers, Angelo Auricchio (CPG Review Coordinator) (Switzerland), Esmeray Acarturk (Turkey),
Felicita Andreotti (Italy), Riccardo Asteggiano (Italy), Urs Bauersfeld (Switzerland), Abdelouahab Bellou4(France),
Athanase Benetos6(France), Johan Brandt (Sweden), Mina K. Chung3(USA), Pietro Cortelli8(Italy),
Antoine Da Costa (France), Fabrice Extramiana (France), Jose ´ Ferro7(Portugal), Bulent Gorenek (Turkey),
Antti Hedman (Finland), Rafael Hirsch (Israel), Gabriela Kaliska (Slovak Republic), Rose Anne Kenny6(Ireland),
Keld Per Kjeldsen (Denmark), Rachel Lampert3(USA), Henning Mølgard (Denmark), Rain Paju (Estonia),
Aras Puodziukynas (Lithuania), Antonio Raviele (Italy), Pilar Roman5(Spain), Martin Scherer (Germany),
Ronald Schondorf9(Canada), Rosa Sicari (Italy), Peter Vanbrabant4(Belgium), Christian Wolpert1(Germany),
Jose Luis Zamorano (Spain)
The disclosure forms of the authors and reviewers are available on the ESC website www.escardio.org/guidelines
*Corresponding authors: Angel Moya (Chairperson), Hospital Vall d’Hebron, P. Vall d’Hebron 119–129, 08035 Barcelona, Spain. Tel: þ34 93 2746166, Fax: þ34 93 2746002,
Richard Sutton (UK) (Co-Chairperson), Imperial College, St Mary’s Hospital, Praed Street, London W2 1NY, UK. Tel: þ44 20 79351011, Fax: þ44 20 79356718, Email: r.sutton@
The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the
ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford
University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC.
Disclaimer. The ESC Guidelines represent the views of the ESC and were arrived at after careful consideration of the available evidence at the time they were written. Health
professionals are encouraged to take them fully into account when exercising their clinical judgement. The guidelines do not, however, override the individual responsibility of health
professionals to make appropriate decisions in the circumstances of the individual patients, in consultation with that patient, and where appropriate and necessary the patient’s
guardian or carer. It is also the health professional’s responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription.
& The European Society of Cardiology 2009. All rights reserved. For permissions please email: email@example.com.
European Heart Journal (2009) 30, 2631–2671
Table of Contents
Abbreviations and acronyms . . . . . . . . . . . . . . . . . . . . . . . 2632
Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2633
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2634
Part 1. Definitions, classification and pathophysiology,
epidemiology, prognosis, impact on quality of life, and
economic issues . . . . . . . . . . . . . . . . . . . . . . . . . . 2635
1.1 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2635
1.2 Classification and pathophysiology . . . . . . . . . . . . . . 2635
1.2.1 Placing syncope in the larger framework of transient
loss of consciousness (real or apparent). . . . . . . . 2635
1.2.2 Classification and pathophysiology of syncope . . . . 2636
126.96.36.199 Reflex syncope (neurally mediated syncope) . . . 2637
188.8.131.52 Orthostatic hypotension and orthostatic
intolerance syndromes . . . . . . . . . . . . . . . . . 2637
184.108.40.206 Cardiac syncope (cardiovascular) . . . . . . . . . . 2639
1.3 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2640
1.3.1 Prevalence of syncope in the general population. . . 2640
1.3.2 Referral from the general population to medical
settings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2640
1.3.3 Prevalence of the causes of syncope . . . . . . . . . . 2641
1.4 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2641
1.4.1 Risk of death and life-threatening events . . . . . . . 2641
1.4.2 Recurrence of syncope and risk of physical injury . 2641
1.5 Impact on quality of life . . . . . . . . . . . . . . . . . . . . . 2641
1.6 Economic issues . . . . . . . . . . . . . . . . . . . . . . . . . . 2643
Part 2. Initial evaluation, diagnosis, and risk stratification. . . . . 2644
2.1 Initial evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . 2644
2.1.1 Diagnosis of syncope . . . . . . . . . . . . . . . . . . . . 2644
2.1.2 Aetiological diagnosis . . . . . . . . . . . . . . . . . . . . 2644
2.1.3 Risk stratification . . . . . . . . . . . . . . . . . . . . . . . 2645
2.2 Diagnostic tests . . . . . . . . . . . . . . . . . . . . . . . . . . 2645
2.2.1 Carotid sinus massage . . . . . . . . . . . . . . . . . . . 2645
2.2.2 Orthostatic challenge . . . . . . . . . . . . . . . . . . . . 2647
220.127.116.11 Active standing . . . . . . . . . . . . . . . . . . . . . . 2647
18.104.22.168 Tilt testing . . . . . . . . . . . . . . . . . . . . . . . . . 2647
2.2.3 Electrocardiographic monitoring (non-invasive and
invasive) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2649
22.214.171.124 In-hospital monitoring . . . . . . . . . . . . . . . . . 2649
126.96.36.199 Holter monitoring . . . . . . . . . . . . . . . . . . . . 2649
188.8.131.52 Prospective external event recorders . . . . . . . 2649
184.108.40.206 External loop recorders . . . . . . . . . . . . . . . . 2649
220.127.116.11 Implantable loop recorders . . . . . . . . . . . . . . 2649
18.104.22.168 Remote (at home) telemetry . . . . . . . . . . . . . 2650
22.214.171.124 Classification of electrocardiographic recordings
126.96.36.199 Electrocardiographic monitoring in syncope—
where in the work-up? . . . . . . . . . . . . . . . . . 2650
2.2.4 Electrophysiological study . . . . . . . . . . . . . . . . . 2651
188.8.131.52 Suspected intermittent bradycardia . . . . . . . . . 2651
184.108.40.206 Syncope in patients with bundle branch block
(impending high degree atrioventricular block) . 2652
220.127.116.11 Suspected tachycardia . . . . . . . . . . . . . . . . . 2652
2.2.5 Adenosine triphosphate test . . . . . . . . . . . . . . . 2652
2.2.6 Echocardiography and other imaging techniques . . 2653
2.2.7 Exercise stress testing . . . . . . . . . . . . . . . . . . . . 2653
2.2.8 Cardiac catheterization . . . . . . . . . . . . . . . . . . . 2653
2.2.9 Psychiatric evaluation . . . . . . . . . . . . . . . . . . . . 2653
2.2.10 Neurological evaluation. . . . . . . . . . . . . . . . . . . 2654
18.104.22.168 Clinical conditions . . . . . . . . . . . . . . . . . . . . 2654
22.214.171.124 Neurological tests . . . . . . . . . . . . . . . . . . . . 2655
Part 3. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2656
3.1 Treatment of reflex syncope and orthostatic
intolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2656
3.1.1 Reflex syncope . . . . . . . . . . . . . . . . . . . . . . . . 2657
126.96.36.199 Therapeutic options . . . . . . . . . . . . . . . . . . . 2657
188.8.131.52 Individual conditions. . . . . . . . . . . . . . . . . . . 2658
3.1.2 Orthostatic hypotension and orthostatic intolerance
syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . 2658
3.2 Cardiac arrhythmias as primary cause . . . . . . . . . . . . 2659
3.2.1 Sinus node dysfunction . . . . . . . . . . . . . . . . . . . 2659
3.2.2 Atrioventricular conduction system disease. . . . . . 2659
3.2.3 Paroxysmal supraventricular and ventricular
tachycardias . . . . . . . . . . . . . . . . . . . . . . . . . . 2659
3.2.4 Implanted device malfunction . . . . . . . . . . . . . . . 2660
3.3 Syncope secondary to structural cardiac or
cardiovascular disease . . . . . . . . . . . . . . . . . . . . . . 2660
3.4 Unexplained syncope in patients with high risk of
sudden cardiac death . . . . . . . . . . . . . . . . . . . . . . . 2661
3.4.1 Ischaemic and non-ischaemic cardiomyopathies . . . 2661
3.4.2 Hypertrophic cardiomyopathy . . . . . . . . . . . . . . 2661
3.4.3 Arrhythmogenic right ventricular cardiomyopathy/
dysplasia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2661
3.4.4 Patients with primary electrical diseases . . . . . . . . 2661
Part 4. Special issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2662
4.1 Syncope in the elderly . . . . . . . . . . . . . . . . . . . . . . 2662
4.2 Syncope in paediatric patients . . . . . . . . . . . . . . . . . 2663
4.3 Driving and syncope . . . . . . . . . . . . . . . . . . . . . . . 2663
Part 5. Organizational aspects . . . . . . . . . . . . . . . . . . . . . . 2664
5.1 Management of syncope in general practice . . . . . . . . 2664
5.2 Management of syncope in the Emergency Department
5.3 Syncope (T-LOC) Management Unit . . . . . . . . . . . . 2664
5.3.1 Existing models of Syncope (T-LOC) Management
Units . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2665
5.3.2 Proposed model . . . . . . . . . . . . . . . . . . . . . . . 2665
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2666
Abbreviations and acronyms
autonomic nervous system
arrhythmogenic right ventricular cardiomyopathy
Antiarrhythmics vs. Implantable Defibrillators
bundle branch block
beats per minute
coronary artery disease
Committee for Practice Guidelines
carotid sinus hypersensitivity
carotid sinus massage
SCD-HeFT Sudden Cardiac Death in Heart Failure Trial
SNRTsinus node recovery time
SVRsystemic vascular resistance
SVT supraventricular tachycardia
TIAtransient ischaemic attack
T-LOCtransient loss of consciousness
VT ventricular tachycardia
carotid sinus syndrome
corrected sinus node recovery time
Evaluation of Guidelines in Syncope Study
European Society of Cardiology
Falls and Syncope Service
Food and Drug Administration
hypertrophic obstructive cardiomyopathy
implantable cardioverter defibrillator
implantable loop recorder
International Study on Syncope of Unknown Etiology
left bundle branch block
loss of consciousness
left ventricular ejection fraction
magnetic resonance imaging
physical counterpressure manoeuvre
personal digital assistant
postural orthostatic tachycardia syndrome
right bundle branch block
sudden cardiac death
Guidelines and Expert Consensus Documents summarize and
evaluate all currently available evidence on a particular issue with
the aim of assisting physicians in selecting the best management
strategies for a typical patient, suffering from a given condition,
taking into account the impact on outcome, as well as the risk/
benefit ratio of particular diagnostic or therapeutic means. Guide-
lines are no substitutes for textbooks. The legal implications of
medical guidelines have been previously discussed.
A great number of Guidelines and Expert Consensus Docu-
ments have been issued in recent years by the European Society
of Cardiology (ESC) as well as by other societies and organizations.
Because of the impact on clinical practice, quality criteria for the
development of guidelines have been established in order to
make all decisions transparent to the user. The recommendations
for formulating and issuing ESC Guidelines and Expert Consensus
Documents can be found on the ESC Web Site (http://www
In brief, experts in the field are selected and undertake a com-
prehensive review of the published evidence for management and/
or prevention of a given condition. A critical evaluation of diagnos-
tic and therapeutic procedures is performed, including assessment
of the risk/benefit ratio. Estimates of expected health outcomes for
larger societies are included, where data exist. The level of evi-
dence and the strength of recommendation of particular treatment
options are weighed and graded according to predefined scales, as
outlined in Tables 1 and 2.
The experts of the writing panels have provided disclosure
statements of all relationships they may have which might be per-
ceived as real or potential sources of conflicts of interest. These
disclosure forms are kept on file at the European Heart House
Headquarters of the ESC. Any changes in conflict of interest that
arise during the writing period must be notified to the ESC. The
Task Force (TF) report was entirely supported financially by the
ESC and was developed without any involvement of industry.
The ESC Committee for Practice Guidelines (CPG) supervises
and coordinates the preparation of new Guidelines and Expert
Consensus Documents produced by TF expert groups or consen-
sus panels. The Committee is also responsible for the endorse-
ment process of these Guidelines and Expert Consensus
Documents or statements. Once the document has been finalized
and approved by all the experts involved in the TF, it is submitted
to outside specialists for review. The document is revised, finally
approved by the CPG,and subsequently published.
After publication, dissemination of the message is of paramount
importance. Pocket-sized versions and personal digital assistant
(PDA)-downloadable versions are useful at the point of care.
Some surveys have shown that the intended end-users are some-
times not aware of the existence of the guidelines, or simply do
not translate them into practice; this is why implementation pro-
grammes for new guidelines form an important component of the
dissemination of knowledge. Meetings are organized by the ESC
and are directed towards its member national societies and key
opinion leaders in Europe. Implementation meetings can also be
undertaken at national levels, once the guidelines have been
endorsed by ESC member societies and translated into the national
language. Implementation programmes are needed because it has
been shown that the outcome of disease may be favourably influ-
enced by thorough application of clinical recommendations.
Thus, the task of writing Guidelines or Expert Consensus Docu-
ments covers not only the integration of the most recent research,
but also the creation of educational tools and implementation pro-
grammes for the recommendations. The loop between clinical
research, the writing of guidelines, and implementing them into
clinical practice can then only be completed if surveys and regis-
tries are performed to verify that real-life daily practice is in
keeping with what is recommended in the guidelines. Such
surveys and registries also make it possible to evaluate the
impact of implementation of the guidelines on patient outcomes.
Guidelines and recommendations should help physicians to make
decisions in their clinical practice; however, the ultimate judgement
regarding the care of an individual patient must be made by the
physician in charge of that patient.
The first ESC Guidelines for the management of syncope, were
published in 2001, and reviewed in 2004.1In March 2008, the
CPG considered that there were enough new data to justify pro-
duction of new guidelines.
There are two main aspects of this document that differentiate it
from its predecessors.
The first is to stress the concept that there are two distinct
reasons for evaluating patients with syncope: one is to identify
the precise cause in order to address an effective mechanism-
specific treatment; the other is to identify the specific risk to the
patient, which frequently depends on the underlying disease
rather than on the mechanism of syncope itself. The background
is provided for physicians to avoid confounding these two
The second aspect is to produce a comprehensive document
which is addressed not only to cardiologists but to all physicians
who are interested in the field. In order to achieve this aim a
great number of other specialists were involved, as either full
members, external contributors, or reviewers nominated by inter-
national societies of neurology, autonomic disease, internal medi-
cine, emergency medicine, geriatrics, and general medicine. In
total 76 specialists from different disciplines participated in this
The most relevant changes are listed here:
† An update of the classification of syncope in the larger frame-
work of transient loss of consciousness (T-LOC).
† New data on epidemiology.
† A new diagnostic approach focusing on risk stratification of
sudden cardiac death (SCD) and cardiovascular events after
initial evaluation, including some recommendations for treat-
ment in patients with unexplained syncope at high risk.
† Emphasis on the increasing role of a diagnostic strategy based on
prolonged monitoring in contrast to the conventional strategy
based on laboratory testing.
† An update of evidence-based therapy.
Classes of recommendations
Levels of evidence
The literature on syncope investigation and treatment is largely
composed of case series, cohort studies, or retrospective analyses
of already existing data. The impact of these approaches on guiding
therapy and reducing syncope recurrences is difficult to discern
without randomization and blinding. Because of these issues, the
panel performed full reviews of the literature on diagnostic tests
but did not use predefined criteria for selection of articles to be
reviewed. This TF recognizes that for some of the recommen-
dations related to diagnostic processes, controlled trials have
never been performed. Consequently, some of these recommen-
dations are based on brief observational studies, accepted clinical
practice, expert consensus and sometimes common sense. In
those cases, according to the current format of recommendations,
a level of evidence C is given.
Part 1. Definitions, classification
epidemiology, prognosis, impact
on quality of life, and economic
Syncope is a T-LOC due to transient global cerebral hypoperfusion
characterized by rapid onset, short duration, and spontaneous
This definition of syncope differs from others by including the
cause of unconsciousness, i.e. transient global cerebral hypoperfu-
sion. 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 T-LOC, a
term purposely meant to encompass all disorders characterized
by self-limited loss of consciousness (LOC), irrespective of mech-
anism (Figure 1). By distinguishing both T-LOC and syncope, the
present definition minimizes conceptual and diagnostic confusion.
In the past, papers often did not define syncope, or did so in differ-
ent ways.2Syncope was sometimes used for T-LOC, thus including
epileptic seizures and even stroke in ‘syncope’. This source of con-
fusion may still be found in the literature.3,4
In some forms of syncope there may be a prodromal period in
which various symptoms (e.g. lightheadedness, nausea, sweating,
weakness, and visual disturbances) warn that syncope is imminent.
Often, however, LOC occurs without warning. An accurate esti-
mate of the duration of spontaneous episodes is rarely obtained.
Typical syncope is brief. Complete LOC in reflex syncope lasts
no longer than 20 s in duration. However, syncope may rarely
be longer, even as much as several minutes.5In such cases, the
differential diagnosis between syncope and other causes of LOC
can be difficult. Recovery from syncope is usually accompanied
by almost immediate restoration of appropriate behaviour and
orientation. Retrograde amnesia, although believed to be uncom-
mon, may be more frequent than previously thought, particularly
in older individuals. Sometimes the post-recovery period may be
marked by fatigue.5
The adjective ‘pre-syncopal’ is used to indicate symptoms and
signs that occur before unconsciousness in syncope, so its
meaning is literal when used in this context and making it a
synonym of ‘warning’ and ‘prodromal’. The noun ‘pre-syncope’
or ‘near-syncope’ is used often to describe a state that resembles
the prodrome of syncope but which is not followed by LOC;
doubts remain as to whether the mechanisms involved are the
same as in syncope.
1.2 Classification and
1.2.1 Placing syncope in the larger
framework of transient loss of
consciousness (real or apparent)
The context of T-LOC is shown in Figure 1. Two decision trees
separating T-LOC from other conditions are whether conscious-
ness appears lost or not, and whether the four features defining
the presentation of T-LOC (transient, with rapid onset, short dur-
ation, and spontaneous recovery) are present.
T-LOC is divided into traumatic and non-traumatic forms. Con-
cussion usually causes LOC; as the presence of a trauma is usually
clear, the risk of diagnostic confusion is limited.
Non-traumatic T-LOC is divided into syncope, epileptic sei-
zures, psychogenic pseudosyncope, and rare miscellaneous
causes. Psychogenic pseudosyncope is discussed elsewhere in
this document. Rare miscellaneous disorders include either those
that are rare (e.g. cataplexy) or those whose presentation
Figure 1 Context of transient loss of consciousness (T-LOC).
SCD ¼ sudden cardiac death.
resembles other forms of T-LOC only in rare circumstances (e.g.
excessive daytime sleepiness).
Several disorders may resemble syncope in two different ways
(Table 3). In some, consciousness is truly lost, but the mechanism
is something other than global cerebral hypoperfusion. Examples
are epilepsy, several metabolic disorders (including hypoxia and
hypoglycaemia), intoxication, and vertebrobasilar transient ischae-
mic attack (TIA). In other disorders, consciousness is only appar-
ently lost; this is the case in cataplexy, drop attacks, falls,
psychogenic pseudosyncope, and TIA of carotid origin. In these
cases, the differential diagnosis from syncope is usually evident,
but sometimes may be difficult because of lack of history, mislead-
ing features, or confusion over the definition of syncope. This
differentiation is important for the clinician being confronted by
patients with sudden LOC (real or apparent), which may be due
to causes not associated with decreased global cerebral blood
flow such as seizure and/or conversion reaction.
1.2.2 Classification and pathophysiology
Table 4 provides a pathophysiological classification of the principal
causes of syncope, emphasizing large groups of disorders with a
common presentation associated with different risk profiles. A dis-
tinction along pathophysiological lines centres on a fall in systemic
blood pressure (BP) with a decrease in global cerebral blood flow
as the basis for syncope. A sudden cessation of cerebral blood flow
for as short as 6–8 s has been shown to be sufficient to cause
complete LOC. Experience from tilt testing showed that a
decrease in systolic BP to 60 mmHg or lower is associated with
syncope.6Systemic BP is determined by cardiac output (CO)
and total peripheral vascular resistance, and a fall in either can
cause syncope, but a combination of both mechanisms is often
present, even if their relative contributions vary considerably.
Figure 2 shows how pathophysiology underpins the classification,
with low BP/global cerebral hypoperfusion at the centre, adjacent
to low or inadequate peripheral resistance and low CO.
A low or inadequate peripheral resistance can be due to inap-
propriate reflex activity depicted in the next ring, causing vasodila-
tation and bradycardia manifesting as vasodepressor, mixed, or
cardioinhibitory reflex syncope, seen in the outer ring. Other
causes of a low or inadequate peripheral resistance are functional
and structural impairments of the autonomic nervous system
(ANS) with drug-induced, primary and secondary autonomic
Classification of syncope
Conditions incorrectly diagnosed as syncope
LOC ¼ loss of consciousness; TIA ¼ transient ischaemic attack.
failure (ANF) in the outer ring. In ANF, sympathetic vasomotor
pathways are unable to increase total peripheral vascular resistance
in response to the upright position. Gravitational stress, in combi-
nation with vasomotor failure, results in venous pooling of blood
below the diaphragm, causing a decrease in venous return and con-
sequently in CO.
The causes of transient low CO are 3-fold. The first is a reflex
causing bradycardia, known as cardioinhibitory type of reflex
syncope. The second is cardiovascular causes, due to arrhythmia
and structural disease including pulmonary embolism/hypertension.
The third is inadequate venous return, due to volume depletion or
venous pooling. The three final mechanisms, reflex, secondary to
orthostatic hypotension (OH), and cardiovascular, are shown
outside the rings in Figure 2; reflex syncope and OH span the
two main pathophysiological categories.
184.108.40.206 Reflex syncope (neurally mediated syncope)
Reflex syncope traditionally refers to a heterogeneous group of
conditions in which cardiovascular reflexes that are normally
useful in controlling the circulation become intermittently inap-
propriate, in response to a trigger, resulting in vasodilatation and/
or bradycardia and thereby in a fall in arterial BP and global cer-
Reflex syncope is usually classified based on the efferent
pathway most involved, i.e. sympathethic or parasympathetic.
The term ‘vasodepressor type’ is commonly used if hypotension,
due to a loss of upright vasoconstrictor tone, predominates. ‘Car-
dioinhibitory’ is used when bradycardia or asystole predominate,
and ‘mixed’ is used if both mechanisms are present.
Reflex syncope may also be classified based on its trigger, i.e. the
afferent pathway (Table 4). It must be recognized that this is a sim-
plification, because many different mechanisms can be present in
the context of a specific situation, such as micturition or defaeca-
tion syncope. The triggering situations vary considerably in and
between individual patients. In most cases the efferent pathway
does not depend strongly on the nature of the trigger [e.g. both
micturition syncope and vasovagal syncope (VVS) may present as
cardioinhibitory or vasodepressor syncope]. Knowing the various
triggers is clinically important, as recognizing them may be instru-
mental in diagnosing syncope:
† ‘Vasovagal’ syncope (VVS), also known as the ‘common faint’, is
mediated by emotion or by orthostatic stress. It is usually pre-
ceded by prodromal symptoms of autonomic activation (sweat-
ing, pallor, nausea).
† ‘Situational’ syncope traditionally refers to reflex syncope associ-
ated with some specific circumstances. Post-exercise syncope
can occur in young athletes as a form of reflex syncope as
well as in middle-aged and elderly subjects as an early manifes-
tation of ANF before they experience typical OH.
† ‘Carotid sinus’ syncope deserves special mention. In its rare spon-
taneous form it is triggered by mechanical manipulation of the
carotid sinuses. In the more common form no mechanical
trigger is found and it is diagnosed by carotid sinus massage
† The term ‘atypical form’ is used to describe those situations in
which reflex syncope occurs with uncertain or even apparently
absent triggers. The diagnosis then rests less on history taking
alone, and more on the exclusion of other causes of syncope
(absence of structural heart disease) and on reproducing
similar symptoms with tilt testing. Such less clear presentations
may overlap with clear-cut occurrences within patients.
The classical form of VVS usually starts in young subjects as an
isolated episode and is distinct from other forms, frequently with
an atypical presentation, starting in old age often associated with
cardiovascular or neurological disorders possibly displaying ortho-
static or post-prandial hypotension. In these latter forms, reflex
syncope appears as an expression of a pathological process,
mainly related to impairment of the ANS to activate compensatory
reflexes, so there is an overlap with ANF.9
A comparison with other conditions causing syncope in the
standing position is presented in Table 5.
220.127.116.11 Orthostatic hypotension and orthostatic
In contrast to reflex syncope, in ANF sympathetic efferent activity
is chronically impaired so that vasoconstriction is deficient. Upon
standing, BP falls and syncope or pre-syncope occurs. OH is
defined as an abnormal decrease in systolic BP upon standing.
Strictly from a pathophysiological point of view there is no
overlap between reflex syncope and ANF, but the clinical manifes-
tations of the two conditions frequently overlap, sometimes
making differential diagnosis difficult. ‘Orthostatic intolerance’ refers
to symptoms and signs in the upright position due to a circulatory
abnormality. Syncope is one symptom, and others are: (i) dizziness/
lightheadedness, pre-syncope; (ii) weakness, fatigue, lethargy; (iii)
palpitations, sweating; (iv) visual disturbances (including blurring,
enhanced brightness, tunnel vision); (v) hearing disturbances
(including impaired hearing, crackles, and tinnitus); and (vi) pain
in the neck (occipital/paracervical and shoulder region), low back
pain, or precordial pain.10,11
Figure 2 Pathophysiological basis of the classification (see
text). ANF ¼ autonomic nervous failure; ANS ¼ autonomic
nervous system; BP ¼ blood pressure; low periph. resist. ¼ low
peripheral resistance; OH ¼ orthostatic hypotension.
Syndromes of orthostatic intolerance which may cause syncope
CO ¼ cardiac output; CSS ¼ carotid sinus syndrome; OH ¼ orthostatic hypotension; POTS¼ postural orthostatic tachycardia syndrome; SBP ¼ systolic blood pressure; SVR ¼ systemic vascular resistance; VVS¼ vasovagal syncope.
Various clinical syndromes of orthostatic intolerance are given in
Table 5. Among these, the forms of reflex syncope in which ortho-
static stress is the main trigger are also included.
† ‘Classical OH’ is a physical sign defined as a decrease in systolic
BP ?20 mmHg and in diastolic BP ?10 mmHg within 3 min
of standing12(Figure 3), described in patients with pure ANF,
hypovolaemia, or other forms of ANF.
† ‘Initial OH’13is characterized by a BP decrease immediately on
standing of .40 mmHg.13BP then spontaneously and rapidly
returns to normal, so the period of hypotension and symptoms
is short (,30 s) (Figure 3).
† ‘Delayed (progressive) OH’14–16is not uncommon in elderly
persons. It is attributed to age-related impairment of com-
pensatory reflexes and stiffer hearts in the elderly sensitive
to a decrease in preload.16Delayed OH is characterized by
a slow progressive decrease in systolic BP on assuming
erect posture. The absence of a bradycardiac reflex (vagal)
differentiates delayed OH from reflex syncope. Delayed
OH may, however, be followed by reflex bradycardia,
where, in the elderly, the fall in BP is less steep than in the
young (Figure 4).
† ‘Postural orthostatic tachycardia syndrome’ (POTS). Some patients,
mostly young women, present with severe complaints of ortho-
static intolerance, but not syncope, with very marked heart rate
(HR) increases [.30 beats per minute (b.p.m.) or to
.120 b.p.m.] and instability of BP.17POTS is frequently associ-
ated with chronic fatigue syndrome. The underlying pathophy-
siology remains to be determined.
18.104.22.168 Cardiac syncope (cardiovascular)
Arrhythmias are the most common cardiac causes of syncope.
They induce haemodynamic impairment, which can cause a critical
decrease in CO and cerebral blood flow. Nonetheless, syncope
often has multiple contributory factors, including HR, type of
arrhythmia (supraventricular or ventricular), left ventricular func-
tion, posture, and adequacy of vascular compensation. The latter
include baroreceptor neural reflexes as well as responses to OH
induced by the arrhythmia.18,19Regardless of such contributing
effects, when an arrhythmia is the primary cause of syncope, it
should be specifically treated.
In intrinsic sick sinus syndrome, the sinoatrial node is damaged,
because of either abnormal automaticity or sinoatrial conduction
abnormalities. In this situation syncope is due to long pauses
caused by sinus arrest or sinoatrial block and a failure of escape
mechanism. These pauses are most frequently encountered
when an atrial tachyarrhythmia suddenly stops (brady-tachy
As a rule, the more severe forms of acquired atrioventricular
(AV) block (Mobitz II block, ‘high grade’, and complete AV
block) are most closely related to syncope. In these cases, the
Figure 3 A case of ‘initial orthostatic hypotension’ (left panel)
and of ‘classical orthostatic hypotension’ (right panel). In the left
panel obtained in an otherwise healthy 17-year-old teenager with
complaints of severe transient lightheadedness upon active stand-
ing, a pronounced initial fall in BP is observed. The nadir is at
7–10 s and followed by recovery of BP. The tracing on the
right is obtained in a 47-year-old male with pure ANF. BP
starts to fall immediately after standing to very low levels after
1 min upright with little increase in HR despite the hypoten-
ANF ¼ autonomic
HR ¼ heart rate; b.p.m. ¼ beats per minute.
failure; BP ¼ bloodpressure;
Figure 4 Reflex syncope (mixed form) induced by tilt testing in
a 31-year-old (upper panel) and in a 69-year-old patient (lower
panel). Note the typical age differences with a much steeper
fall in BP in the younger subject compared with the older
subject (revised after Verheyden et al.16). BP ¼ blood pressure;
HR ¼ heart rate; b.p.m. ¼ beats per minute.
cardiac rhythm may become dependent on subsidiary or escape
(often unreliable) pacemaker sites. Syncope occurs because the
delay before these pacemakers begin to ‘fire’ is long. In addition
these subsidiary pacemaker sites typically have relatively slow
rates (25–40 b.p.m.). Bradycardia also prolongs repolarization
and predisposes to polymorphic ventricular tachycardia (VT),
especially of the torsade de pointes type.
Syncope or near-syncope occurs at the onset of paroxysmal
tachycardia, before vascular compensation develops.18,19Con-
sciousness is, in general, restored before tachycardia terminates.
If haemodynamics remain inadequate due to tachycardia, uncon-
sciousness is maintained. Recovery is then not spontaneous, no
longer classified as syncope, and constitutes cardiac arrest.
Several drugs can cause brady- and tachyarrhythmias. Many
antiarrhythmic drugs can cause bradycardia as a consequence of
their specific effect on sinus node function or AV conduction.
Syncope due to torsade de pointes is not uncommon, especially
in women, and is caused by drugs prolonging the QT interval. It
is particulary frequent in patients affected by the long QT
syndrome. QT-prolonging drugs belong to different categories,
i.e. antiarrhythmics, vasodilators, psychotropics, antimicrobials,
non-sedating antihistamines, etc. Much has been learned about
the inherited long QT syndrome through the collection of data
in an international registry. Far less is known about the
drug-induced syndrome because of the absence of a comprehen-
sive database. Only 1% of serious adverse reactions to drugs are
ever reported to the Food and Drug Administration (FDA).20,21
Owing to the wide variety of these drugs and the need for continu-
ous updating, this TF recommends accessing a dedicated website
Structural cardiovascular diseases can cause syncope when circula-
tory demands outweigh the impaired ability of the heart to
increase its output. Table 4 lists the most frequent cardiovascular
diseases that can cause syncope. Syncope is of great concern
when it is associated with conditions in which there is fixed or
dynamic obstruction to left ventricular outflow. The basis for the
faint is inadequate blood flow due to mechanical obstruction.
Nonetheless, in several cases, syncope is not solely the result of
restricted CO, but may be in part due to an inappropriate reflex
or OH. For instance, in the setting of valvular aortic stenosis,
syncope is not solely the result of restricted CO, but may be in
part due to inappropriate reflex vasodilation and/or primary
cardiac arrhythmia. Furthermore, arrhythmias, particularly atrial
fibrillation, are frequently important causes of faint. Thus, the
mechanism of syncope may be multifactorial. To recognize the
heart as the cause of the problem is justified by the need to
correct the underlying structural disease, when possible.
1.3.1 Prevalence of syncope in the
Syncope is common in the general population and the first episode
presents at characteristic ages (Figure 5). About 1% of toddlers may
have a form of VVS.22,23There is a very high prevalence of first
faints in patients between 10 and 30 years, with a peak of ?47%
in females and 31% in males around the age of 15.24,25Reflex
syncope is by far the most common cause. In contrast, the fre-
quency of epileptic seizures in a similar young age group is much
lower (,1%) and syncope from cardiac arrhythmia is even less
common.26In a cohort study, only 5% of adults in the community
have a first syncope over the age of 40 years. The majority have
experienced reflex-mediated episodes as teenagers and adoles-
cents.26Finally, there appears to be a peak above the age of 65
years in both males and females. In the Framingham study the inci-
dence of syncope shows a sharp rise after the age of 70 years, from
5.7 events per 1000 person-years in men aged 60–69, to 11.1 in
men aged 70–79.3,26However, in older adults and elderly subjects
(.60 years) the lifetime cumulative incidence of syncope becomes
increasingly difficult to obtain due to recollection bias of fainting
episodes decades ago.26,27
1.3.2 Referral from the general
population to medical settings
A very small fraction of patients with syncope in the general popu-
lation, present in any clinical setting (Figure 6). In the Framingham
offspring study, 44% of the participants (mean age 51 years,
Figure 5 Schematic presentation of the distribution of age and
cumulative incidence of first episode of syncope in the general
population from subjects up to 80 years is shown. The data
from subjects 5–60 years come from a study by Ganzeboom
et al.24The data from subjects ,5 years are based on those of
Lombroso et al.22and those from subjects aged 60–80 years
on the study by Soteriades et al.3
range 20–96 years) with an episode of LOC reported that they did
not seek medical advice.3The proportion of patients not seeking
medical evaluation in the younger population is much higher.25,26
In The Netherlands the prevalence of the complaint of fainting in
general practice is estimated at 9.3 per 1000 encounter-years.26,28
Recent studies report a remarkably constant frequency of syncope
in community-based Emergency Departments (EDs) in Europe,
with an incidence of ?1% of all attendances (range 0.9–
1.3.3 Prevalence of the causes of syncope
The prevalence of the causes of syncope is different depending on
the clinical settings in which the patient is evaluated (Table 6) and
the age of the patients (Table 7). Furthermore, other differences
depend on diagnostic definitions, geographical factors, and local
care pathways, making a comparison between different studies
Some general comments are however possible:
† Reflex syncope is the most frequent cause of syncope in any
† Syncope secondary to cardiovascular disease is the second most
common cause. The number of patients with a cardiovascular
cause varies widely between studies; higher frequencies are
observed in emergency settings mainly in older subjects, and
in settings oriented toward cardiology.
† In patients ,40 years OH is a rare cause of syncope; OH is fre-
quent in very old patients.
† Non-syncopal conditions, misdiagnosed as syncope at initial
evaluation, are more frequent in emergency referrals and
reflect the multifactorial complexity of these patients.
† The high unexplained syncope rate in all settings justifies new
strategies for evaluation and diagnosis.
While in the young reflex syncope is by far the most frequent
cause of T-LOC, in the elderly multiple causes are often present
and the medical history may be less reliable than in the
With regard to the prognosis (i.e. risk stratification) associated
with syncope, two important elements should be considered: (i)
risk of death and life-threatening events; and (ii) risk of recurrence
of syncope and physical injury.
1.4.1 Risk of death and life-threatening
Structural heart disease40–49and primary electrical disease50–52
are major risk factors for SCD and overall mortality in patients
with syncope. OH is associated with a 2-fold higher risk of death
owing to the severity of co-morbidities compared with the
general population.11Conversely, young patients in whom struc-
tural or electrical heart disease have been excluded and are
affected by reflex syncope have an excellent prognosis.3Most of
the deaths and many poor outcomes seem to be related to the
severity of the underlying disease rather than to syncope per se.
Several clinical factors able to predict outcome have been ident-
ified in some prospective population studies involving a validation
cohort (Table 8).
1.4.2 Recurrence of syncope and risk
of physical injury
In population studies, approximately one-third of patients have
recurrence of syncope in 3 years follow-up. The number of epi-
sodes of syncope during life is the strongest predictor of recur-
rence. For example, in patients with uncertain diagnosis, low risk
and age .40 years, a history of one or two episodes of syncope
during life predicted a recurrence of 15 and 20% after 1 and 2
years, respectively, whereas a history of three episodes of
syncope during life predicted a recurrence of 36 and 42% after 1
and 2 years, respectively.53
A psychiatric disease and age ,45 years are also associated with
higher rates of pseudosyncope. Conversely, gender, tilt test
response, severity of presentation, and presence or absence of
structural heart disease have minimal or absent predictive value.1,53
Major morbidity, such as fractures and motor vehicle acci-
dents, were reported in 6% of patients, and minor injury, such
as laceration and bruises, in 29%. Recurrent syncope is associated
with fractures and soft tissue injury in 12% of patients.1In
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 older patients with carotid sinus syn-
Morbidity is particulary high in the elderly and ranges from loss
of confidence, depressive illness, and fear of falling, to fractures and
1.5 Impact on quality of life
Recurrent syncope has serious effects on quality of life. The
physical impairment due to syncope is comparable with
chronic illnesses such as chronic arthritis, recurrent moderate
depressive disorders, and end-stage renal disease.57–59
Figure 6 Syncope events/visits per 1000 patient-years in The
Netherlands (from Ganzeboom et al.27with permission). ED ¼
Frequency of the causes of syncope in general population, Emergency Department and specialized clinical settings from some recent studies
ED ¼ Emergency Department; OH ¼ orthostatic hypotension; T-LOC ¼ transient loss of consciousness.
patients with frequent recurrent syncope, psychosocial impair-
ment had an estimated average adverse impact on 33% of the
assessed aspects of daily life. Syncope reduces mobility, usual
abilities, and self-caring, and increases depression, pain, and dis-
comfort. Female gender, high level of co-morbidity, number of
episodes of syncope, and presence of pre-syncope seemed to
be associated with poorer quality of life. Finally, it should be
stressed that, while syncope occurs intermittently, its threat of
recurrence continuously impairs quality of life. Although
quality of life usually improves over time, it remains poor,
especially in older age due to recurrences and higher level of
1.6 Economic issues
The management of syncope is expensive for a number of reasons:
(1) As syncope is very frequent in the general population, it inevi-
tably results in high direct clinical and indirect social costs.
Approximately 1% of referrals to the ED are for syncope; of
these, ?40% are hospitalized.30,31,33,61In a large study32the
median in-hospital stay was 5.5 days (interquartile range
3–9). Hospitalization costs account for .75% of the total
(2) A wide range of conditions may cause syncope. Consequently,
without strict adherence to published management guidelines
the evaluation of syncope patients has proved to be inefficient.
The absence of a gold standard clinical test able to provide a
certain, easy, and cheap diagnosis, and the widespread inap-
propriate use of multiple but inefficiently directed diagnostic
tests (‘shotgun approach’) results in overuse of medical
resources and increased costs. By following a well defined
standardized care pathway a considerable improvement in
diagnostic yield and cost-effectiveness (i.e. cost per reliable
diagnosis) can be achieved64(see section 5.3).
Although a comparison of costs between different studies is dif-
ficult, owing to differences in methods of calculation and between
healthcare systems in different countries, it is generally believed
that costs associated with syncope management are high. In the
USA, estimated total annual costs for syncope-related admissions,
derived from the Medicare database, were US$2.4 billion, with a
mean cost of US$5400 per hospitalization.65In the UK,63the
overall cost per patient was £611, with 74% attributed to the
costs of hospital stay. Cost per diagnosis of patients admitted to
hospital was £1080. In a multicentre study performed in Italy.64
929 patients evaluated according to usual practice were compared
with 725 patients evaluated using a standardized guideline-based
approach. In the usual practice group, the cost per diagnosis was
E1753+2326 per patient; it increased to E3506+2729 for hos-
pitalized patients. When compared with the usual-care group, the
standardized-care group had a 17% lower hospitalization rate, 24%
fewer tests performed, and 11% shorter in-hospital stay. As a con-
sequence, the mean cost per diagnosis was 29% lower (E1240+
521 P ¼ 0.0001).
Frequency of the causes of syncope according to age
ED ¼ Emergency Department; OH ¼ orthostatic hypotension; T-LOC ¼ transient loss of consciousness.
Part 2. Initial evaluation,
diagnosis, and risk stratification
2.1 Initial evaluation
The initial evaluation of a patient presenting with T-LOC consists
of careful history, physical examination, including orthostatic BP
measurements, and electrocardiogram (ECG). Based on these find-
ings, additional examinations may be performed:
† CSM in patients .40 years.
† Echocardiogram when there is previous known heart disease or
data suggestive of structural heart disease or syncope secondary
to cardiovascular cause.
† Immediate ECG monitoring when there is a suspicion of
† Orthostatic challenge (lying-to-standing orthostatic test and/or
head-up tilt testing) when syncope is related to the standing
position or there is a suspicion of a reflex mechanism.
† Other less specific tests such as neurological evaluation or
blood tests are only indicated when there is suspicion of non-
The initial evaluation should answer three key questions:
(1) Is it a syncopal episode or not?
(2) Has the aetiological diagnosis been determined?
(3) Are there data suggestive of a high risk of cardiovascular events
2.1.1 Diagnosis of syncope
The differentiation between syncope and non-syncopal conditions
with real or apparent LOC can be achieved in most cases with a
detailed clinical history,66–68but sometimes can be extremely
The following questions should be answered:
† Was LOC complete?
† Was LOC transient with rapid onset and short duration?
† Did the patient recover spontaneously, completely and without
† Did the patient lose postural tone?
If the answers to these questions are positive, the episode has a
high likelihood of being syncope. If the answer to one or more of
these questions is negative, exclude other forms of LOC before
proceeding with syncope evaluation.
2.1.2 Aetiological diagnosis
Initial evaluation is able to define the cause of syncope in 23–50%
of patients.33,69Table 9 lists some of the most important questions
that must be answered by the clinical history. There are some find-
ings in the clinical history, physical examination, or ECG that can be
Risk stratification at initial evaluation in prospective population studies including a validation cohort
This table shows several different studies that have analysed the impact of different clinical data on the follow-up of patients presenting with syncope. Overall, the
presence of abnormal ECG, increased age, or data suggestive of heart disease imply a worse prognosis at 1–2 year follow-up
bWarm-crowded place/ prolonged orthostasis/fear–pain–emotion.
ECG ¼ electrocardiogram
considered diagnostic of the cause of syncope, permiting no
further evaluation and institution of treatment.
In many other situations, the findings of initial evaluation do
not permit a definite diagnosis to be made, but suggest some
causes (Table 10). In these cases, additional testing is usually
2.1.3 Risk stratification
When the cause of syncope remains uncertain after initial evalu-
ation the next step is to assess the risk of major cardiovascular
events or SCD. Figure 7 shows the diagnostic flow chart to be fol-
lowed in these patients.
The main high risk features, in accordance with recent guidelines
on SCD and cardiac pacing,70–73are listed in Table 11.
2.2 Diagnostic tests
2.2.1 Carotid sinus massage
It has long been observed that pressure at the site where the
common carotid artery bifurcates produces a slowing in HR
and fall in BP. In some individuals, this reflex initiated by CSM
results in an abnormal response. A ventricular pause lasting .3
s and/or a fall in systolic BP of .50 mmHg defines carotid
sinus hypersensitivity (CSH). When associated with spontaneous
syncope, CSH defines CSS. Precise methodology and results of
CSM are reported in the previous guidelines on syncope.1Diag-
nosis of CSS requires the reproduction of spontaneous symp-
toms during 10 s sequential right and left CSM performed
supine and erect, under continuous monitoring of HR and peri-
odic measurement of BP, permitting better evaluation of the
vasodepressor component.74In up to 30% of patients, an abnor-
mal reflex is present only in the upright position. It should be
stressed that CSH is a common finding in older male individuals,8
but patients with CSS are more unusual.75CSS is exceptional in
patients ,40 years old.74
Recommendations: diagnostic criteria with initial
aClass of recommendation.
bLevel of evidence.
AV ¼ atrioventricular; BBB ¼ bundle branch block; ECG ¼ electrocardiogram;
ICD ¼ implantable cardioverter defibrillator; OH ¼ orthostatic hypotension;
SVT ¼ supraventricular tachycardia; VVS ¼ vasovagal syncope; VT ¼ ventricular
The relationship between abnormal response to CSM
and syncope is a crucial point that has been studied by
two different methods. The first was a pre–post comparison
of the recurrence rate of syncope after pacing. Non-
follow-up in patients implanted than in patients without
Important historical features
pacing, and these results were confirmed by two randomized
trials.76,77The second method was to analyse the occurrence
of asystolic episodes registered in patients with cardioinhibi-
tory response to CSM by an implanted device. In the two
trials that employed this methodology, recordings of long
pauses were very common.78,79These results suggest that
a positive response to CSM in patients with syncope is
highly predictive of the occurrence of spontaneous asystolic
The main complications of CSM are neurological. Pooling the
data of three studies74,80,81in which 7319 patients were analysed,
neurological complications were observed in 21 (0.29%). CSM
Recommendations: carotid sinus massage
aClass of recommendation.
bLevel of evidence.
BP ¼ blood pressure; CSM ¼ carotid sinus massage; TIA ¼ transient ischaemic
should be avoided in patients with previous TIA, stroke within the
past 3 months, or with carotid bruits, except if carotid Doppler
studies excluded significant stenosis.80
on initial evaluation
Clinical features that can suggest a diagnosis
ARVC ¼ arrhythmogenic right ventricularcardiomyopathy; AV ¼ atrioventricular;
LBBB ¼ left bundle branch block; OH ¼ orthostatic hypotension; RBBB ¼ right
bundle branch block; VT ¼ ventricular tachycardia.
Figure 7 Diagnostic flowchart in patients with suspected
T-LOC. ECG ¼ electrocardiographic; T-LOC ¼ transient loss
2.2.2 Orthostatic challenge
displacement of blood from the thorax to the lower limbs
that leads to a decrease in venous return and CO. In the
absence of compensatory mechanisms, a fall in BP may lead to
Currently, there are two different methods for assessing the
response to change in posture from supine to erect11(Table 5).
One is ‘active standing’, in which patients arise actively from
supine to erect, and the other is head up tilt at 60 or 708.
22.214.171.124 Active standing
This test is used to diagnose different types of orthostatic intoler-
ance; see section 126.96.36.199 and Table 5.
The sphygmomanometer is adequate for routine clinical testing
because of its ubiquity and simplicity. Automatic arm-cuff devices,
as they are programmed to repeat and confirm measurements
when discrepant values are recorded, may be a disadvantage due
to the rapidly falling BP during OH. With a sphygmomanometer
more than four measurements per minute cannot be obtained
without venous obstruction in the arm. When more frequent
values are required continuous beat-to-beat non-invasive BP
measurement can be used.
Recommendations: active standing
aClass of recommendation.
bLevel of evidence.
BP ¼ blood pressure; OH ¼ orthostatic hypotension.
188.8.131.52 Tilt testing
Tilt testing enables the reproduction of a neurally mediated reflex
in laboratory settings. Blood pooling and decrease in venous return
due to orthostatic stress and immobilization trigger the reflex. The
final effect, hypotension and usually concomitant HR slowing, is
related to impaired vasoconstrictor capability followed by sym-
pathetic withdrawal and vagal overactivity.
The clinical situation corresponding to tilt testing is reflex
syncope triggered by prolonged standing. However, this test can
also be positive in patients with other forms of reflex syncope83
and in patients with sick sinus syndrome.84
Tilt testing was introduced into clinical evaluation of patients with
syncope of unknown origin by Kenny et al. in 1986.85Since then,
many protocols have been reported with variations in the initial
stabilization phase, duration, tilt angle, type of support, and differ-
ent pharmacological provocation. The sensitivity and specificity of
different protocols are described in detail in different reviews.1,86
The most commonly used protocols are the low-dose intrave-
nous isoproterenol test, which uses incremental doses in order
to increase average HR by ?20–25% over baseline (usually
?3 mg/min)87and the protocol using 300–400 mg of sublingual
nitroglycerine after a 20 min unmedicated phase.88In older
patients omission of the passive phase and commencing the test
with nitroglycerine may be effective and improve compliance.89
Both protocols have a similar rate of positive responses (61–
69%), with a high specificity (92–94%). Patients should be fasted
for 4 h prior to the test. Due to the need for venous cannulation
ARVC ¼ arrhythmogenic right ventricular cardiomyopathy; b.p.m. ¼ beats per
minute; LBBB ¼ left bundle branch block; LVEF ¼ left ventricular ejection fraction;
RBBB ¼ right bundle branch block; SCD ¼ sudden cardiac death; VT ¼
in the isoproterenol protocol a pre-tilt phase of stabilization of
20 min is required, whereas with sublingual nitroglycerine the
pre-tilt phase can be shortened to 5 min.
Indications. In most studies the main indication for tilt testing has
been to confirm a diagnosis of reflex syncope in patients in
whom this diagnosis was suspected but not confirmed by initial
Tilt testing is not usually needed in patients whose reflex syncope
is already diagnosed by clinical history and in patients with single or
rare syncope unless special situations (e.g. injury, anxiety, occu-
pational implications such as aircraft pilots, etc.). In patients with a
high risk profile for cardiovascular events or with data suggestive
of arrhythmic syncope, tilt testing has been reported to be useful
when a cardiovascular cause has been reasonably excluded by a
comprehensive evaluation. In patients with T-LOC associated with
jerking movements tilt testing has been demonstrated to be
helpful in discriminating syncope from epilepsy.90Tilt testing has
been used in patients with frequent episodes of T-LOC and suspi-
cion of psychiatric problems, even with traumatic injury, to investi-
gate the reflex nature of the syncope.91Similarly, tilt testing has
been used in the elderly in order to distinguish syncope from falls.92
The pattern of response to tilt testing has recently been used to
discriminate pure reflex syncope from non-classical forms of
delayed OH (see Table 5).14
Tilt testing has no value in assessing the treatment efficacy.93
strate susceptibility of the patient to reflex syncope, and thereby to
initiate treatment (e.g. physical manoeuvres, see Part 3).94–96
Responses to tilt testing. The endpoint of tilt testing is the induction
of either reflex hypotension/bradycardia or delayed OH associated
with syncope or pre-syncope. When a reflex is induced, according
to the predominance of vasodepressor or cardioinhibitory com-
ponents, the responses have been classified as cardioinhibitory,
vasodepressor, or mixed.97A negative tilt table response does
not exclude the diagnosis of reflex syncope. The clinical signifi-
cance of the type of response to tilt testing in predicting the behav-
iour of BP and HR during spontaneous syncope has recently been
questioned.98,99Some studies have compared the response to tilt
testing with spontaneous syncope recorded by implantable loop
recorder (ILR). While a positive cardioinhibitory response to tilt
testing predicts with a high probability an asystolic spontaneous
syncope, the presence of a positive vasodepressor or mixed
response or even a negative response does not exclude the pres-
ence of asystole during spontaneous syncope.98,99
Complications and contraindications. Tilt testing is safe. There have
been no reported deaths during the test. However, some rare
life-threatening ventricular arrhythmias with isoproterenol in the
presence of ischaemic heart disease100or sick sinus syndrome101
have been reported. No complications have been published with
the use of nitroglycerine. Minor side effects are common and
include palpitations with isoproterenol and headache with
ommended that resuscitation equipment should available.
Contraindications to the administration of isoproterenol include
ischaemic heart disease, uncontrolled hypertension, left ventricular
outflow tract obstruction, and significant aortic stenosis. Caution
should be used in patients with known arrhythmias.
Recommendations: tilt testing
aClass of recommendation.
bLevel of evidence.
BP ¼ blood pressure; CSM ¼ carotidsinus massage; HR ¼ heart rate; LOC ¼ loss
of consciousness; OH ¼ orthostatic hypotension; TIA ¼ transient ischaemic
attack; mg ¼ micrograms.
2.2.3 Electrocardiographic monitoring
(non-invasive and invasive)
ECG monitoring is a procedure for diagnosing intermittent brady-
and tachyarrhythmias. Currently several systems of ECG ambulat-
ory monitoring are available: conventional ambulatory Holter
monitoring, in-hospital monitoring, event recorders, external or
implantable loop recorders, and remote (at home) telemetry.
The gold standard for the diagnosis of syncope is when a corre-
lation between the symptoms and a documented arrhythmia is
recorded.103,104The presence of some asymptomatic significant
arrhythmias, defined by prolonged asystole (?3 s), rapid supraven-
tricular tachycardias (SVTs) (i.e. ?160 b.p.m. for .32 beats), or
VTs, has been considered by several authors as a diagnostic
finding.105–107On the other hand, although the absence of docu-
mentation of an arrhythmia during a syncopal episode cannot be
considered a specific diagnosis, it allows exclusion of an arrhythmia
as the mechanism of the syncope.
As a general rule, ECG monitoring is indicated only when there
is a high pre-test probability of identifying an arrhythmia associated
with syncope (see Table 11). However, it has been observed that in
patients .40 years, with recurrent syncope, without significant
structural heart disease, and a normal ECG, an arrhythmia,
usually asystole, is present during syncope in up to 50%.108–111
184.108.40.206 In-hospital monitoring
In-hospital monitoring(in bed or telemetry) is warranted only when
of ECG monitoring may be of value in patients with clinical features
or ECG abnormalities suggesting arrhythmic syncope such as those
listed in Table 11, especially if the monitoring is applied immediately
ECG monitoring may be only as high as 16%,69it is justified by the
need to avoid immediate risk to the patient.
220.127.116.11 Holter monitoring
In current practice ECG monitoring is usually undertaken with
conventional 24–48 h, or even 7 day, Holter recorders.
However, since in most of the patients symptoms do not recur
during the monitoring period, the true yield of Holter in
syncope may be as low as 1–2% in an unselected population. In
15% of patients, symptoms were not associated with arrhyth-
mia.112Thus, in these patients, a rhythm disturbance could poten-
tially be excluded as a cause of syncope. Holter monitoring in
syncope is inexpensive in terms of set-up costs, but expensive in
terms of cost per diagnosis. Holter monitoring in syncope may
be of more value if symptoms are very frequent. Daily single or
multiple episodes of LOC might increase the potential for
symptom–ECG correlation. Experience in patients with very
frequent symptoms suggests that many have psychogenic pseudo-
syncope. Undoubtedly, in such patients, true negative findings of
Holter monitoring may be useful in confirming the underlying
18.104.22.168 Prospective external event recorders
Event recorders are external devices which are applied by the
patient when symptoms occur. Whereas these types of recorders
can be useful in the investigation of patients with palpitations,113
they have no role in the evaluation of syncope.
22.214.171.124 External loop recorders
These devices have a loop memory that continuously records and
deletes ECG. When activated by the patient, typically after a
symptom has occurred, 5–15 min of pre-activation ECG is
stored and can be retrieved for analysis. They are connected to
the patient through cutaneous patch electrodes. Previous studies
gave conflicting results about the usefulness of external loop
recorders: one study showed that external retrospective loop
recorders allowed ECG documentation of syncope in up to 25%
of enrolled patients114monitored for 1 month, whereas in
another115external loop recorders were not useful. A recent
study found that external loop recorders had an increased diagnos-
tic yield, when compared with Holter monitoring.116However,
since patients usually do not comply for more than a few weeks,
symptom–ECG correlation cannot be achieved when syncope
recurrence is infrequent.
126.96.36.199 Implantable loop recorders
ILRs are implanted subcutaneously under local anaesthesia and have
a battery life of up to 36 months. These devices have a solid-state
loop memory that stores retrospective ECG recordings, when acti-
vated either by the patient or a bystander, usually after a syncopal
episode,103,104or automatically activated in the case of occurrence
of predefined arrhythmias.105–107Some of these devices have the
capability of transmitting the signals transtelephonically. Advantages
of ILRs include continuous loop high-fidelity ECG recording. Disad-
vantages include: the need for a minor surgical procedure, the fact
that sometimes it can be difficult to differentiate between supraven-
tricular or ventricular arrhythmias, the presence of under- or over-
sensing that may fill the memory, and the high cost of the
implantable device. The ILR has a high initial cost. However, if
symptom–ECG correlation can be achieved in a substantial
number of patients during the active life of the device, then analysis
of the cost per symptom–ECG yield has shown than the implanted
device may be morecost-effective than a strategy using convention-
al investigation.117,118In the initial experience, ILRs were used for
diagnosis in patients with unexplained syncope at the end of com-
plete negative work-up. In a small series of highly selected patients,
symptom–ECG correlation was achieved in 88% of patients within
a mean of 5 months of implantation.103Pooled data from nine
studies,103,104,108,119–124including 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
a few cases) at the time of the recorded event, 11% had tachycardia
and 33% had no arrhythmia. In pooled data from seven
studies104,108,119–123pre-syncope was much less likely to be associ-
absence of a documented arrhythmia pre-syncope cannot be con-
sidered a surrogate for syncope; in contrast, the documentation
of a significant arrhythmia at the time of pre-syncope can be con-
sidered a diagnostic finding.
Recommendations: electrocardiograhic monitoring
aClass of recommendation.
bLevel of evidence.
AV ¼ atrioventricular; ECG ¼ electrocardiogram; ILR ¼ implantable loopr
recorder; SVT ¼ supraventricular tachyradia; VT ¼ ventricular tachycardia.
There are several areas of interest other than unexplained
syncope in which ILRs have been investigated:
† Patients in whom epilepsy was suspected but the treatment has
† Patients who have suspected recurrent neurally mediated
syncope when the understanding of the mechanism of spon-
taneous syncope may alter the therapeutic approach.110
† Patients with bundle branch block (BBB) in whom paroxysmal
AV block is likely despite negative complete electrophysiological
† Patients with definite structural heart disease and/or non-
sustained ventricular tachyarrhythmia in whom a ventricular
tachyarrhythmia is likely despite a negative complete electro-
physiological study (EPS).119
† Patients with unexplained falls.125
188.8.131.52 Remote (at home) telemetry
Most recently, external and implantable device systems that are
able to provide continuous ECG recording or 24 h loop
memory, with wireless transmission (real time) to a service
centre, have been developed. Daily and warning reports for prede-
fined events are sent from the centre to the physician. Initial data
showed that a mobile cardiac outpatient telemetry system had a
higher diagnostic yield than a patient-activated external looping
event monitor in patients with syncope or pre-syncope.126The
potential role of these systems in the diagnostic work-up of
patients with syncope needs to be further evaluated.
184.108.40.206 Classification of electrocardiographic recordings
disturbances recorded with an ILR at the time of syncope, the Inter-
nationalStudyon Syncope of Unknown Etiology (ISSUE) investigators
have proposed a classification aimed to group the observations into
homogeneous patterns in order to define an acceptable standard
useful for future studies and clinical practice.127This classification
divided ECG recordings into four groups according to the main
rhythm change and the suggested mechanism of syncope (Table 12).
220.127.116.11 Electrocardiographic monitoring in syncope—
where in the work-up?
will be guided by the results of initial evaluation. In some situations,
where the clinical evidence strongly suggests a diagnosis of reflex
syncope, and especially when syncope occurs occasionally, ECG
monitoring may be deemed unnecessary. In those patients with fre-
quent symptoms or in those in whom arrhythmic syncope is sus-
pected, but who are not at high risk, an ILR can be useful. In the
initial experience, ILRs were used as last resort in the evaluation of
syncope after all investigations were negative. In one study,12860
patients with unexplained syncopewere randomized to‘convention-
provide a diagnosis than the conventional strategy (52 vs. 20%).
However, patients at high risk of life-threatening arrhythmias, as
well as those with a left ventricular ejection fraction (LVEF) ,35%,
were excluded. According to these data and due to the limited diag-
nostic value of tilt testing,98,99adenosine triphosphate (ATP)
test,99,129EPS,119,120and short-term ECG monitoring (Holter,
nostic work-up might become the reference standard to be adopted
proven to allow treatment based on aetiology.
Future technology may allow recording of multiple signals in
addition to the ECG and will place emphasis on the features occur-
ring during spontaneous syncope, rather than provoked syncope.
For this reason it is likely that implantable monitors will become
increasingly emphasized in syncope and that their use will be antici-
pated in the diagnostic work-up instead or before many other con-
ventional investigations. However, in patients with important
structural heart disease that expose them to a high risk of life-
threatening arrhythmias, the implantation of an implantable
cardioverter defibrillator (ICD) or an EPS preceding the use of
ECG monitoring systems should be performed. Although the
documentation of a bradyarrhythmia concurrent with syncope is
considered diagnostic, further evaluation may sometimes be
necessary in order to discriminate between an intrinsic cardiac
abnormality and a reflex mechanism, the latter being the most fre-
quent cause of paroxysmal bradyarrhythmia in patients without
structural heart disease and normal ECG.
2.2.4 Electrophysiological study
The diagnostic efficacy of EPS to determine the cause of syncope is
highly dependent on the degree of suspicion of the abnormality
(pre-test probability), and also on the EPS protocol.
In an overview of eight studies including 625 patients with
syncope undergoing EPS,130it was shown that positive results
occurred predominantly in patients with structural heart disease.
Sensitivity and specificity of EPS in general are not good. For a
complete review of this topic please refer to previous guidelines.1
In addition, in recent years the development of powerful non-
invasive methods, i.e. prolonged monitoring, showing a higher diag-
nostic value has decreased the importance of EPS as a diagnostic
test. Moreover, EPS is no longer indicated in the setting of patients
with severely depressed LVEF, because in these cases there is
general consensus that ICD implantation should be performed
regardless of mechanism of syncope, as discussed elsewhere in
this document. In clinical practice, data from some registries
show that nowadays ?2% of patients with unexplained syncope
evaluated by cardiologists undergo EPS and even fewer if they
are evaluated by other specialists.27,31,36,40,56,131Nevertheless,
this test still remains useful for diagnosis in specific clinical situ-
ations listed below.
18.104.22.168 Suspected intermittent bradycardia
The pre-test probability of syncope-related bradycardia is relatively
high when there is asymptomatic sinus bradycardia (,50 b.p.m.)
or sinoatrial block, usually documented by 12-lead ECG or ECG
The prognostic value of a prolonged sinus node recovery time
(SNRT) is not well defined. An abnormal response is defined as
Classification of ECG recordings obtained with ILR, with their probable-related mechanism (adapted from
AV ¼ atrioventricular; b.p.m. ¼ beats per minute; ECG ¼ electrocardiographic; HR ¼ heart rate; ILR ¼ implantable loop recorder; ISSUE ¼ International Study on Syncope of
Unknown Etiology; SVT ¼ supraventricular tachycardia; VT ¼ ventricular tachycardia.
?1.6 or 2 s for SNRT or ?525 ms for corrected sinus node recov-
ery time (CSNRT).132,133One observational study, however,
showed a relationship between the presence of prolonged SNRT
at EPS and the effect of pacing on symptoms. Another small pro-
spective study showed that patients with a CSNRT ?800 ms had
an eight times higher risk of syncope than patients with a
CSNRT below this value.134
22.214.171.124 Syncope in patients with bundle branch block
(impending high degree atrioventricular block)
Patients with BBB are at higher risk of developing high degree AV
block. Two factors were shown to increase the risk of AV block in
BBB patients: a history of syncope and a prolonged His-ventricular
(HV) interval. The risk of developing AV block increased from 2%
in patients without syncope to 17% in patients with syncope during
42 months follow-up.135The progression rate to AV block at 4
years was 4, 12, and 24%, respectively, for patients with an HV
interval ,55 ms (normal), ?70 ms and ?100 ms.136
The development of intra- or infra-His block on incremental
atrial pacing is highly predictive of impending AV block, but has
low sensitivity. The development of intra- or infra-His block with
pharmacological challenge by class I antiarrhythmic drugs predicts
the subsequent development of spontaneous AV block with higher
sensitivity. The prognostic value of a pharmacologically prolonged
HV interval to a value of ?120 ms without induction of AV block is
uncertain. On the other hand, about one-third of patients with
negative EPS in whom an ILR was implanted developed intermit-
tent or permanent AV block on follow-up.120Thus EPS has a
low sensitivity and specifity.
In pooled data from nine studies (1761 patients) the total mor-
tality was 28% at 40 months; 32% of deaths were sudden.1
However, neither syncope nor prolonged HV interval were associ-
ated with a higher risk of death, and pacemaker therapy did not
decrease this risk.135
In conclusion, prolonged HV interval or induction of AV block
by pacing or by pharmacological stress identifies a group of
patients at higher risk of developing AV block in follow-up, but
the absence of abnormal findings does not exclude the develop-
ment of AV block.
126.96.36.199 Suspected tachycardia
In patients with syncope preceded by sudden-onset brief palpita-
tions suggesting SVT, an EPS may be indicated in order to assess
the exact mechanism especially when a curative catheter ablation
procedure can be performed.
In patients with previous myocardial infarction and preserved
LVEF, induction of sustained monomorphic VT is strongly predic-
tive of the cause of syncope,137whereas the induction of ventricu-
lar fibrillation is considered a non-specific finding.138The absence
of induction of ventricular arrhythmias identifies a group of
patients at lower risk of arrhythmic syncope.139
The role of EPS and the use of pharmacological challenge by
class I antiarrhythmic drugs in patients with syncope and suspected
Brugada syndrome is controversial.52In a meta-analysis of world-
wide published data, concerning 1036 patients, in 54% of whom
VT or ventricular fibrillation had been induced by premature
ventricular stimulation, no difference in outcome was observed
in 34 months follow-up.140
Recommendations: electrophysiological study
aClass of recommendation.
bLevel of evidence.
ARVC ¼ arrhythmogenic right ventricular cardiomyopathy; BBB ¼ bundle branch
block; CSNRT ¼ corrected sinus node recovery time; DCM ¼ dilated
cardiomyopathy; EPS ¼ electrophysiological study; ICD ¼ implantable
cardioverter defibrillator; HV ¼ His-ventricle; SVT ¼ supraventricular
tachycardia; VT ¼ ventricular tachycardia.
2.2.5 Adenosine triphosphate test
The test requiresthe rapid (,2 s) injection of a 20 mg bolus of ATP
(or adenosine) during ECG monitoring. The induction of AV block
with ventricular asystole lasting .6 s, or the induction of AV block
lasting .10 s, are considered abnormal. ATP testing produced an
abnormal response in some patients with syncope of unknown
origin (especially older women without structural heart disease),
but not in controls, thus suggesting that paroxysmal AV block
could be the cause of unexplained syncope. Nevertheless, recent
studies showed no correlation between AV block induced by ATP
and the ECG findings (documented by ILR) during spontaneous
syncope.98,99Thus, the low predictive value of the test does not
support its use in selecting patients for cardiac pacing. The role of
endogenous adenosine release in triggering some forms of syncope
due to otherwise unexplained paroxysmal AV block (the so-called
‘adenosine-sensitive syncope’) remains under investigation.
Recommendations: adenosine triphosphate test
aClass of recommendation.
bLevel of evidence.
ATP ¼ adenosine triphosphate test.
2.2.6 Echocardiography and other
functional haemodynamic data is a key technique to diagnose the
presence of structural cardiac disease. Echocardiography plays an
important role in risk stratification on the basis of LVEF. In the pres-
ence of structural heart disease, other tests to evaluate a cardiac
cause of syncope should be performed. Echocardiography identifies
the cause of syncope in very few patients when no more tests are
needed (e.g. aortic stenosis, atrial myxoma, tamponade, etc.).
Transoesophageal echocardiography, computed tomography
(CT), and magnetic resonance imaging (MRI) may be performed
in selected cases (e.g. aortic dissection and haematoma, pulmonary
embolism, cardiac masses, pericardial and myocardial diseases,
congenital anomalies of coronary arteries).
aClass of recommendation.
bLevel of evidence.
2.2.7 Exercise stress testing
Exercise-induced syncope is infrequent. Exercise testing should be
performed in patients who have experienced episodes of syncope
during or shortly after exertion. Careful ECG and BP monitoring
should be performed during both the test and the recovery
phase as syncope can occur during or immediately after exercise.
These two situations should be considered separately. Indeed,
syncope occurring during exercise may be due to cardiac causes
(even if some case reports showed that it might be a manifestation
of an exaggerated reflex vasodilatation), whereas syncope occur-
ring after exercise is almost invariably due to a reflex mechanism.
Tachycardia-related exercise-induced second and third degree AV
block has been shown to be located distal to the AV node and pre-
dicts progression to permanent AV block. Resting ECG frequently
shows intraventricular conduction abnormalities.141There are no
data supporting an indication for exercise testing in a general popu-
lation with syncope.
Recommendations: exercise testing
aClass of recommendation.
bLevel of evidence.
AV ¼ atrioventricular; ECG ¼ electrocardiogram.
2.2.8 Cardiac catheterization
Cardiac catheterization techniques (e.g. coronary angiogram)
should be carried out in suspected myocardial ischaemia or infarc-
tion and to rule out ischaemia-driven arrhythmias.
2.2.9 Psychiatric evaluation
Syncope and psychiatry interact in two ways. Various psychiatric
drugs can contribute to syncope through OH and prolonged QT
intervals. Disruption of a psychiatric drug regimen may have
severe psychiatric consequences and should not be undertaken
without relevant expertise.
The second interaction concerns ‘functional’ attacks. ‘Functional’
is used for conditions that resemble known somatic conditions
without a somatic explanation being found, and with a presumed
psychological mechanism. Two types of patients have to be
included in the differential diagnosis of T-LOC. In both, patients
are non-responsive and do not show normal motor control,
implying that falls are common. In one type gross movements
resemble epileptic seizures; these attacks have been described
as ‘pseudoepilepsy’, ‘non-epileptic seizures’, ‘psychogenic non-
epileptic seizures’, and ‘non-epileptic attack disorder’. In the
other type there are no gross movements, so the attacks resemble
syncope or longer lasting LOC. These attacks have been described
as ‘psychogenic syncope’, ‘pseudosyncope’, ‘syncope of psychiatric
origin’, and ‘medically unexplained syncope’. Note that the latter two
no cerebral hypoperfusion in functional T-LOC.
The basic difference between functional T-LOC and what it
resembles is the absence of a somatic mechanism: in pseudoepilepsy
there is no epileptiform brain activity, and in pseudosyncope BP and
HR are not low, and the electroencephalogram (EEG) does not
show delta activity or flattening during the attack.
The frequency of such attacks is not known, as they vary with
the setting. Functional T-LOC mimicking epilepsy occurs in 15–
20% of cases in specialized epilepsy clinics and in up to 6% in
Pseudosyncope usually lasts longer than syncope: patients may lie on
the floor for many minutes; 15 min is not exceptional. Other clues
are a high frequency including numerous attacks in a day, and lack of
a recognizable trigger. Injury does not exclude functional T-LOC:
trauma occurred in .50% in pseudoseizures. The eyes are usually
open in epileptic seizures and syncope but are usually closed in func-
tional T-LOC. Documenting attacks is very helpful; parameters to
assess are posture and muscle tone (video recording or neurological
investigation), BP, HR, and EEG. The latter is feasible as functional
disorders are prone to suggestion, allowing a near certain diagno-
sis.142During tilt testing, the combination of apparent unconscious-
ness with loss of motor control, normal BP, HR, and EEG rules out
syncope and most forms of epilepsy.
Proving the nature of attacks is useful in confirming the diagnosis.
Announcing a ‘psychogenic’ diagnosis to patients may be difficult,
fake attacks on purpose. Patients see their attacks as involuntary, as
they probably are. Stressing that attacks are as involuntary as
syncope or an epileptic seizure avoids stigmatization, avoids counter-
productive clashes, and provides a therapeutic opening.
Recommendations: psychiatric evaluation
aClass of recommendation.
bLevel of evidence.
EEG ¼ electroencephalogram; T-LOC ¼ transient loss of consciousness.
2.2.10 Neurological evaluation
This section discusses neurological disorders causing syncope or
resembling it, and neurological tests in syncope.
188.8.131.52 Clinical conditions
In ANF the ANS cannot cope with physiological demands, which is
expressed as OH. Post-exercise hypotension, a related condition,
concerns hypotension directly following the cessation of physical
exercise. There are three categories of ANF.
Primary ANF comprises degenerative neurological disease such as
pure ANF, multiple system atrophy, Parkinson’s disease, and Lewy
as diabetes mellitus, amyloidosis, and various polyneuropathies.143
Drug-induced OH is the most frequent cause of OH; drugs com-
monly causing OH are antihypertensives, diuretics, tricyclic anti-
depressives, phenothiazines, and alcohol. While in primary and
secondary ANF the dysfunction is due to structural damage to
the ANS system (either central or peripheral), in drug-induced
OH the failure is functional.
Neurological evaluation should be considered in primary ANF.
Warning signs are early impotence and disturbed micturition,
and later Parkinsonism and ataxia. Referral in secondary ANF
and in drug-induced OH depends on which physician treats the
‘Subclavian steal’ refers to rerouting of blood flow to the arm
through the vertebral artery due to stenosis or occlusion of the
subclavian artery. TIA may occur when flow through the vertebral
artery cannot supply both the arm and part of the brain, during for-
ceful use of the arm. Steal most often affects the left side. When
detected with ultrasound, ‘steal’ is asymptomatic in 64%.144
A TIA is only likely to be due to steal when it is vertebrobasilar
(see below) and associated with exercise of one arm. There are
no reliable reports of isolated LOC without focal neurological
symptoms and signs in subclavian steal.
TIA related to a carotid artery does not cause T-LOC. When
almost all cerebral arteries are occluded, transient obstruction of
the remaining vessel subtending a large portion of the brain may
extremely rarely affect consciousness only in the standing position.
Moreover, focal neurological signs are much more prevalent.
TIA of the vertebrobasilar system can cause LOC, but there are
always focal signs, usually limb weakness, gait and limb ataxia, ocu-
lomotor palsies, and oropharyngeal dysfunction. For all practical
purposes a TIA concerns a focal deficit without LOC, and
syncope the opposite.
Syncope occurs more often in patients with migraine, who have a
higher lifetime prevalence of syncope and often frequent
syncope.145Syncopal and migraine attacks do not usually occur
together in these patients.
Epilepsy can cause T-LOC: patients are non-responsive, fall, and later
have amnesia. This only occurs in tonic, clonic, tonic–clonic, and
atonic generalized seizures. In absence epilepsy in children and
partial complex epilepsy in adults consciousness is altered, not lost;
these patients remain upright during attacks, in contrast to T-LOC.
Complete flaccidity during unconsciousness argues against epi-
lepsy. The only exception is ‘atonic seizure’, but it is rare, and
occurs without a trigger in children with pre-existing neurological
problems. Movements can be present in both epilepsy and
syncope. In epilepsy movements last ?1 min and, in syncope,
seconds. The jerks in epilepsy are coarse, rhythmic, and usually
synchronous, whereas those in syncope are usually asynchronous,
small, and non-rhythmic. However, synchronous jerks may occur
movements.147In syncope movements only occur after the
onset of unconsciousness and after the fall; this is not the case
Syncope is usually triggered; epilepsy rarely is. The triggers in
reflex epilepsy such as flashing lights differ from those in
syncope. A typical aura consists of a rising sensation in the
abdomen (epigastric aura) and/or an unusual unpleasant smell. A
rising sensation may rarely occur in syncope. Sweating and pallor
are uncommon in epilepsy. A tongue bite occurs much more
often in epilepsy and is on the side of the tongue whereas it is
the tip in syncope.5,147Urinary incontinence occurs in both.
Patients may be confused post-ictally a long time in epilepsy,
whereas in syncope clearheadedness is usually immediate
(Table 13). Headache, muscle pain, and elevation of creatinine
kinase and prolactin are more frequent after epilepsy.
daytime sleepiness cataplexy ensures a diagnosis of narcolepsy.
Falls may be due to syncope; elderly subjects may not be aware
of having lost consciousness. In some subjects disorders of posture,
gait, and equilibrium may mimic falls in syncope.
The term ‘drop attacks’ is variably used for Menie `re’s disease,
atonic epileptic seizures, and unexplained falls. The clearest use
of the term concerns middle-aged women (rarely men) who sud-
denly find themselves falling.148They remember hitting the floor.
Unexplained falls deserve medical attention.148
184.108.40.206 Neurological tests
Interictal EEGs are normal in syncope.5,149An interictal normal
EEG cannot rule out epilepsy, but must always be interpreted in
a clinical context. When uncertain it is better to postpone the diag-
nosis of epilepsy than falsely diagnose it.
An EEG is not recommended when syncope is the most likely
cause of T-LOC, but it is when epilepsy is the likely cause or when
clinical data are equivocal. The EEG may be useful to establish psy-
chogenic pseudosyncope, if recorded during a provoked attack.
The value of history for distinguishing seizure from syncope (adapted from Hoefnagels et al.5)
Computed tomography and magnetic resonance imaging
No studies evaluated the use of brain imaging for syncope. CT or
MRI in uncomplicated syncope should be avoided. Imaging may be
needed based on a neurological evaluation.
No studies suggest that carotid Doppler ultrasonography is valu-
able in patients with typical syncope
Recommendations: neurological evaluation
aClass of recommendation.
bLevel of evidence.
ANF ¼ autonomic failure; EEG ¼ electroencephalography; TIA ¼ transient
ischaemic attack; T-LOC ¼ transient loss of consciousness.
Part 3. Treatment
General principles of treatment of syncope
The principal goals of treatment for patients with syncope are to
prolong survival, limit physical injuries, and prevent recurrences.
The importance and priority of these different goals are depen-
dent on the cause of syncope. For example, in patients with VT
causing syncope, the mortality risk is clearly predominant, while
in patients with reflex syncope it is the prevention of recurrences
and/or limitation of injuries.
Knowledge of the cause of syncope has a key role in selection of
treatment. Once the cause has been ascertained, the second goal is
to assess the mechanism leading to syncope. For example, the
mechanism is obvious in the case of AV block in the context of
intraventricular conduction defects, but it could be more
complex in the context of reflex syncope: is it cardioinhibitory,
vasodepressor, or a mixed response?
Investigations of the cause and mechanism of syncope are
generally performed at the same time and could lead to different
treatments (or absence of treatment). For example, syncope
during the acute phase of an inferior myocardial infarction is
generally of reflex origin, and consequent severe bradycardia,
hypotension, or both are just a part of the infarction and have to
be treated as a complication of the infarct. On the other hand,
recurrent reflex syncope due to severe bradycardia, hypotension,
or both in the absence of an acute disease has to be treated for
what it is. Finally, the optimal treatment of syncope must be
directed to the responsible cause of the global cerebral
hypoperfusion. However, to the extent that these causes are
either unknown or not responsive to present therapy (e.g. there is
no specific treatment for degenerative AV block) treatment is
directed to the mechanisms leading to global cerebral hypoperfu-
sion (pacing in the above-mentioned example). The general frame-
work of treatment is based on risk stratification and the
identification of specific mechanisms when possible, as summarized
in Figure 8.
3.1 Treatment of reflex syncope
and orthostatic intolerance
This section deals with measures and interventions for prevention
of reflex syncope (vasovagal, situational, CSS) and syncope second-
ary to ANF with OH. Although there are many physiological mech-
anisms that lead to syncope, the strategies for prevention of
syncope apply to the entire range of causes. The goal of therapy
is primarily prevention of recurrence and associated injuries, and
improvement in quality of life, but not to prolong survival.
Since the 2004 guidelines, the greatest advances in treatment lie in
the field of lifestyle measures, stemming from basic physiological
knowledge and controlled trials.
The cornerstone of the non-pharmacological management of
patients with reflex syncope is education and reassurance regard-
ing the benign nature of the condition. In general, initial treatment
comprises education regarding awareness and possible avoidance
of triggers (e.g. hot crowded environments, volume depletion),
early recognition of prodromal symptoms, and performing
manoeuvres to abort the episode [e.g. supine posture, physical
counterpressure manoeuvres (PCMs)]. If possible, triggers should
be addressed directly, such as cough suppression in cough
Figure 8 Treatment of syncope. ARVC ¼ arrythmogenic right
ventricular cardiomyopathy; CAD ¼ coronary artery disease;
DCM ¼ dilated cardiomyopathy; ECG ¼ electrocardiographic;
HOCM ¼ hypertrophic
implantable cardioverter defibrillator; SCD ¼ sudden cardiac
syncope. Careful avoidance of agents that lower BP (including
a-blockers, diuretics, and alcohol) is important.
Additional treatment may be necessary in unpredictable and fre-
quent syncope. In particular when:
† very frequent syncope alters quality of life
† recurrent syncope without, or with very short prodrome
exposes patients to risk of trauma
† syncope occurs during high risk activity (e.g. driving, machine
operation, flying, competitive athletics, etc.).
3.1.1 Reflex syncope
220.127.116.11 Therapeutic options
Physical counterpressure manoeuvres
Non-pharmacological ‘physical’ treatments are emerging as a new
front-line treatment of reflex syncope. Two clinical trials94,95
have shown that isometric PCMs of the legs (leg crossing), or of
the arms (hand grip and arm tensing), are able to induce a signifi-
cant BP increase during the phase of impending reflex syncope that
allows the patient to avoid or delay losing consciousness in most
cases. The results have been confirmed in a multicentre prospec-
tive trial96which assessed the effectiveness of PCMs in daily life in
223 patients, aged 38+15 years, with recurrent reflex syncope
and recognizable prodromal symptoms: 117 patients were ran-
domized to standardized conventional therapy alone and 106
patients received conventional therapy plus training in PCMs.
The median yearly syncope burden during follow-up was signifi-
cantly lower in the group trained in PCMs than in the control
group (P ,0.004); overall 51% of the patients with conventional
treatment and 32% of the patients trained in PCMs experienced
recurrence of syncope (P ,0.005). Actuarial recurrence-free sur-
vival was better in the treatment group (log-rank P ,0.018), result-
ing in a relative risk reduction of 39% (95% confidence interval,
11–53%). No adverse events were reported.
triggered by orthostatic stress, the prescription of progressively pro-
longed periods of enforced upright posture (so-called ‘tilt training’)
may reduce syncope recurrence.150,151However, this treatment is
programme for a long period, and four randomized controlled trials
failed to confirm short-term effectiveness of tilt training in reducing
the positive response rate of tilt testing.152–155
Many drugs have been tested in the treatment of reflex syncope,
for the most part with disappointing results. The list includes
b-blockers, disopyramide, scopolamine, theophylline, ephedrine,
etilefrine, midodrine, clonidine, and serotonin reuptake inhibitors.
While results have been satisfactory in uncontrolled trials or short-
term controlled trials, several long-term placebo-controlled pro-
spective trials have been unable to show a benefit of the active
drug over placebo, with some exceptions.
Since failure to achieve proper vasoconstriction of the peripheral
vessels is common in reflex syncope, a-agonist vasoconstrictors (eti-
lefrine and midodrine) have been used. Two double-blind acute tilt
studies have showed apparent contrasting effects. Moya et al.93admi-
nistered etilefrine for 1 week, then repeated the test and found no
difference between active and placebo treatment. In contrast,
Kaufman et al.156administered a single dose of midodrine just 1 h
before tilt testing, and found a significant reduction in syncope
placebo-controlled double-blind clinical trial.157During follow-up,
patients treated with etilefrine 25 mg twice daily or placebo showed
dencefailstosupportuse ofetilefrine.Midodrinewasstudied inthree
small, open label, randomized trials in patients affected by very fre-
quent ‘hypotensive’ symptoms (.1 syncope/month).158–160Even if
defined as ‘neurally mediated’, there is overlap in clinical features of
patients in these studies with other forms of orthostatic intolerance,
rendering the results difficult to interpret. Positive results were
obtained in one small, randomized trial of paediatric patients.161The
major limitation of midodrine is frequent dosing, limiting long-term
compliance. Caution in its use in older males is necessary because of
adverse effects on urinary outflow. Overall, these data suggest that
chronic pharmacological treatment with a-agonists alone may be of
little use in reflex syncope, and long-term treatment cannot be
advised for occasional symptoms. Even if not proven, a self-
administered single dose,forexampleone dose 1 hbefore prolonged
standing or performing an activity that usually triggers syncope (the
in addition to lifestyle measures and PCMs. It must be advised,
however, that currently, midrodine is not available in all countries in
Fludrocortisone has been shown to be ineffective in a small, ran-
domized double-blind trial in children.162Fludrocortisone has been
widely used in adults with reflex syncope, but there is no trial evi-
dence to support this.
b-Blockers have been presumed to lessen the degree of ventri-
cular mechanoreceptor activation owing to their negative inotropic
effect in reflex syncope. This theory has not been supported by the
outcome of clinical trials. A rationale for use of b-blockers in other
forms of neurally mediated syncope is lacking. They may enhance
bradycardia in CSS. b-Blockers have failed to be effective in five
of six long-term follow-up studies.163–167
Paroxetine was shown to be effective in one placebo-controlled
trial, which included highly symptomatic patients from one insti-
tution.168This has not been confirmed by other studies. Paroxe-
tine may reduce anxiety, which precipitates events. Paroxetine is
a psychotropic drug requiring caution in use in patients without
severe psychiatric disease.
Pacing for reflex syncope has been the subject of five major multi-
centre, randomized controlled trials, which gave contrasting
results.169–173In all the patients 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). A recent meta-analysis of all studies suggested a non-
significant 17% reduction in syncope from the double-blinded
studies, and an 84% reduction in the studies where the control
group did not receive a pacemaker.174The suboptimal 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
Two non-randomized trials evaluated the efficacy of pacing by
selecting patients with documented asystole during spontaneous
syncope by ILR. In the study of Sud et al.,175after the insertion
of a cardiac pacemaker, syncope burden decreased from 2.7
per year to 0.45 per year (P ¼ 0.02). The ISSUE 2 study110
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 reflex
syncope with an ILR. Of the 102 patients with a symptom–
therapy, predominantly pacing for asystole. These patients experi-
enced a striking reduction in recurrence of syncope compared
with non-loop recorder-guided therapy (10% vs. 41%, P ¼
0.002). It must be stressed that ISSUE 2 was not a randomized
trial. It merely provides the basis for such a trial, now ongoing,
In conclusion, pacing plays a small role in therapy for reflex
syncope, unless severe spontaneous bradycardia is detected
during prolonged monitoring.
18.104.22.168 Individual conditions
Management of this condition has been covered above.
A few points require emphasis. Tilt table testing can be
employed to teach the patient to recognize early prodromal symp-
toms. All patients should be taught PCMs, which now form the
cornerstone of therapy together with education and reassurance.
In patients that continue to faint despite adequate lifestyle
measures and PCMs, tilt training may be considered, particularly
in the younger, very symptomatic, well-motivated patients,
despite lack of proven efficacy, because it can act by reassuring
the patient without side effects.
Treatment strategies are similar to VVS and have been covered.
Treatment of most forms of situational syncope relies heavily on
avoiding or ameliorating the triggering event. Avoidance of the
trigger may be difficult, but the response may be attenuated by
maintenance of central volume, protected posture, and slower
changes in posture.
Carotid sinus syndrome
Cardiac pacing appears to be beneficial in CSS,75–77,176and,
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.76,77Single-
chamber atrial pacing is not appropriate for CSS, and dual-chamber
pacing is generally preferred over single-chamber ventricular
pacing.78,177There are as yet no randomized studies examining
treatment of dominant vasodepressor CSS, which also pertains
for other vasodepressor conditions.
Recommendations: treatment of reflex syncope
aClass of recommendation.
bLevel of evidence.
CSS ¼ carotid sinus syndrome; PCM ¼ physical isometric counterpressure
manouuvre; VVS ¼ vasovagal syncope.
3.1.2 Orthostatic hypotension and
orthostatic intolerance syndromes
Education regarding the nature of the condition in conjunction
with lifestyle advice outlined above can improve orthostatic symp-
toms markedly, even though the rise in BP is relatively small (10–
15 mmHg); raising the standing BP just enough to be within the
autoregulatory zone can make a substantial functional difference.
Ambulatory BP recordings may be helpful in identifying abnormal
diurnal patterns. These recordings may also help identify supine
or nocturnal hypertension in treated patients.
The principal treatment strategy in drug-induced ANF is elimin-
ation of the offending agent. Expansion of extracellular volume is
an important goal. In the absence of hypertension, patients
should be instructed to take sufficient salt and water intake, target-
ing 2–3 L of fluids per day and 10 g of NaCl.178Rapid cool water
ingestion is reported to be effective in combating orthostatic intol-
erance and post-prandial hypotension.179Sleeping with the head of
the bed elevated (108) prevents nocturnal polyuria, maintains a
more favourable distribution of body fluids, and ameliorates noc-
Gravitational venous pooling in older patients can be treated
with abdominal binders or compression stockings.14,182PCMs
such as leg crossing and squatting should be encouraged in patients
with warning symptoms able to perform them.180
In contrast to reflex syncope, the use of the a-agonist, mido-
drine, is a useful addition to the first-line treatment in patients
with chronic ANF. It cannot be regarded as a cure, nor is it
helpful in all affected patients, but it is very useful in some.
There is no doubt that midodrine increases BP in both supine
and upright posture and that it amelioriates the symptoms of
OH. Midodrine (5–20 mg, three times daily) has been shown to
be effective in three randomized placebo-controlled trials.183–185
Fludrocortisone (0.1–0.3 mg once daily) is a mineralocorticoid
that stimulates renal sodium retention and expands fluid
volume.186The evidence in favour of fludrocortisone is from
two small observational studies (in combination with head-up
sleeping) and one double-blind trial in 60 patients; the observa-
tional studies showed haemodymanic benefit and, in the trial,
treated patients were less symptomatic with higher blood press-
Additional and less frequently used treatments, alone or in com-
bination, include desmopressin in patients with nocturnal polyuria,
octeotride in post-prandial hypotension, erythropoietin in anaemia,
pyridostigmine, use of walking-sticks, frequent small meals, and
judicious exercise of leg and abdominal muscles, especially
Recommendations: treatment of orthostatic
aClass of recommendation.
bLevel of evidence.
PCM ¼ physical counterpressure manoeuvre.
3.2 Cardiac arrhythmias as
Treatment goals are prevention of symptom recurrence, improve-
ment of quality of life, and prolongation of survival.
The basis of syncope in these situations is multifactorial, and is
influenced by the ventricular rate, left ventricular function, and
the adequacy of vascular compensation (including the potential
impact of neurally mediated reflex).
3.2.1 Sinus node dysfunction
In general, cardiac pacemaker therapy is indicated and has
proved highly effective in patients with sinus node dysfunction
when bradyarrhythmia has been demonstrated to account for
syncope by means of ECG documentation during spontaneous
syncope, or as a consequence of abnormal SNRT.134,189Per-
manent pacing frequently relieves symptoms but may not
affect survival. Despite adequate pacing, syncope recurs in
?20% of patients in long-term follow-up.190This is due to
the frequent association of a vasodepressor reflex mechanism
with sinusnodedisease. Newly
minimal ventricular pacing modes are recommended as an
adaptive pacemaker) pacing in patients essentially needing
Elimination of drugs that may exacerbate or unmask underlying
preventing syncope recurrence. However, when substitution is
not feasible, cardiac pacing may be necessary. Percutaneous
cardiac ablative techniques for atrial tachyarrhythmia control
have become of increasing importance in selected patients
with the bradycardia–tachycardia
syndrome, but are only infrequently used primarily for prevention
form ofsick sinus
3.2.2 Atrioventricular conduction system
Cardiac pacing is the treatment of syncope associated with
symptomatic AV block. The indications and preferential modes
of pacing in AV block have been updated recently. The possible
deleterious role of permanent right ventricular apical pacing has
recently been underscored, but alternative pacing sites are still a
matter of debate. Biventricular pacing should be considered in
those patients with an indication for pacing due to AV bock and
depressed LVEF, heart failure
(HF), andprolonged QRS
3.2.3 Paroxysmal supraventricular and
In patients with paroxysmal AV nodal reciprocating tachycardia, AV
reciprocating tachycardia, or typical atrial flutter associated with
syncope, catheter ablation is the first-choice treatment. In those
patients, the role of drug therapy is limited to being a bridge to
ablation or when ablation has failed. In patients with syncope
associated with atrial fibrillation or atypical left atrial flutter, the
decision should be individualized.
Syncope due to torsade de pointes is not uncommon and is,
in its acquired form, the result of drugs which prolong the
QT interval. Treatment is the immediate discontinuation of the
suspected drug. Catheter ablation or drug therapy should be con-
sidered in patients with syncope due to VT in the setting of a
normal heart or of heart disease with mild cardiac dysfunction.
ICD is indicated in patients with syncope and depressed
cardiac function, and VT or fibrillation without correctable
cause.71,72Although in these patients ICD usually does not
prevent syncopal recurrences, it is indicated to reduce the risk
Recommendations: treatment of syncope due to cardiac
aClass of recommendation.
bLevel of evidence.
AV ¼ atrioventricular; BBB ¼ bundle branch block; CSNRT ¼ corrected sinus node
recovery time; ECG ¼ electrocardiogram; EPS ¼ electrophysiological study; ICD ¼
implantable cardioverter defibrillator; SVT ¼ supraventricular tachycardia; VT ¼
3.2.4 Implanted device malfunction
Infrequently, implantable pacing systems have been associated with
provoking near-syncope or syncope. More often, however,
syncope in such patients may be unrelated to the device.191
When syncope is attributable to the implanted device, it may
occur as a result of pulse generator battery depletion or failure, or
lead failure. Device/lead replacement is indicated and eliminates the
problem. Alternatively, some patients may experience syncope due
to pacemaker syndrome, a condition, which incorporates many poss-
ible mechanisms of hypotension. In pacemaker syndrome with retro-
grade AV conduction, device re-programming to eliminate the
problem is usually feasible, although replacement is occasionally
needed (e.g. replace a single-chamber ventricular with a dual
chamber-pacing system). ICDs may also be associated with
syncope most commonly because even appropriate intervention is
too late to prevent LOC.49Re-programming of the device (more
aggressive antitachycardia pacing and/or earlier shock) is only
seldom able to solve the problem. In those patients, antiarrhythmic
drugs or catheter ablation may be helpful.
3.3 Syncope secondary to
structural cardiac or
In patients with syncope secondary to structural cardiac disease,
including congenital heart malformations, or cardiopulmonary
disease, the goal of treatment is not only to prevent syncopal
recurrence, but also to treat the underlying disease and to
decrease the risk of SCD.
Structural cardiac or cardiopulmonary disease can be present in
some patients with syncope, and its incidence increases in older
patients. The mere presence of heart disease does not imply
that syncope is related to the underlying cardiac disorder. Some
of these patients have typical reflex syncope, but in others, such
as those with inferior myocardial infarction or aortic stenosis,
the underlying cardiac disease may play a role in triggering or
potentiating a reflex mechanism. In addition, in many of these
patients the underlying cardiac disease may be the substrate for
supraventricular or ventricular arrhythmia that cause syncope.
Treatment of syncope associated with structural heart disease
varies with the diagnosis. In patients with syncope secondary to
severe aortic stenosis or to atrial myxoma, surgical treatment of
the underlying disease is indicated. In patients with syncope sec-
ondary to acute cardiovascular disease, such as pulmonary embo-
lism, myocardial infarction, or pericardial tamponade, treatment
should be directed to the underlying process. In hypertrophic car-
diomyopathy (with or without left ventricle outflow tract obstruc-
tion), specific treatment of the arrhythmia is usually warranted; in
most of these patients, an ICD should be implanted to prevent
SCD. There are no data on the effect of reducing the outflow gra-
dient on relief of syncope. In syncope associated with myocardial
ischaemia, pharmacological therapy and/or revascularization is
clearly the appropriate strategy in most cases. On the other
hand, when syncope is caused by primary pulmonary hypertension
or restrictive cardiomyopathy, it is often impossible adequately to
ameliorate the underlying problem. Other less common causes of
syncope include left ventricular inflow tract obstruction in patients
with mitral stenosis, right ventricular outflow tract obstruction, and
right to left shunting secondary to pulmonary stenosis or pulmon-
3.4 Unexplained syncope in
patients with high risk of sudden
In patients at high risk of SCD a disease-specific treatment is
warranted in order to reduce the risk of death and of life-
threatening events, even if the exact mechanism of syncope is
still unknown or uncertain at the end of a complete work-up. In
these patients the goal of treatment is primarily the reduction of
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 recurrence of syncope. For example, ICD-treated
patient may remain at risk for fainting because only the SCD risk is
being addressed and not the cause of syncope. An analysis of the
Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)50has
shown that ICD did not protect patients against syncope recur-
rence compared with those treated with amiodarone or placebo.
This implies the need for precise identification of the mechanism
of syncope and specific treatment as far as possible.
3.4.1 Ischaemic and non-ischaemic
The risk of death in patients with acute or chronic coronary artery
disease and depressed LVEF is increased. This necessitates evalu-
ation of ischaemia and, if indicated, revascularization. However,
arrhythmia evaluation, including EPS with premature ventricular
stimulation, can still be needed because, when present, the sub-
strate for malignant ventricular arrhythmia may not be ameliorated
by revascularization. Patients with HF and an established ICD indi-
cation by current guidelines should receive an ICD before and
independently of the evaluation of the mechanism of syncope.
This group includes, for example, patients with ischaemic or
dilated cardiomyopathy and depressed LVEF (ranging from
,30% to , 40% and New York Heart Association (NYHA)
class ?II according to current guidelines).70–73
Few data exist concerning the therapeutic implications of unex-
plained syncope in patients with ischaemic or dilated cardiomyopa-
thy. A prospective substudy from the Antiarrhythmics Versus
Implantable Defibrillators (AVID) trial47showed that syncope
patients derived important survival benefit from ICDs. A survival
benefit from the device is also suggested by small retrospective
studies.49,192However, patients with syncope and HF carry a
high risk of death regardless of the cause of syncope.45A recent
analysis of the SCD-HeFT49has shown that appropriate ICD
shocks are more likely in patients with syncope; yet ICD did not
protect against either syncope recurrence or risk of death.
At the two ends of the spectrum, we find on one side the
group of syncope patients with preserved LVEF and negative
EPS that do not warrant aggressive treatment with an ICD,119
and on the other those with congestive HF and severely
depressed LVEF who warrant an ICD despite the fact that it
will not provide protection against syncope. In this group, it
was found that mortality was higher in patients with syncope
compared with those without.49
3.4.2 Hypertrophic cardiomyopathy
Unexplained syncope is a major risk factor for SCD in hyper-
trophic cardiomyopathy particularly if it has occurred in close
temporal proximity (,6 months) to the evaluation (relative
risk .5). Conversely, older (.40 years) patients with remote
episodes of syncope (.5 years before evaluation) and patients
with a typical history of VVS have low risk of SCD.193
However, in addition to self-terminating ventricular arrhythmia,
many other mechanisms can cause syncope in hypertrophic car-
diomyopathy, including SVT, severe outflow tract obstruction,
bradyarrhythmia, decreased BP in response to exercise, and
reflex syncope. The presence or absence of other SCD risk
factors such as family history of SCD, frequent non-sustained
VT, hypotension during exercise, or marked hypertrophy may
help in the determination of risk. Observational studies have
demonstrated that ICD therapy is effective in high risk patients
with hypertrophic cardiomyopathy.71,72
3.4.3 Arrhythmogenic right ventricular
Syncope occurs in about one-third of patients with arrhythmogenic
right ventricular cardiomyopathy (ARVC) referred to tertiary
centres. Young age, extensive right ventricular dysfunction, left ven-
tricular involvement, polymorphic VT, late potentials, epsilon waves,
and family history of SD, in the absence of other competing diag-
noses, indicates therapy with an ICD.71,72In a multicentre study con-
ducted on 132 patients in order to evaluate the impact of ICD for
prevention of SCD, the patients with unexplained syncope had a
rate of appropriate ICD intervention of ?15% per year, a figure
which was similar to that of patients with cardiac arrest or ventricu-
lar tachycardia with haemodynamic compromise.194
3.4.4 Patients with primary electrical
Unexplained syncope is regarded as an ominous finding in patients
with inherited cardiac ion channel abnormalities. An ICD should be
carefully considered in the absence of another competing diagnosis
or when ventricular tachyarrhythmia cannot be excluded as a cause
of syncope. Nevertheless, the mechanism of syncope may be het-
erogeneous, being caused by life-threatening arrhythmias in some,
but being of a more benign origin, i.e. reflex, in many others. There-
fore, in these settings, it seems that syncope does not necessarily
carry a high risk of major life-threatening cardiac events and yields
a lower sensitivity than a history of documented cardiac
arrest.52,53In long QT syndrome, especially those with LQTS2
and LQTS3, the number of cardiac events before the age of 18
years, very prolonged QT intervals, and female gender predict a
worse outcome.195Brugada syndrome patients with a spontaneous
type 1 ECG pattern have a worse outcome than those with a type 2
or drug-induced pattern.52,140The usefulness of ICD in patients with
syncope is controversial, but it is undoubtely more questionable
than in cardiac arrest survivors. In the largest multicentre study,196
in 220 patients with Brugada syndrome and ICD including 18 (8%)
with a history of cardiac arrest and 88 (40%) with a history of
syncope, the rates of appropriate ICD shocks were 22 and 10%,
respectively, during a mean follow-up period of 38+27 months.
Recommendations: indications for ICD in patients with unexplained syncope and a high risk of SCD
aClass of recommendation.
bLevel of evidence.
HF ¼ heart failure; ECG ¼ electrocardiogram; ICD ¼ implantable cardioverter defibrillator; ILR ¼ implantable loop recorder; LVEF ¼ left ventricular ejection fraction; SCD ¼
sudden cardiac death.
ICD discharge in syncope patients was similar to that of asympto-
matic patients. In a recent study197that evaluated the outcome of
59 Brugada patients treated with ICD, none of the 31 patients with
syncope received an appropriate ICD shock during a mean of 39
months follow-up, and appropriate device therapy was limited to
cardiac arrest survivors; conversely, the overall complication rate
However, the differential diagnosis between benign and malig-
nant forms is usually very difficult in the setting of an inherited
disease based on conventional investigations. Consequently, in
some patients there is a rationale for more precise diagnosis (i.e.
ILR documentation) of the mechanism of syncope before embark-
ing on ICD therapy, although existing data are insufficient to make
recommendations. The few available data in the literature on
patients with syncope and short QT syndrome do not permit
Part 4. Special issues
4.1 Syncope in the elderly
The most common causes of syncope in the elderly are OH, reflex
syncope, especially CSS, and cardiac arrhythmias.198,199Different
forms may often co-exist in a patient, making diagnosis difficult.
Hospitalization related to OH increases progressively with age:
4.2% of 65- to 74-year-old patients and 30.5% of patients older
than 75 years.57In symptomatic patients, 25% have ‘age-related’
OH; in the remainder OH is predominantly due to medication
and primary or secondary atrial fibrillation. Supine systolic hyper-
tension is often present in older patients with OH and complicates
treatment, given that most agents used for treatment of OH
exacerbate supine hypertension and vice versa.
Cardioinhibitory CSS is the recognized cause of symptoms in up
to 20% of elderly patients with syncope. CSH of predominantly
vasodepressor form is equally prevalent,198but its potential role
in syncope is much less clear.
Following a standardized algorithm a definite diagnosis may be
obtained in .90% of older patients with syncope.199
Some aspects of the history, which may be difficult to obtain, are
pertinent in older patients. Syncope occurring in the morning
favours OH. One-third of individuals over 65 years are taking
three or more prescribed medications, which may cause or contrib-
ute to syncope. Their withdrawal reduces recurrences of syncope
and falls.200Medication history should include the time relationship
with onset of syncope. History should include co-morbidity, associ-
ation with physical frailty, and locomotor disability.
Gait,balanceinstability, andslowprotective reflexesare presentin
erate haemodynamic changes, insufficient to cause syncope, may
result in falls. Therefore, it is important to pursue a witness account
of episodes, although this is not available in up to 60% of cases.200
Cognitive impairment is present in 5% of 65 year olds and 20% of
80 year olds. This may attenuate the patient’s memory of syncope
and falls.40The cognitive status should be determined in addition
to details of social circumstances, injurious events, impact of
events on confidence, and ability to carry out activities of daily life.
Initial evaluation determines a definite diagnosis in a lower pro-
portion than in the young because symptoms suggestive of VVS are
less frequent in older patients.40,198In all, assessment of the auto-
nomic system (CSM, tilt test) may be necessary.
Evaluation of neurological and locomotor systems, including
observation of gait and balance, is useful. If cognitive impairment
is suspected, the Mini-Mental State Examination should be per-
formed. Otherwise, the clinical examination and diagnostic
work-up is the same as for younger adults with the exception of
routine supine and upright CSM at the first assessment.
Some important aspects of diagnostic testing and use of devices
in older patients are illustrated:
† OH is not always reproducible in older adults (particularly
medication- and age-related). Therefore, orthostatic BP apprai-
sal should be repeated, preferably in the morning and/or
promptly after syncope.
† CSM is particularly important to use even if non-specific CSH is
frequent without history of syncope.
† In evaluation of reflex syncope in older patients, tilt testing is well
tolerated and safe, with positivity rates similar to those observed
in younger patients, particularly after nitroglycerine challenge.
† Twenty-four hour ambulatory BP recordings may be helpful if
instability of BP is suspected (e.g. medication or post-prandial).
† Duetothe highfrequencyofarrhythmias,anILRmaybe especially
useful in the elderly with unexplained syncope.108,119,120
Evaluation of the frail elderly
Being old is not a contraindication to assessment and treatment.
However, in frail patients, the rigour of assessment will depend
on compliance with tests and on prognosis. Evaluation of mobile,
independent, cognitively normal older adults must be performed
as for younger individuals.
Orthostatic BP measurements, CSM, and tilt testing are well tol-
erated, even in the frail elderly with cognitive impairment.
Multiple risk factors are more common in the frail elderly and
distinguishing falls from syncope may be difficult. In one recent
study, symptomatic elderly patients with cognitive impairment
had a median of five risk factors for syncope or falls.57There is
some evidence that modification of cardiovascular risk factors
for falls/syncope reduces the incidence of subsequent events in
community-dwelling frail elderly, even in those with dementia,
but not in institutionalized elderly.201The influence of hypotension
or arrhythmia on cognitive decline in patients with dementia
4.2 Syncope in paediatric patients
Diagnostic evaluation in paediatric patients is similar to that in
adults. Reflex syncope represents the vast majority of the aetiol-
ogy, but in rare cases syncope is the manifestation of life-
Syncope should also be differentiated from epilepsy and psycho-
genic pseudosyncope, which are rare but important causes of
T-LOC in paediatric patients.
Two specific conditions202occur in early childhood:
(1) Infantile reflex syncopal attacks (also called pallid breath-
holding spells or reflex anoxic seizures), elicited by a brief
unpleasant stimulus, are caused by vagally mediated cardiac
(2) Apnoeic hypoxic T-LOC (also called cyanotic breath-holding
spells), are characterized by an expiratory cessation of respir-
ation during crying, leading to cyanosis and usually T-LOC.
Careful personal and family history and standard ECG are most
important in distinguishing benign reflex syncope (also including
reflex anoxic seizure or breath-holding spells) from other causes.
If the family history is positive, genetic causes of electrical
disease of the heart should be considered first. Some children
with reflex syncope also have a positive family history,203the gen-
etics of which are not understood. In patients with a typical history
of reflex syncope, normal physical examination and ECG are
usually sufficient to cease investigation. Tilt testing seems to have
high false-negative and false-positive rates and should be used
with caution for primary identification of patients with reflex
syncope. A remarkably high incidence of near-fainting (40%) was
reported during tilt testing after placement of a simple intravenous
line in healthy children and teenagers. Since tilt protocols com-
monly used in adults may lack specificity in teenage patients, in
one study a shorter tilt test duration of 10 min at 60 or 708 was
used and showed a specificity .85%.204
Inyoung patients,syncope mayrarelybe the initialmanifestationof
unusual but life-threatening conditions, like the long QT syndrome,
Kearns–Sayre syndrome (external ophthalmoplegia and progressive
heart block), Brugada syndrome, catecholaminergic polymorphic
genic cardiomyopathy, hypertrophic cardiomyopathy, pulmonary
arterialhypertension,myocarditis,arrhythmia after repaired congeni-
tal heart disease, or anomalous origin of a coronary artery.
Some aspects of the history can suggest a cardiac origin, and
should prompt cardiac evaluation:
† Family history: premature SCD ,30 years; familial heart disease.
† Known or suspected heart disease.
† Event triggers: loud noise, fright, extreme emotional stress.
† Syncope during exercise, including swimming.
† Syncope without prodrome, while supine or sleeping, or pre-
ceded by chest pain or palpitations.
be stressed that effectiveness ofpharmacological agentsand tilttrain-
ing for recurrent syncope is undetermined in the absence of well-
designed paediatric trials. Furthermore, even in the presence of VVS
with prolonged asystole, pacemakers should be avoided due to the
relatively transient and benign nature of the syndrome.205
In summary, the key points for the evaluation of syncope in pae-
diatrics are as follows:
† Syncope in childhood is common, the vast majority being of
reflex origin, with only a minority having a potentially life-
† Discrimination between benign and serious causes is made pri-
marily by history, physical examination, and ECG.
† The cornerstone of therapy for young patients with reflex
syncope includes education and reassurance.
4.3 Driving and syncope
In a survey206among 104 patients, 3% of patients with syncope
reported it to have occurred while they were driving; only 1%
crashed their vehicles. Among those advised not to drive, only
9% followed this advice. Among patients with life-threatening ven-
tricular arrhythmias enrolled in the AVID trial,207symptoms sug-
gestive of tachyarrhythmia recurred frequently while driving, but
they were unlikely to lead to motor vehicle accidents (0.4% per
patient-year). The probability of an accident was lower than the
Recommendations concerning driving in patients with syncope
Group 1: private drivers of motorcycles, cars and other small vehicles with and without a trailer; Group 2: professional drivers of vehicles over 3.5 tons or passenger-carrying
vehicles exceeding eight seats excluding the driver. Drivers of taxicabs, small ambulances, and other vehicles form an intermediate category between the ordinary private driver
and the vocational driver and should follow local legislation.
*Neurally mediated syncope is defined as severeif it is veryfrequent, oroccurring during the prosecution of a ‘high risk’ activity,or recurrentor unpredictable in ‘high risk’ patients
(see Part 3, treatment).
annual accident rate in the general population and was independent
of the duration of abstinence from driving. A recent study208pro-
vided long-term follow-up information on recurrence of syncope
in a large population who had syncope while driving. Among 3877
consecutive patients evaluated for syncope, 380 (9.8%) had
syncope while driving, which was commonly caused by reflex
syncope (37%) or cardiac arrhythmia (12%). Recurrence of
syncope during driving occurred in only 10 patients. The cumulative
probability of recurrence while driving was 7% in 8 years. Total
recurrence rate and long-term survival in the driving group was
comparable with that of patients who did not have syncope while
driving. For public safety, the risk of syncope-mediated driving acci-
dents (0.8% per year) appeared to be substantially less than in young
(16–24 years) and in elderly drivers (high risk accident groups).
The 2004 ESC Guidelines on syncope made recommendations on
driving and syncope.1This TF has the benefit of a further relevant
publication.208Data suggest that the risk of vehicle accident in
patients with a history of syncope is not different from that of the
general population of drivers without syncope. Specific recommen-
dations for driving in patients with an implanted ICD have been
recently published.209The mere presence of syncope while driving
should not change the clinical evaluation.
Part 5. Organizational aspects
5.1 Management of syncope
in general practice
(Figure 6).26,28Recurrent typical VVS is the most common diagnosis
isa common phenomenon ingeneral practice
in this setting. The diagnosis is based upon a carefully taken medical
history and the context of the event. Most of these typical common
only reassurance. An active searching for alarming symptoms is rec-
ommended. Alarming symptoms are: syncope during exertion,
syncope in the lying position, absence of external factors, family
history of SCD, or slow recovery from syncope (Tables 9 and 10).
If the diagnosis remains uncertain and there is potential risk of
dangerous consequences then the patient should be referred to
cardiologist, internist, neurologist, psychologist/psychiatrist as
appropriate or to a specialized syncope facility if available.
5.2 Management of syncope in the
The evaluation of syncope in the setting of ED has changed from
attempts to make a diagnosis of the cause of syncope to risk stra-
tification (Table 8) in order to: (i) recognize patients with life-
threatening conditions and admit them to the hospital; (ii) recog-
nize patients with low risk conditions to be discharged and
referred later to local syncope facilities; (iii) recognize those who
do not need any further evaluation and treatment;210and (iv)
choose a timing and setting where further diagnostic tests should
be performed in patients with inconclusive initial evaluation.
5.3 Syncope (T-LOC)
Despite publication of several guidelines, current strategies for the
assessment of T-LOC suspected of being syncope vary widely
among physicians and hospitals. This results in inappropriate use of
diagnostic tests and in many misdiagnosed and/or unexplained
Itisthe opinion ofthis Syncope TF that acohesive, structured care
pathway delivered either within a single syncope facility or as a more
multifaceted service, is optimal for quality service delivery. Further-
more, considerable improvement in diagnostic yield and cost-
effectiveness (i.e. cost per reliable diagnosis) can be achieved.
5.3.1 Existing models of Syncope
(T-LOC) Management Units
Models of care delivery vary from a single ‘one site–one stop’
syncope facility to a wider multifaceted service with many special-
ists involved in syncope management.
The Rapid Access Falls and Syncope Service (FASS) adopted by the
Newcastle group is a rapid access, multidisciplinary approach,
based on standardized algorithms,211to referrals with syncope
and falls for adults of all ages, but with the addition of particular
expertise in the evaluation of older patients with these overlapping
problems. There is a rapid access pathway for inpatients and for
those attending the ED, with as many investigations as possible
completed at the initial assessment. FASS has a full range of tilt
testing, beat-to-beat BP monitoring, and ambulatory monitoring
equipment as well as physiotherapy, occupational therapy, and
specialist nursing expertise. All patients have an initial detailed
assessment by a general physician, geriatrician, or general prac-
titioner with falls and syncope expertise, and then are either
managed at the Service or referred to colleagues associated with
the Service in neurology, neurophysiology, cardiology, or ear
nose and throat surgery, depending on the symptoms and the find-
ings at the initial assessment. This group showed a significant saving
in emergency hospital costs. The savings were attributed to a com-
bination of factors—reduced re-admission rates, rapid access to
day case facilities for ED staff and community physicians, and
reduced event rates because of effective targeted treatment strat-
egies for syncope and falls.64
The Manchester experience is a model of a T-LOC Facility where
cardiologists (with an interest in syncope) and neurologists (with
an interest in epilepsy) developed a multidisciplinary facility for a
comprehensive evaluation of T-LOC with special emphasis on
differential diagnosis between syncope, epilepsy, and psychogenic
vation Unit in the ED, with appropriate resources and multidisciplin-
for up to 6 h, hourly vital signs and orthostatic BP checks, and echo-
ination. Tilt table testing,
After completion of syncope observational unit evaluation,
follow-up appointment at the outpatient syncope management
unit can be arranged, if the patient is not admitted to hospital.
The model adopted in some Italian hospitals is a functional
Syncope Management Unit managed by cardiologists inside the
Department of Cardiology, with dedicated personnel. Patients
attending this Syncope Unit have preferential access to all other
facilities within the department including admission to the intensive
care unit. Patients are referred to the syncope unit from the ED
and from inpatient or outpatient clinics, but the personnel of the
unit are not usually involved in the initial evaluation of the
patient. In the Evaluation of Guidelines in Syncope Study
(EGSYS) 232,131implementation of this practice was facilitated by
decision-making software based on the ESC Guidelines, a desig-
nated physician trained in syncope evaluation, and a central super-
visor. Among 19 Italian hospitals, these investigators demonstrated
that 78% of study subjects adhered to the guideline-based evalu-
ation, resulting in a lower hospitalization rate (39% vs. 47%),
shorter in-hospital stay (7.2+5.7 vs. 8.1+5.9 days), and fewer
tests performed per patient (median 2.6% vs. 3.4) than historical
controls. More standardized-care patients had a diagnosis of
reflex (65% vs. 46%) and orthostatic syncope (10% vs. 6%). The
mean cost per patient and the mean cost per diagnosis were 19
and 29% lower in the standardized-care group.
5.3.2 Proposed model
The model of care delivery should be that which is most appropri-
ate to existing practice and resources. Referral sources, extent of
screening prior to presentation at the facility, and presenting age
are issues which influence the model of care delivery.
Referral can be directly from family practitioners, ED, acute hos-
pital inpatients, or from institutional settings after the initial screen-
ing and risk stratification (Figure 7, Table 10). In general, half of the
patients with T-LOC are referred to a Syncope Unit for diagnosis
Anysyncope (T-LOC) facility isaimed at reaching thefollowing goals:
† Provide state-of-the-art guideline-based assessment of sympto-
matic patients in order to risk-stratify them, then obtain an accu-
rate aetiological diagnosis and assess prognosis.
† Physician(s) in charge of the syncope facility lead the process of
comprehensive management from those listed above to therapy,
and, if necessary, follow-up. They perform the core laboratory
tests and have preferential access to hospitalization, diagnostic
tests, and therapeutic procedures.
† Reduce hospitalizations. The majority of patients can be investi-
gated as out-patients or day cases.
† Set standards for clinical excellence in adherence to the rec-
ommendations on syncope.
Professional skill mix for the Syncope Unit. It is not appropriate to be
dogmatic regarding the training of personnel responsible for a
syncope facility. In a single dedicated facility the skill mix will
depend on the specialty of the physician in charge of the unit. Car-
diologists (with interest in pacing and electrophysiology), neurol-
ogists (with interest in autonomic disorders and epilepsy),
general physicians, internists, and geriatricians (with interest in
age-related cardiology and falls) have led syncope facilities
without evidence of superiority of any model. If referrals hail
directly from the community and/or from the ED, a broader skill
mix is required. Experience and training in key components of car-
diology, neurology, emergency and geriatric medicine are perti-
nent, in addition to access to psychiatry and clinical psychology.
Core medical and support personnel should be involved full time
or most of the time in the management of the Unit and should
interact with other stakeholders within
the hospital and
Core equipment for the Syncope Unit includes: ECG recorders, BP
monitors, tilt table, external and implantable ECG monitoring
systems, 24 h ambulatory BP monitoring, and autonomic function
testing. The facility should have preferential access to echocardio-
graphy, EPS, coronary angiography, stress testing, and, when
needed, CT, MRI, and electroencephalography. Patients should
have preferential access to hospitalization for dedicated thera-
peutic procedures: pacemaker and defibrillator implantation, cath-
eter ablation, etc.
Key points for standardized care delivery:
† A cohesive, structured care pathway—delivered either within a
single syncope facility or as a more multifaceted service—is rec-
ommended for global assessment of patients with T-LOC (sus-
† Referral can be directly from: family practitioners, ED, acute
hospital inpatients, institutional settings.
† Objectives are to: give the patient continuity of care, reduce
inappropriate hospitalizations, and set standards of clinical
† Experience and training in key components of cardiology, neu-
rology, emergency and geriatric medicine are pertinent.
The CME Text ‘Guidelines for the diagnosis and management of syncope’ is accredited by the European Board for Accreditation in Cardiology (EBAC). EBAC works according to
the quality standards of the European Accreditation Council for Continuing Medical Education (EACCME), which is an institution of the European Union of Medical Specialists
(UEMS). In compliance with EBAC/EACCME guidelines, all authors participating in this programme have disclosed potential conflicts of interest that might cause a bias in the
article. The Organizing Committee is responsible for ensuring that all potential conflicts of interest relevant to the programme are declared to the participants prior to the
CME questions for this article are available at: European Heart Journal http://cme.oxfordjournals.org/cgi/hierarchy/oupcme_node;ehj and European Society of Cardiology
1. Brignole M, Alboni P, Benditt DG, Bergfeldt L, Blanc JJ, Bloch Thomsen PE, van
Dijk JG, Fitzpatrick A, Hohnloser S, Janousek J, Kapoor W, Kenny RA,
Kulakowski P, Masotti G, Moya A, Raviele A, Sutton R, Theodorakis G,
Ungar A, Wieling W; Task Force on Syncope, European Society of Cardiology.
Guidelines on management (diagnosis and treatment) of syncope—update 2004.
2. Thijs RD, Benditt DG, Mathias CJ, Schondorf R, Sutton R, Wieling W, van
Dijk JG. Unconscious confusion—a literature search for definitions of syncope
and related disorders. Clin Auton Res 2005;15:35–39.
3. Soteriades ES, Evans JC, Larson MG, Chen MH, Chen L, Benjamin EJ, Levy D.
Incidence and prognosis of syncope. N Engl J Med 2002;347:878–885.
4. Strickberger SA, Benson DW, Biaggioni I, Callans DJ, Cohen MI, Ellenbogen KA,
Epstein AE, Friedman P, Goldberger J, Heidenreich PA, Klein GJ, Knight BP,
Morillo CA, Myerburg RJ, Sila CA; American Heart Association Councils on
Clinical Cardiology, Cardiovascular Nursing, Cardiovascular Disease in the
Young, and Stroke; Quality of Care and Outcomes Research Interdisciplinary
Working Group; American College of Cardiology Foundation; Heart Rhythm
Society. AHA/ACCF scientific statement on the evaluation of syncope. J Am
Coll Cardiol 2006;47:473–484.
5. Hoefnagels WA, Padberg GW, Overweg J, van der Velde EA, Roos RA. Transi-
ent loss of consciousness: the value of the history for distinguishing seizure from
syncope. J Neurol 1991;238:39–43.
6. Stephenson J. Fits and Faints. Oxford: Blackwell Scientific Publications; 1990.
7. van Dijk JG, Sheldon R. Is there any point to vasovagal syncope? Clin Auton Res
8. Tea SH, Mansourati J, L’Heveder G, Mabin D, Blanc JJ. New insights into the
pathophysiology of carotid sinus syndrome. Circulation 1996;93:1411–1416.
9. Alboni P, Alboni M, Bertorelle G. The origin of vasovagal syncope: to protect the
heart or to escape predation? Clin Auton Res 2008;18:170–178.
10. Mathias CJ, Mallipeddi R, Bleasdale-Barr K. Symptoms associated with ortho-
static hypotension in pure autonomic failure and multiple system atrophy.
J Neurol 1999;246:893–898.
11. Naschitz J, Rosner I. Orthostatic hypotension: framework of the syndrome. Post-
grad Med J 2007;83:568–574.
12. Consensus statement on the definition of orthostatic hypotension, pure auto-
nomic failure, and multiple system atrophy. J Neurol Sci 1996;144:218–219.
13. Wieling W, Krediet P, van Dijk N, Linzer M, Tschakovsky M. Initial orthostatic
hypotension: review of a forgotten condition. Clin Sci (Lond) 2007;112:157–165.
14. Podoleanu C, Maggi R, Brignole M, Croci F, Incze A, Solano A, Puggioni E,
Carasca E. Lower limb and abdominal compression bandages prevent progress-
ive orthostatic hypotension in the elderly. A randomized placebo-controlled
study. J Am Coll Cardiol 2006;48:1425–1432.
15. Gibbons CH, Freeman R. Delayed orthostatic hypotension: a frequent cause of
orthostatic intolerance. Neurology 2006;67:28–32.
16. Verheyden B, Gisolf J, Beckers F, Karemaker JM, Wesseling KH, Aubert A,
Wieling W. Impact of age on the vasovagal response provoked by sublingual
nitroglycerine in routine tilt testing. Clin Sci (Lond) 2007;113:329–337.
17. Grubb BP, Kosinski DJ, Boehm K, Kip K. The postural orthostatic tachycardia
syndrome: a neurocardiogenic variant identified during head-up tilt table
testing. Pacing Clin Electrophysiol 1997;20:2205–2212.
18. Leitch JW, Klein GJ, Yee R, Leather RA, Kim YH. Syncope associated with supra-
ventricular tachycardia: an expression of tachycardia or vasomotor response?
19. Brignole M, Gianfranchi L, Menozzi C, Raviele A, Oddone D, Lolli G, Bottoni N.
Role of autonomic reflexes in syncope associated with paroxysmal atrial fibrilla-
tion. J Am Coll Cardiol 1993;22:1123–1129.
20. Ebert SN, Liu XK, Woosley RL. Female gender as a risk factor for drug-induced
cardiac arrhythmias: evaluation of clinical and experimental evidence. J Womens
21. Zareba W, Moss AJ, Le Cessie S, Locati EH, Robinson JL, Hall WJ, Andrews ML.
Risk of cardiac events in family members of patients with Long QT syndrome.
J Am Coll Cardiol 1995;26:1685–1691.
22. Lombroso CT, Lerman P. Breathholding spells (cyanotic and pallid infantile
syncope). Pediatrics 1967;39:563–581.
23. Wieling W, Ganzeboom KS, Saul JP. Reflex syncope in children and adolescents.
24. Ganzeboom KS, Colman N, Reitsma JB, Shen WK, Wieling W. Prevalence and
triggers of syncope in medical students. Am J Cardiol 2003;91:1006–1008.
25. Serletis A, Rose S, Sheldon AG, Sheldon RS. Vasovagal syncope in medical stu-
dents and their first-degree relatives. Eur Heart J 2006;27:1965–1970.
26. Colman N, Nahm K, Ganzeboom KS, Shen WK, Reitsma J, Linzer M, Wieling W,
Kaufmann H. Epidemiology of reflex syncope. Clin Auton Res 2004;14(Suppl 1):
27. Ganzeboom KS, Mairuhu G, Reitsma J, Linzer M, Wieling W, van Dijk N. Lifetime
cumulative incidence of syncope in the general population: a study of 549 Dutch
subjects aged 35–60 years. J Cardiovasc Electrophysiol 2006;17:1172–1176.
28. Olde Nordkamp LAR, van Dijk N, Ganzeboom KS, Reitsma JB, Luitse JSK,
Dekker LRC, Shen WK, Wieling W. Syncope prevalence in the ED compared
to that in the general practice and population: a strong selection process. Am
J Emerg Med 2009;27:271–279.
29. Ammirati F, Colivicchi F, Santini M. Diagnosing syncope in clinical practice.
Implementation of a simplified diagnostic algorithm in a multicentre prospective
trial—the OESIL 2 study (Osservatorio Epidemiologico della Sincope nel Lazio).
Eur Heart J 2000;21:935–940.
30. Blanc JJ, L’Her C, Touiza A, Garo B, L’Her E, Mansourati J. Prospective evaluation
and outcome of patients admitted for syncope over a 1 year period. Eur Heart J
31. Blanc JJ, L’Her C, Gosselin G, Cornily JC, Fatemi M. Prospective evaluation of an
educational programme for physicians involved in the management of syncope.
32. Brignole M, Menozzi C, Bartoletti A, Giada F, Lagi A, Ungar A, Ponassi I, Mussi C,
Maggi R, Re G, Furlan R, Rovelli G, Ponzi P, Scivales A. A new management of
syncope: prospective systematic guideline-based evaluation of patients referred
urgently to general hospitals. Eur Heart J 2006;27:76–82.
33. Crane SD. Risk stratification of patients with syncope in an accident and emer-
gency department. Emerg Med J 2002;19:23–27.
34. Disertori M, Brignole M, Menozzi C, Raviele A, Rizzon P, Santini M, Proclemer A,
Tomasi C, Rossillo A, Taddei F, Scivales A, Migliorini R, De Santo T. Management
of patients with syncope referred urgently to general hospitals. Europace 2003;5:
35. Sarasin FP, Louis-Simonet M, Carballo D, Slama S, Rajeswaran A, Metzger JT,
Lovis C, Unger PF, Junod AF. Prospective evaluation of patients with syncope:
a population-based study. Am J Med 2001;111:177–184.
36. Chen LY, Gersh BJ, Hodge DO, Wieling W, Hammill SC, Shen WK. Prevalence
and clinical outcomes of patients with multiple potential causes of syncope.
Mayo Clin Proc 2003;78:414–420.
37. Kenny RA. Syncope in the elderly: diagnosis, evaluation, and treatment.
J Cardiovasc Electrophysiol 2003;14:S74–S77.
38. Romme JJ, van Dijk N, Boer KR, Dekker LR, Stam J, Reitsma JB, Wieling W. Influ-
ence of age and gender on the occurrence and presentation of reflex syncope.
Clin Auton Res 2008;18:127–133.
39. Del Rosso A, Alboni P, Brignole M, Menozzi C, Raviele A. Relation of clinical
presentation of syncope to the age of patients. Am J Cardiol 2005;96:1431–1435.
40. Martin TP, Hanusa BH, Kapoor WN. Risk stratification of patients with syncope.
Ann Emerg Med 1997;29:459–466.
41. Colivicchi F, Ammirati F, Melina D, Guido V, Imperoli G, Santini M; OESIL
(Osservatorio Epidemiologico sulla Sincope nel Lazio) Study Investigators.
Development and prospective validation of a risk stratification system for
patients with syncope in the emergency department: the OESIL risk score.
Eur Heart J 2003;24:811–819.
42. Del Rosso A, Ungar A, Maggi R, Giada F, Petix NR, De Santo T, Menozzi C,
Brignole M. Clinical predictors of cardiac syncope at initial evaluation in patients
referred urgently to a general hospital: the EGSYS score. Heart 2008;94:
43. Sarasin FP, Hanusa BH, Perneger T, Louis-Simonet M, Rajeswaran A,
Kapoor WN. A risk score to predict arrhythmias in patients with unexplained
syncope. Acad Emerg Med 2003;10:1312–1317.
44. Quinn J, McDermott D, Stiell I, Kohn M, Wells G. Prospective validation of the
San Francisco Syncope Rule to predict patients with serious outcomes. Ann
Emerg Med 2006;47:448–454.
45. Middlekauff R, Stevenson WG, Stevenson LW, Saxon LA. Syncope in advanced
heart failure; high risk of sudden death regardless of origin of syncope. J Am Coll
46. Brembilla-Perrot B, Suty-Selton C, Beurrier D, Houriez P, Nippert M, de la
Chaise AT, Louis P, Claudon O, Andronache M, Abdelaal A, Sadoul N,
Juillie `re Y. Differences in mechanism and outcomes of syncope patients with
coronary artery disease or idiopathic left ventricular dysfunction as assessed
by electrophysiologic testing. J Am Coll Cardiol 2004;44:594–601.
47. Steinberg JS, Beckman K, Greene HL, Marinchak R, Klein RC, Greer SG, Ehlert F,
Foster P, Menchavez E, Raitt M, Wathen MS, Morris M, Hallstrom A. Follow-up
of patients with unexplained syncope and inducible ventricular tachyarrhythmias:
analysis of the AVID registry and AVID substudy.Antiarrhythmics versus Implan-
table Defibrillators. J Cardiovasc Electrophysiol 2001;12:996–1001.
48. Pezawas T, Stix G, Kastner J, Wolzt M, Mayer C, Moertl D, Schmidinger H.
Unexplained syncope in patients with structural heart disease and no documen-
ted ventricular arrhythmias: value of electrophysiologically guided implantable
cardioverter defibrillator therapy. Europace 2003;5:305–312.
49. Olshansky B, Poole JE, Johnson G, Anderson J, Hellkamp AS, Packer D, Mark DB,
Lee KL, Bardy GH; SCD-HeFT Investigators. Syncope predicts the outcome of
cardiomyopathy patients: analysis of the SCD-HeFT study. J Am Coll Cardiol
50. Wehrens XH, Vos MA, Doevendans PA, Wellens HJ. Novel insights in the con-
genital long QT syndrome. Ann Intern Med 2002;137:981–992.
51. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D,
Gussak I, LeMarec H, Nademanee K, Perez Riera AR, Shimizu W,
Schulze-Bahr E, Tan H, Wilde A. Brugada syndrome: report of the Second Con-
sensus Conference: endorsed by the Heart Rhythm Society and the European
Heart Rhythm Association. Circulation 2005;111:659–670.
52. Giustetto C, Di Monte F, Wolpert C, Borggrefe M, Schimpf R, Sbragia P,
Leone G, Maury P, Anttonen O, Haissaguerre M, Gaita F. Short QT syndrome:
clinical findings and diagnostic–therapeutic implications. Eur Heart J 2006;27:
53. Brignole M, Vardas P, Hoffman E, Huikuri H, Moya A, Ricci R, Sulke N,
Wieling W. Indications for the use of diagnostic implantable and external
ECG loop recorders. Europace 2009;11;671–687.
54. Bartoletti A, Fabiani P, Bagnoli L, Cappelletti C, Cappellini M, Nappini G,
Gianni R, Lavacchi A, Santoro G. Physical injuries caused by a transient loss of
consciousness: main clinical characteristics of patients and diagnostic contri-
bution of carotid sinus massage. Eur Heart J 2008;29:618–624.
55. Costantino G, Perego F, Dipaola F, Borella M, Galli A, Cantoni G, Dell’Orto S,
Dassi S, Filardo N, Duca PG, Montano N, Furlan R; STePS Investigators. Short-
and long-term prognosis of syncope, risk factors, and role of hospital admission:
results from the STePS (Short-Term Prognosis of Syncope) study. J Am Coll
56. Ungar A, Mussi C, Del Rosso A, Noro G, Abete P, Ghirelli L, Cellai T, Landi A,
Salvioli G, Rengo F, Marchionni N, Masotti G. Diagnosis and characteristics of
syncope in older patients referred to geriatric departments. J Am Geriatr Soc
57. Linzer M, Pontinen M, Gold DT, Divine GW, Felder A, Brooks WB. Impairment
of physical and psychosocial function in recurrent syncope. J Clin Epidemiol 1991;
58. Rose MS, Koshman ML, Spreng S, Sheldon R, The relationship between
health-related quality of life and the frequency of spells in patients with
syncope. J. Clin. Epidemiol 2000;53:1209–1216.
59. van Dijk N, Sprangers M, Colman N, Boer K, Wieling W, Linzer M. Clinical
factors associated with quality of life in patients with transient loss of conscious-
ness. J Cardiovasc Electrophysiol 2006;17:998–1003.
60. van Dijk N, Sprangers MA, Boer KR, Colman N, Wieling W, Linzer M. Quality of
life within one year following presentation after transient loss of consciousness.
Am J Cardiol 2007;100:672–676.
61. Brignole M, Disertori M, Menozzi C, Raviele A, Alboni P, Pitzalis MV, Delise P,
Puggioni E, Del Greco M, Malavasi V, Lunati M, Pepe M, Fabrizi D. On behalf
of the Evaluation of Guidelines in Syncope Study (EGSYS) group. Management
of syncope referred urgently to general hospitals with and without syncope
units. Europace 2003;5:293–298.
62. Ammirati F, Colaceci R, Cesario A, Strano S, Della Scala A, Colangelo I,
De Santo T, Toscano E, Ricci R, Santini M. Management of syncope: clinical
and economic impact of a Syncope Unit. Europace 2008;10:471–476.
63. Kenny RA, O’Shea D, Walker HF. Impact of a dedicated syncope and falls facility
for older adults on emergency beds. Age Ageing 2002;31:272–275.
64. Brignole M, Ungar A, Bartoletti A, Lagi A, Mussi C, Ribani MA, Tava G,
Disertori M, Quartieri F, Alboni P, Raviele A, Ammirati F, Scivales A, De
Santo T. Standardized-care pathway vs. usual management of syncope patients
presenting as emergencies at general hospitals. Europace 2006;8:644–650.
65. Sun B Jr., Emond J, Comargo C Jr. Direct medical costs of syncope-related hos-
pitalizations in the United States. Am J Cardiol 2005;95:668–671.
66. Wieling W, Ganzeboom KS, Krediet CT, Grundmeijer HG, Wilde AA, van
Dijk JG. Initial diagnostic strategy in the case of transient losses of consciousness:
the importance of the medical history. Ned Tijdschr Geneeskd 2003;147:849–854.
67. Sheldon R, Rose S, Ritchie D, Connolly SJ, Koshman ML, Lee MA, Frenneaux M,
Fisher M, Murphy W. Historical criteria that distinguish syncope from seizures.
J Am Coll Cardiol 2002;40:142–148.
68. Alboni P, Brignole M, Menozzi C, Raviele A, Del Rosso A, Dinelli M, Solano A,
Bottoni N. Diagnostic value of history in patients with syncope with or without
heart disease. J Am Coll Cardiol 2001;37:1921–1928.
69. Croci F, Brignole M, Alboni P, Menozzi C, Raviele A, Del Rosso A, Dinelli M,
Solano A, Bottoni N, Donateo P. The application of a standardized strategy of
evaluation in patients with syncope referred to three Syncope Units. Europace
70. Vardas PE, Auricchio A, Blanc JJ, Daubert JC, Drexler H, Ector H, Gasparini M,
Linde C, Morgado FB, Oto A, Sutton R, Trusz-Gluza M; European Society of
Cardiology; European Heart Rhythm Association. Guidelines for cardiac
pacing and cardiac resynchronization therapy. Eur Heart J 2007;28:2256–2295.
71. Goldberger JJ, Cain ME, Hohnloser SH, Kadish AH, Knight BP, Lauer MS,
Maron BJ, Page RL, Passman RS, Siscovick D, Stevenson WG, Zipes DP; Amer-
ican Heart Association; American College of Cardiology Foundation; Heart
Rhythm Society. American Heart Association/American College of Cardiology
Foundation/Heart Rhythm Society scientific statement on noninvasive risk stra-
tification techniques for identifying patients at risk for sudden cardiac death: a
scientific statement from the American Heart Association Council on Clinical
Cardiology Committee on Electrocardiography and Arrhythmias and Council
on Epidemiology and Prevention. Circulation 2008;118:1497–1518.
72. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M,
Gregoratos G, Klein G, Moss AJ, Myerburg RJ, Priori SG, Quinones MA,
Roden DM, Silka MJ, Tracy C, Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V,
Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M,
Morais J, Osterspey A, Tamargo JL, Zamorano JL, Smith SC
Adams CD, Antman EM, Anderson JL, Hunt SA, Halperin JL, Nishimura R,
Ornato JP, Page RL, Riegel B; American College of Cardiology; American
Heart Association Task Force; European Society of Cardiology Committee for
Jr, Jacobs AK,
Practice Guidelines; European Heart Rhythm Association; Heart Rhythm
Society. ACC/AHA/ESC 2006 guidelines for management of patients with ven-
tricular arrhythmias and the prevention of sudden cardiac death: a report of
the American College of Cardiology/American Heart Association Task Force
and the European Society of Cardiology Committee for Practice Guidelines.
73. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA 3rd, Freedman RA, Gettes LS,
Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK,
Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO, Smith SC Jr,
Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM,
Faxon DP, Halperin JL, Hiratzka LF, Hunt SA, Krumholz HM, Kushner FG,
Lytle BW, Nishimura RA, Ornato JP, Page RL, Riegel B, Tarkington LG,
Yancy CW ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of
Cardiac Rhythm Abnormalities: a report of the American College of Cardiol-
ogy/American Heart Association Task Force on Practice Guidelines (Writing
Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implan-
tation of Cardiac Pacemakers and Antiarrhythmia Devices) developed in collab-
oration with the American Association for Thoracic Surgery and Society of
Thoracic Surgeons. J Am Coll Cardiol 2008;51:e1–e62.
74. Puggioni E, Guiducci V, Brignole M, Menozzi C, Oddone D, Donateo P, Croci F,
Solano A, Lolli G, Tomasi C, Bottoni N. Results and complications of the carotid
sinus massage performed according to the ‘methods of symptoms’. Am J Cardiol
75. Kerr SR, Pearce MS, Brayne C, Davis RJ, Kenny RA. Carotid sinus hypersensitiv-
ity in asymptomatic older persons: implications for diagnosis of syncope and falls.
Arch Intern Med 2006;166:515–520.
76. Brignole M, Menozzi C, Lolli G, Bottoni N, Gaggioli G. Long-term outcome of
paced and non paced patients with severe carotid sinus syndrome. Am J
77. Claesson JE, Kristensson BE, Edvardsson N, Wahrborg P. Less syncope and
milder symptoms in patients treated with pacing for induced cardioinhibitory
carotid sinus syndrome: a randomized study. Europace 2007;9:932–936.
78. Menozzi C, Brignole M, Lolli G, Bottoni N, Oddone D, Gianfranchi L, Gaggioli G.
Follow-up of asystolic episodes in patients with cardioinhibitory, neurally
mediated syncope and VVI pacemaker. Am J Cardiol 1993;72:1152–1155.
79. Maggi R, Menozzi C, Brignole M, Podoleanu C, Iori M, Sutton R, Moya A, Giada F,
Orazi S, Grovale N. Cardioinhibitory carotid sinus hypersensitivity predicts an
asystolic mechanism of spontaneous neurally-mediated syncope. Europace
80. Munro NC, McIntosh S, Lawson J, Morley CA, Sutton R, Kenny RA. The inci-
dence of complications after carotid sinus massage in older patients with
syncope. J Am Geriatr Soc 1994;42:1248–1251.
81. Davies AG, Kenny RA. Frequency of neurologic complications following carotid
sinus massage. Am J Cardiol 1998;81:1256–1257.
82. Smit AAJ, Halliwill JR, Low PA, Wieling W. Topical review. Pathophysiological
basis of orthostatic hypotension in autonomic failure. J Physiol 1999;519:1–10.
83. Accurso V, Winnicki M, Shamsuzzaman AS, Wenzel A, Johnson AK, Somers VK.
Predisposition to vasovagal syncope in subjects with blood/injury phobia. Circula-
84. Brignole M, Menozzi C, Gianfranchi L, Oddone D, Lolli G, Bertulla A. Neurally
mediated syncope detected by carotid sinus massage and head-up tilt test in sick
sinus syndrome. Am J Cardiol 1991;68:1032–1036.
85. Kenny RA, Ingram A, Bayliss J, Sutton R. Head-up tilt: a useful test for investi-
gating unexplained syncope. Lancet 1986;1:1352–1355.
86. Benditt DG, Ferguson DW, Grubb BP, Kapoor WN, Kugler J, Lerman BB,
Maloney JD, Raviele A, Ross B, Sutton R, Wolk MJ, Wood DL. Tilt table
testing for assessing syncope. American College of Cardiology. J Am Coll
87. Morillo CA, Klein GJ, Zandri S, Yee R. Diagnostic accuracy of a low-dose isopro-
terenol head-up tilt protocol. Am Heart J 1995;129:901–906.
88. Bartoletti A, Alboni P, Ammirati F, Brignole M, Del Rosso A, Foglia Manzillo G,
Menozzi C, Raviele A, Sutton R. ‘The Italian Protocol’: a simplified head-up tilt
testing potentiated with oral nitroglycerin to assess patients with unexplained
syncope. Europace 2000;2:339–342.
89. Parry SW, Gray JC, Baptist M, O’Shea D, Newton JL, Kenny RA. ‘Front-loaded’
glyceryl trinitrate-head-up tilt table testing: validation of a rapid first line tilt pro-
tocol for the diagnosis of vasovagal syncope. Age Ageing 2008;37:411–415.
90. Zaidi A, Clough P, Cooper P, Scheepers B, Fitzpatrick AP. Misdiagnosis of epi-
lepsy: many seizure-like attacks have a cardiovascular cause. J Am Coll Cardiol
91. Petersen ME, Williams TR, Sutton R. Psychogenic syncope diagnosed by pro-
longed head-up tilt testing. QJM 1995;88:209–213.
92. Heitterachi E, Lord SR, Meyerkort P, McCloskey I, Fitzpatrick R. BP changes on
upright tilting predict falls in older people. Age Ageing 2002;31:181–186.
93. Moya A, Permanyer-Miralda G, Sagrista-Sauleda J, Carne X, Rius T, Mont L,
Soler-Soler J. Limitations of head-up tilt test for evaluating the efficacy of thera-
peutic interventions in patients with vasovagal syncope: results of a controlled
study of etilefrine versus placebo. J Am Coll Cardiol 1995;25:65–69.
94. Brignole M, Croci F, Menozzi C, Solano A, Donateo P, Oddone D, Puggioni E,
Lolli G. Isometric arm counter-pressure maneuvers to abort impending vasova-
gal syncope. J Am Coll Cardiol 2002;40:2053–2059.
95. Krediet CT, van Dijk N, Linzer M, van Lieshout JJ, Wieling W. Management of
vasovagal syncope: controlling or aborting faints by leg crossing and muscle
tensing. Circulation 2002;106:1684–1689.
96. van Dijk N, Quartieri F, Blanc JJ, Garcia-Civera R, Brignole M, Moya A,
Wieling W; PC-Trial Investigators. Effectiveness of physical counterpressure
maneuvers in preventing vasovagal syncope: the Physical Counterpressure
Manoeuvres Trial (PC-Trial). J Am Coll Cardiol 2006;48:1652–1657.
97. Brignole M, Menozzi C, Del Rosso A, Costa S, Gaggioli G, Bottoni N, Bartoli P,
Sutton R. New classification of haemodynamics of vasovagal syncope: beyond
the VASIS classification. Analysis of the pre-syncopal phase of the tilt test
without and with nitroglycerin challenge. Vasovagal Syncope International
Study. Europace 2000;2:66–76.
98. Deharo JC, Jego C, Lanteaume A, Djiane P. An implantable loop recorder study
of highly symptomatic vasovagal patients: the heart rhythm observed during a
spontaneous syncope is identical to the recurrent syncope but not correlated
with the head-up tilt test or adenosine triphosphate test. J Am Coll Cardiol
99. Brignole M, Sutton R, Menozzi C, Garcia-Civera R, Moya A, Wieling W,
Andresen D, Benditt DG, Grovale N, De Santo T, Vardas P; International
Study on Syncope of Uncertain Etiology 2 (ISSUE 2) Group. Lack of correlation
between the responses to tilt testing and adenosine triphosphate test and the
mechanism of spontaneous neurally mediated syncope. Eur Heart J 2006;27:
100. Leman RB, Clarke E, Gillette P. Significant complications can occur with ischemic
heart disease and tilt table testing. Pacing Clin Electrophysiol 1999;22:675–677.
101. Kenny RA, O’Shea D, Parry SW. The Newcastle protocols for head-up tilt table
testing in the diagnosis of vasovagal syncope, carotid sinus hypersensitivity, and
related disorders. Heart 2000;83:564–569.
102. de Castro RR, Mesquita ET, da Nobrega AC. Parasympathetic-mediated atrial
fibrillation during tilt test associated with increased baroreflex sensitivity. Euro-
103. Krahn A, Klein G, Norris C, Yee R. The etiology of syncope in patients with
negative tilt table and electrophysiologic testing. Circulation 1995;92:1819–1824.
104. Krahn AD, Klein GJ, Yee R, Takle-Newhouse T, Norris C. Use of an extended
monitoring strategy in patients with problematic syncope. Reveal Investigators.
Circulation 1999; 26:99:406–410.
105. Krahn AD, Klein GL, Tee R, Skanes AC. Detection of asymptomatic arrhythmias
in unexplained syncope. Am Heart J 2004;148:326–332.
106. Ermis C, Zhu AX, Pham S, Li JM, Guerrero M, Vrudney A, Hiltner L, Lu F,
Sakaguchi S, Lurie KG, Benditt DG. Comparison of automatic and patient-
activated arrhythmia recordings by implantable loop recorders in the evaluation
of syncope. Am J Cardiol 2003;92:815–819.
107. Moya A, Brignole M, Sutton R, Menozzi C, Garcia-Civera R, Wieling W,
Andresen D, Benditt D, Garcia-Sacristan JF, Beiras X, Grovale N, De Santo T,
Vardas P. Reproducibility of electrocardiographic findings in patients with
neurally-mediated syncope. Am J Cardiol 2008;102:1518–1523.
108. Moya A, Brignole M, Menozzi C, Garcia-Civera R, Tognarini S, Mont L, Botto G,
Giada F, Cornacchia D. Mechanism of syncope in patients with isolated syncope
and in patients with tilt-positive syncope. Circulation 2001;104:1261–1267.
109. Solano A, Menozzi C, Maggi R, Donateo P, Bottoni N, Lolli G, Tomasi C, Croci F,
Oddone D, Puggioni E, Brignole M. Incidence, diagnostic yield and safety of the
implantable loop-recorder to detect the mechanism of syncope in patients with
and without structural heart disease. Eur Heart J 2004;25:1116–1119.
110. Brignole M, Sutton R, Menozzi C, Garcia-Civera R, Moya A, Wieling W,
Andresen D, Benditt DG, Vardas P; International Study on Syncope of Uncertain
Etiology 2 (ISSUE 2) Group. Early application of an implantable loop recorder
allows effective specific therapy in patients with recurrent suspected neurally
mediated syncope. Eur Heart J 2006;27:1085–1092.
111. Pezawas T, Stix G, Kastner J, Schneider B, Wolzt M, Schmidinger H. Implantable
loop recorder in unexplained syncope: classification, mechanism, transient loss
of consciousness and role of major depressive disorder in patients with and
without structural heart disease. Heart 2008;94:e17.
112. Bass EB, Curtiss EI, Arena VC, Hanusa BH, Cecchetti A, Karpf M, Kapoor WN.
The duration of Holter monitoring in patients with syncope: is 24 h enough? Arch
Intern Med 1990;150:1073–1078.
113. Kinlay S, Leitch JW, Neil A, Chapman BL, Hardy DB, Fletcher PJ. Cardiac event
recorders yield more diagnoses and are more cost-effective than 48-hour Holter
monitoring in patients with palpitations. A controlled clinical trial. Ann Intern Med
114. Linzer M, Pritchett EL, Pontinen M, McCarthy E, Divine GW. Incremental diag-
nostic yield of loop electrocardiographic recorders in unexplained syncope. Am J
115. Schuchert A, Maas R, Kretzschmar C, Behrens G, Kratzmann I, Meinertz T. Diag-
nostic yield of external loop recorders in patients with recurrent syncope and
negative tilt table test. Pacing Clin Electrophysiol 2003;26:1837–1840.
116. Rockx MA, Hoch JS, Klein GJ, Yee R, Skanes AC, Gula LJ, Krahn AD. Is ambu-
latory monitoring for ‘community-acquired’ syncope economically attractive?
A cost-effectiveness analysis of a randomized trial of external loop recorders
versus Holter monitoring. Am Heart J 2005;150:1065.
117. Krahn A, Klein GJ, Yee R, Skanes AC. Randomized assessment of syncope trial.
Conventional diagnostic testing versus a prolonged monitoring strategy. Circula-
118. Farwell D, Freemantle N, Sulke N. The clinical impact of implantable loop recor-
ders in patients with syncope. Eur Heart J 2006;27:351–356.
119. Menozzi C, Brignole M, Garcia-Civera R, Moya A, Botto G, Tercedor L,
Migliorini R, Navarro X; International Study on Syncope of Uncertain Etiology
(ISSUE) Investigators. Mechanism of syncope in patients with heart disease
and negative electrophysiologic test. Circulation 2002;105:2741–2745.
120. Brignole M, Menozzi C, Moya A, Garcia-Civera R, Mont L, Alvarez M,
Errazquin F, Beiras J, Bottoni N, Donateo P; International Study on Syncope
of Uncertain Etiology (ISSUE) Investigators. Mechanism of syncope in patients
with bundle branch block and negative electrophysiological test. Circulation
121. Nierop P, van Mechelen R, Elsacker A, Luijten RH, Elhendy A. Heart rhythm
during syncope and presyncope: results of implantable loop recorders. Pacing
Clin Electrophysiol 2000;23:1532–1538.
122. Boersma L, Mont L, Sionis A, Garcia E, Brugada J. Value of implantable loop
recorder for the management of patients with unexplained syncope. Europace
123. Lombardi F, Calosso E, Mascioli G, Marangoni E, Donato A, Rossi S, Pala M,
Foti F, Lunati M. Utility of implantable loop recorder (Reveal Plus) in the diag-
nosis of unexplained syncope Europace 2005;7:19–24.
124. Pierre B, Fauchier L, Breard L, Marie O, Poret F, Babuty D. Implantable loop
recorder for recurrent syncope: influence of cardiac conduction abnormalities
showing up on resting electrocardiogram and of underlying cardiac disease on
follow-up developments. Europace 2008;10:477–481.
125. Kenny RA, Richardson DA, Steen N, Bexton RS, Shaw FE, Bond J. Carotid sinus
syndrome: a modifiable risk factor for nonaccidental falls in older adults (SAFE
PACE). J Am Coll Cardiol 2001;38:1491–1496.
126. Rothman SA, Laughlin JC, Seltzer J, Walia JS, Baman RI, Siouffi SY, Sangrigoli RM,
Kowey PR. The diagnosis of cardiac arrhythmias: a prospective multi-center ran-
domized study comparing mobile cardiac outpatient telemetry versus standard
loop event monitoring. J Cardiovasc Electrophysiol 2007;18:241–247.
127. Brignole M, Moya A, Menozzi C, Garcia-Civera R, Sutton R. Proposed electro-
cardiographic classification of spontaneous syncope documented by an implan-
table loop recorder. Europace 2005;7:14–18.
128. Krahn AD, Klein GJ, Yee R, Hoch JS, Skanes AC. Cost implications of testing
strategy in patients with syncope: randomized assessment of syncope trial.
J Am Coll Cardiol 2003;42:495–501.
129. Donateo P, Brignole M, Menozzi C, Bottoni N, Alboni P, Dinelli M, Del Rosso A,
Croci F, Oddone D, Solano A, Puggioni E. Mechanism of syncope in patients with
positive adenosine triphosphate tests J Am Coll Cardiol 2003;41:93–98.
130. Linzer M, Yang EH, Estes NA 3rd, Wang P, Vorperian VR, Kapoor WN. Part 2:
Unexplained syncope. Clinical Efficacy Assessment Project of the American
College of Physicians. Ann Intern Med 1997;127:76–86.
131. Brignole M, Ungar A, Bartoletti A, Ponassi I, Lagi A, Mussi C, Ribani MA, Tavav G,
Disertori M, Quartieri F, Alboni P, Raviele A, Ammirati F, Scivales A, De Santo T;
Evaluation of Guidelines in Syncope Study 2 (EGSYS-2) GROUP. Standardized-
care pathway vs. usual management of syncope patients presenting as emergen-
cies at general hospitals. Europace 2006;8:644–650.
132. Narula OS, Samet P, Javier RP. Significance of the sinus-node recovery time.
133. Gann D, Tolentino A, Samet P. Electrophysiologic evaluation of elderly patients
with sinus bradycardia. A long-term follow-up study. Ann Intern Med 1979;90:
134. Menozzi C, Brignole M, Alboni P, Boni L, Paparella N, Gaggioli G, Lolli G. The
natural course of untreated sick sinus syndrome and identification of the vari-
ables predictive of unfavourable outcome. Am J Cardiol 1998;82:1205–1209.
135. McAnulty JH, Rahimtoola SH, Murphy E, DeMots H, Ritzmann L, Kanarek PE,
Kauffman S. Natural history of ‘high risk’ bundle branch block. Final report of
a prospective study. N Engl J Med 1982;307:137–143.
136. Scheinman MM, Peters RW, Suave ´ MJ, Desai J, Abbott JA, Cogan J, Wohl B,
Williams K. Value of the H–Q interval in patients with bundle branch block
and the role of prophylactic permanent pacing. Am J Cardiol 1982;50:1316–1322.
137. Olshansky B, Hahn EA, Hartz VL, Prater SP, Mason JW. Clinical significance of
syncope in the electrophysiologic study versus electrocardiographic monitoring
(ESVEM) trial. The ESVEM Investigators. Am Heart J 1999;137:878–886.
138. Mittal S, Hao SC, Iwai S, Stein KM, Markowitz SM, Slotwiner DJ, Lerman BB. Sig-
nificance of inducible ventricular fibrillation in patients with coronary artery
disease and unexplained syncope. J Am Coll Cardiol 2001;38:371–376.
139. Link MS, Kim KM, Homoud MK, Estes NA, Wang PJ. Long-term outcome of
patients with syncope associated with coronary artery disease and a non diag-
nostic electrophysiological evaluation. Am J Cardiol 1999;83:1334–1337.
140. Paul M, Gerss J, Schulze-Bahr E, Wichter T, Vahlhaus C, Wilde AA, Breithardt G,
Eckardt L. Role of programmed ventricular stimulation in patients with Brugada
syndrome: a meta-analysis of worldwide published data. Eur Heart J 2007;28:
141. Woelfel AK, Simpson RJ Jr, Gettes LS, Foster JR. Exercise induced distal atrio-
ventricular block. J Am Coll Cardiol 1983;2:578–581.
142. Benbadis SR, Chichkova R. Psychogenic pseudosyncope: an underestimated and
provable diagnosis. Epilepsy Behav 2006;9:106–110.
143. Freeman R. Clinical practice. Neurogenic orthostatic hypotension. N Engl J Med
144. Hennerici M, Klemm C, Rautenberg W. The subclavian steal phenomenon: a
common vascular disorder with rare neurologic deficits. Neurology 1988;38:
145. Thijs RD, Kruit MC, van Buchem MA, Ferrari MD, Launer LJ, van Dijk JG.
Syncope in migraine: the population-based CAMERA study. Neurology 2006;66:
146. Lempert T, Bauer M, Schmidt D. Syncope: a videometric analysis of 56 episodes
of transient cerebral hypoxia. Ann Neurol 1994;36:233–237.
147. Sheldon R, Rose S, Connolly S, Ritchie D, Koshman ML, Frenneaux M. Diagnos-
tic criteria for vasovagal syncope based on a quantitative history. Eur Heart J
148. Parry SW, Kenny RA. Drop attacks in older adults: systematic assessment has a
high diagnostic yield. J Am Geriatr Soc 2005;53:74–78.
149. Abubakr A, Wambacq I. The diagnostic value of EEGs in patients with syncope.
Epilepsy Behav 2005;6:433–434.
150. Di Girolamo E, Di Iorio C, Leonzio L, Sabatini P, Barsotti A. Usefulness of a tilt
training program for the prevention of refractory neurocardiogenic syncope in
adolescents: a controlled study. Circulation 1999;100:1798–1801.
151. Reybrouck T, Heidbuchel H, Van De Werf F, Ector H. Long-term follow-up
results of tilt training therapy in patients with recurrent neurocardiogenic
syncope. Pacing Clin Electrophysiol 2002;25:1441–1446.
152. Foglia-Manzillo G, Giada F, Gaggioli G, Bartoletti A, Lolli G, Dinelli M, Del
Rosso A, Santarone M, Raviele A, Brignole M. Efficacy of tilt training in the treat-
ment of neurally mediated syncope. A randomized study. Europace 2004;6:
153. Kinay O, Yazici M, Nazli C, Acar G, Gedikli O, Altinbas A, Kahraman H,
Dogan A, Ozaydin M, Tuzun N, Ergene O. Tilt training for recurrent neurocar-
diogenic syncope: effectiveness, patient compliance, and scheduling the fre-
quency of training sessions. Jpn Heart J 2004;45:833–843.
154. On YK, Park J, Huh J, Kim JS. Is home orthostatic self-training effective in pre-
venting neurocardiogenic syncope? A prospective and randomized study.
Pacing Clin Electrophysiol 2007;30:638–643.
155. Duygu H, Zoghi M, Turk U, Akyuz S, Ozerkan F, Akilli A, Erturk U, Onder R,
Akin M. The role of tilt training in preventing recurrent syncope in patients
with vasovagal syncope: a prospective and randomized study. Pacing Clin Electro-
156. Kaufman H, Saadia D, Voustianiouk A. Midodrine in neurally mediated syncope: a
double-blind randomized cross-over study. Ann Neurol 2002;52:342–345.
157. Raviele A, Brignole M, Sutton R, Alboni P, Giani P, Menozzi C, Moya A. Effect of
etilefrine in preventing syncopal recurrence in patients with vasovagal syncope: a
double-blind, randomized, placebo-controlled trial. The Vasovagal Syncope
International Study. Circulation 1999;99:1452–1457.
158. Samniah N, Sakaguchi S, Lurie KG, Iskos D, Benditt DG. Efficacy and safety of
midodrine hydrochloride in patients with refractory vasovagal syncope. Am J
159. Perez-Lugones A, Schweikert R, Pavia S, Sra J, Akhtar M, Jaeger F, Tomassoni GF,
Saliba W, Leonelli FM, Bash D, Beheiry S, Shewchik J, Tchou PJ, Natale A. Useful-
ness of midodrine in patients with severely symptomatic neurocardiogenic
syncope: a randomized control study. J Cardiovasc Electrophysiol 2001;12:
160. Ward CR, Gray JC, Gilroy JJ, Kenny RA. Midodrine: a role in the management of
neurocardiogenic syncope. Heart 1998;79:45–49.
161. Qingyou Z, Junbao D, Chaoshu T. The efficacy of midodrine hydrochloride in
the treatment of children with vasovagal syncope. J Pediatr 2006;149:777–780.
162. Salim MA, Di Sessa TG. Effectiveness of fludrocortisone and salt in preventing
syncope recurrence in children: a double blind, placebo-controlled, randomized
trial. J Am Coll Cardiol 2005:45;484–488.
163. Sheldon R, Rose S, Flanagan P, Koshman ML, Killam S. Effect of beta blockers on
the time to first syncope recurrence in patients after a positive isoproterenol tilt
table test. Am J Cardiol 1996;78:536–539.
164. Madrid AH, Ortega J, Rebollo JG, Manzano JG, Segovia JG, Sa ´nchez A, Pen ˜a G,
Moro C. Lack of efficacy of atenolol for the prevention of neurally mediated
syncope in a highly symptomatic population: a prospective, double-blind, ran-
domized and placebo-controlled study. J Am Coll Cardiol 2001;37:554–559.
165. Flevari P, Livanis EG, Theodorakis GN, Zarvalis E, Mesiskli T, Kremastinos DT.
Vasovagal syncope: a prospective, randomized, crossover evaluation of the
effect of propranolol, nadolol and placebo on syncope recurrence and patients’
well-being. J Am Coll Cardiol 2002;40:499–504.
166. Brignole M, Menozzi C, Gianfranchi L, Lolli G, Bottoni N, Oddone D. A con-
trolled trial of acute and long-term medical therapy in tilt-induced neurally
mediated syncope. Am J Cardiol 1992;70:339–342.
167. Sheldon R, Connolly S, Rose S, Klingenheben T, Krahn A, Morillo C, Talajic M,
Ku T, Fouad-Tarazi F, Ritchie D, Koshman ML; POST Investigators. Prevention of
Syncope Trial (POST): a randomized, placebo-controlled study of metoprolol in
the prevention of vasovagal syncope. Circulation 2006;113:1164–1170.
168. Di Girolamo E, Di Iorio C, Sabatini P, Leonzio L, Barbone C, Barsotti A. Effects
of paroxetine hydrochloride, a selective serotonin reuptake inhibitor, on refrac-
tory vasovagal syncope: a randomized, double-blind, placebo-controlled study.
J Am Coll Cardiol 1999;33:1227–1230.
169. Sutton R, Brignole M, Menozzi C, Raviele A, Alboni P, Giani P, Moya A. Dual-
chamber pacing in the treatment of neurally mediated tilt-positive cardioinhibi-
tory syncope: pacemaker versus no therapy: a multicenter randomized study.
The Vasovagal Syncope International Study (VASIS) Investigators. Circulation
170. Ammirati F, Colivicchi F, Santini M. Permanent cardiac pacing versus medical
treatment for the prevention of recurrent vasovagal syncope: a multicenter, ran-
domized, controlled trial. Circulation 2001;104:52–57.
171. Connolly SJ, Sheldon R, Roberts RS, Gent M. The North American Vasovagal
Pacemaker Study (VPS). A randomized trial of permanent cardiac pacing for
the prevention of vasovagal syncope. J Am Coll Cardiol 1999;33:16–20.
172. Connolly SJ, Sheldon R, Thorpe KE, Roberts RS, Ellenbogen KA, Wilkoff BL,
Morillo C, Gent M; VPS II Investigators. Pacemaker therapy for prevention of
syncope in patients with recurrent severe vasovagal syncope: Second Vasovagal
Pacemaker Study (VPS II): a randomized trial. JAMA 2003;289:2224–2229.
173. Raviele A, Giada F, Menozzi C, Speca G, Orazi S, Gasparini G, Sutton R,
Brignole M; Vasovagal Syncope and Pacing Trial Investigators. A randomized,
double-blind, placebo-controlled study of permanent cardiac pacing for the
treatment of recurrent tilt-induced vasovagal syncope. The vasovagal syncope
and pacing trial (SYNPACE). Eur Heart J 2004;25:1741–1748.
174. Sud S, Massel D, Klein GJ, Leong-Sit P, Yee R, Skanes AC, Gula LJ, Krahn AD.
The expectation effect and cardiac pacing for refractory vasovagal syncope.
Am J Med 2007;120:54–62.
175. Sud S, Klein GJ, Skanes AC, Gula LJ, Yee R, Krahn AD. Implications of mechanism
of bradycardia on response to pacing in patients with unexplained syncope. Euro-
176. Morley CA, Perrins EJ, Grant PL, Chan SL, Mc Brien DJ, Sutton R. Carotid sinus
syncope treated by pacing. Analysis of persistent symptoms and role of atrioven-
tricular sequential pacing. Br Heart J 1982;47:411–418.
177. Brignole M, Sartore B, Barra M, Menozzi C, Lolli G. Ventricular and dual
chamber pacing for treatment of carotid sinus syndrome. Pacing Clin Electrophysiol
178. Claydon VE, Hainsworth R. Salt supplementation improves orthostatic cerebral
and peripheral vascular control in patients with syncope. Hypertension 2004;43:
179. Schroeder C, Bush VE, Norcliffe LJ, Luft FC, Tank J, Jordan J, Hainsworth R.
Water drinking acutely improves orthostatic tolerance in healthy subjects. Circu-
lation 2002; 106:2806–2811.
180. van Lieshout JJ, ten Harkel AD, Wieling W. Physical manoeuvres for combating
orthostatic dizziness in autonomic failure. Lancet 1992;339:897–898.
181. Omboni S, Smit AA, van Lieshout JJ, Settels JJ, Langewouters GJ, Wieling W.
Mechanisms underlying the impairment in orthostatic tolerance after nocturnal
recumbency in patients with autonomic failure. Clin Sci (Lond) 2001;101:
182. Smit AA, Wieling W, Fujimura J, Denq JC, Opfer-Gehrking TL, Akarriou M,
Karemaker JM, Low PA. Use of lower abdominal compression to combat ortho-
static hypotension in patients with autonomic dysfunction. Clin Auton Res 2004;
183. Jankovic J, Gilden JL, Hiner BC, Kaufmann H, Brown DC, Coghlan CH, Rubin M,
Fouad-Tarazi FM. Neurogenic orthostatic hypotension: a double-blind, placebo-
controlled study with midodrine. Am J Med 1993;95:38–48.
184. Low PA, Gilden JL, Freeman R, Sheng KN, McElligott MA. Efficacy of midodrine
vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind
multicenter study. Midodrine Study Group. JAMA 1997;277:1046–1051.
185. Wright RA, Kaufman HC, Perera R, Opfer-Gehrking TL, McEllogott MA,
Sheng KN, Low PA. A double-blind, dose–response study of midodrine in neu-
rogenic orthostatic hypotension. Neurology 1998;51:120–124.
186. van Lieshout JJ, ten Harkel AD, Wieling W. Fludrocortisone and sleeping in the
head-up position limit the postural decrease in CO in autonomic failure. Clin
Auton Res 2000;10:35–42.
187. Finke J, Sagemu ¨ller I. Fludrocortisone in the treatment of orthostatic hypoten-
sion: ophthalmodynamography during standing Dtsch Med Wochenschr 1975;
188. ten Harkel AD, van Lieshout JJ, Wieling W. Treatment of orthostatic hypoten-
sion with sleeping in the head-up tilt position, alone and in combination with flu-
drocortisones. J Intern Med 1992;232:139–145.
189. Alboni P, Menozzi C, Brignole M, Paparella N, Gaggioli G, Lolli G, Cappato R.
Effects of permanent pacemaker and oral theophylline in sick sinus syndrome
the THEOPACE study: a randomized controlled trial. Circulation 1997;96:
190. Sgarbossa EB, Pinski SL, Jaeger FJ, Trohman RG, Maloney JD. Incidence and pre-
dictors of syncope in paced patients with sick sinus syndrome. Pacing Clin Electro-
191. Pavlovic SU, Kocovic D, Djordjevic M, Belkic K, Kostic D, Velimirovic D. The
etiology of syncope in pacemaker patients. Pacing Clin Electrophysiol 1991;14:
192. Andrews NP, Fogel RI, Pelargonio G, Evans JJ, Prystowsky EN. Implantable defi-
brillator event rates in patients with unexplained syncope and inducible sus-
tained ventricular tachyarrhythmias: a comparison with patients known to
have sustained ventricular tachycardia. J Am Coll Cardiol 1999;34:2023–2030.
193. Spirito P, Autore C, Rapezzi C, Bernabo ` P, Badagliacca R, Maron MS,
Bongioanni S, Coccolo F, Estes NA, Barilla ` CS, Biagini E, Quarta G,
Conte MR, Bruzzi P, Maron BJ. Syncope and risk of sudden death in hypertrophic
cardiomyopathy. Circulation 2009;119:1703–1710.
194. Corrado D, Leoni L, Link MS, Della Bella P, Gaita F, Curnis A, Salerno JU,
Igidbashian D, Raviele A, Disertori M, Zanotto G, Verlato R, Vergara G,
Delise P, Turrini P, Basso C, Naccarella F, Maddalena F, Estes NA 3rd, Buja G,
Thiene G. Implantable cardioverter-defibrillator therapy for prevention of
sudden death in patients with arrhythmogenic right ventricular cardiomyopa-
thy/dysplasia. Circulation 2003;108:3084–3091.
195. Goldenberg J, Moss AJ. Long QT syndrome. J Am Coll Cardiol 2008;51:
196. Sacher F, Probst V, Iesaka Y, Jacon P, Laborderie J, Mizon-Ge ´rard F, Mabo P,
Reuter S, Lamaison D, Takahashi Y, O’Neill MD, Garrigue S, Pierre B, Jaı ¨s P,
Pasquie ´ JL, Hocini M, Salvador-Mazenq M, Nogami A, Amiel A, Defaye P,
Bordachar P, Boveda S, Maury P, Klug D, Babuty D, Haı ¨ssaguerre M,
Mansourati J, Cle ´menty J, Le Marec H. Outcome after implantation of a
cardioverter-defibrillator in patients with Brugada syndrome: a multicenter
study. Circulation 2006;114:2317–2324.
197. Rosso R, Glick A, Glikson M, Wagshal A, Swissa M, Rosenhek S, Shetboun I,
Khalamizer V, Fuchs T, Boulos M, Geist M, Strasberg B, Ilan M, Belhassen B;
Israeli Working Group on Cardiac Pacing and Electrophysiology. Outcome
after implantation of cardioverter defibrillator [corrected] in patients with
Brugada syndrome: a multicenter Israeli study (ISRABRU). Isr Med Assoc J
198. McIntosh SJ, Lawson J, Kenny RA. Clinical characteristics of vasodepressor, car-
dioinhibitory, and mixed carotid sinus syndrome in the elderly. Am J Med 1993;
199. Galizia A, Abete P, Mussi C, Noro A, Morrione A, Langellotto A, Landi A,
Cacciatore F, Masotti G, Rengo F, Marchionni N, Ungar A. Role of the early
symptoms in assessment of syncope in the elderly people. Results from the
Italian Group for the Study of Syncope in the elderly (GIS STUDY). J Am
Geriatr Soc 2009;57:18–23.
200. Van der Velde N, van den Meiracker AH, Pols HA, Stricker BH, van der
Cammen TJ. Withdrawal of fall-risk-increasing drugs in older persons: effect
on tilt-table test outcomes. J Am Geriatr Soc 2007;55:734–739.
201. Shaw FE, Bond J, Richardson DA, Dawson P, Steen IN, McKeith IG, Kenny RA.
Multifactorial intervention after a fall in older people with cognitive impairment
and dementia presenting to the accident and emergency department: random-
ised controlled trial. Br Med J 2003;326:73–80.
202. DiMario FJ. Prospective study of children with cyanotic and pallid breath-holding
spells. Pediatrics 2001;107:265–269.
203. Vlahos AP, Kolettis TM. Family history of children and adolescents with neuro- Download full-text
cardiogenic syncope. Pediatr Cardiol 2008;29:227.
204. Vlahos AP, Tzoufi M, Katsouras CS, Barka T, Sionti I, Michalis LK,
Siamopoulou A, Kolettis TM. Provocation of neurocardiogenic syncope during
head-up tilt testing in children: comparison between isoproterenol and nitrogly-
cerin. Pediatrics 2007;119:e419–e425.
205. McLeod KA, Wilson N, Hewitt J, Norrie J, Stephenson JB. Cardiac pacing for
severe childhood neurally mediated syncope with reflex anoxic seizures. Heart
206. Maas R, Ventura R, Kretzschmar C, Aydin A, Schuchert A. Syncope, driving rec-
ommendations, and clinical reality: survey of patients. Br Med J 2003;326:21.
207. Akiyama T, Powell JL, Mitchell LB, Ehlert FA, Baessler C; Antiarrhythmics versus
Implantable Defibrillators Investigators. Resumption of driving after life-
threatening ventricular tachyarrhythmia. N Engl J Med 2001;345:391–397.
208. Sorajja D, Nesbitt G, Hodge D, Low P, Hammill S, Gersh B, Shen WK. Syncope
while driving: clinical characteristics, causes, and prognosis. Circulation 2009,
209. Vijgen J, Botto G, Camm J, Hoijer C, Jung W, Le Heuzey J, Lubinski A,
Norekva ˚l TM, Santomauro M, Schalij M, Schmid J, Vardas P. Consensus
statement of the European Heart Rhythm Association: updated recommen-
dations for driving of patients with implantable cardioverter defibrillators. Euro-
210. Huff JS, Decker WW, Quinn JV, Perron AD, Napoli AM, Peeters S, Jagoda AS;
American College of Emergency Physicians. Clinical policy: critical issues in
the evaluation and management of adult patients presenting to the emergency
department with syncope. Ann Emerg Med 2007;49:431–444.
211. Parry SW, Frearson R, Steen N, Newton JL, Tryambake P, Kenny RA. Evidence-
based algorithms and the management of falls and syncope in the acute medical
setting. Clinical Medicine 2008;8:157–162.
212. Petkar S, Cooper P, Fitzpatrick AP. How to avoid a misdiagnosis in patients
presenting with transient loss of consciousness. Postgrad Med J 2006;82:
213. Shen WK, Decker WW, Smars PA, Goyal DG, Walker AE, Hodge DO,
Trusty JM, Brekke KM, Jahangir A, Brady PA, Munger TM, Gersh BJ,
Hammill SC, Frye RL. Syncope Evaluation in the Emergency Department
Study (SEEDS): a multidisciplinary approach to syncope management. Circulation