Syncope

Syncope
A Diagnostic and
Treatment Strategy
David G. Benditt, M.D.
Richard Sutton, DScMed
University of Minnesota Medical School
Minneapolis, MN USA
Royal Brompton Hospital
London, UK
Transient Loss of Consciousness (TLOC)
Classification of Transient Loss of Consciousness (TLOC)
Real or Apparent TLOC
Syncope
• Neurally-mediated reflex
syndromes
• Orthostatic hypotension
• Cardiac arrhythmias
• Structural cardiovascular
disease
Brignole M, et al. Europace, 2004;6:467-537.
Disorders Mimicking
Syncope
• With loss of consciousness, i.e.,
seizure disorders, concussion
• Without loss of consciousness,
i.e., psychogenic “pseudosyncope”
Syncope – A Symptom, Not a Diagnosis

Self-limited loss of consciousness and postural tone

Relatively rapid onset

Variable warning symptoms

Spontaneous, complete, and usually prompt recovery without
medical or surgical intervention
Underlying mechanism is
transient global cerebral hypoperfusion.
Brignole M, et al. Europace, 2004;6:467-537.
Presentation Overview
I. Etiology, Prevalence, Impact
II. Diagnosis
III. Specific Conditions and Treatment
IV. Special Issues
Section I:
Etiology, Prevalence, Impact
Causes of True Syncope
NeurallyMediated
1
• VVS
• CSS
• Situational
Cough
PostMicturition
Orthostatic
Cardiac
Arrhythmia
Structural
CardioPulmonary
2
3
4
• Drug-Induced
• ANS Failure
Primary
Secondary
• Brady
SN
Dysfunction
AV Block
• Tachy
VT
SVT
• Long QT
Syndrome
Unexplained Causes = Approximately 1/3
DG Benditt, MD. U of M Cardiac Arrhythmia Center
• Acute
Myocardial
Ischemia
• Aortic
Stenosis
• HCM
• Pulmonary
Hypertension
• Aortic
Dissection
Syncope Mimics

Acute intoxication (e.g., alcohol)

Seizures

Sleep disorders

Somatization disorder (psychogenic pseudo-syncope)

Trauma/concussion

Hypoglycemia

Hyperventilation
Brignole M, et al. Europace, 2004;6:467-537.
Impact of Syncope

40% will experience syncope
at least once in a lifetime1

1-6% of hospital admissions2

1% of emergency room visits
per year3,4

10% of falls by elderly are due
to syncope5

Major morbidity reported in 6%1
eg, fractures, motor vehicle accidents

Minor injury in 29%1
eg, lacerations, bruises
1Kenny
RA, Kapoor WN. In: Benditt D, et al. eds. The Evaluation and
Treatment of Syncope. Futura;2003:23-27.
2Kapoor W. Medicine. 1990;69:160-175.
3Brignole
M, et al. Europace. 2003;5:293-298.
Blanc J-J, et al. Eur Heart J. 2002;23:815-820.
5Campbell A, et al. Age and Ageing. 1981;10:264-270.
4
Impact of Syncope: US Trends
Inpatient Trend*
Physician Office Visits**
(000s)
(000s)
440
1,200
420
1,100
1,000
400
900
380
800
360
700
340
600
320
500
300
400
'96
'97
'98
'99
'00
'01
'02
*All patients discharged with syncope and collapse
(ICD-9 Code:780.2) listed among diagnoses.
NHDS 2003.
'96
'97
'98
'99
'00
**Syncope and collapse (ICD-9 Code: 780.2)
listed as primary reason for visit.
NAMCS 2002.
'01
Impact of Syncope: US Trends
Emergency
Department Visits*
(000s)
Hospital
Outpatient Visits*
(000s)
900
80
70
800
60
700
50
600
40
+
30
500
'96
'97
'98
'99
'00
'01
'02
*Syncope and collapse (ICD-9 Code:780.2) listed as
primary reason for visit.
NHAMCS 2002.
'96
'97
+ Not available
'98
'99
'00
'01
'02
Impact of Syncope:
NHS Hospitals, England, 2002-2003*

74,813 hospital consults for
syncope and collapse

80% required hospital admission

Average length of stay: 6.1 days

327,201 hospital bed days,
second only to senility
*Hospital Episode Statistics, Dept. of Health, Eng. 2002-2003.
Impact of Syncope: Costs

Estimated hospital costs exceeded $10 billion US1

Estimated physician office expenses exceeded $470 million2

£104,285 spent on 1,334 patients with syncopal codes (UK)
(EaSyAS)3
• Hospital admission: 67% of investigational costs

Over $7 billion is spent annually in the US
to treat falls in older adults4
1Kenny
RA, Kapoor WN. In: Benditt D, et al. eds. The Evaluation and Treatment of Syncope. Futura;2003:23-27.
v. 6.0. Solucient LLC, Evanston IL.
3Farwell D, et al. J Cardiovasc Electrophysiol. 2002;13(Supp):S9-S13.
4Olshansky B. In: Grubb B and Olshansky B. eds. Syncope: Mechanisms and Management. Futura. 1998:15-71.
2OutPatientView
Impact of Syncope: Quality of Life
100
80
73%1
71%2
60%2
60
37%2
40
20
0
1Linzer
2Linzer
Anxiety/
Depression
M. J Clin Epidemiol. 1991;44:1037.
M. J Gen Int Med. 1994;9:181.
Alter Daily
Activities
Restricted
Driving
Change
Employment
Quality of Life:
UK Population Norms vs. Syncope Patients
50
UK Population Norms
Patients with Syncope
43%
37%
40
% Prevalence
49%
30
36%
26%
19%
20
9%
10
3%
0
Mobility
4%
1%
Usual
Activities
Rose M, et al. J Clin Epidemiol. 2000;53:1209-1216.
Self-Care
Pain/
Discomfort
Anxiety/
Depression
Syncope Mortality

Low mortality vs.
high mortality

Neurally-mediated
syncope vs. syncope
with a cardiac cause
Soteriades ES, Evans JC, Larson MG, et al. Incidence and prognosis of syncope.
N Engl J Med. 2002;347(12):878-885. [Framingham Study Population]
Implications of Syncope for Driving a Vehicle
 Those
who drive and have
recurrent syncope risk their
lives and the lives of others

If the patient has sufficient
warning of impending syncope
– Driving may be permitted
 Places
considerable burden
on the physician
 Essential
to know local laws
and physician responsibilities
states – Invasion of
privacy to notify motor
vehicle department*
 Some
• Other states – Reporting
is mandatory*
Olshansky B, Grubb B. In: Syncope: Mechanisms and Management. Futura. Armonk, NY. 1998.
*Medtronic, Inc. Follow-up Forum. 1995/96;1(3):8-10.
Challenges of Syncope

Diagnosis
• Complex

Quality of life implications
• Work
• Mobility (automobiles)
• Psychological

Cost
• Cost/year
• Cost/diagnosis
Section II:
Diagnosis
Diagnostic Objectives

Distinguish true syncope from syncope mimics

Determine presence of heart disease

Establish the cause of syncope with
sufficient certainty to:
• Assess prognosis confidently
• Initiate effective preventive treatment
A Diagnostic Plan is Essential

Initial Examination
• Detailed patient history
• Physical exam
• ECG
• Supine and upright
blood pressure
Monitoring
• Holter
• Event
• Insertable Loop Recorder (ILR)
 Cardiac Imaging
 Special Investigations
• Head-up tilt test
• Hemodynamics
• Electrophysiology study

Brignole M, et al. Europace, 2004;6:467-537.
Diagnostic Flow Diagram for TLOC
Initial Evaluation
Syncope
Certain
Diagnosis
Not Syncope
Suspected
Diagnosis
Unexplained
Syncope
Cardiac
Likely
Neurally-Mediated or
Orthostatic Likely
Frequent or Severe
Episodes
Single/Rare
Episodes
Cardiac
Tests
Tests for NeurallyMediated Syncope
Tests for NeurallyMediated Syncope
No Further
Evaluation
+
-
+
Re-Appraisal
Treatment
Treatment
Brignole M, et al. Europace, 2004;6:467-537.
+
Confirm with
Specific Test or
Specialist
Consultation
Re-Appraisal
Treatment
Treatment
Initial Exam: Detailed Patient History
Circumstances of recent event
• Eyewitness account of event
• Symptoms at onset of event
• Sequelae
• Medications
 Circumstances of more
remote events
 Concomitant disease,
especially cardiac
 Pertinent family history
• Cardiac disease
• Sudden death
• Metabolic disorders
 Past medical history
• Neurological history
• Syncope

Brignole M, et al. Europace, 2004;6:467-537.
Initial Exam: Thorough Physical

Vital signs
• Heart rate
• Orthostatic blood pressure change

Cardiovascular exam: Is heart disease present?
• ECG: Long QT, pre-excitation, conduction system disease
• Echo: LV function, valve status, HCM

Neurological exam

Carotid sinus massage
• Perform under clinically appropriate conditions preferably
during head-up tilt test
• Monitor both ECG and BP
Brignole M, et al. Europace, 2004;6:467-537.
Carotid Sinus Massage (CSM)

Method1

• Massage, 5-10 seconds
• Carotid bruit, known significant
carotid arterial disease,
previous CVA, MI last 3 months
• Don’t occlude
• Supine and upright posture
(on tilt table)

Outcome
• 3 second asystole and/or
50 mmHg fall in systolic BP
with reproduction of symptoms
= Carotid Sinus Syndrome
1Kenny
RA. Heart. 2000;83:564.
M. Ann Intern Med. 1997;126:989.
3Munro N, et al. J Am Geriatr Soc. 1994;42:1248-1251.
2Linzer
Absolute contraindications2

Complications
• Primarily neurological
• Less than 0.2%3
• Usually transient
Other Diagnostic Tests

Ambulatory ECG
• Holter monitoring
• Event recorder

−
Intermittent vs. Loop
−
Insertable Loop Recorder (ILR)
Head-Up Tilt (HUT)
• Includes drug provocation (NTG, isoproterenol)
• Carotid Sinus Massage (CSM)

Adenosine Triphosphate Test (ATP)

Electrophysiology Study (EPS)
Brignole M, et al. Europace, 2004;6:467-537.
Heart Monitoring Options
OPTION
12-Lead 10 Seconds
2 Days
Holter Monitor
Event Recorders
7-30 Days
(non-lead and loop)
Up to 14
Months
ILR
0
1
2
3
4
5
6
7
8
TIME (Months)
Brignole M, et al. Europace, 2004;6:467-537.
9
10
11
12
13
14
Diagnostic Assessment: Yields
(N=3411 to 4332)
Yield (%)
Initial Evaluation
History, Physical Exam, ECG, Cardiac Massage
38-40
Other Tests/Procedures
Head-Up Tilt
External Cardiac Monitoring
Insertable Loop Recorder (ILR)
EP Study
Exercise Test
27
5-13
43-883-5
<2-5
0.5
EEG
0.3-0.5
MRI
No data
available6
References Available
Neurological Tests:
Rarely Diagnostic for Syncope

EEG, Head CT, Head MRI

May help diagnose seizure
Brignole M, et al. Europace. 2004;6:467-537.
Head-Up Tilt Test (HUT)

Protocols vary

Useful as diagnostic adjunct
in atypical syncope cases

Useful in teaching patients
to recognize prodromal
symptoms

Not useful in assessing
treatment
Brignole M, et al. Europace. 2004;6:467-537.
60° - 80°
Head-up Tilt Test
Click once on image to play video.
Carlos Morillo, MD, FRCPC
Professor, Faculty of Health Sciences
McMaster University, Hamilton Ontario
Head-Up Tilt Test:
ECG Leads and Intra-Arterial Pressure Tracing
2
1
DG Benditt, MD. U of M Cardiac Arrhythmia Center
Adenosine Triphosphate (ATP) Test

Ongoing investigation
in the US

Provokes a short and
potent cardioinhibitory
vasovagal response

Advantages
• Simple
• Inexpensive
• Correlation with
pacing benefit
Brignole M. Heart. 2000;83:24-28.
Donateo P. J Am Coll Cardiol. 2003;41:93-98.
Flammang D. Circ. 1999;99:2427-2433.

Seems to identify a unique
mechanism of syncope found
in patients with:
• Advanced age
• More hypertension
• More ECG abnormalities
Insertable Loop Recorder (ILR)
Click once on black screen to play video.
Reveal® Plus ILR
Typical Location of the
Reveal® Plus ILR
Insertable Loop Recorder (ILR)
The ILR is an implantable patient – and automatically – activated
monitoring system that records subcutaneous ECG and is
indicated for:
 Patients with clinical syndromes or situations at increased risk of
cardiac arrhythmias
 Patients who experience transient symptoms that may suggest a
cardiac arrhythmia
Insertable Loop Recorder (ILR)
Click once on black screen to play video.
Symptom-Rhythm Correlation with the ILR
CASE: 56 year-old woman with
refractory syncope accompanied
with seizures.
Medtronic data on file.
CASE: 65 year-old man with
syncope accompanied by brief
retrograde amnesia.
Randomized Assessment of Syncope Trial (RAST)
60 Patients
Unexplained Syncope
EF > 35%
30 Patients
30 Patients
ILR
Conventional
Testing
(AECG, Tilt, EPS)
Primary
Strategy
14
+
Crossover
+
Diagnosis
–
AECG, Tilt,
EP Study
6
1
+
–
8
+
ILR
Results:
 Combining primary strategy with crossover, the diagnostic yield is
43% ILR only vs. 20% conventional only1
 Cost/diagnosis is 26% less than conventional testing2
1Krahn
AD, et al. Circ. 2001;104:46-51. 2Krahn AD, et al. JACC. 2003;42:495-501.
Conventional EP Testing in Syncope

Greater diagnostic value in older patients or those with SHD

Less diagnostic value in healthy patients without SHD

Useful diagnostic observations:
• Inducible monomorphic VT
• SNRT > 3000 ms or CSNRT > 600 ms
• Inducible SVT with hypotension
• HV interval ≥ 100 ms (especially in absence of inducible VT)
• Pacing induced infra-nodal block
Benditt D. In: Topol E, ed. Textbook of Cardiovascular Medicine. Lippencott;2002:1529-1542.
Lu F, et al. In: Benditt D, et al. The Evaluation and Treatment of Syncope. Futura. 2003;80-95.
Brignole M, et al. Europace. 2004;6:467-537.
Diagnostic Limitations of EPS

Difficult to correlate spontaneous events and
laboratory findings

Positive findings1
• Without SHD: 6-17%
• With SHD: 25-71%

Less effective in assessing bradyarrhythmias
than tachyarrhythmias2

EPS findings must be consistent with clinical history
• Beware of false positive
1Linzer
2Lu
M, et al. Ann Int Med. 1997;127:76-86.
F, et al. In: Benditt D, et al. The Evaluation and Treatment of Syncope. Futura. 2003;80-95.
ISSUE
International Study of Syncope of Uncertain Etiology

Multicenter, international, prospective study

Analyzed the diagnostic contribution of an ILR in
three predefined groups of patients with syncope of
uncertain origin:
1) Isolated syncope: No SHD, Normal ECG1
•
Negative tilt
•
Positive tilt
2) Patients with heart disease and negative EP test2
3) Patients with bundle branch block and negative EP test3
1Moya
A. Circulation. 2001; 104:1261-1267.
C, et al. Circulation. 2002;105:2741-2745.
3Brignole M, et al. Circulation. 2001;104:2045-2050.
2Menozzi
ISSUE
Patients with Isolated Syncope and Tilt-Positive Syncope
111 Patients with Syncope
No SHD, Normal ECG
Tilt Test Followed by
Insertable Loop Recorder
82: Tilt-Negative
“Isolated Syncope”
Follow-Up to Recurrent
Spontaneous Episode
Moya A. Circulation.
2001;104:1261-1267.
29: Tilt-Positive
ISSUE
Isolated Syncope vs. Tilt-Positive Syncope
Conclusions

Results similar in the two arms, including syncope
recurrence and ECG correlation

Tilt-negative patients had as many bradycardias (18%) as
tilt-positive patients (21%)

Most frequent finding was asystole secondary to progressive
sinus bradycardia, suggesting a neuro-mediated origin

Homogeneous findings from tilt-negative and tilt-positive
infer low sensitivity of tilt-testing
Moya A. Circulation. 2001;104:1261-1267.
ISSUE
Patients with Heart Disease and a Negative EP Test
35 Pts with Heart Disease
and Insertable Loop Recorder
Syncope: 6 Pts (17%)
Pre-Syncope: 13 Pts (37%)
ECG-Documented: 6 Pts (17%)
ECG-Documented: 8 Pts (23%)
AV block + asystole: 1
A.Fib + asystole: 1
Sinus arrest: 1
Sinus tachycardia: 1
Rapid A.Fib: 2
Menozzi C, et al. Circulation. 2002;105:2741-2745.
Sustained VT: 1
Parox. A.Fib/AT: 1
Post tachycardia pause: 1
No rhythm variations: 4
Sinus tachycardia: 1
ISSUE
Patients with Heart Disease and a Negative EP Test
Conclusions

Patients with unexplained syncope, overt heart disease, and
negative EP study had a favorable medium-term outcome

Mechanism of syncope was heterogeneous

Ventricular tachyarrhythmia was unlikely

“ILR-guided strategy seems reasonable, with specific therapy
safely delayed until a definite diagnosis is made.”
Menozzi C, et al. Circulation. 2002;105:2741-2745.
ISSUE
Patients with Bundle Branch Block and Negative EP Test
52 Pts with BBB
and Insertable Loop Recorder
Syncope:
22 Pts (42%)*
ILR-Detected: 19
Stable AVB:
3 Pts (6%)
ILR-Detected
Pre-Syncope:
2 Pts (4%)**
Death:
1 Pt (2%)
Not Detected: 3
AVB: 2 (4%)
AVB: 12 (63%)
SA: 4 (21%)
Asystole-undefined: 1 (5%)
NSR: 1 (5%)
Sinus tachy: 1 (5%)
Brignole M., ET AL.,Circulation. 2001;104:2045-2050.
* 5 of these also had ≥1 presyncope
** Drop-out before primary-end point
ISSUE
Patients with Bundle Branch Block and Negative EP Test
Conclusion:

In patients with BBB and negative EP study, most syncopal
recurrences have a homogeneous mechanism that is
characterized by prolonged asystolic pauses mainly attributable
to sudden-onset paroxysmal AV block
Brignole M. Circulation. 2001;104:2045-2050.
Section III:
Specific Conditions and Treatment
Specific Conditions
 Cardiac
arrhythmia
• Brady/Tachy
• Long QT syndrome
• Torsade de pointes
• Brugada
• Drug-induced
 Structural
cardio-pulmonary
 Neurally-mediated
• Vasovagal Syncope (VVS)
• Carotid Sinus Syndrome (CSS)
 Orthostatic
Cardiac Syncope

Includes cardiac arrhythmias and SHD

Often life-threatening

May be warning of critical CV disease
• Tachy and brady arrhythmias
• Myocardial ischemia, aortic stenosis, pulmonary hypertension,
aortic dissection

Assess culprit arrhythmia or structural abnormality aggressively

Initiate treatment promptly
Brignole M, et al. Europace. 2004;6:467-537.
“…cardiac syncope can be a harbinger of sudden death.”
Survival with and
without syncope

6-month mortality rate
of greater than 10%


Cardiac syncope
doubled the risk
of death
Includes cardiac
arrhythmias and SHD
1.0
Probability of Survival

0.8
0.6
0.4
0.2
0.0 0
Soteriades ES, et al. N Engl J Med. 2002;347:878.
No Syncope
Vasovagal and
Other Causes
Cardiac Cause
5
10
Follow-Up (yr)
15
Syncope Due to Structural Cardiovascular Disease:
Principle Mechanisms

Acute MI/Ischemia

• 2° neural reflex bradycardia –
• Neural reflex, inadequate
Vasodilatation, arrhythmias,
low output (rare)

Hypertrophic cardiomyopathy
• Limited output during exertion
(increased obstruction, greater
demand), arrhythmias, neural
reflex

Acute aortic dissection
• Neural reflex mechanism,
pericardial tamponade
Brignole M, et al. Europace. 2004;6:467-537.
Pulmonary embolus/
pulmonary hypertension
flow with exertion

Valvular abnormalities
• Aortic stenosis – Limited output,
neural reflex dilation in periphery
• Mitral stenosis, atrial myxoma –
Obstruction to adequate flow
Syncope Due to Cardiac Arrhythmias

Bradyarrhythmias
• Sinus arrest, exit block
• High grade or acute complete AV block
• Can be accompanied by vasodilatation (VVS, CSS)

Tachyarrhythmias
• Atrial fibrillation/flutter with rapid ventricular rate
(eg, pre-excitation syndrome)
• Paroxysmal SVT or VT
• Torsade de pointes
Brignole M, et al. Europace. 2004;6:467-537.
ILR Recordings
CASE: 83 year-old woman with
syncope due to bradycardia:
Pacemaker implanted.
Reveal ® ILR recordings; Medtronic data on file.
CASE: 28 year-old man presents
to ER multiple times after falls
resulting in trauma. VT: Ablated
and medicated.
Cardiac Rhythms During Unexplained Syncope
Composite: N=133 to 7109
Bradycardia
16%
(11-21%)
Arrhythmia
22%
No Recurrence
36%
(31-48%)
(13-32%)
Tachycardia 6%
(2-11%)
Other 11%
Seidl K. Europace. 2000;2(3):256-262.
Krahn AD. PACE. 2002;25:37-41.
Medtronic ILR Replacement Data. FY03, 04. On file.
Normal Sinus Rhythm
31%
(17-44%)
Long QT Syndromes

Mechanism
• Abnormalities of sodium and/or potassium channels
• Susceptibility to polymorphic VT (Torsade de pointes)

Prevalence
• Drug-induced forms – Common
• Genetic forms – Relatively rare, but increasingly being recognized
• “Concealed” forms:
−
May be common
−
Provide basis for drug-induced torsade
Schwartz P, Priori S. In: Zipes D and Jalife J, eds. Cardiac Electrophysiology. Saunders;2004:651-659.
Syncope: Torsade de Pointes
From the files of DG Benditt, MD. U of M Cardiac Arrhythmia Center
Long QT Syndromes: 12-Lead ECG
From the files of DG Benditt, MD. U of M Cardiac Arrhythmia Center
Drug-Induced QT Prolongation
(List is continuously being updated)

Antiarrhythmics

• Erythromycin, Pentamidine,
• Class IA ...Quinidine,
Fluconazole, Ciprofloxacin and
its relatives
Procainamide, Disopyramide
• Class III…Sotalol, Ibutilide,
Dofetilide, Amiodarone, NAPA*



Psychoactive Agents
• Phenothiazines, Amitriptyline,
Imipramine, Ziprasidone
*Removed from U.S. Market
Brignole M, et al. Europace, 2004;6:467-537.
Nonsedating antihistamines
• Terfenadine*, Astemizole
Antianginal Agents
• Bepridil*
Antibiotics

Others
• Cisapride*, Droperidol,
Haloperidol
Treatment of Long QT

Suspicion and recognition are critical

Emergency treatment
•
•
•
•
•
Intravenous magnesium
Pacing to overcome bradycardia or pauses
Isoproterenol to increase heart rate and shorten repolarization
ICD if prior SCA or strong family history
If drug induced:
−
Reverse bradycardia
−
Withdraw drug
−
Avoid ALL long-QT provoking agents
• If genetic:
−

Avoid ALL long-QT provoking agents
For more information visit www.longqt.org
Schwartz P, Priori S. In: Zipes D and Jalife J, eds. Cardiac Electrophysiology. Saunders;2004:651-659.
Treatment of Syncope
Due to Bradyarrhythmia

Class I indication for
pacing using dual
chamber system
wherever possible
0.4 nV
0.2
08:23:21
0.0
-0.2
-0.4
:21
:22
:23
:24
:25
:26
:27
:28
:29
0.4
0.2

Ventricular pacing in
atrial fibrillation with
slow ventricular
response
8:23:29
0.0
-0.2
-0.4
:29
:30
:31
:32
:33
:34
:35
:36
:37
0.4
0.2
08:23:37
0.0
-0.2
-0.4
:37
ACC/AHA/NASPE 2002 Guideline Update. Circ. 2002;106:2145-2161.
:38
:39
:40
:41
:42
:43
:44
:45
Treatment of Syncope
Due to Tachyarrhythmia

Atrial tachyarrhythmias
• AVRT due to accessory pathway – Ablate pathway
• AVNRT – Ablate AV nodal slow pathway
• Atrial fib – Pacing, linear/focal ablation for paroxysmal AF
• Atrial flutter – Ablate the IVC-TV isthmus of the re-entrant circuit
for ‘typical’ flutter

Ventricular tachyarrhythmias
• Ventricular tachycardia – ICD or ablation where appropriate
• Torsade de pointes – Withdraw offending drug or implant ICD
(long QT/Brugada/short QT)

Drug therapy may be an alternative in many cases
Brignole M, et al. Europace. 2004;6:467-537.
Neurally-Mediated Reflex Syncope

Vasovagal Syncope (VVS)

Carotid Sinus Syndrome (CSS)

Situational syncope
• Post-micturition
• Cough
• Swallow
• Defecation
• Blood drawing, etc.
Brignole M, et al. Europace, 2004;6:467-537.
Pathophysiology
Autonomic
Nervous
System
Benditt D, et al. Neurally mediated syncope:
Pathophysiology, investigations and treatment. Blanc JJ,
et al. eds. Futura. 1996.
VVS
Clinical Pathophysiology

Neurally-mediated physiologic reflex mechanism with
two components:
1. Cardioinhibitory (↓ HR)
2. Vasodepressor (↓ BP) despite heart beats, no significant
BP generated

Both components are usually present
1
2
Wieling W, et al. In: Benditt D, et al. The Evaluation and Treatment of Syncope. Futura. 2003;11-22.
VVS
Incidence

Most common form of syncope
• 8% to 37% (mean 18%) of syncope cases

Depends on population sampled
• Young without SHD, ↑ incidence
• Older with SHD, ↓ incidence
Linzer M, et al. Ann Intern Med. 1997;126:989.
VVS vs. CSS

In general:
• VVS patients younger than CSS patients
• Ages range from adolescence to older adults
(median 43 years)
Linzer M, et al. Ann Intern Med. 1997;126:989.
VVS
Recurrences

35% of patients report syncope recurrence during follow-up
≤3 years1

Positive HUT with >6 lifetime syncope episodes: recurrence risk
>50% over 2 years2
Total Number of Syncopal Episodes
1000
> 75%
800
Two Year Risk
100
50
25
50-75%
8
4
25-50%
2
< 25%
1
1
1Savage
D, et al. STROKE. 1985;16:626-29.
2Sheldon R, et al. Circulation. 1996;93:973-81.
2
3
6
24
84
Months Since Symptoms Began
480
VVS
Spontaneous
16 year-old male, healthy, athletic, monitored for fainting.
16.3
sec
Continuous Tracing
1 sec
From the files of DG Benditt, MD. U of M Cardiac Arrhythmia Center
VVS
Diagnosis

History and physical exam,
ECG and BP

Head-Up Tilt (HUT) – Protocol:
• Fast > 2 hours
• ECG and continuous blood
pressure, supine, and upright
• Tilt to 70°, 20 minutes
• Isoproterenol/Nitroglycerin if
necessary
• End point – Loss of consciousness
Benditt D, et al. JACC. 1996;28:263-275.
Brignole M, et al. Europace, 2004;6:467-537.
60° - 80°
VVS
General Treatment Measures


Optimal treatment
strategies for VVS are
a source of debate
Treatment goals
• Acute intervention
−
Physical maneuvers, eg,
crossing legs or tugging arms
−
Lowering head
−
Lying down
Brignole M, et al. Europace, 2004;6:467-537.

Long-term prevention
•
•
•
•
•
•
Tilt training
Education
Diet, fluids, salt
Support hose
Drug therapy
Pacing
VVS
Tilt Training Protocol

Objectives
• Enhance orthostatic tolerance
• Diminish excessive autonomic
reflex activity
• Reduce syncope
susceptibility/recurrences

Technique
• Prescribed periods of upright
posture against a wall
• Start with 3-5 min BID
• Increase by 5 min each
week until a duration of
30 min is achieved
Reybrouck T, et al. PACE. 2000;23(4 Pt. 1):493-498.
VVS
Tilt Training: Clinical Outcomes

Treatment of recurrent VVS

Reybrouck, et al.*: Long-term study
• 38 patients performed home tilt training
• After a period of regular tilt training, 82% remained free of
syncope during the follow-up period
• However, at the 43-month follow-up, 29 patients had
abandoned the therapy
• Conclusion: The abnormal autonomic reflex activity
of VVS can be remedied. Compliance may be an issue.
*Reybrouck T, et al. PACE. 2000;23:493-498.
VVS
Tilt Training: Clinical Outcomes

Foglia-Manzillo, et al.*: Short-term study
• 68 patients
•
•
•
•
–
35 tilt training
–
33 no treatment (control)
Tilt table test conducted after 3 weeks
19 (59%) of tilt trained and 18 (60%) of controls had a positive test
Tilt training was not effective in reducing tilt testing positivity rate
Poor compliance in the majority of patients with recurrent VVS
*Foglio-Manzillo G, et al. Europace. 2004;6:199-204.
VVS
Pharmacologic Treatment

Fludrocortisone

Beta-adrenergic blockers
• Preponderance of clinical evidence
suggests minimal benefit1

SSRI (Selective Serotonin
Re-Uptake Inhibitor)
• 1 small controlled trial2

Vasoconstrictors
• 1 negative controlled trial
(etilefrine)3
• 2 positive controlled trials
(midodrine)4,5
1Brignole
M, et al. Europace, 2004;6:467-537.
Girolamo E, et al. JACC. 1999;33:1227-1230.
3Raviele A, et al. Circ. 1999;99:1452-1457.
2Di
4Ward
C, et al. Heart. 1998;79:45-49.
A, et al. J Cardiovasc Electrophysiol. 2001;12(8):935-938.
5Perez-Lugones
Midodrine for VVS
100
Symptom-Free Interval
80
60
Midodrine
Fluid
40
20
p < 0.001
0
0
20
40
60
80
100
Months
Perez-Lugones A, Schweikert R, Pavia S, et al. J Cardiovasc Electrophysiol. 2001;12(8):935-938.
120
140
160
180
The Role of Pacing as Therapy for Syncope

VVS with +HUT and cardioinhibitory response:
Class IIb indication for pacing

Three randomized, prospective trials reported benefits
of pacing in select VVS patients:
• VPS I1
• VASIS2
• SYDIT3

Subsequent study results less clear
• VPS II4
• Synpace5
• INVASY6
1Connolly
SJ. J Am Coll Cardiol. 1999;33:16-20.
2Sutton R. Circulation. 2000;102:294-299.
3Ammirati F. Circ. 2001;104:52-57.
4Connolly
S. JAMA. 2003;289:2224-2229.
F. PACE . 2003;26:1016 (abstract).
6Occhetta E, et al. Europace. 2004;6:538-547.
5Giada
VPS I
(North American Vasovagal Pacemaker Study)

Objective: To evaluate pacemaker therapy for severe recurrent
vasovagal syncope

Randomized, prospective, single center

N=54 patients
• 27: DDD pacemaker with rate drop response
• 27: No pacemaker

Inclusion: Vasodepressor response

Primary outcome: First recurrence of syncope
Connolly SJ. J Am Coll Cardiol. 1999;33:16-20.
VPS I
(North American Vasovagal Pacemaker Study)
100
Cumulative Risk (%)
90
80
No Pacemaker (PM)
70
60
2P=0.000022
50
40
30
Pacemaker
20
10
0
0
3
6
9
Time in Months
12
Results:
 6 (22%) with PM had recurrence vs. 19 (70%) without PM
 84% RRR (2p=0.000022)
Connolly SJ. J Am Coll Cardiol. 1999;33:16-20.
15
VASIS
(VAsovagal Syncope International Study)

Objective: To evaluate pacemaker therapy for severe
cardioinhibitory tilt-positive neurally mediated syncope

Randomized, prospective, multi-center

N=42 patients
• 19: DDI pacemaker (80 bpm) with rate hysteresis (45 bpm)
• 23: No pacemaker

Inclusion: Positive cardioinhibitory response

Primary outcome: First recurrence of syncope
Sutton R. Circulation. 2000;102:294-299.
VASIS
(VAsovagal Syncope International Study)
Pacemaker (PM)
% Syncope-Free
100
80
p=0.0004
60
40
No Pacemaker
20
0
2
3
4
5
Years
Results:
 1 (5%) with PM had recurrence vs. 14 (61%) without PM
Sutton R. Circulation. 2000;102:294-299.
6
SYDIT
(SYncope DIagnosis and Treatment)

Objective: To compare the effects of cardiac pacing
with pharmacological therapy in patients with
recurrent vasovagal syncope

Randomized, prospective, multi-center

N=93 patients
• 46: DDD pacemaker with rate drop response
• 47: Atenolol 100 mg/d

Inclusion: Positive HUT with relative bradycardia

Primary outcome: First recurrence of syncope
Ammirati F. Circulation. 2001;104:52-57.
SYDIT
(SYncope DIagnosis and Treatment)
1.0
% Syncope-Free
Pacemaker (PM)
0.9
p=0.0032
0.8
0.7
Drug
0.6
0
100
200
300
400
500
600
700
800
900
1000
Time (Days)
Results:
 2 (4%) with PM had syncope recurrence vs. 12 (26%) without PM
Ammirati F. Circulation. 2001;104:52-57.
VPS II
(Vasovagal Pacemaker Study II)

Objective: To determine if pacing therapy reduces the risk
of syncope in patients with vasovagal syncope

Randomized, double-blind, prospective, multi-center

N=100 patients
• 52: Only sensing without pacing
• 48: DDD pacemaker with rate drop response

Inclusion: Positive HUT with (HRxBP) < 6000/min x mm Hg

Primary outcome: First recurrence of syncope
Connolly S. JAMA. 2003;289:2224-2229.
VPS II
(Vasovagal Pacemaker Study II)
1.0
Cumulative Risk
0.8
0.6
Only Sensing Without
Pacing (ODO)
0.4
Dual Chamber Pacing
(DDD)
0.2
0
0
1
2
3
4
Months Since Randomization
5
Results:
 33% with pacing had recurrence vs. 42% with only sensing
(not statistically significant)
Connolly S. JAMA. 2003;289:2224–2229.
6
SYNPACE
(Vasovagal SYNcope and PACing)

Objective: To determine if pacing therapy will reduce syncope
relapses in patients with recurrent vasovagal syncope,
compared to those with a pacemaker programmed to OFF

Randomized, double-blind, prospective, multi-center,
placebo-controlled

N=29 patients
• 16: DDD PM with rate drop response programmed ON
• 13: PM programmed OFF (OOO mode)

Inclusion: Recurrent VVS and +HUT with asystolic
or mixed response

Primary outcome: First recurrence of syncope
Raviele A.. Europace. 2001;3:336–341.
Raviele A, et al. Eur Heart J. 2004;25:1741-1748.
SYNPACE
(Vasovagal SYNcope and PACing)
1.0
p=0.58
0.9
% Syncope-Free
0.8
0.7
Pacemaker OFF
0.6
0.5
Pacemaker ON
0.4
0.3
0.2
0.1
0.0
0
200
400
600
800
Days Since Randomization
Results:
 50% with pacing ON had recurrence vs. 38% with pacing OFF
(not statistically significant)
Raviele A, et al. Eur Heart J. 2004;25:1741-1748.
1000
INVASY
(INotropy Controlled Pacing in VAsovagal Syncope)

Objective: To evaluate Closed Loop Stimulation (CLS), a form of
rate-adaptive pacing using RV impedance, in preventing
recurrence of VVS

Randomized, prospective, single-blind, multi-center

N=50 patients
• 41: CLS therapy
• 9: Control (pacemaker programmed in DDI)

Inclusion: Recurrent VVS and +HUT with cardioinhibition

Primary outcome: Recurrence of two VVSs during
a minimum of 1 year of follow-up
Occhetta E, et al. Europace. 2004;6:538-547.
INVASY
(INotropy Controlled Pacing in VAsovagal SYncope)
100
Closed Loop Stimulation (CLS)
% Syncope-Free
0
60
P < 0.0001
40
Control (DDI only)
20
3m
6m
9m
1y
2y
3y
Time Since Randomization
Results:
 Patients with CLS had no syncope recurrence and improved quality of life
Occhetta E, et al. Europace. 2004;6:538-547.
Role of Pacing as Therapy for Syncope: Summary

Three earlier studies single blind – Bias?

Pacemaker implantation may modulate reflex syncope
and autonomic responses1

Study results may differ based on pre-implant selection
criteria and tilt-testing techniques

Pacing therapy is effective in some but not all (cardioinhibition
vs. vasodepression)

In five pacing studies, syncope recurred in 33/156
(21%) of paced patients, 72/162 (44%) in non-paced
patients (p<0.000)2
1Kapoor
W. JAMA. 2003;289:2272-2275.
M, et al.. Europace. 2004;6:467-537.
2Brignole
CSS
Carotid Sinus Syndrome

Syncope clearly associated with carotid sinus stimulation is
rare (≤1% of syncope)

CSS may be an important cause of unexplained syncope/falls
in older individuals

Prevalence higher than previously believed

Carotid Sinus Hypersensitivity (CSH)
• No symptoms
• No treatment
Kenny RA, et al. J Am Coll Cardiol. 2001;38:1491-1496.
Brignole M, et al. Europace. 2004;6:467-537.
Sutton R. In: Neurally Mediated Syncope: Pathophysiology, Investigation and Treatment. Blanc JJ, et al. eds. Armonk, NY: Futura;1996:138.
CSS
Etiology

Sensory nerve endings in
the carotid sinus walls respond
to deformation

“Deafferentation” of neck
muscles may contribute

Increased afferent signals to
brain stem

Reflex increase in efferent vagal
activity and diminution of
sympathetic tone results in
bradycardia and vasodilatation
Carotid Sinus
Falls:
Incidence, Recurrence, CSH*
75
50% 1
50
30% 1
23% 2
25
0
Incidence
> Age 65
*Carotid Sinus Hypersensitivity
1J
2
Am Geriatr Soc. 1995.
Richardson D, et al. PACE. 1997;20:820.
Recurrence
CSH* Present
in Fallers > Age 50
Presenting at ER
CSS
Role of Pacing – Syncope Recurrence Rate


Class I indication for pacing
(AHA and BPEG)
Limit pacing to CSS
that is:
• Cardioinhibitory
• Mixed
DDD/DDI superior to VVI
• Mean follow-up = 6 months
75
57%
50
25
%6

0
No Pacing
Brignole M, et al. Eur JCPE. 1992;4:247-254.
Pacing
SAFE PACE
Syncope And Falls in the Elderly – Pacing And Carotid Sinus Evaluation


Objective

Results
• Determine whether cardiac
• More than 1/3 of adults over
pacing reduces falls in
older adults with carotid
sinus hypersensitivity
50 years presented to the
Emergency Department
because of a fall
Randomized controlled
trial (N=175)
• Adults > 50 years,
non-accidental fall,
positive CSM
• Pacing (n=87) vs.
No Pacing (n=88)
Kenny RA. J Am Coll Cardiol. 2001;38:1491-1496.
• With pacing, falls  70%
• Syncopal events  53%
• Injurious events  70%
SAFE PACE

Conclusions
• Strong association between non-accidental falls and
cardioinhibitory CSH
• These patients usually not referred for cardiac assessment
• Cardiac pacing significantly reduced subsequent falls
• CSH should be considered in all older adults who have
non-accidental falls
Kenny RA, J Am Coll Cardiol. 2001; 38:1491-1496.
Orthostatic Hypotension

Etiology

Drug-induced (very common)
• Diuretics
• Vasodilators

Primary autonomic failure
• Multiple system atrophy
• Parkinson’s Disease
• Postural Orthostatic Tachycardia
Syndrome (POTS)
Brignole M, et al. Europace, 2004;6:467-537.

Secondary autonomic failure
• Diabetes
• Alcohol
• Amyloid
Treatment Strategies for Orthostatic Intolerance

Patient education, injury avoidance

Hydration
• Fluids, salt, diet
• Minimize caffeine/alcohol

Sleeping with head of bed elevated

Tilt training, leg crossing, arm pull

Support hose

Drug therapies
• Fludrocortisone, midodrine, erythropoietin

Tachy-Pacing (probably not useful)
Brignole M, et al. Europace, 2004;6:467-537.
Section IV:
Special Issues
Syncope:
Diagnostic Testing in Hospital Strongly Recommended

Suspected/known ‘significant’ heart disease

ECG abnormalities suggesting potential life-threatening
arrhythmic cause

Syncope during exercise

Severe injury or accident

Family history of premature sudden death
Brignole M, et al. Europace. 2004;6:467-537.
SEEDS:
Syncope Evaluation in the Emergency Department Study
Long-Term Clinical Outcomes
Survival Free from Death
Survival Free from Recurrence
100%
100%
90%
90%
Syncope Unit Group
80%
Syncope Unit Group
80%
Standard Care Group
Standard Care Group
P=0.30
P=0.72
70%
70%
0
1
Years
2
0
1
Years
Results:
 Syncope unit improved diagnostic yield in the ED and reduced
hospital admission and length of stay
Shen W, et al. Circ. 2004;110(24):3636-3645.
2
The Integrated Syncope Unit

To optimize the effectiveness of the evaluation and treatment
of syncope patients at a given center

Best accomplished by:
• Cohesive, structured care pathway
• Multidisciplinary approach
• Core equipment available
• Preferential access to other tests or therapy

Majority of syncope evaluations – Out-patient or day cases
1Kenny
RA, Brignole M. In: Benditt D, et al. eds. The Evaluation and Treatment of Syncope. Futura;2003:55-60.
M, et al. Europace, 2004;6:467-537.
2Brignole
Conclusion

Syncope is a common symptom with many causes

Deserves thorough investigation and appropriate treatment

A disciplined approach is essential

ESC guidelines offer current best practices
Brignole M, et al. Europace, 2004;6:467-537.
Challenges of Syncope

Cost

Quality of life implications

Diagnosis and treatment
• Diagnostic yield and repeatability of tests
• Frequency and clustering of events
• Difficulty in managing/treating/controlling future events
• Appropriate risk stratification
• Complex etiology
Olshansky B. In: Grubb B and Olshansky B. eds. Syncope: Mechanisms and Management. Futura. 1998:15-71.
Brignole M, et al. Europace, 2004;6:467-537.
Brief Statement
Indications
9526 Reveal® Plus Insertable Loop Recorder
The Reveal Plus ILR is an implantable patient- and automatically activated monitoring system that records subcutaneous ECG and is indicated for
Patients with clinical syndromes or situations at increased risk of cardiac arrhythmias
Patients who experience transient symptoms that may suggest a cardiac arrhythmia
6191 Activator
The Model 6191 Activator is intended for use in combination with a Medtronic Model 9526 Reveal Plus Insertable Loop Recorder.
Contraindications
There are no known contraindications for the implantation of the Reveal Plus ILR. However, the patient’s particular medical condition may dictate
whether or not a subcutaneous, chronically implanted device can be tolerated.
Warnings/Precautions
9526 Reveal Plus Insertable Loop Recorder
Patients with the Reveal Plus ILR should avoid sources of magnetic resonance imaging, diathermy, high sources of radiation, electrosurgical cautery,
external defibrillation, lithotripsy, and radiofrequency ablation to avoid electrical reset of the device, and/or inappropriate sensing.
6191 Activator
Operation of the Model 6191 Activator near sources of electromagnetic interference, such as cellular phones, computer monitors, etc., may adversely
affect the performance of this device.
Potential Complications
Potential complications include, but are not limited to, body tissue rejection phenomena, including local tissue reaction, infection, device migration and
erosion of the device through the skin.
2090 Programmer
The Medtronic/Vitatron CareLink programmer system is comprised of prescription devices indicated for use in the interrogation and programming of
implantable medical devices. Prior to use, refer to the Programmer Reference Guide as well as the appropriate programmer software and implantable
device technical manuals for more information related to specific implantable device models. Programming should be attempted only by appropriately
trained personnel after careful study of the technical manual for the implantable device and after careful determination of appropriate parameter values
based on the patient's condition and pacing system used. The Medtronic/Vitatron CareLink programmer must be used only for programming implantable
devices manufactured by Medtronic or Vitatron.
See the device manual for detailed information regarding the implant procedure, indications, contraindications, warnings, precautions, and potential
complications/adverse events. For further information, please call Medtronic at 1-800-328-2518 and/or consult Medtronic’s website at
www.medtronic.com. To learn more about syncope, visit www.fainting.com.
Caution: Federal law (USA) restricts this device to sale by or on the order of a physician.