Syncope A Diagnostic and Treatment Strategy

1
SyncopeA Diagnostic and Treatment Strategy
David G. Benditt, M.D.University of Minnesota
Medical SchoolMinneapolis, MN USA
Richard Sutton, DScMed Royal Brompton Hospital
London, UK
2
Transient Loss of Consciousness (TLOC)
3
Classification of Transient Loss of Consciousness
(TLOC)
Real or Apparent TLOC

• Syncope
• Neurally-mediated reflex syndromes
• Orthostatic hypotension
• Cardiac arrhythmias
• Structural cardiovascular disease

• Disorders Mimicking Syncope
• With loss of consciousness, i.e., seizure
  disorders, concussion
• Without loss of consciousness, i.e., psychogenic
  pseudo-syncope

Brignole M, et al. Europace, 20046467-537.
4
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, 20046467-537.
5
Presentation Overview

• I. Etiology, Prevalence, Impact
• II. Diagnosis
• III. Specific Conditions and Treatment
• IV. Special Issues

6
Section IEtiology, Prevalence, Impact
7
Causes of True Syncope
Orthostatic
Cardiac Arrhythmia
Structural Cardio- Pulmonary
Neurally- Mediated

• 3
• Brady
• SN Dysfunction
• AV Block
• Tachy
• VT
• SVT
• Long QT Syndrome

• 1
• VVS
• CSS
• Situational
• Cough
• Post-
• Micturition

• 2
• Drug-Induced
• ANS Failure
• Primary
• Secondary

• 4
• Acute Myocardial Ischemia
• Aortic Stenosis
• HCM
• Pulmonary Hypertension
• Aortic Dissection

Unexplained Causes Approximately 1/3
DG Benditt, MD. U of M Cardiac Arrhythmia Center
8
Syncope Mimics

• Acute intoxication (e.g., alcohol)
• Seizures
• Sleep disorders
• Somatization disorder (psychogenic
  pseudo-syncope)
• Trauma/concussion
• Hypoglycemia
• Hyperventilation

Brignole M, et al. Europace, 20046467-537.
9
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 61eg, fractures,
  motor vehicle accidents
• Minor injury in 291eg, lacerations, bruises

1Kenny RA, Kapoor WN. In Benditt D, et al. eds.
The Evaluation and Treatment of Syncope.
Futura200323-27. 2Kapoor W. Medicine.
199069160-175.
3Brignole M, et al. Europace. 20035293-298. 4
Blanc J-J, et al. Eur Heart J.
200223815-820. 5Campbell A, et al. Age and
Ageing. 198110264-270.
10
Impact of Syncope US Trends
Inpatient Trend
Physician Office Visits
(000s)
(000s)
All patients discharged with syncope and
collapse (ICD-9 Code780.2) listed among
diagnoses.
Syncope and collapse (ICD-9 Code 780.2)
listed as primary reason for visit.
NHDS 2003.
NAMCS 2002.
11
Impact of Syncope US Trends
HospitalOutpatient Visits
EmergencyDepartment Visits
(000s)
(000s)

Not available
Syncope and collapse (ICD-9 Code780.2) listed
as primary reason for visit.
NHAMCS 2002.
12
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.
13
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.
Futura200323-27. 2OutPatientView v. 6.0.
Solucient LLC, Evanston IL. 3Farwell D, et al. J
Cardiovasc Electrophysiol. 200213(Supp)S9-S13. 4
Olshansky B. In Grubb B and Olshansky B. eds.
Syncope Mechanisms and Management. Futura.
199815-71.
14
Impact of Syncope Quality of Life
731
712
602
Percent of Patients
372
Anxiety/Depression
Alter DailyActivities
RestrictedDriving
ChangeEmployment
1Linzer M. J Clin Epidemiol. 1991441037. 2Linzer
M. J Gen Int Med. 19949181.
15
Quality of Life UK Population Norms vs. Syncope
Patients
49
43
37
36
26
Prevalence
19
9
4
3
1
Mobility
Usual Activities
Self-Care
Pain/Discomfort
Anxiety/Depression
Rose M, et al. J Clin Epidemiol.
2000531209-1216.
16
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. 2002347(12)878-885. Framingham Study
Population
17
Implications of Syncope for Driving a Vehicle

• Those who drive and have recurrent syncope risk
  their lives and the lives of others
• Places considerable burden on the physician
• Essential to know local laws and physician
  responsibilities
• Some states Invasion of privacy to notify motor
  vehicle department
• Other states Reporting is mandatory

• If the patient has sufficient warning of
  impending syncope Driving may be permitted

Olshansky B, Grubb B. In Syncope Mechanisms and
Management. Futura. Armonk, NY. 1998. Medtronic,
Inc. Follow-up Forum. 1995/961(3)8-10.
18
Challenges of Syncope

• Diagnosis
• Complex
• Quality of life implications
• Work
• Mobility (automobiles)
• Psychological
• Cost
• Cost/year
• Cost/diagnosis

19
Section IIDiagnosis
20
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

21
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, 20046467-537.
22
Diagnostic Flow Diagram for TLOC
Brignole M, et al. Europace, 20046467-537.
23
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, 20046467-537.
24
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, 20046467-537.
25
Carotid Sinus Massage (CSM)

• Method1
• Massage, 5-10 seconds
• Dont 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

• Absolute contraindications2
• Carotid bruit, known significant carotid arterial
  disease, previous CVA, MI last 3 months
• Complications
• Primarily neurological
• Less than 0.23
• Usually transient

1Kenny RA. Heart. 200083564.2Linzer M. Ann
Intern Med. 1997126989. 3Munro N, et al. J Am
Geriatr Soc. 1994421248-1251.
26
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, 20046467-537.
27
Heart Monitoring Options
OPTION
10 Seconds
12-Lead
2 Days
Holter Monitor
Event Recorders(non-lead and loop)
7-30 Days
Up to 14 Months
ILR
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
TIME (Months)
Brignole M, et al. Europace, 20046467-537.
28
Diagnostic Assessment Yields (N3411 to 4332)
References Available
29
Neurological Tests Rarely Diagnostic for Syncope

• EEG, Head CT, Head MRI
• May help diagnose seizure

Brignole M, et al. Europace. 20046467-537.
30
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. 20046467-537.
31
Head-up Tilt Test
Click once on image to play video.
Carlos Morillo, MD, FRCPC Professor, Faculty of
Health Sciences McMaster University, Hamilton
Ontario
32
Head-Up Tilt TestECG Leads and Intra-Arterial
Pressure Tracing
2
1
DG Benditt, MD. U of M Cardiac Arrhythmia Center
33
Adenosine Triphosphate (ATP) Test

• Ongoing investigation in the US
• Provokes a short and potent cardioinhibitory
  vasovagal response
• Advantages
• Simple
• Inexpensive
• Correlation with pacing benefit

• Seems to identify a unique mechanism of syncope
  found in patients with
• Advanced age
• More hypertension
• More ECG abnormalities

Brignole M. Heart. 20008324-28. Donateo P.
J Am Coll Cardiol. 20034193-98. Flammang D.
Circ. 1999992427-2433.
34
Insertable Loop Recorder (ILR)
Click once on black screen to play video.
Reveal Plus ILR
Typical Location of theReveal Plus ILR
35
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

36
Insertable Loop Recorder (ILR)
Click once on black screen to play video.
37
Symptom-Rhythm Correlation with the ILR
CASE 56 year-old woman with refractory syncope
accompanied with seizures.
CASE 65 year-old man with syncope accompanied by
brief retrograde amnesia.
Medtronic data on file.
38
Randomized Assessment of Syncope Trial (RAST)

• 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. 200110446-51. 2Krahn
AD, et al. JACC. 200342495-501.
39
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 gt 3000 ms or CSNRT gt 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. Lippencott20021529-1542
. Lu F, et al. In Benditt D, et al. The
Evaluation and Treatment of Syncope. Futura.
200380-95. Brignole M, et al. Europace.
20046467-537.
40
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 M, et al. Ann Int Med. 199712776-86. 2Lu
F, et al. In Benditt D, et al. The Evaluation
and Treatment of Syncope. Futura. 200380-95.
41
ISSUEInternational 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
• Isolated syncope No SHD, Normal ECG1
• Negative tilt
• Positive tilt
• Patients with heart disease and negative EP test2
• Patients with bundle branch block and negative EP
  test3

1Moya A. Circulation. 2001 1041261-1267.
2Menozzi C, et al. Circulation.
20021052741-2745. 3Brignole M, et al.
Circulation. 20011042045-2050.
42
ISSUEPatients with Isolated Syncope and
Tilt-Positive Syncope

Moya A. Circulation. 20011041261-1267.
43
ISSUEIsolated 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) astilt-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. 20011041261-1267.
44
ISSUE Patients with Heart Disease and a Negative
EP Test
AV block asystole 1 A.Fib asystole 1 Sinus
arrest 1 Sinus tachycardia 1 Rapid A.Fib 2
Sustained VT 1 Parox. A.Fib/AT 1 Post
tachycardia pause 1 No rhythm variations
4 Sinus tachycardia 1
Menozzi C, et al. Circulation.
20021052741-2745.
45
ISSUEPatients 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.
20021052741-2745.
46
ISSUEPatients with Bundle Branch Block and
Negative EP Test
ILR-DetectedPre-Syncope2 Pts (4)
ILR-Detected 19
Not Detected 3
AVB 2 (4)
AVB 12 (63) SA 4 (21) Asystole-undefined 1
(5) NSR 1 (5) Sinus tachy 1 (5)
5 of these also had 1 presyncope Drop-out
before primary-end point
Brignole M., ET AL.,Circulation.
20011042045-2050.
47
ISSUEPatients 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. 20011042045-2050.
48
Section IIISpecific Conditions and Treatment
49
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

50
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. 20046467-537.
51
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

Soteriades ES, et al. N Engl J Med. 2002347878.
52
Syncope Due to Structural Cardiovascular Disease
Principle Mechanisms

• Acute MI/Ischemia
• 2 neural reflex bradycardia 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

• Pulmonary embolus/pulmonary hypertension
• Neural reflex, inadequate flow with exertion
• Valvular abnormalities
• Aortic stenosis Limited output, neural reflex
  dilation in periphery
• Mitral stenosis, atrial myxoma Obstruction to
  adequate flow

Brignole M, et al. Europace. 20046467-537.
53
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. 20046467-537.
54
ILR Recordings
CASE 28 year-old man presents to ER multiple
times after falls resulting in trauma. VT
Ablated and medicated.
CASE 83 year-old woman with syncope due to
bradycardia Pacemaker implanted.
Reveal ILR recordings Medtronic data on file.
55
Cardiac Rhythms During Unexplained Syncope
Composite N133 to 7109
Bradycardia 16(11-21)
No Recurrence 36(31-48)
Arrhythmia 22(13-32)
Tachycardia 6(2-11)
Other 11
Normal Sinus Rhythm 31(17-44)
Seidl K. Europace. 20002(3)256-262. Krahn AD.
PACE. 20022537-41. Medtronic ILR Replacement
Data. FY03, 04. On file.
56
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.
Saunders2004651-659.
57
Syncope Torsade de Pointes
From the files of DG Benditt, MD. U of M Cardiac
Arrhythmia Center
58
Long QT Syndromes 12-Lead ECG
From the files of DG Benditt, MD. U of M Cardiac
Arrhythmia Center
59
Drug-Induced QT Prolongation(List is
continuously being updated)

• Antiarrhythmics
• Class IA ...Quinidine, Procainamide, Disopyramide
• Class IIISotalol, Ibutilide, Dofetilide,
  Amiodarone, NAPA
• Antianginal Agents
• Bepridil
• Psychoactive Agents
• Phenothiazines, Amitriptyline, Imipramine,
  Ziprasidone

• Antibiotics
• Erythromycin, Pentamidine, Fluconazole,
  Ciprofloxacin and its relatives
• Nonsedating antihistamines
• Terfenadine, Astemizole
• Others
• Cisapride, Droperidol, Haloperidol

Removed from U.S. Market
Brignole M, et al. Europace, 20046467-537.
60
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.
Saunders2004651-659.
61
Treatment of Syncope Due to Bradyarrhythmia

• Class I indication for pacing using dual chamber
  system wherever possible
• Ventricular pacing in atrial fibrillation with
  slow ventricular response

ACC/AHA/NASPE 2002 Guideline Update. Circ.
20021062145-2161.
62
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. 20046467-537.
63
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, 20046467-537.
64
Pathophysiology
Autonomic Nervous System
Benditt D, et al. Neurally mediated syncope
Pathophysiology, investigations and treatment.
Blanc JJ, et al. eds. Futura. 1996.
65
VVSClinical 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.
200311-22.
66
VVSIncidence

• 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. 1997126989.
67
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. 1997126989.
68
VVS Recurrences

• 35 of patients report syncope recurrence during
  follow-up 3 years1
• Positive HUT with gt6 lifetime syncope episodes
  recurrence risk gt50 over 2 years2

1Savage D, et al. STROKE. 198516626-29.
2Sheldon R, et al. Circulation. 199693973-81.
69
VVS Spontaneous
16 year-old male, healthy, athletic, monitored
for fainting.
From the files of DG Benditt, MD. U of M Cardiac
Arrhythmia Center
70
VVSDiagnosis

• History and physical exam, ECG and BP
• Head-Up Tilt (HUT) Protocol
• Fast gt 2 hours
• ECG and continuous blood pressure, supine, and
  upright
• Tilt to 70, 20 minutes
• Isoproterenol/Nitroglycerin if necessary
• End point Loss of consciousness

60 - 80
Benditt D, et al. JACC. 199628263-275. Brignole
M, et al. Europace, 20046467-537.
71
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

• Long-term prevention
• Tilt training
• Education
• Diet, fluids, salt
• Support hose
• Drug therapy
• Pacing

Brignole M, et al. Europace, 20046467-537.
72
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. 200023(4 Pt.
1)493-498.
73
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. 200023493-498.
74
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.
20046199-204.
75
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, 20046467-537. 2Di
Girolamo E, et al. JACC. 1999331227-1230. 3Ravi
ele A, et al. Circ. 1999991452-1457.
4Ward C, et al. Heart. 19987945-49. 5Perez-Lugon
es A, et al. J Cardiovasc Electrophysiol.
200112(8)935-938.
76
Midodrine for VVS
Midodrine
Symptom-Free Interval
Fluid
p lt 0.001
0
Months
Perez-Lugones A, Schweikert R, Pavia S, et al. J
Cardiovasc Electrophysiol. 200112(8)935-938.
77
The Role of Pacing as Therapy for Syncope

• VVS with HUT and cardioinhibitory
  responseClass 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

4Connolly S. JAMA. 20032892224-2229. 5Giada F.
PACE . 2003261016 (abstract). 6Occhetta E, et
al. Europace. 20046538-547.
1Connolly SJ. J Am Coll Cardiol.
19993316-20. 2Sutton R. Circulation.
2000102294-299. 3Ammirati F. Circ.
200110452-57.
78
VPS I (North American Vasovagal Pacemaker Study)

• Objective To evaluate pacemaker therapy for
  severe recurrent vasovagal syncope
• Randomized, prospective, single center
• N54 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. 19993316-20.
79
VPS I (North American Vasovagal Pacemaker Study)
100
90
80
No Pacemaker (PM)
70
60
2P0.000022
Cumulative Risk ()
50
40
30
Pacemaker
20
10
0
0
3
6
9
12
15
Time in Months

• Results
• 6 (22) with PM had recurrence vs. 19 (70)
  without PM
• 84 RRR (2p0.000022)

Connolly SJ. J Am Coll Cardiol. 19993316-20.
80
VASIS (VAsovagal Syncope International Study)

• Objective To evaluate pacemaker therapy for
  severe cardioinhibitory tilt-positive neurally
  mediated syncope
• Randomized, prospective, multi-center
• N42 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. 2000102294-299.
81
VASIS (VAsovagal Syncope International Study)
Pacemaker (PM)
100
80
p0.0004
Syncope-Free
60
40
No Pacemaker
20
0
2
3
4
5
6
Years

• Results
• 1 (5) with PM had recurrence vs. 14 (61)
  without PM

Sutton R. Circulation. 2000102294-299.
82
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
• N93 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. 200110452-57.
83
SYDIT (SYncope DIagnosis and Treatment)
1.0
Pacemaker (PM)
0.9
Syncope-Free
p0.0032
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. 200110452-57.
84
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
• N100 patients
• 52 Only sensing without pacing
• 48 DDD pacemaker with rate drop response
• Inclusion Positive HUT with (HRxBP) lt 6000/min x
  mm Hg
• Primary outcome First recurrence of syncope

Connolly S. JAMA. 20032892224-2229.
85
VPS II (Vasovagal Pacemaker Study II)
1.0
0.8
0.6
Only Sensing Without Pacing (ODO)
Cumulative Risk
0.4
Dual Chamber Pacing (DDD)
0.2
0
2
1
0
5
4
3
6
Months Since Randomization

• Results
• 33 with pacing had recurrence vs. 42 with only
  sensing(not statistically significant)

Connolly S. JAMA. 200328922242229.
86
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
• N29 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. 20013336341. Raviele A,
et al. Eur Heart J. 2004251741-1748.
87
SYNPACE(Vasovagal SYNcope and PACing)
1.0
0.9
p0.58
0.8
0.7
Pacemaker OFF
0.6
Syncope-Free
0.5
Pacemaker ON
0.4
0.3
0.2
0.1
0.0
0
200
400
600
800
1000
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. 2004251741-1748.
88
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
• N50 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. 20046538-547.
89
INVASY(INotropy Controlled Pacing in VAsovagal
SYncope)
Closed Loop Stimulation (CLS)
P lt 0.0001
Syncope-Free
Control (DDI only)
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. 20046538-547.
90
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 (plt0.000)2

1Kapoor W. JAMA. 20032892272-2275.2Brignole M,
et al.. Europace. 20046467-537.
91
CSSCarotid 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.
2001381491-1496. Brignole M, et al. Europace.
20046467-537. Sutton R. In Neurally Mediated
Syncope Pathophysiology, Investigation and
Treatment. Blanc JJ, et al. eds. Armonk, NY
Futura1996138.
92
CSSEtiology

• Sensory nerve endings in the carotid
  sinus walls respond to deformation
• Deafferentation of neck muscles may contribute
• Increased afferent signals tobrain stem
• Reflex increase in efferent vagal activity and
  diminution of sympathetic tone results in
  bradycardia and vasodilatation

Carotid Sinus
93
FallsIncidence, Recurrence, CSH
50 1
30 1
of Population
23 2
Incidencegt Age 65
Recurrence
CSH Presentin Fallers gt Age 50Presenting at ER
Carotid Sinus Hypersensitivity
1 J Am Geriatr Soc. 1995. 2 Richardson D, et al.
PACE. 199720820.
94
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

57
Recurrence
6
Brignole M, et al. Eur JCPE. 19924247-254.
95
SAFE PACESyncope And Falls in the Elderly
Pacing And Carotid Sinus Evaluation

• Objective
• Determine whether cardiac pacing reduces falls in
  older adults with carotid sinus
  hypersensitivity
• Randomized controlled trial (N175)
• Adults gt 50 years, non-accidental fall,
  positive CSM
• Pacing (n87) vs. No Pacing (n88)

• Results
• More than 1/3 of adults over 50 years presented
  to the Emergency Department because of a fall
• With pacing, falls ? 70
• Syncopal events ? 53
• Injurious events ? 70

Kenny RA. J Am Coll Cardiol. 2001381491-1496.
96
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 381491-1496.
97
Orthostatic Hypotension

• Etiology
• Drug-induced (very common)
• Diuretics
• Vasodilators
• Primary autonomic failure
• Multiple system atrophy
• Parkinsons Disease
• Postural Orthostatic Tachycardia Syndrome (POTS)

• Secondary autonomic failure
• Diabetes
• Alcohol
• Amyloid

Brignole M, et al. Europace, 20046467-537.
98
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, 20046467-537.
99
Section IV

• Special Issues

100
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. 20046467-537.
101
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
Syncope Unit Group
80
80
Standard Care Group
Standard Care Group
P0.30
P0.72
70
70
2
1
0
2
1
0
Years
Years

• Results
• Syncope unit improved diagnostic yield in the ED
  and reducedhospital admission and length of stay

Shen W, et al. Circ. 2004110(24)3636-3645.
102
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.
Futura200355-60. 2Brignole M, et al. Europace,
20046467-537.
103
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, 20046467-537.
104
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.
199815-71. Brignole M, et al. Europace,
20046467-537.
105
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
  patients 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 Medtronics website
  at www.medtronic.com. To learn more about
  syncope, visit www.fainting.com.