Syncope Diagnostic and Treatment Strategy

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					                              Syncope
                         A Diagnostic and
                        Treatment Strategy


  David G. Benditt, M.D.                 Richard Sutton, DScMed
University of Minnesota Medical School      Royal Brompton Hospital
         Minneapolis, MN USA                      London, UK
Transient Loss of Consciousness (TLOC)
Classification of Transient Loss of Consciousness (TLOC)



                                               Real or Apparent TLOC



                       Syncope                                 Disorders Mimicking
     • Neurally-mediated reflex                                     Syncope
        syndromes                                          • With loss of consciousness, i.e.,
     • Orthostatic hypotension                               seizure disorders, concussion

     • Cardiac arrhythmias                                 • Without loss of consciousness,
                                                             i.e., psychogenic “pseudo-
     • Structural cardiovascular                             syncope”
        disease


Brignole M, et al. Europace, 2004;6:467-537.
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


                                                                          Structural
     Neurally-                                            Cardiac
                                         Orthostatic                       Cardio-
     Mediated                                            Arrhythmia
                                                                          Pulmonary


            1                                      2           3                4
  • VVS                                 • Drug-Induced   • Brady          • Acute
  • CSS                                 • ANS Failure      SN              Myocardial
                                                            Dysfunction     Ischemia
  • Situational                             Primary
                                                           AV Block      • Aortic
      Cough                                Secondary
                                                         • Tachy            Stenosis
      Post-
                                                           VT            • HCM
       Micturition
                                                           SVT           • Pulmonary
                                                         • Long QT          Hypertension
                                                           Syndrome       • Aortic
                                                                            Dissection



                            Unexplained Causes = Approximately 1/3
DG Benditt, MD. U of M Cardiac Arrhythmia Center
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   3BrignoleM, et al. Europace. 2003;5:293-298.
 Treatment of Syncope. Futura;2003:23-27.                             4Blanc J-J, et al. Eur Heart J. 2002;23:815-820.
2Kapoor W. Medicine. 1990;69:160-175.                                 5Campbell A, et al. Age and Ageing. 1981;10:264-270.
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            '96     '97      '98       '99      '00      '01

          *All patients discharged with syncope and collapse            **Syncope and collapse (ICD-9 Code: 780.2)
          (ICD-9 Code:780.2) listed among diagnoses.                    listed as primary reason for visit.
          NHDS 2003.                                                    NAMCS 2002.
Impact of Syncope: US Trends

                        Emergency                                                          Hospital
                     Department Visits*                                                Outpatient Visits*
 (000s)                                                        (000s)
900                                                               80




                                                                  70
800



                                                                  60

700

                                                                  50



600
                                                                  40



                                                                                          +
500                                                               30
      '96      '97    '98     '99    '00     '01    '02                  '96     '97      '98   '99   '00   '01   '02

          *Syncope and collapse (ICD-9 Code:780.2) listed as            + Not available
           primary reason for visit.
           NHAMCS 2002.
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.
2OutPatientView    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.
Impact of Syncope: Quality of Life



               100
                                      73%1
                 80                                 71%2
                                                                  60%2
                 60
                                                                               37%2
                 40

                 20

                   0
                               Anxiety/        Alter Daily   Restricted     Change
                              Depression       Activities     Driving     Employment




1Linzer   M. J Clin Epidemiol. 1991;44:1037.
2Linzer   M. J Gen Int Med. 1994;9:181.
Quality of Life:
UK Population Norms vs. Syncope Patients


                                                                                49%
               50         UK Population Norms
                          Patients with Syncope                                              43%

               40                                     37%                36%
% Prevalence




               30              26%

                                                                                      19%
               20

                                                                   9%
               10
                      3%                        4%
                                                             1%
                0
                      Mobility                 Usual        Self-Care      Pain/       Anxiety/
                                              Activities                Discomfort    Depression



Rose M, et al. J Clin Epidemiol. 2000;53:1209-1216.
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                                            If the patient has sufficient
  recurrent syncope risk their                                          warning of impending syncope
  lives and the lives of others                                         – Driving may be permitted
 Places considerable burden
  on the physician
 Essentialto know local laws
  and physician responsibilities
 Some   states – Invasion of
  privacy to notify motor
  vehicle department*
    • 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                                                       Not Syncope

     Certain                    Suspected                                        Unexplained
    Diagnosis                   Diagnosis                                         Syncope



                      Cardiac         Neurally-Mediated or      Frequent or Severe             Single/Rare    Confirm with
                       Likely          Orthostatic Likely           Episodes                    Episodes     Specific Test or
                                                                                                               Specialist
                                                                                                              Consultation

                      Cardiac          Tests for Neurally-      Tests for Neurally-            No Further
                       Tests           Mediated Syncope         Mediated Syncope               Evaluation




                  +             -          +          -           +              -

                                                 Re-Appraisal             Re-Appraisal

        Treatment                       Treatment               Treatment                                     Treatment


Brignole M, et al. Europace, 2004;6:467-537.
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                                                Absolute contraindications2
      • Massage, 5-10 seconds                               • Carotid bruit, known significant
                                                              carotid arterial disease,
      • Don‟t occlude                                         previous CVA, MI last 3 months
      • Supine and upright posture
          (on tilt table)
                                                           Complications
                                                            • Primarily neurological
   Outcome
                                                            • Less than 0.2%3
      • 3 second asystole and/or
          50 mmHg fall in systolic BP                       • Usually transient
          with reproduction of symptoms
          = Carotid Sinus Syndrome




1Kenny RA. Heart. 2000;83:564.
2LinzerM. Ann Intern Med. 1997;126:989.
3Munro N, et al. J Am Geriatr Soc. 1994;42:1248-1251.
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
                   ILR                                                                                Months


                         0       1       2       3   4   5     6   7    8    9   10   11   12   13   14


                                                             TIME (Months)




  Brignole M, et al. Europace, 2004;6:467-537.
Diagnostic Assessment: Yields
 (N=3411 to 4332)


                                                             Yield (%)
           Initial Evaluation

              History, Physical Exam, ECG, Cardiac Massage
                                                               38-40
           Other Tests/Procedures
              Head-Up Tilt                                      27
              External Cardiac Monitoring                      5-13
              Insertable Loop Recorder (ILR)                 43-883-5
              EP Study                                         <2-5
              Exercise Test                                     0.5
              EEG                                             0.3-0.5
                                                              No data
              MRI
                                                             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
                                               60° - 80°
   Useful in teaching patients
    to recognize prodromal
    symptoms
   Not useful in assessing
    treatment




Brignole M, et al. Europace. 2004;6:467-537.
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                         Seems to identify a unique
    in the US                                      mechanism of syncope found
                                                   in patients with:
   Provokes a short and
    potent cardioinhibitory                        • Advanced age
    vasovagal response                             • More hypertension
   Advantages                                     • More ECG abnormalities
     • 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.
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
Symptom-Rhythm Correlation with the ILR




  CASE: 56 year-old woman with     CASE: 65 year-old man with
  refractory syncope accompanied   syncope accompanied by brief
  with seizures.                   retrograde amnesia.


Medtronic data on file.
Randomized Assessment of Syncope Trial (RAST)

                                                                         60 Patients
                                                                  Unexplained Syncope
                                                                       EF > 35%



                               30 Patients                                                           30 Patients
                                                                                                     Conventional
         Primary                       ILR                                                             Testing
         Strategy                                                   14                 6           (AECG, Tilt, EPS)
                                                        +                Diagnosis             +
                                   –                                                                           –
                                                                     1                 8

                                                            +                              +
     Crossover                   AECG, Tilt,                                                             ILR
                                  EP Study

                       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   M, et al. Ann Int Med. 1997;127:76-86.
2Lu   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.
2Menozzi  C, et al. Circulation. 2002;105:2741-2745.
3Brignole M, et al. Circulation. 2001;104:2045-2050.
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
                                                               29: Tilt-Positive
                   “Isolated Syncope”




                                    Follow-Up to Recurrent
                                     Spontaneous Episode

Moya A. Circulation.
2001;104:1261-1267.
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                                        Sustained VT: 1
            A.Fib + asystole: 1                                           Parox. A.Fib/AT: 1
            Sinus arrest: 1                                               Post tachycardia pause: 1
            Sinus tachycardia: 1                                          No rhythm variations: 4
            Rapid A.Fib: 2                                                Sinus tachycardia: 1



Menozzi C, et al. Circulation. 2002;105:2741-2745.
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:                       Stable AVB:       ILR-Detected                  Death:
                       22 Pts (42%)*                    3 Pts (6%)       Pre-Syncope:                 1 Pt (2%)
                                                                          2 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
Brignole M., ET AL.,Circulation. 2001;104:2045-2050.                                    ** 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                                                         1.0
    without syncope
                                                                              0.8
   6-month mortality rate




                                                    Probability of Survival
    of greater than 10%
                                                                              0.6
   Cardiac syncope
    doubled the risk
                                                                              0.4
    of death
                                                                                      No Syncope
                                                                                      Vasovagal and
   Includes cardiac                                                          0.2     Other Causes
                                                                                      Cardiac Cause
    arrhythmias and SHD
                                                                              0.0 0           5                10   15
                                                                                                  Follow-Up (yr)




Soteriades ES, et al. N Engl J Med. 2002;347:878.
Syncope Due to Structural Cardiovascular Disease:
Principle Mechanisms

   Acute MI/Ischemia                             Pulmonary embolus/
                                                   pulmonary hypertension
      • 2° neural reflex bradycardia –
          Vasodilatation, arrhythmias,             • Neural reflex, inadequate
          low output (rare)                          flow with exertion
   Hypertrophic cardiomyopathy                   Valvular abnormalities
      • Limited output during exertion             • Aortic stenosis – Limited output,
          (increased obstruction, greater            neural reflex dilation in periphery
          demand), arrhythmias, neural
          reflex                                   • Mitral stenosis, atrial myxoma –
                                                     Obstruction to adequate flow
   Acute aortic dissection
      • Neural reflex mechanism,
          pericardial tamponade



Brignole M, et al. Europace. 2004;6:467-537.
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                    CASE: 28 year-old man presents
   syncope due to bradycardia:                     to ER multiple times after falls
   Pacemaker implanted.                            resulting in trauma. VT: Ablated
                                                   and medicated.

Reveal ® ILR recordings; Medtronic data on file.
Cardiac Rhythms During Unexplained Syncope

Composite: N=133 to 7109



                                                 Bradycardia
                                                    16%                 No Recurrence
                                                  (11-21%)                   36%
                                                                           (31-48%)
          Arrhythmia
             22%
            (13-32%)

                                            Tachycardia 6%
                                                (2-11%)

                                                          Other 11%   Normal Sinus Rhythm
                                                                              31%
                                                                           (17-44%)




Seidl K. Europace. 2000;2(3):256-262.
Krahn AD. PACE. 2002;25:37-41.
Medtronic ILR Replacement Data. FY03, 04. On file.
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                           Antibiotics
          • Class IA ...Quinidine,                 • Erythromycin, Pentamidine,
              Procainamide, Disopyramide             Fluconazole, Ciprofloxacin and
                                                     its relatives
          • Class III…Sotalol, Ibutilide,
              Dofetilide, Amiodarone, NAPA*       Nonsedating antihistamines
       Antianginal Agents                         • Terfenadine*, Astemizole
          • Bepridil*                             Others
       Psychoactive Agents                        • Cisapride*, Droperidol,
                                                     Haloperidol
          • Phenothiazines, Amitriptyline,
              Imipramine, Ziprasidone




*Removed from U.S. Market
Brignole M, et al. Europace, 2004;6:467-537.
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                                                                                            0.4 nV
                                                                                                                      0.2
    pacing using dual                                08:23:21                                                         0.0

    chamber system                                                                                                    -0.2
                                                                                                                      -0.4

    wherever possible                                           :21   :22   :23   :24   :25   :26   :27   :28   :29
                                                                                                                      0.4
                                                                                                                      0.2

   Ventricular pacing in                             8:23:29                                                         0.0
                                                                                                                      -0.2
    atrial fibrillation with                                                                                          -0.4


    slow ventricular                                            :29   :30   :31   :32   :33   :34   :35   :36   :37
                                                                                                                      0.4
                                                                                                                      0.2
    response                                         08:23:37                                                         0.0
                                                                                                                      -0.2
                                                                                                                      -0.4

                                                                :37   :38   :39   :40   :41   :42   :43   :44   :45




ACC/AHA/NASPE 2002 Guideline Update. Circ. 2002;106:2145-2161.
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
                                                          1000
                                                                                                > 75%
                                                           800
                      Total Number of Syncopal Episodes




                                                                         Two Year Risk


                                                           100

                                                            50

                                                            25

                                                                                                50-75%
                                                             8

                                                             4
                                                                                                25-50%
                                                             2

                                                             1                                  < 25%

                                                                 1   2   3        6               24            84   480

                                                                                      Months Since Symptoms Began
1Savage D, et al. STROKE. 1985;16:626-29.
2Sheldon R, et al. Circulation. 1996;93:973-81.
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:
                                               60° - 80°
      • 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.
VVS
General Treatment Measures

   Optimal treatment                             Long-term prevention
    strategies for VVS are                         •   Tilt training
    a source of debate
                                                   •   Education
   Treatment goals
                                                   •   Diet, fluids, salt
     • Acute intervention                          •   Support hose
           −   Physical maneuvers, eg,
               crossing legs or tugging arms       •   Drug therapy
           −   Lowering head                       •   Pacing
           −   Lying down




Brignole M, et al. Europace, 2004;6:467-537.
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


1BrignoleM, et al. Europace, 2004;6:467-537.
2Di                                              4Ward   C, et al. Heart. 1998;79:45-49.
   Girolamo E, et al. JACC. 1999;33:1227-1230.
3Raviele A, et al. Circ. 1999;99:1452-1457.      5Perez-Lugones     A, et al. J Cardiovasc Electrophysiol. 2001;12(8):935-938.
Midodrine for VVS


                               100



                               80
       Symptom-Free Interval




                               60                                                                        Midodrine

                                                                                                         Fluid
                               40



                               20
                                         p < 0.001

                                 0
                                     0   20      40      60          80           100             120   140      160   180

                                                                        Months

Perez-Lugones A, Schweikert R, Pavia S, et al. J Cardiovasc Electrophysiol. 2001;12(8):935-938.
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                                         4Connolly S. JAMA. 2003;289:2224-2229.
          SJ. J Am Coll Cardiol. 1999;33:16-20.
2Sutton R. Circulation. 2000;102:294-299.         5GiadaF. PACE . 2003;26:1016 (abstract).
3Ammirati F. Circ. 2001;104:52-57.                6Occhetta 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.
2Brignole M, et al.. Europace. 2004;6:467-537.
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   Carotid Sinus
    activity and diminution of
    sympathetic tone results in
    bradycardia and vasodilatation
Falls:
Incidence, Recurrence, CSH*


                  75

                                                           50% 1

                  50
                                              30% 1
                                                                            23% 2
                  25



                    0
                                   Incidence          Recurrence      CSH* Present
                                    > Age 65                       in Fallers > Age 50
                                                                    Presenting at ER

*Carotid Sinus Hypersensitivity


1J   Am Geriatr Soc. 1995.
2   Richardson D, et al. PACE. 1997;20:820.
CSS
Role of Pacing – Syncope Recurrence Rate

   Class I indication for pacing              75
    (AHA and BPEG)                                      57%
   Limit pacing to CSS
    that is:                                   50

     • Cardioinhibitory
     • Mixed
                                               25
   DDD/DDI superior to VVI                                       %6
     • Mean follow-up = 6 months
                                                0
                                                    No Pacing   Pacing




Brignole M, et al. Eur JCPE. 1992;4:247-254.
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                         50 years presented to the
        older adults with carotid                       Emergency Department
        sinus hypersensitivity                          because of a fall

   Randomized controlled                             • With pacing, falls  70%
    trial (N=175)                                     • Syncopal events  53%
     • Adults > 50 years,                             • Injurious events  70%
        non-accidental fall,
        positive CSM
     • Pacing (n=87) vs.
        No Pacing (n=88)



Kenny RA. J Am Coll Cardiol. 2001;38:1491-1496.
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                                      Secondary autonomic failure
   Drug-induced (very common)                     • Diabetes
      • Diuretics                                  • Alcohol
      • Vasodilators                               • Amyloid

   Primary autonomic failure
      • Multiple system atrophy
      • Parkinson‟s Disease
      • Postural Orthostatic Tachycardia
          Syndrome (POTS)




Brignole M, et al. Europace, 2004;6:467-537.
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                                     Syncope Unit Group
 80%                Standard Care Group                     80%            Standard Care Group

           P=0.30                                                     P=0.72
 70%                                                        70%
       0                             1              2             0                   1               2
                                  Years                                             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.
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.
2Brignole M, et al. Europace, 2004;6:467-537.
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.