Transient Loss of Consciousness (TLOC)

Syncope A Diagnostic and Treatment Strategy
David G. Benditt, M.D. University of Minnesota Medical School Minneapolis, MN USA Richard Sutton, DScMed Royal Brompton Hospital London, UK

Transient Loss of Consciousness (TLOC)
Transient Loss of Consciousness, or TLOC, is just that. It can be as simple as a benign ‘faint’ or a symptom of an underlying disease that may lead to sudden death. Or it may not be syncope at all.

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, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Brignole M, et al. Europace, 2004;6:

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, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Brignole M, et al. Europace, 2004;6:

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

Section I: Etiology, Prevalence, Impact

Unexplained Causes = Approximately 1/3
Causes of True Syncope Neurally- Mediated Orthostatic Cardiac Arrhythmia Structural Cardio- Pulmonary 1 VVS CSS • Situational Cough Post- Micturition 2 Drug-Induced • ANS Failure Primary Secondary 3 Brady SN Dysfunction AV Block • Tachy VT SVT Long QT Syndrome 4 Acute Myocardial Ischemia Aortic Stenosis HCM Pulmonary Hypertension Aortic Dissection This slide provides a simple classification of the principal causes of syncope, listed from the most commonly observed (left) to the least common (right). This ranking may be helpful in thinking about the strategy for evaluating syncope in individual patients. Within the boxes, the most common causes of syncope are indicated for each of the major diagnostic groups. The terms ‘neurally-mediated syncope’, ‘neurally-mediated reflex syncope,’ and ‘neurocardiogenic syncope’ are generally used synonymously. For purposes of this presentation, ‘neurally-mediated syncope’ is used to define a broad category; ‘neurocardiogenic’ or ‘vasovagal syncope’ refer to a specific condition. VVS—Vasovagal Syncope CSS—Carotid Sinus Syndrome ANS—Autonomic Nervous System HCM—Hypertrophic Cardiomyopathy DG Benditt, MD. University of Minnesota Cardiac Arrhythmia Center 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, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Brignole M, et al. Europace, 2004;6:

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. Epidemiology and social costs. In: Benditt D, Blanc J-J, et al. eds. The Evaluation and Treatment of Syncope. Elmsford, NY: Futura;2003:23-27. 2Kapoor W. Evaluation and outcome of patients with syncope. Medicine. 1990;69: 3Brignole M, Disertori M, Menozzi C, et al. Management of syncope referred urgently to general hospitals with and without syncope units. Europace. 2003;5: 4 Blanc J-J, L’ Her C, Touiza A, et al. Prospective evaluation and outcome of patients admitted for syncope over a 1 year period. Eur Heart J. 2002;23: 5Campbell A, Reinken J, Allan B, et al. Falls in old age: A study of frequency and related clinical factors. Age and Ageing. 1981;10: 1Kenny RA, Kapoor WN. In: Benditt D, et al. eds. The Evaluation and Treatment of Syncope. Futura;2003:23-27. 2Kapoor W. Medicine. 1990;69: 3Brignole M, et al. Europace. 2003;5: 4 Blanc J-J, et al. Eur Heart J. 2002;23: 5Campbell A, et al. Age and Ageing. 1981;10:

Impact of Syncope: US Trends
Inpatient Trend* Physician Office Visits** (000s) (000s) National Hospital Discharge Survey (NHDS) 2003. National Ambulatory Medical Care Survey (NAMCS) 2002. Syncope is a growing problem. More patients are being seen in outpatient visits and are being admitted with this problem. *All patients discharged with syncope and collapse (ICD-9 Code:780.2) listed among diagnoses. **Syncope and collapse (ICD-9 Code: 780.2) listed as primary reason for visit. NHDS 2003. NAMCS 2002.

Impact of Syncope: US Trends
Emergency Department Visits* Hospital Outpatient Visits* (000s) (000s) The National Hospital Ambulatory Medical Care Survey (NHAMCS) is a national probability survey, conducted by the National Center for Health Statistics (NCHS). The NCHS is a part of the Centers for Disease Control and Prevention (CDC), U.S. Department of Health and Human Services, 2002. Likewise, the trends indicate an increase in emergency room visits and a slight increase in hospital outpatient visits. + *Syncope and collapse (ICD-9 Code:780.2) listed as primary reason for visit. + Not available 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, Department of Health, England *Hospital Episode Statistics, Dept. of Health, Eng

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. Epidemiology and social costs. In: Benditt D, Blanc J-J, et al. eds. The Evaluation and Treatment of Syncope. Elmsford, NY: Futura;2003:23-27. 2 Solucient Outpatient View: OutPatientView v Solucient LLC, Evanston IL. 3Farwell D and Sulke N. How do we diagnose syncope? J Cardiovasc Electrophysiol. 2002;13(Supp):S9-S13. 4Olshansky B. Syncope: Overview and approach to management. In: Grubb B and Olshansky B. eds. Syncope: Mechanisms and Management. Armonk, NY:Futura;1998:15-71. 1Kenny RA, Kapoor WN. In: Benditt D, et al. eds. The Evaluation and Treatment of Syncope. Futura;2003:23-27. 2OutPatientView v 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
73%1 71%2 60%2 Percent of Patients 37%2 Syncope results in substantial cost to patients and to society. For example, syncope patients live with lifestyle altering restrictions that affect daily activities, mobility, and employment. Linzer M, Pontinen M, Gold DT, et al. Impairment of physical and psychological function in recurrent syncope. J Clin Epidemiol. 1991;44: Linzer M, Gold DT, Pontinen M, et al. Recurrent syncope as a chronic disease: Preliminary validation of a disease-specific measure of functional impairment. J Gen Int Med ;9: Anxiety/ Depression Alter Daily Activities Restricted Driving Change 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% 43% 37% 36% 26% % Prevalence 19% To measure health-related quality of life (HRQL), Rose1 and colleagues used the EQ-5D. This tool has been designed as an international, standardized, generic instrument for describing and valuing health-related quality of life.2 The study showed evidence of substantially impaired HRQL in syncope patients, compared to the reference population norms in all five dimensions of health. The increase in the prevalence of impaired health was approximately 10-fold for mobility, usual activities, and self-care, and 2-fold for anxiety/depression. 1Rose M, Koshman ML, Spreng S, et al. The relationship between health-related quality of life and frequency of spells in patients with syncope. J Clin Epidemiol. 2000;53: 2The EuroQol Group. EuroQol: A new facility for the measurement of health related quality of life. Health Policy. 1990;16: 9% 4% 3% 1% Mobility Usual Activities Self-Care Pain/ Discomfort Anxiety/ Depression Rose M, et al. J Clin Epidemiol. 2000;53:

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): [Framingham Study Population]

Implications of Syncope for Driving a Vehicle
Those who drive and have recurrent syncope risk their lives and the lives of others 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. Driving and Syncope. In: Olshansky B and Grubb B, eds. Syncope: Mechanisms and Management. Armonk, NY: Futura Publishing Co; 1998: *Medtronic, Inc. When may patients with implanted defibrillators drive? Follow-up Forum. Winter. 1995/96;1(3):8-10. Olshansky B, Grubb B. In: Syncope: Mechanisms and Management. Futura. Armonk, NY *Medtronic, Inc. Follow-up Forum. 1995/96;1(3):8-10.

Challenges of Syncope Diagnosis Quality of life implications Cost
Complex Quality of life implications Work Mobility (automobiles) Psychological Cost Cost/year Cost/diagnosis Syncope impacts patient quality of life and health care costs in important ways. Establishing a precise diagnosis is often challenging due to the unpredictability of events and the limited positive predictive value of most available tests. The ‘gold standard’ remains the recording of the cardiac rhythm (and if possible the arterial pressure) during a spontaneous faint.

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, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Brignole M, et al. Europace, 2004;6:

Diagnostic Flow Diagram for TLOC
Initial Evaluation Treatment Syncope Not Syncope Certain Diagnosis Unexplained Syncope Cardiac Likely Cardiac Tests Neurally-Mediated or Orthostatic Likely Tests for Neurally-Mediated Syncope Frequent or Severe Episodes Single/Rare Episodes No Further Evaluation Confirm with Specific Test or Specialist Consultation Suspected Diagnosis + - Re-Appraisal Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Brignole M, et al. Europace, 2004;6:

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 The history must include detailed summary of events leading up to and following syncope events. Additionally, it is important to ascertain whether there is any evidence of underlying structural heart disease. The direction of subsequent evaluation differs in patients with and without heart disease. Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Raviele A, Alboni P, Sutton D, Kenny RA. Initial evaluation of the syncope patient. In: Benditt D, Blanc J-J, Brignole M, Sutton R, eds. The Evaluation and Treatment of Syncope. Elmsford, NY: Futura. 2003:38-45. Brignole M, et al. Europace, 2004;6:

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 HCM—Hypertrophic Cardiomyopathy Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Brignole M, et al. Europace, 2004;6:

Carotid Sinus Massage (CSM)
Method1 Massage, 5-10 seconds Don’t occlude Supine and upright posture (on tilt table) Outcome 3 second asystole and/or 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 0.2%3 Usually transient Carotid sinus massage (CSM) is an often overlooked, yet highly cost effective test, especially in older syncope patients. CSM must be applied with care, and the method described here1 has proven both safe and effective. Note that an abnormal response to CSM (i.e., Carotid Sinus Hypersensitivity, CSH) is not diagnostic of Carotid Sinus Syndrome (CSS). Reproduction of symptoms is a crucial diagnostic element. To achieve symptom reproduction, it may be useful to conduct CSM with the patient in the upright posture. If the latter is to be done, the patient should be safely secured to a tilt table in order to prevent injury from a fall. 1Kenny RA, O’Shea D, Parry SW. The Newcastle protocols for head-up tilt table testing in the diagnosis of vasovagal syncope, carotid sinus hypersensitivity, and related disorders. Heart. 2000;83: 2Linzer M, Yang EH, Estes M, et al. Diagnosing Syncope: Part 1: Value of history, physical examination, and electrocardiography. Ann Intern Med. 1997;126(12): 3Munro N, McIntosh S, Lawson J, et al. Incidence of complications after carotid sinus massage in older patients with syncope. J Am Geriatr Soc. 1994;42: Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: 1Kenny RA. Heart. 2000;83:564. 2Linzer M. Ann Intern Med. 1997;126:989. 3Munro N, et al. J Am Geriatr Soc. 1994;42:

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) NTG = nitroglycerin Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Brignole M, et al. Europace, 2004;6:

Heart Monitoring Options
12-Lead 10 Seconds 2 Days Holter Monitor Event Recorders (non-lead and loop) 7-30 Days Up to 14 Months ILR Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 TIME (Months) Brignole M, et al. Europace, 2004;6:

Diagnostic Assessment: Yields (N=3411 to 4332)
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) EP Study <2-5 Exercise Test 0.5 EEG MRI No data available6 1Alboni P, Brignole M, Menozzi C, et al. Diagnostic value of history in patients with syncope with or without heart disease. J Am Coll Cardiol. 2001;37: 2Kapoor W. Evaluation and outcome of patients with syncope. Medicine. 1990;69: 3Krahn AD, Klein GJ, Yee R, et al. for the Reveal Investigators. Use of an extended monitoring strategy in patients with problematic syncope. Circulation. 1999;99; 4Krahn AD, Klein GJ, Yee R, et al. Randomized Assessment of Syncope Trial. Conventional diagnostic testing versus a prolonged monitoring strategy. Circulation. 2001;104:46-51. 5Krahn AD, Klein GJ, Yee R, et al. The high cost of syncope: Cost implications of a new insertable loop recorder in the investigation of recurrent syncope. Am Heart J. 1999;137: 6Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: References Available

Neurological Tests: Rarely Diagnostic for Syncope
EEG, Head CT, Head MRI May help diagnose seizure Neurological studies (Head CT and MRI, EEG) are rarely useful in the diagnostic evaluation for syncope. Imaging may be justified if there is concern that syncope may have resulted in a head injury. Otherwise, without apparent abnormal neurological signs, such testing should be relegated to low priority. Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Brignole M, et al. Europace. 2004;6:

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 60° - 80° The rationale for undertaking tilt table testing in patients suspected of having vasovagal (VVS) syncope is summarized here. The test may provide useful diagnostic information and also an opportunity for patients to become more familiar with the condition and its possible warning signs. Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Brignole M, et al. Europace. 2004;6:

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 This strip from ECG leads and an intra-arterial pressure tracing illustrates the final moments of a tilt table test just prior to induced syncope. Note that blood pressure tended to fall (1) in advance of the bradycardia (2). Even after the patient is returned to supine posture and the heart rate returns to normal, it may take time for the arterial pressure to fully recover due to persistent vasodilatation. DG Benditt, MD. University of Minnesota Cardiac Arrhythmia Center DG Benditt, MD. U of M Cardiac Arrhythmia Center

Adenosine Triphosphate (ATP) Test
Ongoing investigation in the US Provokes a short and potent cardioinhibitory vasovagal response Advantages Simple Inexpensive Correlation with pacing benefit Seems to identify a unique mechanism of syncope found in patients with: Advanced age More hypertension More ECG abnormalities 1Brignole M, Gaggioli G, Menozzi C, et al. Clinical features of adenosine sensitive syncope and tilt induced vasovagal syncope. Heart. 2000;83:24-28. 2Donateo P, Brignole M, Menozzi C, et al. Mechanism of syncope in patients with positive adenosine triphosphate tests. J Am Coll Cardiol. 2003;41:93-98. 3Flammang D, Erickson M, McCarville S. Contribution of head-up tilt testing and ATP testing in assessing the mechanisms of vasovagal syndrome. Circulation. 1999;99: Brignole M. Heart. 2000;83: Donateo P. J Am Coll Cardiol. 2003;41:93-98. Flammang D. Circ. 1999;99:

Insertable Loop Recorder (ILR)
The Reveal® Plus Insertable Loop Recorder system offers long-term, continuous, subcutaneous ECG monitoring and event-specific recording. The system includes an implanted loop recorder, a hand-held patient Activator, and a programmer with telemetry head that communicates noninvasively with the implanted device. When a patient experiences an episode, the device stores an ECG using the Activator or through the use of a auto-activating feature. The Reveal® Plus ILR can monitor continuously for up to 14 months. The probability of capturing an event is high—approximately 65-88%.1,2 The ECG captured during the episode may “reveal” the ECG during the patient’s episode or may allow the clinician to rule in or rule out arrhythmic causes. The stored ECG data is retrieved, viewed, and printed or saved to a disk, using a Medtronic programmer. The Reveal ILR can then be re-started for continued monitoring. 1Krahn A, et al. Final results from a pilot study with an insertable loop recorder to determine the etiology of syncope in patients with negative noninvasive and invasive testing. Am J Cardiol. 1998;82: 2Krahn A, Klein GJ, Yee R, Skanes AC. Randomized assessment of syncope trial. Conventional diagnostic testing versus a prolonged monitoring strategy. Circulation. 2001;104:46-51. Click once on black screen to play video. Reveal® Plus ILR Typical Location of the Reveal® Plus 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

Click once on black screen to play video.

Symptom-Rhythm Correlation with the ILR
These are examples of ECG recordings obtained by the Reveal® ILR system in two symptomatic patients. The gold standard for determining if a syncope episode may be due to an arrhythmia is to record the rhythm during symptoms, i.e., symptom-rhythm correlation. The ILR may help rule-in or rule-out arrhythmogenic causes. These strips depict findings from an ILR interrogation as they appear on the programmer screen. In order to view the event in greater detail, one taps the screen over the ECG of interest. On-screen calipers are available at every zoom level to measure cycle length in milliseconds or beats per minute. Note that the ‘A’ represents an auto-activated event; the ‘P’ indicates when the patient activated the device. Left strip: Infra-Hisian AV block: dual chamber pacemaker. Right strip: VT and VF: ICD, meds. Medtronic data on file. 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.

Randomized Assessment of Syncope Trial (RAST)
Unexplained Syncope EF > 35% 60 Patients AECG, Tilt, EP Study Diagnosis ILR + – Conventional Testing (AECG, Tilt, EPS) 30 Patients Primary Strategy Crossover 14 6 1 8 Dr. Andrew Krahn and his team at the University of Western Ontario authored the Randomized Assessment of Syncope Trial (RAST) in then followed up with a cost analysis of the same study in Prospective, randomized trial 60 patients with unexplained syncope after history, physical exam, ECG, and Holter monitor. EF > 35% (lower risk) 2 testing strategies: conventional, using an exterior loop recorder (ELR) or Holter, tilt test, and electrophysiology study, or prolonged ILR monitoring. If patients remained undiagnosed after their assigned strategy, they were offered crossover to the alternate strategy. Overall, prolonged monitoring was more likely to result in a diagnosis than conventional testing, 43% vs. 20%, p=0.026. Subsequent cost studies showed a 26% reduction in cost per diagnosis ($2,016) with a strategy of primary monitoring (p=0.002). Prior to this study, the ILR was generally used as a last resort after other evaluation. 1 Krahn AD, et al. Randomized Assessment of Syncope Trial: Conventional diagnostic testing versus a prolonged monitoring strategy. Circulation. 2001:104(1):46-51. 2 Krahn AD, et al. Cost implications of testing strategy in patients with syncope (RAST). JACC. 2003;42: 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: Krahn AD, et al. JACC. 2003;42:

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 Conventional EP testing (i.e., electrical stimulation without autonomic studies such as HUT) has not been highly effective in substantiating a basis for syncope. In this regard, EPS has been more effective in patients with structural cardiovascular disease than in those with normal cardiovascular status. The most important findings at EPS in regard to the evaluation of syncope patients are listed in this slide. SHD—Structural Heart Disease SNRT—Sinus Node Recovery Time CSNRT—Corrected Sinus Node Recovery Time Benditt D. Syncope. In: Topol E, ed. Textbook of Cardiovascular Medicine. Philadelphia, PA: Lippencott Williams & Wilkins;2002: Lu F and Bergfeldt L. Role of electrophysiologic testing in the syncope evaluation. In: Benditt D, et al. The Evaluation and Treatment of Syncope. Futura. 2003;80-95. Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Benditt D. In: Topol E, ed. Textbook of Cardiovascular Medicine. Lippencott;2002: 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:

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 *SHD—Structural Heart Disease 1Linzer M, Yang E, Estes M, et al. Diagnosing Syncope. Part 2: Unexplained Syncope. Ann Int Med. 1997;127:76-86. 2Lu F and Bergfeldt L. Role of electrophysiologic testing in the syncope evaluation. In: Benditt D, et al. The Evaluation and Treatment of Syncope. Futura. 2003;80-95. 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: 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, Brignole M, Menozzi C. Mechanism of syncope in patient with isolated syncope and in patients with tilt-positive syncope. Circulation ;104: 2Menozzi C, Brignole M, Garcia-Civera R, et al. Mechanism of syncope in patients with heart disease and negative electrophysiological test. Circulation. 2002;105: 3Brignole M, Menozzi C, Moya A, et al. Mechanism of syncope in patients with bundle branch block and negative electrophysiological test. Circulation. 2001;104: 1Moya A. Circulation ; 104: 2Menozzi C, et al. Circulation. 2002;105: 3Brignole M, et al. Circulation. 2001;104:

ISSUE Patients with Isolated Syncope and Tilt-Positive Syncope
Follow-Up to Recurrent Spontaneous Episode 111 Patients with Syncope No SHD, Normal ECG 29: Tilt-Positive 82: Tilt-Negative “Isolated Syncope” Tilt Test Followed by Insertable Loop Recorder Moya A, Brignole M, Menozzi C. Mechanism of syncope in patient with isolated syncope and in patients with tilt-positive syncope. Circulation ;104: Moya A. Circulation. 2001;104:

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 If isolated (tilt-negative) syncope and tilt-positive syncope have similar clinical presentation, outcome, and cause, a logical inference is that tilt-testing lacks sensitivity. Moya A, Brignole M, Menozzi C. Mechanism of syncope in patient with isolated syncope and in patients with tilt-positive syncope. Circulation ;104: Moya A. Circulation. 2001;104:

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%) Menozzi C, et al. Mechanism of syncope in patients with heart disease and negative electrophysiological test. Circulation. 2002;105: 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. 2002;105:

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, Brignole M, Garcia-Civera R, et al. Mechanism of syncope in patients with heart disease and negative electrophysiological test. Circulation. 2002;105: Menozzi C, et al. Circulation. 2002;105:

ISSUE Patients with Bundle Branch Block and Negative EP Test
52 Pts with BBB and Insertable Loop Recorder Syncope: 22 Pts (42%)* Stable AVB: 3 Pts (6%) ILR-Detected Pre-Syncope: 2 Pts (4%)** Death: 1 Pt (2%) 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%) Brignole M, Menozzi C, Moya A, et al. Mechanism of syncope in patients with bundle branch block and negative electrophysiological test. Circulation. 2001;104: * 5 of these also had ≥1 presyncope ** Drop-out before primary-end point Brignole M., ET AL.,Circulation. 2001;104:

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, Menozzi C, Moya A, et al. Mechanism of syncope in patients with bundle branch block and negative electrophysiological test. Circulation. 2001;104: Brignole M. Circulation. 2001;104:

Section III: Specific Conditions and Treatment
The next section deals with some of the more important causes of syncope.

Specific Conditions Cardiac arrhythmia Structural cardio-pulmonary
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 Syncope occurring as a result of cardiac arrhythmias or in association with underlying structural heart disease requires careful and aggressive evaluation. Whereas syncope in patients with normal hearts is often relatively benign, syncope in the presence of cardiac disease is often indicative of a potentially life-threatening problem. Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Brignole M, et al. Europace. 2004;6:

“…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 No Syncope Vasovagal and Other Causes Cardiac Cause Follow-Up (yr) Probability of Survival 1.0 0.8 0.6 0.4 0.2 0.0 Cardiac causes include both arrhythmias and structural heart problems, both of which contribute to high mortality rates. One of the goals, therefore, is to attempt to either rule out or rule in arrhythmic disorders. The statistic of a 1-year mortality rate ranging from 18-33% was validated in the September 19th, 2002 issue of the New England Journal of Medicine. The incidence and prognosis of syncope was studied in more than 7,800 participants in the Framingham Heart Study from 1971 to 1998. The study found a 6-month mortality rate of greater than 10%.1 Cardiac syncope doubled the risk of death .1 Syncope of unknown cause was the largest category of causes.2 50% of syncope cases could not be diagnosed after conventional evaluation of detailed history, physical exam, and ECG.3 Because the precise cause of syncope is identified in fewer than half the patients during initial evaluation, the challenge lies in identifying those at high risk for death. Cardiac syncope is not benign. 1 Soteriades ES, Evans JC, Larson MG, et al. Incidence and prognosis of syncope. N Engl J Med ;347(12): 2 Kapoor WN. Evaluation and outcome of patients with syncope. Medicine. 1990;69: 3 Linzer M, Yang E, Estes N, et al. Diagnosing syncope. Ann Intern Med. 1997;126(12): Soteriades ES, et al. N Engl J Med. 2002;347:878.

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 This slide lists important structural cardiovascular abnormalities to be considered during the diagnostic evaluation of syncope. Obstruction of blood flow and arrhythmias are often the mechanisms for the syncope; all are high risk. The list is not intended to be exhaustive of the possibilities, but provides some of the more commonly found conditions. MI—myocardial infarction HCM—hypertrophic cardiomyopathy Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Brignole M, et al. Europace. 2004;6:

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 Both excessively slow as well as excessively rapid heart rates may result in sufficient drop in systemic pressure to cause syncope. In the case of tachycardias, the syncope tends to occur at the onset of the episode, before vascular constriction has an opportunity to occur. Syncope may also occur at termination of tachyarrhythmias, if a prolonged pause occurs prior to resumption of a stable rhythm. Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Brignole M, et al. Europace. 2004;6:

ILR Recordings These are Reveal® ILR recordings from patients with syncopal symptoms. The left recording was obtained in an 83 year old woman and suggests bradycardic episodes as a cause of syncope. The right recording was obtained in a younger patient with idiopathic ventricular tachycardia. Reveal ® ILR recordings; Medtronic data on file. CASE: 83 year-old woman with syncope due to bradycardia: Pacemaker implanted. CASE: 28 year-old man presents to ER multiple times after falls 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% (11-21%) No Recurrence 36% (31-48%) Arrhythmia 22% (13-32%) Tachycardia 6% (2-11%) Other 11% The chart is a composite of several studies showing cardiac rhythms during syncope. Fortunately, most of the patients are in normal sinus rhythm. But since it is impossible to determine which patients have arrhythmias, one of the primary goals is to attempt to either rule out or rule in arrhythmic disorders. The disconcerting piece is this seemingly small 6% - those with ventricular tachycardia, ventricular fibrillation, nonsustaining VT, or supraventricular VT—a cardiac cause that can lead to sudden death, as we saw from the Framingham data.* The ‘Other’ category includes conditions such as vasovagal-related causes and failed activation. Medtronic ILR Replacement Data includes Medtronic devices that were implanted when the ILR was explanted. Seidl K, Rameken M, Breunung S, et al. Diagnostic assessment of recurrent unexplained syncope with a new subcutaneously implantable loop recorder. Europace. 2000;2(3): Krahn AD, Klein GJ, Fitzpatrick A, et al. Predicting the outcome of patients with unexplained syncope undergoing prolonged monitoring. PACE. 2002;25:37-41. Medtronic ILR Replacement Data. FY03, 04. On file. * Soteriades ES, Evans JC, Larson MG, et al. Incidence and prognosis of syncope. N Engl J Med ;347(12): Normal Sinus Rhythm 31% (17-44%) Seidl K. Europace. 2000;2(3): Krahn AD. PACE. 2002;25:37-41. Medtronic ILR Replacement Data. FY03, 04. On file. Author/Date N= No Recurrence/% Brady/% Tachy/% NSR/%(+No Rec) Other Seidl/2000 133 50/38% 21/16% 10/8% 40/30% 12 Krahn/2002 206 64/31% 35/17% 12/6% 63/31% 32 MDT ILR Replacement Data (FY03) 6200 924/15% 114/2% MDT ILR Replacement Data (FY04) 7109 1121/16% 148/2%

Long QT Syndromes Mechanism Prevalence
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 and Priori S. Long QT syndrome: Genotype-Phenotype correlations. In: Zipes D and Jalife J, eds. Cardiac Electrophysiology. From Cell to Bedside. Philadelphia, PA: Saunders;2004: Schwartz P, Priori S. In: Zipes D and Jalife J, eds. Cardiac Electrophysiology. Saunders;2004:

Syncope: Torsade de Pointes
Torsade de pointes ventricular tachycardia often presents as syncope, although life-threatening sustained tachyarrhythmias may also occur. The underlying factors are most often either acquired or congenital long QT syndrome. In this case, the patient had been treated with quinidine for several weeks in an attempt to suppress episodes of atrial fibrillation. From the files of DG Benditt, MD. University of Minnesota Cardiac Arrhythmia Center 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. University of Minnesota Cardiac Arrhythmia Center From the files of DG Benditt, MD. U of M Cardiac Arrhythmia Center

Drug-Induced QT Prolongation (List is continuously being updated)
Antiarrhythmics Class IA ...Quinidine, Procainamide, Disopyramide Class III…Sotalol, 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 Numerous drugs have been associated with QT interval prolongation leading to susceptibility to torsade de pointes ventricular tachycardia. Some of these agents have been removed from the market in the USA, as noted with an asterisk. Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: *Removed from U.S. Market Brignole M, et al. Europace, 2004;6:

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: For more information visit Schwartz P and Priori S. Long QT syndrome: Genotype-Phenotype correlations. In: Zipes D and Jalife J, eds. Cardiac Electrophysiology. From Cell to Bedside. Philadelphia, PA: Saunders;2004: Schwartz P, Priori S. In: Zipes D and Jalife J, eds. Cardiac Electrophysiology. Saunders;2004:

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 nV 0.4 0.2 0.0 -0.2 -0.4 :45 :44 :43 :42 :41 :40 :39 :38 :37 :36 :35 :34 :33 :32 :31 :30 :29 :28 :27 :26 :25 :24 :23 :22 :21 08:23:21 8:23:29 08:23:37 The treatment of syncope associated with bradyarrhythmias resulting from intrinsic conduction system disease is usually cardiac pacing. On occasion, removal of an offending drug may be sufficient. The problem of neurally-mediated reflex bradyarrhythmias is dealt with separately. ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices: Summary Article. Circulation. 2002;106: ACC/AHA/NASPE 2002 Guideline Update. Circ. 2002;106:

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 This slide provides an overview of the multiple tachyarrhythmias that may cause syncope. An EP study has proven more valuable in assessing tachyarrhythmia causes of syncope than those due to bradycardia. IVC-TV =Inferior Vena Cava-Tricuspid Valve AVRT =Atrioventricular Reentry Tachycardia AVNRT =Atrioventricular Nodal Reentry Tachycardia Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Brignole M, et al. Europace. 2004;6:

Neurally-Mediated Reflex Syncope
Vasovagal Syncope (VVS) Carotid Sinus Syndrome (CSS) Situational syncope Post-micturition Cough Swallow Defecation Blood drawing, etc. The neurally-mediated reflex causes of syncope are a group of related conditions in terms of symptomatic hypotension being caused by a variable combination of bradycardia and vasodilatation. Vasovagal syncope and carotid sinus syndrome are the most frequent conditions in this group. The others occur occasionally and are usually recognized only if a detailed medical history is obtained. Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Brignole M, et al. Europace, 2004;6:

Autonomic Nervous System
Pathophysiology Autonomic Nervous System The physiology of syncope is depicted graphically in this slide. The afferent trigger signals (eg, pain, emotional upset, dehydration) are not depicted. In the efferent loop of the neural reflex: Parasympathetic signals from the cerebral cortex reduce heart rate and slow (or block) AV conduction. Decreased sympathetic activity results in vasodilatation. Bradycardia and/or hypotension occur. Carotid baroreceptors and other mechanoreceptors provide paradoxical feedback to the central nervous system, aggravating bradycardia and vasodilatation. The result may be a downward spiral in heart rate and blood pressure leading to syncope. Benditt DG, Lurie KG, Adler SW, et al. Pathophysiology of vasovagal syncope. In: Neurally mediated syncope: Pathophysiology, investigations and treatment. Blanc JJ, Benditt D, Sutton R. Bakken Research Center Series, v. 10. Armonk, NY: Futura, 1996. Benditt D, et al. Neurally mediated syncope: Pathophysiology, investigations and treatment. Blanc JJ, et al. eds. Futura

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 Vasovagal syncope, as in other forms of neurally-mediated reflex syncope, is due to systemic hypotension resulting in a transient period of inadequate cerebral blood flow. Hypotension is the result of two pathophysiologic components: Marked bradycardia or inappropriately slow heart rate for the blood pressure (i.e., cardioinhibitory feature) Vasodilatation The relative contribution of these two components varies among patients. Wieling W, Gert van Dijk J, van Lieshout J, Benditt D. Pathophysiology and clinical presentation. In: Benditt D, Blanc J-J, et al. eds. The Evaluation and Treatment of Syncope. Elmsford, NY: Futura. 2003;11-22. 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 The incidence of vasovagal syncope is poorly known. The published data that exists mostly dates from before the advent of tilt table testing. Linzer surveyed the literature and found published prevalences varying from 8% to 37% (mean 18%) of cases of syncope. Standards for diagnosis and reporting are still emerging. Linzer MD, Yang EH, Estes M, et al. Diagnosing syncope. Part 1: Value of history, physical examination, and electrocardiography. Ann Intern Med. 1997;126(12): 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) It is generally recognized that: Vasovagal syncope patients are usually younger than Carotid Sinus Syndrome patients (age range is from adolescent to older adults, median 43 years) Vasovagal syncope is more common in females. Linzer MD, Yang EH, Estes M, et al. Diagnosing syncope. Part 1: Value of history, physical examination, and electrocardiography. Ann Intern Med. 1997;126(12): 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 800 50 100 25 8 4 2 1 3 6 24 84 480 Months Since Symptoms Began Two Year Risk Total Number of Syncopal Episodes > 75% 50-75% 25-50% < 25% Studies suggest that vasovagal syncope tends to recur in a substantial percentage of patients.1 Individuals who have historically experienced multiple syncopes over a long period of time are the ones at greatest risk for future recurrences.2 1Savage D, Corwin L, McGee D, et al. Epidemiologic features of isolated syncope: the Framingham Study. Stroke. 1985;16: 2Sheldon R, Rose S, Flanagan P, et al. Risk factors for syncope recurrence after a positive tilt-table test in patients with syncope. Circulation. 1996;93: 1Savage D, et al. STROKE. 1985;16: 2Sheldon R, et al. Circulation. 1996;93:

VVS Spontaneous 16 year-old male, healthy, athletic, monitored for fainting. 16.3 sec Continuous Tracing 1 sec Example of marked bradycardia recorded during a spontaneous vasovagal syncope. The asystolic periods may be impressive in their duration but do not in themselves constitute an indication for cardiac pacing. From the files of DG Benditt, MD. University of Minnesota Cardiac Arrhythmia Center From the files of DG Benditt, MD. U of M Cardiac Arrhythmia Center

VVS Diagnosis History and physical exam, ECG and BP
Head-Up Tilt (HUT) – Protocol: Fast > 2 hours ECG and continuous blood pressure, supine, and upright Tilt to 70°, 20 minutes Isoproterenol/Nitroglycerin if necessary End point – Loss of consciousness 60° - 80° Vasovagal syncope is most effectively diagnosed if the detailed medical history is ‘classic’. However, this is not often the case, and supporting evidence is needed. Such supportive evidence may include: Patient history, physical examination, including ECG and blood pressure Patient experiences syncope during tilt table testing. Test completion without syncope is a negative result. The following is one tilt table protocol: At least a 2 hour fast Measure ECG, at least 3 leads, and continuous supine and upright blood pressure at time of symptoms. Patient remains supine on the table for minutes. Tilt to 70 degrees for 20 minutes. Lower to horizontal and administer isoproterenol at 1-5 μg/min until heart rate increases 25%. Re-tilt for 10 minutes Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Benditt D, Ferfuson D, Grubb B, et al. Tilt table testing for assessing syncope. ACC expert consensus document. J Am Coll Cardiol. 1996;28: Benditt D, et al. JACC. 1996;28: Brignole M, et al. Europace, 2004;6:

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 Optimal management strategies for VVS are a source of debate. Long-term prevention measures include: Patient education, reassurance, and instruction. Control of fluids, salt, and diet may help reduce incidence. Support hose may limit blood pooling in the legs and feet. Drug therapy should be used as a second line option. Midodrine and beta-adrenergic blockers are the agents most thoroughly studied to date Pacing may benefit some patients. Subsequent slides will examine the utility of pacing in very symptomatic VVS patients. When the patient has a relatively long prodrome, evasive action may prevent injury if not syncope. This might include physical maneuvers such as crossing the legs, lowering the head, or lying down. Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Brignole M, et al. Europace, 2004;6:

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, Heidbuchel H, Van de Werf F, Ector H, et al. Tilt training: A treatment for malignant and recurrent neurocardiogenic syncope. PACE. 2000;23(4 Pt. 1): Reybrouck T, et al. PACE. 2000;23(4 Pt. 1):

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, et al. have demonstrated that the use of tilt training may be beneficial in a select population of patients who have frequent episodes of vasovagal syncope. It may also be of value in some forms of orthostatic hypotension. Results may be related to more of a placebo effect than an actual effect. Tilt training may have short-lived benefit when patients fail to comply with the regime for an extended period of time. *Reybrouck T, Heidbuchel H, Van de Werf F, Ector H, et al. Long-term follow-up results of tilt-training therapy in patients with recurrent neurocardiogenic syncope. PACE. 2002;25: Additional references on tilt-training: Ector H, Reybrouck T, Heidbuchel H, Gewillig M, Van de Werf F. Tilt-training: A new treatment for recurrent neurocardiogenic syncope or severe orthostatic intolerance. PACE. 1998;21: Di Girolamo E, Di Iorio C, Leonzio L, Sabatini P, Barsotti A. Usefulness of a tilt-training program for prevention of refractory neurocardiogenic syncope in adolescents. A controlled study. Circulation. 1999;100: *Reybrouck T, et al. PACE. 2000;23:

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, Giada F, Gaggioli G, et al. Efficacy of tilt training in the treatment of neurally mediated syncope. A randomized study. Europace. 2004;6: *Foglio-Manzillo G, et al. Europace. 2004;6:

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 This slide summarizes the key pharmacologic treatment options in VVS patients. Drug therapy should be reserved as a second-line option. 1Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: 2Di Girolamo E, Di Iorio C, Sabatini O, et al. Effects of paroxetine hydrochloride, a selective serotonin reuptake inhibitor, on refractory vasovagal syncope: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol. 1999;33: 3Raviele A, Brignole M, Sutton R, et al. Effect of etilefrine in preventing syncopal recurrence in patients with vasovagal syncope: a double-blind, randomized, placebo-controlled trial. The Vasovagal Syncope International Study. Circulation. 1999;99: 4Ward C, Gray J, Gilroy J, et al. Midodrine: a role in the management of neurocardiogenic syncope. Heart. 1998;79:45-49. 5Perez-Lugones A, Schweikert R, Pavia S, et al. Usefulness of midodrine in patients with severely symptomatic neurocardiogenic syncope: A randomized control study. J Cardiovasc Electrophysiol. 2001;12(8): 1Brignole M, et al. Europace, 2004;6: 2Di Girolamo E, et al. JACC. 1999;33: 3Raviele A, et al. Circ. 1999;99: 4Ward C, et al. Heart. 1998;79:45-49. 5Perez-Lugones A, et al. J Cardiovasc Electrophysiol. 2001;12(8):

Symptom-Free Interval
Midodrine for VVS 100 80 60 40 20 Midodrine Symptom-Free Interval Fluid Findings from a clinical trial in which salt/volume therapy and midodrine treatment were compared in VVS patients. Midodrine proved to be more effective than volume alone in this selected patient population. Perez-Lugones A, Schweikert R, Pavia S, et al. Usefulness of midodrine in patients with severely symptomatic neurocardiogenic syncope: A randomized control study. J Cardiovasc Electrophysiol. 2001;12(8): p < 0.001 180 160 140 120 100 80 60 40 20 Months Perez-Lugones A, Schweikert R, Pavia S, et al. J Cardiovasc Electrophysiol. 2001;12(8):

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 The role of pacing therapy for the treatment of vasovagal syncope is controversial. Some studies have shown a benefit1-3 and others have not.4-6 Outcomes with pacing depend in part on the patient population and the selection criteria for a pacemaker. Older patients, and those with long asystolic pauses and little vasodilatation, are the most likely to benefit from a pacemaker. This should be considered the therapy of last resort if no other medical therapy is effective for the patient.7 1Connolly SJ, Sheldon R, Roberts RS, Gent M. Vasovagal pacemaker study investigators. The North American vasovagal pacemaker study (VPS): A randomized trial of permanent cardiac pacing for the prevention of vasovagal syncope. J Am Coll Cardiol. 1999;33:16-20. 2Sutton R, Brignole M, Menozzi C, et al. Dual-chamber pacing is efficacious in treatment of neurally-mediated tilt-positive cardioinhibitory syncope. Pacemaker versus no therapy: a multicenter randomized study. Circulation. 2000;102: 3Ammirati F, Colivicchi F, Santini M. Permanent cardiac pacing versus medical treatment for the prevention of recurrent vasovagal syncope. Circulation. 2001;104:52-57. 4Connolly S, Sheldon R, Thorpe K, et al. Pacemaker therapy for prevention of syncope in patients with recurrent severe vasovagal syncope (VPS II) JAMA. 2003;289:2224–2229. 5Giada F, Raviele A, Menozzi C, et al. The vasovagal syncope and pacing trial (Synpace). A randomized placebo-controlled study of permanent pacing for treatment of recurrent vasovagal syncope. PACE. 2003;26:1016 (abstract). 6Occhetta E, Bortnik M, Audoglio R, et al. Closed loop stimulation in prevention of vasovagal syncope. Inotropy controlled pacing in vasovagal syncope (INVASY): a multicentre randomized, single blind, controlled study. Europace. 2004;6: 7Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: 1Connolly SJ. J Am Coll Cardiol. 1999;33:16-20. 2Sutton R. Circulation. 2000;102: 3Ammirati F. Circ. 2001;104:52-57. 4Connolly S. JAMA. 2003;289: 5Giada F. PACE ;26:1016 (abstract). 6Occhetta E, et al. Europace. 2004;6:

VPS I (North American Vasovagal Pacemaker Study)
Objective: To evaluate pacemaker therapy for severe recurrent vasovagal syncope Randomized, prospective, single center N=54 patients 27: DDD pacemaker with rate drop response 27: No pacemaker Inclusion: Vasodepressor response Primary outcome: First recurrence of syncope 54 patients were enrolled in the prospective North American Vasovagal Pacemaker study. Patients were randomized to rate drop response feature or to current therapy. These were patients who had standard vasovagal syncope with frequent episodes and a positive tilt table test. The tilt table test was positive by criteria of relative bradycardia and hypotension, the standard response on the tilt table test. Patients with long asystolic pauses were not included. Connolly SJ, Sheldon R, Roberts RS, Gent M. Vasovagal pacemaker study investigators. The North American vasovagal pacemaker study (VPS): A randomized trial of permanent cardiac pacing for the prevention of vasovagal syncope. J Am Coll Cardiol. 1999;33:16-20. Connolly SJ. J Am Coll Cardiol. 1999;33:16-20.

VPS I (North American Vasovagal Pacemaker Study)
100 90 80 No Pacemaker (PM) 70 60 2P= Cumulative Risk (%) 50 40 30 Pacemaker 20 Final analysis found: 6/27 (22%) with pacemakers had syncope recurrence 19/27 (70%) without pacemakers had syncope recurrence The study reported an 84% relative risk reduction (RRR) in pacemaker group versus standard therapy. The study was halted when early stopping criteria were achieved (p<0.001 in favor of pacing). Connolly SJ, Sheldon R, Roberts RS, Gent M. Vasovagal pacemaker study investigators. The North American vasovagal pacemaker study (VPS): A randomized trial of permanent cardiac pacing for the prevention of vasovagal syncope. J Am Coll Cardiol ;33:16-20. 10 3 6 9 12 15 Time in Months Results: 6 (22%) with PM had recurrence vs. 19 (70%) without PM 84% RRR (2p= ) Connolly SJ. J Am Coll Cardiol. 1999;33:16-20.

VASIS (VAsovagal Syncope International Study)
Objective: To evaluate pacemaker therapy for severe cardioinhibitory tilt-positive neurally mediated syncope Randomized, prospective, multi-center N=42 patients 19: DDI pacemaker (80 bpm) with rate hysteresis (45 bpm) 23: No pacemaker Inclusion: Positive cardioinhibitory response Primary outcome: First recurrence of syncope The VASIS trial examined the effectiveness of cardiac pacing in patients with recurrent VVS symptoms and evidence of a bradycardia component during evaluation. Differences between this study and the VPS 1 Trial were that these patients had cardioinhibitory tilt-positive neurally-mediated syncope. Sutton R, Brignole M, Menozzi C, et al. Dual-chamber pacing is efficacious in treatment of neurally-mediated tilt-positive cardioinhibitory syncope. Pacemaker versus no therapy: a multicenter randomized study. Circulation. 2000;102: Sutton R. Circulation. 2000;102:

VASIS (VAsovagal Syncope International Study)
Pacemaker (PM) 100 80 p=0.0004 % Syncope-Free 60 40 No Pacemaker 20 As was the case in the VPS 1 study, pacing was more effective than conventional therapy in terms of preventing syncope recurrences. The VASIS intention-to-treat data are presented in Kaplan-Meier format. Sutton R, Brignole M, Menozzi C, et al. Dual-chamber pacing is efficacious in treatment of neurally-mediated tilt-positive cardioinhibitory syncope. Pacemaker versus no therapy: a multicenter randomized study. Circulation. 2000;102: 2 3 4 5 6 Years Results: 1 (5%) with PM had recurrence vs. 14 (61%) without PM Sutton R. Circulation. 2000;102:

SYDIT (SYncope DIagnosis and Treatment)
Objective: To compare the effects of cardiac pacing with pharmacological therapy in patients with recurrent vasovagal syncope Randomized, prospective, multi-center N=93 patients 46: DDD pacemaker with rate drop response 47: Atenolol 100 mg/d Inclusion: Positive HUT with relative bradycardia Primary outcome: First recurrence of syncope SYDIT is a randomized, prospective, multi-center trial of 93 patients that compared the effects of cardiac pacing with pharmacological therapy in patients with recurrent vasovagal syncope. Patients were randomized to DDD pacemaker with rate drop response, or atenolol, 100 mg/d. To be enrolled, patients had to have a positive HUT with relative bradycardia. The primary outcome was the first recurrence of syncope. Ammirati F, Colivicchi F, Santini M. Permanent cardiac pacing versus medical treatment for the prevention of recurrent vasovagal syncope. Circulation. 2001;104:52-57. Ammirati F. Circulation. 2001;104:52-57.

SYDIT (SYncope DIagnosis and Treatment)
1.0 Pacemaker (PM) 0.9 % Syncope-Free 0.8 p=0.0032 0.7 Drug Final analysis found: 2 (4%) with pacemakers had syncope recurrence 12 (26%) without pacemakers had syncope recurrence DDD pacing with rate drop response function is more effective than β-blockage for the prevention of syncopal recurrences in patients with highly symptomatic vasovagal syncope with relative bradycardia during tilt-induced syncope. The SYDIT intention-to-treat data are presented in Kaplan-Meier format. Ammirati F, Colivicchi F, Santini M. Permanent cardiac pacing versus medical treatment for the prevention of recurrent vasovagal syncope. Circulation. 2001;104:52-57. 0.6 100 200 300 400 500 600 700 800 900 1000 Time (Days) Results: 2 (4%) with PM had syncope recurrence vs. 12 (26%) without PM Ammirati F. Circulation. 2001;104:52-57.

VPS II (Vasovagal Pacemaker Study II)
Objective: To determine if pacing therapy reduces the risk of syncope in patients with vasovagal syncope Randomized, double-blind, prospective, multi-center N=100 patients 52: Only sensing without pacing 48: DDD pacemaker with rate drop response Inclusion: Positive HUT with (HRxBP) < 6000/min x mm Hg Primary outcome: First recurrence of syncope The VPS II trial was designed to investigate whether the dramatic changes observed with pacing therapy were due to the actual pacing or to a placebo effect. This was a highly select population of patients. To be included, patients had to experience frequent syncope and have a positive head up tilt test with a heart rate x blood pressure product less than 6000/min x mm Hg. The objective was to determine if pacing therapy reduces the risk of syncope in patients with vasovagal syncope. The study was randomized, double-blind, prospective, multi-center, and included 100 patients. Fifty-two had a pacemaker implanted but set to sense only. The remaining patients had a pacemaker programmed to DDD pacing with rate drop response. The primary outcome of the study was time to the first recurrence of syncope. Connolly S, Sheldon R, Thorpe K, et al. Pacemaker therapy for prevention of syncope in patients with recurrent severe vasovagal syncope (VPS II) JAMA. 2003;289:2224–2229. Connolly S. JAMA. 2003;289:

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 Final analysis found: 22/52 (42%) with only sensing had syncope recurrence within 6 months 16/48 (33%) with DDD pacemaker had syncope recurrence within 6 months The relative risk reduction in time to syncope with DDD pacing was 30% (not statistically significant). Results favored pacing but the treatment effect was not statistically significant. The study results raise the question of whether pacemakers have any role in the treatment of vasovagal syncope beyond a placebo effect. The VPS II trial did not show any advantage of a pacemaker for this population but this population was select. Patients with long asystolic episodes may benefit from a pacemaker but first the episodes need to be documented. The patient should be considered resistant to other medical therapies. The VPS II intention-to-treat data are presented in Kaplan-Meier format. Connolly S, Sheldon R, Thorpe K, et al. Pacemaker therapy for prevention of syncope in patients with recurrent severe vasovagal syncope (VPS II). JAMA. 2003;289:2224–2229. 1 2 3 4 5 6 Months Since Randomization Results: 33% with pacing had recurrence vs. 42% with only sensing (not statistically significant) Connolly S. JAMA. 2003;289:2224–2229.

SYNPACE (Vasovagal SYNcope and PACing)
Objective: To determine if pacing therapy will reduce syncope relapses in patients with recurrent vasovagal syncope, compared to those with a pacemaker programmed to OFF Randomized, double-blind, prospective, multi-center, placebo-controlled N=29 patients 16: DDD PM with rate drop response programmed ON 13: PM programmed OFF (OOO mode) Inclusion: Recurrent VVS and +HUT with asystolic or mixed response Primary outcome: First recurrence of syncope PM=Pacemaker SYNPACE is a randomized, double-blind, prospective, multi-center, placebo-controlled trial of 29 patients. The aim was to ascertain whether, in patients with recurrent tilt-induced vasovagal syncope, a dual chamber pacemaker programmed to ON reduced the number syncopal relapses and/or prolonged the time to the first recurrence, compared to patients with a pacemaker programmed to OFF. Raviele A, Giada F, Sutton R, et al. The vasovagal syncope and pacing (Synpace) trial: Rationale and study design. Europace. 2001;3: Raviele A, Giada F, Menozzi C, et al. Vasovagal Syncope and Pacing Trial Investigators. A randomized, double-blind, placebo-controlled study of permanent cardiac pacing for the treatment of recurrent tilt-induced vasovagal syncope. The vasovagal syncope and pacing trial (SYNPACE). Eur Heart J. 2004;25: Raviele A.. Europace. 2001;3:336–341. Raviele A, et al. Eur Heart J. 2004;25:

SYNPACE (Vasovagal SYNcope and PACing)
1.0 0.9 p=0.58 0.8 0.7 Pacemaker OFF 0.6 % Syncope-Free 0.5 Pacemaker ON 0.4 0.3 0.2 Final analysis found that during a median of 715 days of follow-up: 8/16 (50%) patients randomized to pacemaker programmed ON had recurrence of syncope 5/13 (38%) patients randomized to pacemaker programmed to OFF had recurrence of syncope Median time to first syncope was longer in the pacemaker ON group, although not significantly so (p=0.38) No significant difference in the subgroups of patients who had had a mixed response and in those who had had an asystolic response during head-up tilt testing The SYNPACE intention-to-treat data are presented in Kaplan-Meier format. Raviele A, Giada F, Menozzi C, et al. Vasovagal Syncope and Pacing Trial Investigators. A randomized, double-blind, placebo-controlled study of permanent cardiac pacing for the treatment of recurrent tilt-induced vasovagal syncope. The vasovagal syncope and pacing trial (SYNPACE). Eur Heart J. 2004;25: 0.1 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. 2004;25:

INVASY (INotropy Controlled Pacing in VAsovagal Syncope)
Objective: To evaluate Closed Loop Stimulation (CLS), a form of rate-adaptive pacing using RV impedance, in preventing recurrence of VVS Randomized, prospective, single-blind, multi-center N=50 patients 41: CLS therapy 9: Control (pacemaker programmed in DDI) Inclusion: Recurrent VVS and +HUT with cardioinhibition Primary outcome: Recurrence of two VVSs during a minimum of 1 year of follow-up INVASY is a randomized, prospective, single-blind, multi-center trial with the objective to determine whether dual chamber, rate-adaptive Closed Loop Stimulation (CLS) could prevent recurrence of vasovagal syncope (VVS). The CLS algorithm is a form of rate-adaptive pacing which responds to myocardial contraction dynamics, by measuring variations in right ventricular intracardiac impedance. Fifty patients with severe and recurrent VVS and positive head-up tilt test with cardioinhibition, received a CLS pacemaker. Randomization between DDD-CLS and DDI mode pacing was performed only during the first stage of the study which included 26 patients: 17/26—DDD-CLS mode 9/26—DDI mode (control group) All 24 patients recruited in the second stage of the study were programmed in DDD-CLS mode. Occhetta E, Bortnik M, Audoglio R, et al. Closed loop stimulation in prevention of vasovagal syncope. Inotropy controlled pacing in vasovagal syncope (INVASY): A multicentre randomized, single blind, controlled study. Europace. 2004;6: Occhetta E, et al. Europace. 2004;6:

INVASY (INotropy Controlled Pacing in VAsovagal SYncope)
20 40 60 100 Closed Loop Stimulation (CLS) P < % Syncope-Free Control (DDI only) Final analysis found: 7/9 patients in the DDI mode had recurrence of syncope during the first year These 9 patients were then reprogrammed to the CLS mode and no more syncope occurred 0/41 patients programmed to CLS reported VVS A main limitation of this study is the low number of control subjects. The INVASY intention-to-treat data are presented in Kaplan-Meier format. Occhetta E, Bortnik M, Audoglio R, et al. Closed loop stimulation in prevention of vasovagal syncope. Inotropy controlled pacing in vasovagal syncope (INVASY): a multicentre randomized, single blind, controlled study. Europace. 2004;6: 3m 6m 9m 1y 2y 3y Time Since Randomization Results: Patients with CLS had no syncope recurrence and improved quality of life Occhetta E, et al. Europace. 2004;6:

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/ (21%) of paced patients, 72/162 (44%) in non-paced patients (p<0.000)2 A comparison of the patient populations of the four pacemaker trials raises the question of whether the differences in study results could be due to differences in the study populations or in tilt-testing methods. VPS and VPS II – < 30% of patients had relatively severe bradycardia VASIS and SYDIT– patients tended to have more severe bradycardia with a vast majority having asystole VASIS and SYDIT–tilt testing was fairly standardized VPS and VPS II—tilt testing was not standardized VASIS and SYDIT–patients were older Does neurally-mediated syncope in older individuals have a different pathophysiological mechanism requiring different treatments1? In the five pacing studies, 318 patients were evaluated. Syncope recurred in 33/156 (21%) of the paced patients and 72/162 (44%) of non-paced patients (p<0.000). Follow-up studies are necessary to address the limitations found in all of the studies,2 including pre-implant selection criteria of the patients who might benefit from pacemaker therapy. 1Kapoor W. Is there an effective treatment for neurally mediated syncope? JAMA ;289: 2Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: 1Kapoor W. JAMA. 2003;289: Brignole M, et al.. Europace. 2004;6:

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 Carotid sinus syndrome (CSS) is an important and often overlooked cause of syncope, and in addition is believed to be a frequent cause of unexplained falls in older individuals. The underlying cause of CSS is considered to be a hypersensitive carotid sinus. Carotid Sinus Hypersensitivity (CSH) is diagnosed by using Carotid Sinus Massage (CSM). The method of carotid sinus massage, and the findings diagnostic of CSS were presented on previous slides. Kenny RA, Richardson D, Steen N, et al. Carotid sinus syndrome: A modifiable risk factor for nonaccidental falls in older adults (SAFE PACE). J Am Coll Cardiol. 2001;38: Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Sutton R. Carotid sinus syndrome: clinical presentation, epidemiology, and natural history. In: Neurally Mediated Syncope: Pathophysiology, Investigation and Treatment. Blanc JJ, Benditt D, Sutton R. eds. Armonk, NY: Futura;1996:138. Kenny RA, et al. J Am Coll Cardiol. 2001;38: Brignole M, et al. Europace. 2004;6: Sutton R. In: Neurally Mediated Syncope: Pathophysiology, Investigation and Treatment. Blanc JJ, et al. eds. Armonk, NY: Futura;1996:138.

CSS Etiology Carotid Sinus
Sensory nerve endings in the carotid sinus walls respond to deformation “Deafferentation” of neck muscles may contribute Increased afferent signals to brain stem Reflex increase in efferent vagal activity and diminution of sympathetic tone results in bradycardia and vasodilatation Carotid Sinus The etiology of CSS rests in part from afferent signals arising in the carotid baroreceptors, and inappropriate concomitant signals from nearby neck muscles. Sensory nerve endings in the carotid sinus walls respond to deformation. An increase in afferent traffic results in cardioinhibition and vasodilatation. Deafferentation of nearby neck muscles may contribute. The CNS is not informed of neck movement and consequently the carotid baroreceptor afferents are interpreted as indicating a rise in central arterial pressure. Blanc JJ, L’Heveder J, Mansourati J, et al. Pathophysiology of carotid sinus syndrome. In: Neurally mediated syncope: Pathophysiology, investigation and treatment. Blanc JJ, Benditt D, Sutton R. eds. Armonk, NY: Futura;1996:25-29. Kenny RA, McIntosh SJ. Carotid sinus syndrome. In: Syncope in the Older Patient. Kenny RA ed. London: Chapman & Hall Medical; 1996:

Falls: Incidence, Recurrence, CSH*
50% 1 30% 1 % of Population 23% 2 Falls are the leading cause of injury among older adults, according to 1995 U.S. prevalence data.1 30% of the population older than 65 years of age falls each year, or about 9 million people in the U.S. 50% of these fallers have documented recurrence. 8% of the population greater than 70 years of age visit an ER for a fall. 40% of these visits result in hospitalization. Carotid sinus hypersensitivity and CSS increasingly are being recognized as attributable causes for unexplained falls and syncope in older adults. What is the contribution of CSS to these falls? This is an area of active research, but already-published results are suggestive. In one study, 279 fallers 50 years or older presenting to an emergency room with frequent or unexplained falls (at least 3 in previous 12 months) underwent carotid sinus massage, and 65 (23%) exhibited cardioinhibitory carotid sinus hypersensitivity.2 1Falling in the elderly: U.S. prevalence data. J Am Geriatr Soc, December, 1995. 2Richardson D, Bexton R, Shaw F, et al. Prevalence of cardioinhibitory carotid sinus hypersensitivity in patients 50 years or over presenting to the accident and emergency department with “unexplained” or “recurrent” falls. PACE ;20: Incidence > Age 65 Recurrence CSH* Present in Fallers > Age 50 Presenting at ER *Carotid Sinus Hypersensitivity 1 J Am Geriatr Soc 2 Richardson D, et al. PACE. 1997;20:820.

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 CSS is a Class I indication for pacing (AHA and BPEG). Pacing therapy may be effective for CSS that is either Cardioinhibitory or Mixed cardioinhibitory/vasodepressor AV sequential pacing (DDD/DDI) is clearly preferable to ventricular demand (VVI) pacing. Wagshal AB, Wang SKS. Carotid sinus hypersensitivity. In: Syncope: Mechanisms and Management. Grubb BP, Olshansky B. eds. Armonk, NY: Futura;1998: Brignole M, Menozzi C. Carotid sinus syndrome: Diagnosis, natural history and treatment. Eur J C P E. 1992;4: Brignole M, et al. Eur JCPE. 1992;4:

SAFE PACE Syncope 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 (N=175) Adults > 50 years, non-accidental fall, positive CSM Pacing (n=87) vs. No Pacing (n=88) 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% The study was a randomized controlled trial, pacing versus no pacing, performed at the Royal Victoria Infirmary in Newcastle, between April 1998 and May Patients were followed for 12 months after randomization. The inclusion criteria were consecutive adults, over the age of 50 years, presenting with a non-accidental fall, who exhibited a positive response to CSM and who had no evidence of cognitive impairment or dementia. In patients with unexplained falls and a diagnosis of cardioinhibitory carotid sinus hypersensitivity, cardiac pacing reduced the total number of falls by 70%, total syncopal events by 53%, and total injurious events by 70%. There was a statistically significant reduction in the total number of falls among the pacemaker patient group, with a 70% reduction in total falls compared with the control group. Only 28 patients reported syncope; 22 syncopal events were reported by paced patients and 47 by controls. Although there was a 50% reduction in the overall number of syncopal episodes, this did not reach statistical significance. There was also a 70% reduction in the total number of injury events, from 202 in the control group to 61 in paced patients. Kenny RA, Richardson D, Steen N, et al. Carotid sinus syndrome: A modifiable risk factor for nonaccidental falls in older adults (SAFE PACE). J Am Coll Cardiol. 2001;38: Kenny RA. J Am Coll Cardiol. 2001;38:

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, Richardson D, Steen N, et al. Carotid sinus syndrome: A modifiable risk factor for nonaccidental falls in older adults (SAFE PACE). J Am Coll Cardiol. 2001;38: Kenny RA, J Am Coll Cardiol. 2001; 38:

Orthostatic Hypotension
Etiology Drug-induced (very common) Diuretics Vasodilators Primary autonomic failure Multiple system atrophy Parkinson’s Disease Postural Orthostatic Tachycardia Syndrome (POTS) Secondary autonomic failure Diabetes Alcohol Amyloid Orthostatic hypotension is an important cause of syncope. The medical history is usually sufficient to establish the diagnosis. However, defining the specific cause requires careful consideration of a number of important conditions. The most important conditions predisposing to orthostatic syncope are listed here. Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Brignole M, et al. Europace, 2004;6:

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, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Brignole M, et al. Europace, 2004;6:

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, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Brignole M, et al. Europace. 2004;6:

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 Most recently the Syncope Evaluation in the Emergency Department Study (SEEDS) was performed at the Mayo Clinic.* It became clear that a careful evaluation performed in a syncope unit in the Emergency Department was much more beneficial than admission to the hospital. Prospective randomized clinical trial: syncope unit evaluation vs. standard care. N=103 consecutive patients 51 randomized to the syncope unit 52 received standard care Presumptive diagnosis was established in 34 (67%) and 5 (10%) patients (P<0.001), for the syncope unit and standard care groups, respectively Hospital admission was required for 22 (43%) and 51 (98%) patients (P<0.001) Actuarial survival was 97% and 90% (P=0.30) Survival free from recurrent syncope was 88% and 89% (P=0.72) at 2 years Total patient-hospital days were reduced from 140 to 64 Conclusion: A syncope unit designed for this study significantly improved diagnostic yield in the emergency department and reduced hospital admission and total length of hospital stay without affecting recurrent syncope and all-cause mortality among intermediate-risk patients. *Shen W, Decker W, Smars P, et al. Syncope evaluation in the emergency department study (SEEDS). Circulation. 2004;110: 70% 70% 1 2 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):

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 The role of a local integrated syncope service is to set standards for, and optimize effectiveness of, the evaluation and treatment of syncope patients at a given center.1 A cohesive, structured care pathway, either delivered within a single syncope facility or as a more multi-faceted service, is recommended for the global assessment of the patient with syncope. Experience and training in key components of cardiology, neurology, emergency, and geriatric medicine are pertinent. Core equipment for the facility includes: surface ECG recording, phasic blood pressure monitoring, tilt table testing equipment, external and internal (insertable) ECG loop recorder systems, 24 hour ambulatory blood pressure monitoring, 24 hour ambulatory ECG, and autonomic function testing. Preferential access to other tests or therapy for syncope should be guaranteed and standardized. The majority of syncope patients should be investigated as out-patients or day cases.2 1Kenny RA, Brignole M. Organizing management of syncope in the hospital and clinic (the syncope unit). In: Benditt D, Blanc J-J, et al. eds. The Evaluation and Treatment of Syncope. Elmsford, NY: Futura;2003:55-60. 2Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope— Update Europace. 2004;6: 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:

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, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Brignole M, et al. Europace, 2004;6:

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 Syncope impacts patient quality of life and health care costs in important ways. Establishing a precise diagnosis is often challenging due to the unpredictability of events and the limited positive predictive value of most available tests. The ‘gold standard’ remains the recording of the cardiac rhythm and if possible, the arterial pressure, during a spontaneous syncopal event. Olshansky B. Syncope: Overview and approach to management. In: Grubb B and Olshansky B. eds. Syncope: Mechanisms and Management. Armonk, NY:Futura;1998:15-71. Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope—Update Europace. 2004;6: Olshansky B. In: Grubb B and Olshansky B. eds. Syncope: Mechanisms and Management. Futura. 1998:15-71. Brignole M, et al. Europace, 2004;6:

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. 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 and/or consult Medtronic’s website at To learn more about syncope, visit Caution: Federal law (USA) restricts this device to sale by or on the order of a physician. 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. 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 and/or consult Medtronic’s website at To learn more about syncope, visit Caution: Federal law (USA) restricts this device to sale by or on the order of a physician.

Transient Loss of Consciousness (TLOC)

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