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SyncopePeter Netzler
AnMed Health Arrhythmia SpecialistsFebruary 22, 2014
Syncope
I have no disclosures1. Incidence and prevalence2. Broad differential3. Risk Stratification4. Work up and treatment for vasovagal syncope5. Conclusions
Syncope
Transient, abrupt, loss of consciousness, with rapid, usually complete, recovery, with or without a prodrome, caused by cerebral hypoperfusion
Derives from the Greek word synkoptein, meaning “to cut short”
A common, non-specific, alarming, debilitating, symptom with diverse causes and the key in making the diagnosis is in the History and Physical
Dilemma: Avoid over-testing yet avoid under-diagnosing life-threatening causes
1 Engel GL. Psychologic stress, vasodepressor syncope, and sudden death. Ann Intern Med 1978; 89: 403-412.
Cause of Syncope* - Recent Data
Framingham Cohort – 727 patients*
*Soteriades ES et al. N Engl J Med 2002;347:878-885**Linzer M et al Ann Int Med 1997;126:989
Pooled Data Five Studies**
Cause Prevalence %Men Women
Vasovagal 19.8 22.2Orthostatic 8.6 9.9Cardiac 13.2 6.7Seizure 7.2 3.2Stroke/TIA 4.3 4.0Medication 6.3 7.2Other 9.5 6.1Unknown 31.0 40.7
*Full differential diagnosis beyond scope of talk
Cause %Vasovagal 18Situational 5Orthostatic 8Cardiac 18Medication 3Psychiatric 2Neurologic 10Carotid sinus 1Unknown 34
SYNCOPE – Background
Syncope is common in the general population1
Syncope accounts for 3-5% of Emergency Department (ED) visits and 1-3% of all hospital admissions2,3
Not created equal Cardiac syncope doubled the
risk of death from any cause with a 6 mo mortality rate>10%4
Soteriades ES. N Engl J Med 2002;347:878-885
Syncope
Incidence: 500,000/year >1,000,000 evaluated annually 10% of falls due to syncope 10.2 visits/year, 3.2 specialists Cause for disability * * 20-50% of adults experience syncope at least
once in a lifetime
Impact on the Medical Community
*Krahn AD Am Heart Journal 1999;137:870**Linzer, J Clin Epidemiol, 1991;44:1037-43
Linzer, J Gen Int Med, 1994;9:181-6
Syncope: Economic Burden
Per recent data, the overall cost per hospital admission was estimated to be about $10,600.
One study found $17,000 of “unnecessary” testing to diagnosis vasovagal syncope
Overall cost in US estimated to be in excess of $1 billion.
Costs of Test Troponin $156 EKG $274 Telemetry $2,325/d Head CT $1901 MRI brain $3947 Carotid US $1294 EST $1156 Echocardiogram $1835 EEG $978
Syncope: Pathophysiology Common final pathway is
decreased cerebral perfusion Cessation of cerebral
perfusion for as little as 3-5 seconds can result in syncope
Decreased cerebral perfusion may occur as a result of decreased cardiac output or decreased systemic vascular resistance.
Syncope: Etiology
Orthostatic CardiacArrhythmia
StructuralCardio-
Pulmonary
*
1• Vasovagal• Carotid Sinus• SituationalCoughPost-
micturitionDefaecationSwallow
2• Drug Induced
• Volume Depletion
• ANSFailurePrimarySecondary
3• BradySick sinusAV block
• TachyVTSVT
• Inherited
4 • Aortic Stenosis• HOCM• PulmonaryHypertension
5• Psychogenic• Metabolic• Epilepsy• Intoxications• TIA• Falls
Non-Syncopal
Neurally-Mediated
Unknown Cause = 2%
66% 10% 11% 5% 6%
Brigole et al. Heart 2007;93:130-136
Cause of Syncope – By Age Younger patient
Neurocardiogenic Situational Psychiatric Long QT* Brugada’s syndrome* WPW syndrome* RV dysplasia* Hypertrophic
cardiomyopathy*
Older patient Cardiac**
Mechanical Arrhythmic
Orthostatic hypotension Drug-induced Neurally mediated Multifactorial
*infrequent but not benign **generally not benign
Underlined: generally benign
RISK STRATIFICATION
Etiology can be benign…or deadly…
that’s the rub… HISTORY alone identifies the cause up to 85% of
the time POINTS to CONSIDER
Previous episodes Character of the events, witnesses Events preceding the syncope Events during and after the episode
Short-Term High Risk Criteria Severe structural or CAD (CHF, low EF, prior MI) Clinical or EKG ->Arrhythmia
During exertion or supine Palpitations NSVT Bifascicular block Bradycardia Pre-excited QRS complex RBBB with ST elevation in V1-V3 (Brugada pattern) Long or short QT Negative T waves in right precordial leads, epsilon waves or ventricular
late potentials suggestive of ARVC Severe anemia Electrolyte disturbance
Risk Stratification‘Short-term’ Risk (1 week – 1 month)
Study Clinical Markers
San Francisco
Quinn JV, et al. Ann Emerg Med 2004;43:224.
Abnormal ECG, Low Blood Pressure, CHF, SOB,Hematocrit <30%
Rose rule
Reed MJ,et al. J Am Coll Cardiol. 2010;55:713
Abnormal ECG,Elevated BNP, Chest painFecal blood
StePs
Costantino G, et al.J Am Coll Cardiol 2008; 51:276-283
Abnormal ECG, Trauma, No warning, Male gender
Date of download: 2/22/2014
Copyright © The American College of Cardiology. All rights reserved.
From: The ROSE (Risk Stratification of Syncope in the Emergency Department) Study
J Am Coll Cardiol. 2010;55(8):713-721. doi:10.1016/j.jacc.2009.09.049
The ROSE Rule With “BRACES” Mnemonic Aide MemoireA patient should be considered high-risk and admitted if any of the 7 criteria in the ROSE (Risk stratification Of Syncope in the Emergency department) rule are present. BNP = B-type natriuretic peptide; ECG = electrocardiogram.
Figure Legend:
Syncope
History and Physical
ECG
KnownSHD
NoSHD
Echo
EPS
+
Treat
> 30 days; > 2 Events
Tilt ILR
Tilt Holter/ ELR
ILR
Tilt/ILR
< 30 days
-
Diagnostic Algorithm
Neurological Tests Carotid Dopplers, EEG,
Head CT / MRI
• Little value in syncope evaluation• Imaging only if there is concern re
head injury from ‘fall’ or seizure• EEG only if seizure concern, but inter-
ictal EEG may be non-diagnostic • Neurological consultation is advised
prior to tests
Lower Risk Patient
Overall normal EKG??? Normal ECHO or no/little concern for
structural heart disease No high risk features
NEURALLY MEDIATED SYNCOPE
Vasovagal, carotid sinus, situational
Represents 66% of patients with syncope
No increased risk for cardiovascular morbidity or mortality associated with reflex mediated syncope.
Features suggestive of Neurally-Mediated causes?
Prolonged standing in a crowded, warm place
Preceding nausea, feeling cold and sweaty After exertion or post-prandial Tonic-clonic movements are short in
duration and occur after the loss of consciousness
Long duration of symptoms …>4years
Tilt-Table Test Indications:
If a neurocardiogenic cause is suspected Recurrent syncope, no apparent cause, any age Other evaluation unrevealing Treating other potential causes ineffective
Do not tilt if etiology is clear or if tilt has dangers
1. Delepine S. Am J Cardiol 2002; 5:488-912. Raviele, A. Am J Cardiol 2000;85:1194-83. Calkins H. J Cardiovasc Electrophysiol 2001;12:797-9 4. Saadjian, A. Y Circulation 2002;106:569-74
Head-Up Tilt Test (HUT)
• Protocols vary some use provocative drugs Isuprel or nitrogylcerin
• Goals: Unmask VVS susceptibility Reproduce symptoms Patient learns VVS warning
symptoms Patient more confident of diagnosis
• Not recommended for predicting treatment benefit
VVS: Typical HUT Protocols
• Basic Preparation 4 hour fast Continuous ECG monitor Continuous BP monitor
• Finometer® or equivalent preferred• Arterial line
• if placed >1 hour before
• Sphygmomanometer BP discouraged• disruptive to Autonomic Nervous system
Moya A et al, ESC Syncope Guidelines, Eur Heart J 2009; 30: 2631-71
Minimally Disruptive Beat-to beat BP
Typical HUT Protocol Supine rest period 5-20 min Tilt to 60-70°for 20 min Positive end-point: Syncope with reproduction of
symptoms If negative, then add drug provocation while still
upright• Nitroglycerine 0.4mg SL, or• Isoproterenol 1-5 mcg/min, to increase HR to 125%
baseline Extend tilt after drug, duration 10-15 minutes Test completion without syncope is a negative
resultMoya A et al, ESC Syncope Guidelines,
Eur Heart J 2009; 30: 2631-71
Tilt-Table Findings
NeurocardiogenicSudden hypotension with or without bradycardia
DysautonomicGradual parallel decline in systolic and diastolic blood pressure
POTSAn excessive heart rate response to maintain a low normal BP
Cerebral syncopeSyncope associated with cerebral vasoconstriction in the absence of systemic hypotension
PsychogenicNo change in heat rate, BP, EEG, transcranial blood flow
“Neurocardiogenic” Responses
Vasovagal International Study Group Type 1-Mixed: BP falls then HR (<3 sec pause) Type 2A - Cardioinhibitory: BP falls then HR Type 2B - Cardioinhibitory: HR falls >10 sec or >3
sec pause before BP falls Type 3 - Pure vasodepressor: BP falls
What does it all mean? Is it reproducible? How do we treat it?
Vasovagal International Study Group
ILR
Small subcutaneous implantable monitoring device
2009 ESC Guidelines recommend for: Early phase evaluation
Recurrent syncope with absence of high risk features Suspected or proven reflex syncope before pacing
Late evaluation High risk syncope without eitology after exhaustive w/u
Insertable Cardiac Monitors (ICM)
Reveal® System, Medtronic Inc.Minneapolis, MN-manual/auto trigger-remote download (CareLink®)
Confirm®, St Jude MedicalSt Paul, MN-manual/auto trigger-remote download (Merlin®)
Clinical Trials
• RAST (Randomized Assessment of Syncope Trial)1
• EasyAs 1 (Eastbourne Syncope Assessment Study)2
• ISSUE 1 (International Study on Syncope of3,4,5 Unexplained Etiology)
• ISSUE 2 and ISSUE 36,7
• PICTURE81 Krahn AD, et al. Circ. 2001;104:46-51.
1Krahn AD, et al. JACC 2003;42:495-501.2Farwell D et al. Eur Heart J 2006; 27: 351-356
3Moya A. Circulation 2001; 104: 1261-12674Menozzi C. Circulation 2002; 105: 2741-27455Brignole M. Circulation 2001; 104: 2045-2050
6Brignole M et al, Eur Heart J 2006; 27:10857Brignole M, Circulation 2012;125:2566-71
8Edvardsson N et al, Europace 2011;13:2629Hong PS et al, PACE 2010; 33;763-5
Randomized Assessment of Syncope Trial (RAST)
Results: Combining primary strategy with crossover, the diagnostic yield is
43% ILR only vs. 20% conventional only1
Cost/diagnosis is 26% less than conventional testing2
1Krahn AD, et al. Circ. 2001;104:46-51. 2Krahn AD, et al. JACC 2003;42:495-501.
Unexplained SyncopeEF > 35%
60 Patients
AECG, Tilt,EP Study
Diagnosis
ILR
+–
+
–
ILR Conventional Testing(AECG, Tilt, EPS)
30 Patients 30 Patients
PrimaryStrategy
Crossover
14 6
1 8+ +
Neurocardiogenic Syncope Tilt +, High suspicion (pretest probability
despite tilt -) Patient education about pathophysiology of
VVS and benign prognosis Increase salt and water intake If prodrome, sit or lie down Tilt-training or counterpressure manuevers Leg compression
Tilt training: > 90% effective1-3
First line: Treatment Options
1. Di Girolamo E Circulation 1999;100:17982. Reybrouck T PACE 2000;23:4933. Ector H et al PACE 1998; 21:193-6.
Tilt-Training: Clinical Outcomes
Of 42 tilt positive patients (21±13 min), home training: two 30 minute sessions daily
Outcome: 41/42 ->45 min asymptomatic tilt Follow-up: 15.1±7.8 mos
36 syncope free; 4 “presyncope”; 1 recurrence
Reybrouck et al. PACE 2000; 23:493-8
Neurocardiogenic Syncope
Neurocardiogenic Syncope
Beta-blockers SSRIs Midodrine Fludrocortisone
Anticholinergics (disopyramide, scopolamine)
Desmopressin Erythropoietin Theophylline
Drug Therapies: Second Line
Beta Blockers
Initial observations suggest syncope reduction Rationale is that B-receptor involvement in
ventricular baroreceptor reflexes Isuprel (B agonist) can trigger hypotension and
bradycardia and BB can prevent the Isuprel effect
At least 4 randomized trials have failed to show benefit but difficult to demonstrate statistical benefit when placebo effect is so high
Best data from the POST trial
208 patients with recurrent syncope and an abnormal tilt table test
Placebo vs metoprolol (avg dose 122mg daily) with 1 year follow up
Recurrent syncope occurred in 36 percent of both groups.
Withdrawal rates were 22 percent in both groups. Prespecified analyses according to age (categorized as
<42 versus ≥42 years) and tilt table test results did not identify any subgroups that benefited with metoprolol.
Sheldon R et al. Circulation 2006;113:1164-1170
FLUDROCORTISONE
Corticosteroid with primarily mineralcorticoid activity
Sodium and water retention and potassium excretion
POST II (multinational, randomized, controlled) 211 pts (fludrocortisone vs placebo) for 1yr Trend of less events in the fludrocortisone
group but NO statistical difference
MIDODRINE
Pro-drug- active metabolite is a peripheral alpha-1 adrenergic receptor Causes venoconstriction and arteriolar constriction Increases cardiac output and incresases peripheral
resistance
More effective than Na/volume therapy alone Challenge is frequent dosing compliance POST 4 (placebo vs midodrine) results due in
2017
SSRIs
High serotonin levels in the nervous system Serotonin modulates the CNS BP and HR Di Gerolamo et al conducted a randomized,
double-blind, placebo-controlled trial Paroxetine (20mg QD) vs placebo over ~25 mo Reduction in syncope recurrence
18% with Paxil vs 53% with placebo Other studies have found other SSRIs of no benefit Can be helpful in psychosocial stressors due to
syncope
Pacemakers
Any role? Often a significant bradycardic response in VVS But severe vasodepressor reactions often coexist
Does Asystole Cause Syncope?
Asystole
Passed outTilt
VPS-IVasovagal Pacemaker Study I
Connolly S, et al. J Am Coll Cardiol 1999; 33: 16-20.
Study Design:54 patients randomized, prospective, single center
_ 27 DDD pacemaker with rate drop response (RDR)_ 27 no pacemaker
Patient Inclusion Criteria:6 syncopal events ever+HUTRelative bradycardia*
Risk of Syncope Recurrence100
908070605040
30201000 3 6 9 12 15
Time in Months
No Pacemaker
2P=0.000022
PacemakerCum
ulat
ive
Risk
(%)
Control Group n = 27 9 4 2 1 0Pacemaker Group n = 27 21 17 12 11 8
The VPS I Study
Connolly SJ. J Am Coll Cardiol 33:16-20, 1999
Inclusion: vasodepressor response
VPS II Trial – Big Placebo Effect
Connolly S. JAMA 2003:289:2224–2229
Time to First Recurrence of Syncope
•Syncope > 5 total or > 2 episodes in 2 years, positive tilt, age > 19
•RR reduction 29%
ILR FIRST THEN PM???• ISSUE 3 Population• Diagnosis: Reflex (neurally-mediated) VVS• Mean age at presentation: >60 years• Recurrent syncope beginning in middle or older age • Clinical presentation sufficiently severe to require
treatment (high risk and/or high frequency)• Atypical presentation without warning• Injuries related to presentation without warning• ILR documentation of marked bradycardia (mean pause
duration, 11 seconds)Brignole M, Circulation 2012;125:2566-71
ISSUE-3 Study design
-mediated syncope
ILR implantation (Reveal DX/XT)
ILR follow-up (max 2 yrs)
ILR screening phaseILR eligibility criteria:• Asystolic syncope ≥3 s, or• Non-syncopal asystole ≥6 s
ISSUE 3 studyphase
Randomization
PM ON PM OFF
Time to first syncope recurrenceEndpointBrignole M, Circulation 2012;125:2566-71
0
.1
.2
.3
.4
.5
.6
.7
.8
.9
1
Free
dom
from
syn
copa
l rec
urre
nce
38 32 27 22 16 14 13 13 11Pm ON39 31 25 21 21 18 15 12 8Pm OFF
Number at risk
0 3 6 9 12 15 18 21 24Months
Kaplan-Meier survival estimates
log rank: p=0.039RRR at 2 yrs: 57%
PM ON
PM OFF
ISSUE-3: Intention-to-Treat
25%
37%
25%
57%
Brignole M, Circulation 2012;125:2566-71
ISSUE-3 Conclusion
• In patients ≥40 years with severe asystolic NMS:
•Dual-chamber pacing reduces recurrence of syncope
•The 32% absolute and 57% relative syncope reduction rate support use pacing.
• The strategy of using ILR to determine indication for pacing likely explains the positive outcome and difference from prior negative results in pacemaker studies.
Brignole M, Circulation 2012;125:2566-71
Carotid Sinus Syndrome (CSS)
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
Brignole et al. Eur Heart J 2001;22:1256--1306
CSSProposed Mechanisms
• Sensory nerve endings in the carotid sinus walls respond to deformation
• “Deafferentation” of neck muscles may contribute as the CNS doesn’t realize the neck is moving
• Afferent signals to brain stem interpreted as arterial pressure
• Reflex increase in efferent vagal activity and diminution of sympathetic tone results in bradycardia and vasodilation
Carotid Sinus
CSS - Carotid Sinus SyndromeDiagnosis
• Carotid Sinus Hypersensitivity (CSH) implies positive response to carotid massage: ≥50 mmHg drop in systolic pressure ≥6 sec asystolic pause CSS = CSH + Reproduction of symptoms
• CSH without symptoms is not treated• CSS needs a DDD PM
Moya A et al, ESC Syncope Guidelines, Eur Heart J 2009; 30: 2631-71
Conclusion
Syncope is common Risk stratification important High risk patients require further testing and
hospitalization Low risk patients can be discharged for further
evaluation as an outpatient
Etiology can be difficult to decipher Requires good history and physical Treatment is education first Remember that placebo has been very effective
thus education and empowerment should be as effective
Tilt studies and ILR monitoring can be helpful PMs for >3s asystolic syncope, asymptomatic >6s
pause and Carotid Sinus Syndrome
Questions?