Vasovagal Syncope

1
Vasovagal Syncope

• Jeffrey H. Breiner, M.D.
• Resident Grand Rounds
• April 21, 1998

2
Definition

• Syncope that results from a paradoxical imbalance
  between sympathetic and parasympathetic tone, as
  it pertains to heart rate and vascular resistance
  
• This imbalance results in temporary but classic
  hypotension with absolute or relative
  bradycardia.
• a.k.a. Neurocardiogenic or Vasodepressor Syncope.

3
Historical Observations

• First characterized and described by T. Lewis in
  1932
• Observations made by Hunter, over 200 years ago
  and Barcroft Edholm, in 1945
• that during hemorrhagic hypotension induced
  fainting, phlebotomized blood was actually a fine
  scarlet color
• Much speculation over its evolutionarily adaptive
  role --- theplay dead response, in a time when
  predators even more fierce than humans existed

4
Features

• More of a pathologic and paradoxical reflex than
  a disease
• Occurs in people of all ages, both healthy and
  chronically ill
• Can occur during either a sitting or standing
  position

5
Features, cont.

• Usually preceded by prodromal symptoms
• weakness, nausea, diaphoresis, light headedness,
  sense of impending darkness
• Followed by signs/symptoms
• tachycardia, pallor, abrupt bradycardia,
  diaphoresis, pupillary constriction, and finally
  decreased cerebral perfusion resulting in
  syncope.

6
Features, cont.

• Duration is only a few minutes and can be
  reversed by supination and removal from provoking
  environmental conditions
• hot or crowded setting, alcohol, dehydration,
  extreme fatigue, hunger, chronic recumbency,
  prolonged standing, emotionally charged,
  frightening or stressful situations

7
Epidemiology

• Very little epidemiological data on syncope from
  vasovagal etiology
• Syncope of all types accounts for 3 of all ER
  visits and up to 6 of U.S. hospital admissions
• At least 3 of the population will experience a
  syncopal episode (during a 25 year observation
  period)

8
Epidemiology, cont.

• Only 57 of patients (n433) in a long term
  follow-up study had a discrete cause of syncope
  discovered
• Neurally mediated syncope was the single most
  frequent diagnosis (30)
• Vasovagal syncope may account for at least 20 of
  patients referred to tertiary care centers for
  syncope evaluation

9
Economic Impact

• The work-up of syncope is sometimes associated
  with misadventure and increased cost of
  evaluation
• In 1990, Calkins, et al. reported the average
  cost of a diagnostic work-up before tertiary
  referral to be greater than 4,000.00
• In addition to medical costs to the patient and
  the healthcare system, the impact of illness on
  the individual is often underestimated

10
Classification Nomenclature

• Neurally mediated syncope can be broken down into
  the following
• Classic Vasovagal/Neurocardiogenic
• Situational Syncope (vasovagal syncope due to
  predictable/reproducible situations)
• coughing, sneezing, trumpet playing, weight
  lifting and other activities associated with
  valsalva
• defecation/micturition
• barometric changes due to diving
• postprandial
• any form of vagal stimulation

11
Classification Nomenclature, cont.

• Orthostatic Syncope
• NO vagal hyperactivity
• simple result of venous pooling of blood
• hyperadrenergic form
• often in setting of dehydration, venous
  insufficiency, or preload dependant cardiac
  output states (heartfailure, valvular disease)
• typically elderly, diabetic, and associated with
  cardiovascular or psychotropic medications (TCA,
  etc.)
• hypoadrenergic form
• primary autonomic insufficiency
• Shy-Drager or Bradbury-Eggleston Syndrome
• secondary autonomic insufficiency
• commonly due to alcohol or diabetes mellitus

12
Classification Nomenclature, cont.

• Carotid Sinus Syncope/Carotid Hypersensitivity
• the most uncommon form of neurally mediated
  syncope
• results from hypersensitivity of sinus
  baroreceptors
• can result in bradycardia or arrest (the more
  common cardioinhibitory type), vasodilation
  (vasodepressor type), or both (mixed)

13
Normal Physiology

• Normally, from supine to upright position, up to
  one liter of venous blood is shifted from the
  thorax to the lower extremities
• To preserve cerebral perfusion, the baroreceptors
  in the carotid sinus and aortic arch reduce their
  inhibitory control of the vasomotor center of the
  medulla
• Sympathetic tone is enhanced and parasympathetic
  tone is reduced

14
Normal Physiology, cont.

• Next, is a reflexive increase in neurohormones
  such as catecholamines and vasopressin to
  increase cardiac contractility, heart rate, and
  vascular resistance
• Finally, cerebral perfusion is maintained

15
Pathophysiology

• In vasovagal syncope, it is believed that there
  is a paradoxical inhibition of the sympathetic
  response expected from the baroreceptor
  stimulation
• i.e. the sympathetic response is interrupted
  before the body can achieve hemodynamic stability
• the end result is an imbalance of excess vagal
  tone and the associated sudden slowing of heart
  rate in the presence of vasodilitation

16
Afferent Pathway
CNS

• Sympathetic
• rostral ventromedial medulla
• ventrolateral medulla

• Parasympathetic
• nucleus ambiguous
• dorsal motor nucleus

Cardiac mechanoreceptors
Arterial baroreceptors
17
Afferent Pathway
CNS

• Sympathetic
• rostral ventromedial medulla
• ventrolateral medulla

• Parasympathetic
• nucleus ambiguous
• dorsal motor nucleus

Cardiac mechanoreceptors
Arterial baroreceptors
18
Pathophysiology, cont.

• During the catecholamine state, with initial
  sympathetic discharge, there is increased cardiac
  contractility
• This, coupled with low ventricular volume from
  the decreased filling, triggers the cardiac
  mechanoreceptors
• the cardiac mechanoreceptors are located in the
  base of both ventricles, especially the inferior
  wall

19
Pathophysiology, cont.

• Paradoxically and/or mistakenly, the
  mechanoreceptors and the receiving nuclei
  interpret this response to be a high volume/
  hypertensive state
• this is thought to be the pathologic step in the
  vasovagal response
• this has been confirmed with animal and human
  studies, and has been termed the Bezold-Jarisch
  reflex
• clinical examples of this have been shown in
  inferior MI, coronary angiography, and drugs
  such as nitroglycerin

20
Goals

• Define and clarify an often misunderstood but
  important problem
• Explain current, but not absolutely proven
  principles of its pathophysiology
• Examine its main diagnostic modality, the upright
  tilt table test
• Present an overview of its evaluation and
  management

21
Evaluation History

• A classic history in a younger patient with
  minimal co-morbid illness makes things easy, with
  empiric therapy usually acceptable
• Sometimes, syncope can occur with minimal or no
  prodromal symptoms, or it can be quite severe,
  with prolonged asystole
• This is termed malignant vasovagal syncope,
  which prompts aggressive therapy

22
Evaluation History, cont.

• Symptom diaries are very helpful
• to help the physician with diagnosis
• also to help the patient become aware of their
  illness, its prodromal symptoms, and prompt
  behavioral management
• Clue in on antecedent symptoms
• hypoxic convulsions vs. seizure (presence of
  post-ictal state?)
• Try to rule out other, more life threatening
  etiologies

23
Evaluation Exam

• Again, rule out other more life threatening
  illness (i.e. cardiovascular disease, valvular
  disease, cerebrovascular insufficiency, etc.)
• Check thorough orthostatic vital signs and note
  symptoms
• Look for occult traumatic injury from syncope to
  support its severity

24
Data

• This can take many forms depending on the patient
  and their presentation -- again, to evaluate for
  co-morbid illness and other syncopal etiologies
  The only real diagnostic modality besides a good
  history and physical is the Upright Tilt Table
  Test

25
Upright Tilt Table Test

• An old technology, but recently pioneered to be a
  reproducible diagnostic test by Kenny and
  colleagues in the early to mid 1980s
• Has exponentially increased our knowledge base on
  neurally mediated syncope
• Attempts at validation have been troubled due to
  lack of a gold standard (i.e. specificity data
  only, therefore the unclear meaning of a positive
  test)

26
Upright Tilt Table Test, cont.

• Reproducibility is less than perfect (on average,
  80 , higher for negative tests than positive
  ones)
• Although UTT not identical to spontaneous VV
  faint, studies following Sx, signs, temporal
  sequence of HR and BP, and plasma catecholamines
  show significant similarity
• UTT is the best, most controllable, objective and
  reproducible mode of assessment available

27
Upright Tilt Table Test, cont.

• Even despite a recent ACC consensus (1996), there
  still is no uniform protocol for the test, which
  has many variables
• tilt between 60 - 80 degrees, using footboard and
  strap support, for up to 45 minutes
• Most studies show specificity of approximately
  90, without pharmacologic provocation
  (Fitzpatrick et al., Raviele et al.)

28
Upright Tilt Table Test, cont.

• Pharmacologic provocation with isoproterenol can
  be used
• Specificity has been maximized with low dose
  isoproterenol at less steep tilt angles
• 0.5 - 3.0 mcg/min when supine, and continued
  during 10 min upright tilt
• other drugs have been tested (including
  edrophonium, adenosine, NTG), but there is much
  less data and experience with these

29
Upright Tilt Table Test, cont.

• A positive test is accurate recreation of the
  clinical episode of syncope or presyncope,
  associated with hypotension with or without
  bradycardia
• The patterns of response are important
• for example, a gradual (as opposed to abrupt)
  parallel decline in SBP and DBP is more
  characteristic of other types of autonomic
  dysfunction, as in hypoadrenergic orthostatic
  syncope

30
Management

• The main forms of treatment are
• pharmacologic
• invasive dual chamber pacing
• behavioral management
• this is a still important but under-recognized
  form of treatment, and should always be present,
  as primary therapy in very mild cases, or
  adjunctive therapy in more severe ones

31
Management Pharmacologic

• A large variety of drugs have been found to be
  useful
• Most were chosen based on the pathophysiology
  thought to be involved
• Overwhelming majority of agents came into popular
  use based on small studies, without placebo
  control, and had relatively short term follow-up

32
Management Pharmacologic, cont.

• Beta-blockers
• thought to block the early catechol induced
  inotropy in the presence of low ventricular
  filling volume, and decrease the stimulation of
  the mechanoreceptors
• probably the most studied agent, although
  introduced as treatment in only 1989
• data show conflicting results
• the most benefit is shown in patients with
  positive UTT only after isoproterenol provocation

33
Management Pharmacologic, cont.

• Some data supports IV B-blockade trial during UTT
  as a test to predict response
• Most results are from non-controlled,
  non-randomized open-label trials with small
  sample sizes
• The two most tested drugs and dosages are
• metoprolol 25-50mg bid
• atenolol 25-50mg qd

34
Management Pharmacologic, cont.

• Anti-cholinergic agents
• propanthaline (7.5-15 mg tid-qid)
• scopolamine patch (1.5 mg qod)
• supported by fewer, older studies, most with a
  high dropout rate from side effects
• this should be saved for those who have failed
  other forms of more tolerable therapy

35
Management Pharmacologic, cont.

• Disopyramide (Norpace)
• type 1A anti-arrhythmic
• both negative inotropic and anti-cholinergic
  properties
• Morillo et al. , in a recent and well recognized
  placebo-controlled trial, found neither po or IV
  to be effective

36
Management Pharmacologic, cont.

• Selective serotonin reuptake inhibitors
• Grubb et al. noticed through anecdotal
  observation that depressed patients with VVS had
  substantial improvement of their syncope after
  SSRI Rx.
• In animal models, has been shown to reduce CNS
  sympathetic activity and cause hypotension and
  bradycardia
• There also may be suppression of the baroreceptor
  reflex
• Although the exact mechanism is unknown, it is
  theorized that SSRIs blunt the cardiovascular
  response to changing serotonin levels by causing
  down regulation of receptors
• Fluoxetine, sertraline, and nefazedone have been
  shown to work in non-depressed patients in
  uncontrolled trials

37
Management Pharmacologic, cont.

• Volume expanders
• fludrocortisone (0.1 - 0.3 mg qd, with slow
  titration) is a very inexpensive, overall well
  tolerated form of therapy
• obvious side effects are salt retention,
  hypertension, and associated electrolyte
  abnormalities
• mostly anecdotal success in VVS, but considering
  pathophysiology, may seem more appropriate in
  treating hyper- and hypoadrenal orthostatic
  syncope
• empiric Rx vs. Rx after plasma volume studies

38
Management Pharmacologic, cont.

• Other various drugs reported to work, but with
  even less supporting data
• theophylline
• ephedrine
• phenylpropanolamine

39

• Interesting observations
• Morillo et al., in a large and well accepted
  placebo controlled trial, serendipitously found a
  striking decrease in the incidence of positive
  UTT over time (when UTT was repeated on patients)
  regardless of the treatment intervention (drug
  vs. no drug)
• also, recurrence of VVS was infrequent over long
  term follow up regardless of the treatment group

40

• on the contrary, Natale et al. showed repeat UTT
  offers an endpoint against which treatment can be
  assessed
• they also found that neither B-Blockers,
  theophylline, disopyramide, or ephedrine proved
  uniformly effective
• a considerable percentage of patients without
  therapy became symptom free regardless of the
  treatment group

41

• Further interesting observations
• Sheldon et al. studied 101 patients with positive
  UTT without subsequent treatment
• concluded that the most powerful predictor of
  recurrent syncope was the number of preceding
  syncopal spells
• also, the frequency of spells before UTT
  decreased by 90 post-test
• these findings not only justify expectant
  management for many patients, but should also be
  incorporated into study design while examining
  therapeutic efficacy of any intervention

42
Management Permanent Pacing

• Attempts with this alone have been met by
  frustration
• Not surprising when you consider VVS is a result
  of two separate components - heart rate AND
  vascular resistance
• Lewis (1932) wrote the following of atropine
• While raising the pulse rate up to and beyond
  normal levels during the attack, (atropine)
  leaves the blood pressure below normal, and the
  patient still pale and not fully conscious.
• Sra et al. basically made the same statement in a
  prospective, but non- placebo controlled
  comparison of drug therapy vs pacing in NEJM
• (using metoprolol, disopyramide, and theophylline
  vs dual chamber pacing at 20 above their
  baseline HR)

43
Management Permanent Pacing, cont.

• A great review by Benditt et al. in 1995
  attempted to define the role of pacing
• the usefulness of cardiac pacing remains only
  partly understood
• randomized controlled trials are needed for this
  and other aspects treatment
• Later, the ACC released a consensus statement
  after a huge literature review, and supported
  its role in the following
• cardioinhibitory VVS, where BP drops only at or
  after the heart rate drops
• malignant VVS, where there is a prolonged
  profound attack, often without warning, and often
  with associated injury
• adjunctive therapy in cases refractory to drug
  therapy

44
Management Permanent Pacing, cont.

• Existing pacing algorithms consist of a
  hysteresis feature - when it detects a HR of
  50 or less, it then goes into a paced rhythm
  usually at only 80 to 90 bpm
• New directions
• Newer technologies that detects not absolute
  brady, but the slope or the speed of the HR
  decrease, thereby with less false positives, and
  a hysteresis rate up to 110 - 120
• Advantages include earlier pacing rescue before
  florid vagal override manifests, and less false
  positive responses
• Preliminary but yet unpublished multi-center
  trials (including WFUBMC) show promising results

45
Conclusions

• VVS not always a life-threatening problem, but
  should always be taken seriously
• VVS is a very common cause of unexplained syncope
• Happens to people of all ages, and has a very
  wide spectrum of severity
• Pathophysiology is based on paradoxical
  inhibition or interruption of the normal
  sympathetic response, accompanied by
  parasympathetic imbalance, vagal tone,
  bradycardia/asystole, and vascular collapse
• Remember there are two distinct components, heart
  rate, and vascular resistance, the unique
  contribution of each depends on the patient, and
  impacts on treatment

46

• Evaluation is based on a solid history and
  physical
• Its natural history and prognosis depend on
  frequency and severity of attacks
• Refer when
• diagnosis unclear
• problems are recurrent despite conventional/empiri
  c therapy
• malignant VVS, where urgent effective therapy is
  needed, and to use UTT as a guide for Rx.
• Although much improved, UTT still lacking in
  uniformity
• Pharmacologic therapy as well as pacing
  intervention still needs placebo controlled
  randomized testing with longer follow-up

47
Case Presentation

• HPI 19 yo WF with recurrent witnessed syncopal
  episodes since age 2, approx. 5x/year. Prodromal
  symptoms include nausea, roaring sensation in
  ears, graying out, and syncope, sometimes
  associated with incontinence. One episode
  resulted in a closed head injury reqing medical
  attention. Some spells are abated in the
  prodromal phase by lying down.
• All NKDA Meds none FHx N.C.
• SocHx clothing seamstress with high-school
  education, no tob/ ETOH/drugs
• Exam 100/54 p60 supine, 96/58 p66 upright at 1,
  3, and 5min without symptoms r16, afebrile
• AAO,appropriate, pleasant wf in NAD
• HEENT/neck unrevealing

48
Case Presentation, cont.

• lungs CTA
• cor-RRR with accentuated sinus arrhythmia. No
  m/g/r
• abd-benign
• ext-warm/well perfused, no C/C/E
• neuro - non-focal
• Data- CBC/Chem unremarkable, EKG - NSR 60 with
  mild sinus arrhythmia, nl intervals without delta
  wave
• Tilt table test initially negative
• Coarse empiric b-blockers were started and
  increased with a slight improvement in severity
  and frequency
• Later, a repeat episode occurred in public, had 2
  minutes of witnessed apnea, associated with
  incontinence and seizure activity

49
Case Presentation, cont.

• repeat tilt table test showed 12 seconds of
  asystole, followed by sinus brady at 20bpm for
  two minutes
• due to the malignant nature and significant
  cardioinhibitory component, PPM (DDI) was placed
  and pharmacotherapy was continued, without
  recurrence for one year, but was then follow up
  was lost to changing health insurance