CONTEMPORARY REVIEW Evidence-based treatment for vasovagal syncope Vikas Kuriachan, MD, Robert S. Sheldon, MD, PhD, Michael Platonov, MD From the Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada. Only a minority of patients with vasovagal syncope require treatment, and most can be managed conservatively. Patients should be encouraged to liberalize their fluid and salt intake, unless they have contraindications such as hypertension. All pa- tients should be taught physical counterpressure maneuvers. Midodrine is the first-line therapy for patients having frequent presyncope or syncope or for those with brief or no prodromes. The routine use of beta-blockers, serotonin-specific reuptake inhibi- tors, fludrocortisone, and pacemakers is discouraged. Whether loop recorders can be used to target treatment is under investi- gation, as is fludrocortisone. (Heart Rhythm 2008;5:1609 –1614) © 2008 Heart Rhythm Society. All rights reserved. Introduction Vasovagal syncope frustrates patients and clinicians alike with its paucity of effective treatments. About 37% of peo- ple faint at least once in their lives. 1,2 Usually beginning in adolescence or early adulthood, the predilection to fainting persists for decades. 3 Syncope is only one of several causes of transient loss of consciousness. A useful working definition is a transient, self-limited loss of consciousness that usually leads to fall- ing, with a relatively rapid onset and a spontaneous, com- plete, and relatively rapid recovery. Vasovagal syncope is by far the most common cause of syncope in the community and the dominant cause in emergency wards. 4 It is due to a variable combination of reflex bradycardia and hypotension, triggered by prolonged sitting or standing; exposure to pain, blood, or medical procedures; heavy exercise; or getting up and moving abruptly. 5 Even in the same patient, the triggers and presentation vary from spell to spell. The hypotension may be due to a reduction in peripheral sympathetic neural outflow, leading to venous pooling and vasodepression. The central neurophysiology is unknown. Syncope is usually recurrent. In the community, the median number of faints is about two, with a much higher symptom burden in the clinical population. 1,3,4 Many pa- tients injure themselves, and recurrent syncope is associated with significantly impaired quality of life. 5 (Sheldon et al 5 contains reports published before 2004, which therefore precede the articles covered in this review.) Given this reduced quality of life, effective therapies are necessary. The treatments considered to date range from dietary mod- ification through physical training, physical maneuvers, medication, and even permanent pacemaker implantation. Surprisingly, there has not been a focused review of thera- pies with structured recommendations, although overviews of therapy have appeared in more general reviews. Here we review current treatments followed by a suggested manage- ment strategy. Each recommendation is presented with the treatment effect and level of evidence. Treatment effect is rated as probably helpful, debatable, or probably unhelpful. The evidence is summarized as good, moderate, or poor. Good evidence is derived from multiple randomized trials or meta-analyses; moderate evidence is derived from a sin- gle randomized trial or multiple nonrandomized trials; and poor evidence is simply a consensus opinion. The recom- mendations are summarized in Table 1. Important trials that appeared after 2003 are summarized in Table 2. Education and lifestyle interventions Salt and fluid Many patients with syncope are encouraged to increase their salt and fluid intake, although the evidence that this treat- ment is effective is weak. Most patients with a positive tilt test convert to a negative response on a subsequent test after receiving an intravenous volume load, and plasma and blood volumes and orthostatic tolerance all improve with dietary salt supplementation. 5 The usual reported dose of salt tablets is 6 –9 g (100 –150 mmol) per day. Salt supple- mentation should be avoided in patients with hypertension, renal disease, or cardiac dysfunction. Recommendation: In the absence of contraindications, frequently symptomatic patients should liberalize their salt and fluid intake. Probably helpful, moderate evidence. Exercise training Although exercise acutely increases blood volume, 5 there is limited evidence supporting the use of exercise training to prevent syncope. One study subjected 14 patients with syn- Supported in part by grant no. 73–1976 from the Canadian Institutes for Health Research, Ottawa, Ontario, Canada. Address reprint requests and correspondence: Dr. R. Sheldon, Cardiovascular Research Group, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada. E-mail address: [email protected]. (Received November 3, 2007; accepted August 16, 2008.) 1547-5271/$ -see front matter © 2008 Heart Rhythm Society. All rights reserved. doi:10.1016/j.hrthm.2008.08.023
Evidence-based treatment for vasovagal syncope
Dec 26, 2022
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
doi:10.1016/j.hrthm.2008.08.023t s u t M p
I V w p a p
c s i p b a v t b a a m o c
m s t w c p r T
H a U 4 3
1
vidence-based treatment for vasovagal syncope ikas Kuriachan, MD, Robert S. Sheldon, MD, PhD, Michael Platonov, MD
rom the Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
r t l g
(
Only a minority of patients with vasovagal syncope require reatment, and most can be managed conservatively. Patients hould be encouraged to liberalize their fluid and salt intake, nless they have contraindications such as hypertension. All pa- ients should be taught physical counterpressure maneuvers. idodrine is the first-line therapy for patients having frequent
i m S p o r m t r T G o g p m a
E S M s m t r b d s m r
f a
E A l p, 2007; accepted August 16, 2008.)
547-5271/$ -see front matter © 2008 Heart Rhythm Society. All rights reserved
outine use of beta-blockers, serotonin-specific reuptake inhibi- ors, fludrocortisone, and pacemakers is discouraged. Whether oop recorders can be used to target treatment is under investi- ation, as is fludrocortisone.
Heart Rhythm 2008;5:1609–1614) © 2008 Heart Rhythm Society.
resyncope or syncope or for those with brief or no prodromes. The All rights reserved.
ntroduction asovagal syncope frustrates patients and clinicians alike ith its paucity of effective treatments. About 37% of peo- le faint at least once in their lives.1,2 Usually beginning in dolescence or early adulthood, the predilection to fainting ersists for decades.3
Syncope is only one of several causes of transient loss of onsciousness. A useful working definition is a transient, elf-limited loss of consciousness that usually leads to fall- ng, with a relatively rapid onset and a spontaneous, com- lete, and relatively rapid recovery. Vasovagal syncope is y far the most common cause of syncope in the community nd the dominant cause in emergency wards.4 It is due to a ariable combination of reflex bradycardia and hypotension, riggered by prolonged sitting or standing; exposure to pain, lood, or medical procedures; heavy exercise; or getting up nd moving abruptly.5 Even in the same patient, the triggers nd presentation vary from spell to spell. The hypotension ay be due to a reduction in peripheral sympathetic neural
utflow, leading to venous pooling and vasodepression. The entral neurophysiology is unknown.
Syncope is usually recurrent. In the community, the edian number of faints is about two, with a much higher
ymptom burden in the clinical population.1,3,4 Many pa- ients injure themselves, and recurrent syncope is associated ith significantly impaired quality of life.5 (Sheldon et al5
ontains reports published before 2004, which therefore recede the articles covered in this review.) Given this educed quality of life, effective therapies are necessary. he treatments considered to date range from dietary mod-
Supported in part by grant no. 73–1976 from the Canadian Institutes for ealth Research, Ottawa, Ontario, Canada. Address reprint requests nd correspondence: Dr. R. Sheldon, Cardiovascular Research Group, niversity of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N N1, Canada. E-mail address: [email protected]. (Received November
fication through physical training, physical maneuvers, edication, and even permanent pacemaker implantation. urprisingly, there has not been a focused review of thera- ies with structured recommendations, although overviews f therapy have appeared in more general reviews. Here we eview current treatments followed by a suggested manage- ent strategy. Each recommendation is presented with the
reatment effect and level of evidence. Treatment effect is ated as probably helpful, debatable, or probably unhelpful. he evidence is summarized as good, moderate, or poor. ood evidence is derived from multiple randomized trials r meta-analyses; moderate evidence is derived from a sin- le randomized trial or multiple nonrandomized trials; and oor evidence is simply a consensus opinion. The recom- endations are summarized in Table 1. Important trials that
ppeared after 2003 are summarized in Table 2.
ducation and lifestyle interventions alt and fluid any patients with syncope are encouraged to increase their
alt and fluid intake, although the evidence that this treat- ent is effective is weak. Most patients with a positive tilt
est convert to a negative response on a subsequent test after eceiving an intravenous volume load, and plasma and lood volumes and orthostatic tolerance all improve with ietary salt supplementation.5 The usual reported dose of alt tablets is 6–9 g (100–150 mmol) per day. Salt supple- entation should be avoided in patients with hypertension,
enal disease, or cardiac dysfunction. Recommendation: In the absence of contraindications,
requently symptomatic patients should liberalize their salt nd fluid intake. Probably helpful, moderate evidence.
xercise training lthough exercise acutely increases blood volume,5 there is
imited evidence supporting the use of exercise training to
revent syncope. One study subjected 14 patients with syn-
p i
T t a m 1 n s
T t
1610 Heart Rhythm, Vol 5, No 11, November 2008
ope to a regimen of 12 minutes of daily progressive exer- ise training.5 After this, their blood volume increased .9%, and orthostatic tolerance to lower body negative pres- ure increased by 5 minutes. A recent, very underpowered andomized study did not detect a reduction in the likeli- ood of syncope in exercised patients.6
able 1 Suggested levels of recommendations with their reatment effect and level of evidence
reatment Treatment effect Evidence
evidence Physical exercise Debatable effect Weak evidence Physical counterpressure Probably helpful Good evidence
rthostatic training: Tilt training Debatable effect Moderate
evidence Home orthostatic training Probably unhelpful Good evidence
harmacologic therapy: Beta-blockers Probably unhelpful Good evidence SSRI antidepressants Debatable effect Moderate
evidence Midodrine Probably helpful Good evidence Fludrocortisone Debatable effect Weak evidence
ardiac pacemakers: Cardiac pacemakers:
Cardiac pacemakers: selected use in refractory cases with asystole
Debatable effect Weak evidence
able 2 Summary results of major randomized clinical trials of
reatment Senior author Sites, n Subject
hysical counterpressure Van Dijk9 15 223
ome orthostatic Foglia-Manzillo13 8 68
ome orthostatic Duygu14 1 82
ome orthostatic On15 1 42
etoprolol Sheldon16 14 208
idodrine Qingyou18 1 26
ludrocortisone Salim19 1 33
acemakers Connolly21 15 100
acemakers Raviele22 7 29
Only publications after 2003 are cited. NS not stated.
Recommendation: In the absence of contraindications, atients should follow relevant national guidelines regard- ng physical exercise. Debatable effect, weak evidence.
hysical counterpressure maneuvers onsiderable evidence supports the use of physical coun-
erpressure pressure maneuvers (PCMs). During PCMs, the resyncopal patient does isometric contractions of either the egs (by leg crossing) or the arms and hands (by pulling part gripped hands) or squats. These rely on a prodrome ong enough to allow the technique to prevent the progres- ion of presyncope to syncope and usually to prevent syn- ope during tilt tests.
PCM was initially thought to work by reversing the ecline in total peripheral resistance that attends vasovagal esponse. However, Van Dijk et al7,8 showed that leg cross- ng increased cardiac output 9% and arterial blood pressure % while reducing peripheral resistance. Adding leg tension urther increased systolic blood pressure and cardiac output 0% and 8%, respectively, and peripheral resistance dropped ven further. PCMs moved quickly into the clinical arena fter two positive studies of PCMs during tilt testing and ood outcomes in follow-up.9
The Physical Counterpressure Manoeuvres Trial (PC rial) was a randomized controlled trial comparing conven-
ional therapy (fluid and salt intake, counselling, avoidance) gainst conventional therapy augmented by one of three aneuvers in 208 patients with vasovagal syncope.9 After
8 months of follow-up, both groups experienced a similar umber of presyncopal episodes, yet PCMs provided a ignificant relative risk reduction of 36% of patients who
ent for vasovagal syncope
39 Syncope recurrence 51% control, 32% PCM
.005
NS
.1
47% control, 42% training
.99
41% controls, 51% propranolol, 22% fluoxetine
.05
.023
36% controls, 55% fludrocortisone
.14
NS
treatm
c d
T T s c E a c t t q g l c s t s r w c T w c t
p t w q
e t t
f c w s b e q h l d
o s r u r
a a s s
P B B w o n i v p s r
e p O r p c e
T d v 2 M c
p fi
1611Kuriachan et al Treatment of Vasovagal Syncope
ainted. Fifty-six patients on conventional treatment and 31 atients in the PCM group fainted at least once. However, 5% of patients had insufficient prodromes to perform the echniques. Finally, this was an open-label study, and the lacebo effect size is unknown.
PCMs can be adopted easily, without cost or side effects. heir physiologic rationale is well understood and the re- ults of acute and long-term follow-up have been encour- ging. In patients with presyncopal prodromes, these tech- iques should form the evidence-based core of the early, onservative care of vasovagal syncope.
Recommendation: All patients should be taught physical ounterpressure maneuvers. Probably helpful, good evi- ence.
ilt test training he imperfect reproducibility of positive tilt testing prompted peculation that this might be due to a training effect. The redit for initiating this avenue goes mainly to the group of ctor and colleagues.10 Two methods of orthostatic training re in use. Some groups have patients return daily to the linic (or remain in the hospital) for prolonged passive tilt ests culminating in syncope and continuing until the tilt ests remain negative. They are then encouraged to stand uietly against a wall for 30–60 minutes daily. Other roups skip the tilt training and progress directly to pro- onged quiet standing. The Ector group10 first reported suc- ess, tilting 42 patients with syncope in-hospital until they topped having a vasovagal response. Most converted in wo to three sessions, although some required up to eight essions. Abe et al11 trained 24 patients with medically efractory syncope in home exercises, leaning against a wall ith feet away from the base. After 1 month, the entire
ohort stopped having vasovagal responses to tilt testing. hey eventually demonstrated 100% effectiveness over 4 eeks.11 Finally, Ector et al10 tilted 202 patients until two
onsecutive tilts were negative and noted excellent long- erm outcomes in patients who were compliant.
Other acute studies are less encouraging. Kinay et al12
erformed repetitive tilt training in 32 patients and found hat although 20 responded by the second session, three ere resistant even after eight attempts.12 Others relapsed uickly.
Tilt training advocates maintain that there is a sustained esponse. Reybrouck et al5 reported that the 42 patients who ad been trained in-hospital had an 82% freedom from yncope over 43 months, provided that home orthostatic raining was performed assiduously. Those who stopped raining relapsed. Similarly, 81% of the Kinay et al12 cohort as symptom-free at 12 months. The small populations
tudied by Abe et al11 were also asymptomatic after about 0 months. These reports were all open-label, uncontrolled, ohort studies.
Open-label controlled studies of home training are not ncouraging. An early study5 subjected adolescents to tilt raining, with a nonrandomized control group. The tilt-
rained group had fewer syncopal spells during long-term v
ollow-up, provided that they continued training at home. In ontrast, Foglia-Manzillo et al13 randomized 68 patients ith syncope and two positive tilt tests to a daily 30-minute
elf-training regimen. After 3 weeks, 60% of patients in oth groups had positive tilt tests. These patients were then ncouraged to continue with self-training over the subse- uent year, but of the 62, only five actually did so, with 28% aving recurrent syncope. Two recent randomized open- abel studies by Dugyu et al14 and On et al15 also failed to etect a benefit from orthostatic self-training at home.
There is no high-level evidence of the effectiveness of rthostatic training, no obvious physiologic rationale, and three mall negative randomized controlled trials. Whether these esults are due to poor compliance or inefficacious therapy is nclear. Due to these factors, orthostatic training cannot be ecommended yet for routine use.
Recommendation: Frequently symptomatic patients with positive tilt test might undergo tilt table training. Debat-
ble effect, moderate evidence. Self-administered ortho- tatic training with prolonged standing without tilt training hould not be used. Probably unhelpful, good evidence.
harmacological therapy eta-adrenoceptor blockers eta-blockers were used for a variety of reasons and under- ent at least 19 controlled trials of their effect on tilt test utcome. A large majority of patients on beta-blockers have egative tilt tests, particularly if the tilt tests include an soproterenol infusion. Early nonrandomized studies pro- ided conflicting information about whether beta-blockade revents syncope, with some reporting marked reductions in yncope in groups that received beta-blockers and others eporting no benefit at all.
There have been five randomized clinical trials of the fficacy or effectiveness of -adrenergic blockers for the revention of syncope.5 On the whole, they were negative. ne small, early study of atenolol was positive, and one did
eport a remarkable 80%–90% reduction in all measures of resyncope and syncope in all three treatment arms (pla- ebo, propranolol, and nadolol), with no significant differ- nce among the three arms.
We reported the results of the first Prevention of Syncope rial in 2006.16 It was a randomized, placebo-controlled, ouble-blind trial that assessed the effects of metoprolol in asovagal syncope over a 1-year treatment period. A total of 08 patients were randomized to metoprolol or placebo. etoprolol provided no benefit, with nearly identical out-
ome rates in both study arms (Figure 1). Recommendation: Unselected, frequently symptomatic
atients should not receive beta-adrenoceptor blockers as rst-line therapy. Probably unhelpful, good evidence.
elective serotonin reuptake inhibitors (SSRIs) erotonin plays important roles in the regulation of heart ate and blood pressure. This has led to speculation that uctuation in central serotonin levels may contribute to
asovagal syncope. Indeed, a randomized, double blind,
p h p i e t q fl w s s
b e
M T m r v s r t s r
l t p w o t w p
i t f r t a
t a e s d p c i t i t
f d
F F c a u b t a t b fl T a t
P r r o o i s
f
1612 Heart Rhythm, Vol 5, No 11, November 2008
lacebo-controlled study5 of 68 consecutive patients who ad not responded to other treatments was reported to be ositive in 1999. Disappointingly, a recent second random- zed, placebo-controlled study of 96 patients found fluox- tine, propranolol, and placebo to have equal effects, al- hough a post hoc on-treatment analysis found an improved uality of life and decreased syncope and presyncope with uoxetine.17 Therefore, the evidence for the use of SSRIs ith vasovagal syncope is mixed at best. The SSRI drugs
hould not be used early in the treatment of vasovagal yncope.
Recommendation: Frequently symptomatic patients might e prescribed serotonin-specific reuptake inhibitors. Debatable ffect, moderate evidence.
idodrine his drug is a peripherally active alpha-agonist, as is its etabolite. It is used is to ameliorate the reduction in pe-
ipheral sympathetic neural outflow that is responsible for enous pooling and vasodepression that are central to va- ovagal syncope. Its inability to cross the blood-brain bar- ier and lack of gastrointestinal side effects are useful fea- ures. An early randomized crossover placebo-controlled tudy of a small number of highly symptomatic patients
igure 1 Probability of remaining free of syncope in the total population n each treatment arm of metoprolol or placebo in an intent-to-treat analysis bottom panel) and in an on-treatment strategy analysis (top panel) in the revention of Syncope Trial.20
eported a marked reduction in symptoms, and also in the c
ikelihood of a positive tilt test.5 Kaufmann et al5 confirmed hese results when they reported that midodrine obviated the ostural hypotension induced by head-up tilt in patients ith vasovagal syncope.5 An early, randomized, controlled, pen-label trial of midodrine, in which the investigators itrated midodrine from 5 to 15 mg three times a day over 3 eeks in an effort to render tilt tests negative, was also ositive.5
Finally, Qingyou et al18 studied 26 children in a random- zed, open-label trial. The children had experienced at least hree vasovagal episodes per year. Midodrine was titrated rom 1.25 to 2.5 mg twice a day commensurate with tilt test esults in comparison with conservative diet and posture raining. Clinical recurrence rates over 10 months were 20% nd 80% in the midodrine and control groups, respectively.
Midodrine has demonstrated short- and medium-term herapeutic success while being well tolerated in both adult nd pediatric populations. The drug is reasonably well tol- rated, with side effects including supine hypertension, nau- ea, scalp paresthesias, piloerection, and rash. These are ose-related and easily reversible. It should not be used in atients with hypertension or heart failure. It also requires areful attention to both dosing and interdose intervals and s usually best managed in specialty clinics. More robust rial designs with greater patient numbers are required to mprove the strength of evidence behind its recommenda- ion.
Recommendation: In the absence of contraindications, requently symptomatic patients should be prescribed mido- rine. Probably helpful, good evidence.
ludrocortisone ludrocortisone is a corticosteroid with mainly mineralo- orticoid activity resulting in sodium and water retention nd potassium excretion, which would increase blood vol- me. The use of fludrocortisone in vasovagal syncope has een assessed in pediatric studies. Two open-label uncon- rolled studies reported that children had far less syncope nd presyncope while taking fludrocortisone.5 In contrast, he randomized, double-blinded, placebo-controlled study y Salim and Di Sessa19 found more symptoms in the udrocortisone group than in children treated with placebo. here have been no controlled studies of fludrocortisone in dults with vasovagal syncope, and the utility of fludrocor- isone in the prevention of syncope remains unclear.
To assess its effectiveness, we are conducting the second revention of Syncope Trial (POST II), a multinational, andomized, controlled clinical trial.20 Patients with recur- ent vasovagal syncope are receiving either fludrocortisone r placebo for 1 year; the primary outcome is the proportion f patients with at least one syncope recurrence. Enrollment s underway in both North and South America, and the trial hould conclude in 2010.
Recommendation: In the absence of contraindications, requently symptomatic patients might be prescribed fludro-
ortisone. Debatable effect, weak evidence.
P I v l s p I p o d u S d t t r t n a a p t t p t
w s t u a s r c
a e f r p r s e p t d i p s p c i i i
t e d d f
T A a h o p t i p fi o o m b 4 r u fl l i
u w f t r m d
R
F d t r f R S R A c
1613Kuriachan et al Treatment of Vasovagal Syncope
ermanent pacemakers nitial studies reported a benefit from pacing in patients with asovagal syncope. Three observational and three open- abel randomized studies showed impressive and highly ignificant benefits of 80%–87% relative risk reduction with acing.5 However, the second Vasovagal Pacemaker Study I (VPS II), a double blind, placebo-controlled, multicenter, rospective trial randomly allocated 100 patients with a history f recurrent vasovagal syncope and a positive tilt table test to ual-chamber pacing or sensing only. Over a 6-month follow- p, no significant benefit was seen21 (Figure 2). The Vasovagal yncope and Pacing trial (SYNPACE), a similar study, ran- omized 29 patients with recurrent syncope and a positive ilt table test to DDD or OOO mode.22 This study was erminated early because of the first interim analysis and the esults of VPS II. No significant difference was seen be- ween the two groups. Hence, the double-blind studies did ot…
I V w p a p
c s i p b a v t b a a m o c
m s t w c p r T
H a U 4 3
1
vidence-based treatment for vasovagal syncope ikas Kuriachan, MD, Robert S. Sheldon, MD, PhD, Michael Platonov, MD
rom the Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
r t l g
(
Only a minority of patients with vasovagal syncope require reatment, and most can be managed conservatively. Patients hould be encouraged to liberalize their fluid and salt intake, nless they have contraindications such as hypertension. All pa- ients should be taught physical counterpressure maneuvers. idodrine is the first-line therapy for patients having frequent
i m S p o r m t r T G o g p m a
E S M s m t r b d s m r
f a
E A l p, 2007; accepted August 16, 2008.)
547-5271/$ -see front matter © 2008 Heart Rhythm Society. All rights reserved
outine use of beta-blockers, serotonin-specific reuptake inhibi- ors, fludrocortisone, and pacemakers is discouraged. Whether oop recorders can be used to target treatment is under investi- ation, as is fludrocortisone.
Heart Rhythm 2008;5:1609–1614) © 2008 Heart Rhythm Society.
resyncope or syncope or for those with brief or no prodromes. The All rights reserved.
ntroduction asovagal syncope frustrates patients and clinicians alike ith its paucity of effective treatments. About 37% of peo- le faint at least once in their lives.1,2 Usually beginning in dolescence or early adulthood, the predilection to fainting ersists for decades.3
Syncope is only one of several causes of transient loss of onsciousness. A useful working definition is a transient, elf-limited loss of consciousness that usually leads to fall- ng, with a relatively rapid onset and a spontaneous, com- lete, and relatively rapid recovery. Vasovagal syncope is y far the most common cause of syncope in the community nd the dominant cause in emergency wards.4 It is due to a ariable combination of reflex bradycardia and hypotension, riggered by prolonged sitting or standing; exposure to pain, lood, or medical procedures; heavy exercise; or getting up nd moving abruptly.5 Even in the same patient, the triggers nd presentation vary from spell to spell. The hypotension ay be due to a reduction in peripheral sympathetic neural
utflow, leading to venous pooling and vasodepression. The entral neurophysiology is unknown.
Syncope is usually recurrent. In the community, the edian number of faints is about two, with a much higher
ymptom burden in the clinical population.1,3,4 Many pa- ients injure themselves, and recurrent syncope is associated ith significantly impaired quality of life.5 (Sheldon et al5
ontains reports published before 2004, which therefore recede the articles covered in this review.) Given this educed quality of life, effective therapies are necessary. he treatments considered to date range from dietary mod-
Supported in part by grant no. 73–1976 from the Canadian Institutes for ealth Research, Ottawa, Ontario, Canada. Address reprint requests nd correspondence: Dr. R. Sheldon, Cardiovascular Research Group, niversity of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N N1, Canada. E-mail address: [email protected]. (Received November
fication through physical training, physical maneuvers, edication, and even permanent pacemaker implantation. urprisingly, there has not been a focused review of thera- ies with structured recommendations, although overviews f therapy have appeared in more general reviews. Here we eview current treatments followed by a suggested manage- ent strategy. Each recommendation is presented with the
reatment effect and level of evidence. Treatment effect is ated as probably helpful, debatable, or probably unhelpful. he evidence is summarized as good, moderate, or poor. ood evidence is derived from multiple randomized trials r meta-analyses; moderate evidence is derived from a sin- le randomized trial or multiple nonrandomized trials; and oor evidence is simply a consensus opinion. The recom- endations are summarized in Table 1. Important trials that
ppeared after 2003 are summarized in Table 2.
ducation and lifestyle interventions alt and fluid any patients with syncope are encouraged to increase their
alt and fluid intake, although the evidence that this treat- ent is effective is weak. Most patients with a positive tilt
est convert to a negative response on a subsequent test after eceiving an intravenous volume load, and plasma and lood volumes and orthostatic tolerance all improve with ietary salt supplementation.5 The usual reported dose of alt tablets is 6–9 g (100–150 mmol) per day. Salt supple- entation should be avoided in patients with hypertension,
enal disease, or cardiac dysfunction. Recommendation: In the absence of contraindications,
requently symptomatic patients should liberalize their salt nd fluid intake. Probably helpful, moderate evidence.
xercise training lthough exercise acutely increases blood volume,5 there is
imited evidence supporting the use of exercise training to
revent syncope. One study subjected 14 patients with syn-
p i
T t a m 1 n s
T t
1610 Heart Rhythm, Vol 5, No 11, November 2008
ope to a regimen of 12 minutes of daily progressive exer- ise training.5 After this, their blood volume increased .9%, and orthostatic tolerance to lower body negative pres- ure increased by 5 minutes. A recent, very underpowered andomized study did not detect a reduction in the likeli- ood of syncope in exercised patients.6
able 1 Suggested levels of recommendations with their reatment effect and level of evidence
reatment Treatment effect Evidence
evidence Physical exercise Debatable effect Weak evidence Physical counterpressure Probably helpful Good evidence
rthostatic training: Tilt training Debatable effect Moderate
evidence Home orthostatic training Probably unhelpful Good evidence
harmacologic therapy: Beta-blockers Probably unhelpful Good evidence SSRI antidepressants Debatable effect Moderate
evidence Midodrine Probably helpful Good evidence Fludrocortisone Debatable effect Weak evidence
ardiac pacemakers: Cardiac pacemakers:
Cardiac pacemakers: selected use in refractory cases with asystole
Debatable effect Weak evidence
able 2 Summary results of major randomized clinical trials of
reatment Senior author Sites, n Subject
hysical counterpressure Van Dijk9 15 223
ome orthostatic Foglia-Manzillo13 8 68
ome orthostatic Duygu14 1 82
ome orthostatic On15 1 42
etoprolol Sheldon16 14 208
idodrine Qingyou18 1 26
ludrocortisone Salim19 1 33
acemakers Connolly21 15 100
acemakers Raviele22 7 29
Only publications after 2003 are cited. NS not stated.
Recommendation: In the absence of contraindications, atients should follow relevant national guidelines regard- ng physical exercise. Debatable effect, weak evidence.
hysical counterpressure maneuvers onsiderable evidence supports the use of physical coun-
erpressure pressure maneuvers (PCMs). During PCMs, the resyncopal patient does isometric contractions of either the egs (by leg crossing) or the arms and hands (by pulling part gripped hands) or squats. These rely on a prodrome ong enough to allow the technique to prevent the progres- ion of presyncope to syncope and usually to prevent syn- ope during tilt tests.
PCM was initially thought to work by reversing the ecline in total peripheral resistance that attends vasovagal esponse. However, Van Dijk et al7,8 showed that leg cross- ng increased cardiac output 9% and arterial blood pressure % while reducing peripheral resistance. Adding leg tension urther increased systolic blood pressure and cardiac output 0% and 8%, respectively, and peripheral resistance dropped ven further. PCMs moved quickly into the clinical arena fter two positive studies of PCMs during tilt testing and ood outcomes in follow-up.9
The Physical Counterpressure Manoeuvres Trial (PC rial) was a randomized controlled trial comparing conven-
ional therapy (fluid and salt intake, counselling, avoidance) gainst conventional therapy augmented by one of three aneuvers in 208 patients with vasovagal syncope.9 After
8 months of follow-up, both groups experienced a similar umber of presyncopal episodes, yet PCMs provided a ignificant relative risk reduction of 36% of patients who
ent for vasovagal syncope
39 Syncope recurrence 51% control, 32% PCM
.005
NS
.1
47% control, 42% training
.99
41% controls, 51% propranolol, 22% fluoxetine
.05
.023
36% controls, 55% fludrocortisone
.14
NS
treatm
c d
T T s c E a c t t q g l c s t s r w c T w c t
p t w q
e t t
f c w s b e q h l d
o s r u r
a a s s
P B B w o n i v p s r
e p O r p c e
T d v 2 M c
p fi
1611Kuriachan et al Treatment of Vasovagal Syncope
ainted. Fifty-six patients on conventional treatment and 31 atients in the PCM group fainted at least once. However, 5% of patients had insufficient prodromes to perform the echniques. Finally, this was an open-label study, and the lacebo effect size is unknown.
PCMs can be adopted easily, without cost or side effects. heir physiologic rationale is well understood and the re- ults of acute and long-term follow-up have been encour- ging. In patients with presyncopal prodromes, these tech- iques should form the evidence-based core of the early, onservative care of vasovagal syncope.
Recommendation: All patients should be taught physical ounterpressure maneuvers. Probably helpful, good evi- ence.
ilt test training he imperfect reproducibility of positive tilt testing prompted peculation that this might be due to a training effect. The redit for initiating this avenue goes mainly to the group of ctor and colleagues.10 Two methods of orthostatic training re in use. Some groups have patients return daily to the linic (or remain in the hospital) for prolonged passive tilt ests culminating in syncope and continuing until the tilt ests remain negative. They are then encouraged to stand uietly against a wall for 30–60 minutes daily. Other roups skip the tilt training and progress directly to pro- onged quiet standing. The Ector group10 first reported suc- ess, tilting 42 patients with syncope in-hospital until they topped having a vasovagal response. Most converted in wo to three sessions, although some required up to eight essions. Abe et al11 trained 24 patients with medically efractory syncope in home exercises, leaning against a wall ith feet away from the base. After 1 month, the entire
ohort stopped having vasovagal responses to tilt testing. hey eventually demonstrated 100% effectiveness over 4 eeks.11 Finally, Ector et al10 tilted 202 patients until two
onsecutive tilts were negative and noted excellent long- erm outcomes in patients who were compliant.
Other acute studies are less encouraging. Kinay et al12
erformed repetitive tilt training in 32 patients and found hat although 20 responded by the second session, three ere resistant even after eight attempts.12 Others relapsed uickly.
Tilt training advocates maintain that there is a sustained esponse. Reybrouck et al5 reported that the 42 patients who ad been trained in-hospital had an 82% freedom from yncope over 43 months, provided that home orthostatic raining was performed assiduously. Those who stopped raining relapsed. Similarly, 81% of the Kinay et al12 cohort as symptom-free at 12 months. The small populations
tudied by Abe et al11 were also asymptomatic after about 0 months. These reports were all open-label, uncontrolled, ohort studies.
Open-label controlled studies of home training are not ncouraging. An early study5 subjected adolescents to tilt raining, with a nonrandomized control group. The tilt-
rained group had fewer syncopal spells during long-term v
ollow-up, provided that they continued training at home. In ontrast, Foglia-Manzillo et al13 randomized 68 patients ith syncope and two positive tilt tests to a daily 30-minute
elf-training regimen. After 3 weeks, 60% of patients in oth groups had positive tilt tests. These patients were then ncouraged to continue with self-training over the subse- uent year, but of the 62, only five actually did so, with 28% aving recurrent syncope. Two recent randomized open- abel studies by Dugyu et al14 and On et al15 also failed to etect a benefit from orthostatic self-training at home.
There is no high-level evidence of the effectiveness of rthostatic training, no obvious physiologic rationale, and three mall negative randomized controlled trials. Whether these esults are due to poor compliance or inefficacious therapy is nclear. Due to these factors, orthostatic training cannot be ecommended yet for routine use.
Recommendation: Frequently symptomatic patients with positive tilt test might undergo tilt table training. Debat-
ble effect, moderate evidence. Self-administered ortho- tatic training with prolonged standing without tilt training hould not be used. Probably unhelpful, good evidence.
harmacological therapy eta-adrenoceptor blockers eta-blockers were used for a variety of reasons and under- ent at least 19 controlled trials of their effect on tilt test utcome. A large majority of patients on beta-blockers have egative tilt tests, particularly if the tilt tests include an soproterenol infusion. Early nonrandomized studies pro- ided conflicting information about whether beta-blockade revents syncope, with some reporting marked reductions in yncope in groups that received beta-blockers and others eporting no benefit at all.
There have been five randomized clinical trials of the fficacy or effectiveness of -adrenergic blockers for the revention of syncope.5 On the whole, they were negative. ne small, early study of atenolol was positive, and one did
eport a remarkable 80%–90% reduction in all measures of resyncope and syncope in all three treatment arms (pla- ebo, propranolol, and nadolol), with no significant differ- nce among the three arms.
We reported the results of the first Prevention of Syncope rial in 2006.16 It was a randomized, placebo-controlled, ouble-blind trial that assessed the effects of metoprolol in asovagal syncope over a 1-year treatment period. A total of 08 patients were randomized to metoprolol or placebo. etoprolol provided no benefit, with nearly identical out-
ome rates in both study arms (Figure 1). Recommendation: Unselected, frequently symptomatic
atients should not receive beta-adrenoceptor blockers as rst-line therapy. Probably unhelpful, good evidence.
elective serotonin reuptake inhibitors (SSRIs) erotonin plays important roles in the regulation of heart ate and blood pressure. This has led to speculation that uctuation in central serotonin levels may contribute to
asovagal syncope. Indeed, a randomized, double blind,
p h p i e t q fl w s s
b e
M T m r v s r t s r
l t p w o t w p
i t f r t a
t a e s d p c i t i t
f d
F F c a u b t a t b fl T a t
P r r o o i s
f
1612 Heart Rhythm, Vol 5, No 11, November 2008
lacebo-controlled study5 of 68 consecutive patients who ad not responded to other treatments was reported to be ositive in 1999. Disappointingly, a recent second random- zed, placebo-controlled study of 96 patients found fluox- tine, propranolol, and placebo to have equal effects, al- hough a post hoc on-treatment analysis found an improved uality of life and decreased syncope and presyncope with uoxetine.17 Therefore, the evidence for the use of SSRIs ith vasovagal syncope is mixed at best. The SSRI drugs
hould not be used early in the treatment of vasovagal yncope.
Recommendation: Frequently symptomatic patients might e prescribed serotonin-specific reuptake inhibitors. Debatable ffect, moderate evidence.
idodrine his drug is a peripherally active alpha-agonist, as is its etabolite. It is used is to ameliorate the reduction in pe-
ipheral sympathetic neural outflow that is responsible for enous pooling and vasodepression that are central to va- ovagal syncope. Its inability to cross the blood-brain bar- ier and lack of gastrointestinal side effects are useful fea- ures. An early randomized crossover placebo-controlled tudy of a small number of highly symptomatic patients
igure 1 Probability of remaining free of syncope in the total population n each treatment arm of metoprolol or placebo in an intent-to-treat analysis bottom panel) and in an on-treatment strategy analysis (top panel) in the revention of Syncope Trial.20
eported a marked reduction in symptoms, and also in the c
ikelihood of a positive tilt test.5 Kaufmann et al5 confirmed hese results when they reported that midodrine obviated the ostural hypotension induced by head-up tilt in patients ith vasovagal syncope.5 An early, randomized, controlled, pen-label trial of midodrine, in which the investigators itrated midodrine from 5 to 15 mg three times a day over 3 eeks in an effort to render tilt tests negative, was also ositive.5
Finally, Qingyou et al18 studied 26 children in a random- zed, open-label trial. The children had experienced at least hree vasovagal episodes per year. Midodrine was titrated rom 1.25 to 2.5 mg twice a day commensurate with tilt test esults in comparison with conservative diet and posture raining. Clinical recurrence rates over 10 months were 20% nd 80% in the midodrine and control groups, respectively.
Midodrine has demonstrated short- and medium-term herapeutic success while being well tolerated in both adult nd pediatric populations. The drug is reasonably well tol- rated, with side effects including supine hypertension, nau- ea, scalp paresthesias, piloerection, and rash. These are ose-related and easily reversible. It should not be used in atients with hypertension or heart failure. It also requires areful attention to both dosing and interdose intervals and s usually best managed in specialty clinics. More robust rial designs with greater patient numbers are required to mprove the strength of evidence behind its recommenda- ion.
Recommendation: In the absence of contraindications, requently symptomatic patients should be prescribed mido- rine. Probably helpful, good evidence.
ludrocortisone ludrocortisone is a corticosteroid with mainly mineralo- orticoid activity resulting in sodium and water retention nd potassium excretion, which would increase blood vol- me. The use of fludrocortisone in vasovagal syncope has een assessed in pediatric studies. Two open-label uncon- rolled studies reported that children had far less syncope nd presyncope while taking fludrocortisone.5 In contrast, he randomized, double-blinded, placebo-controlled study y Salim and Di Sessa19 found more symptoms in the udrocortisone group than in children treated with placebo. here have been no controlled studies of fludrocortisone in dults with vasovagal syncope, and the utility of fludrocor- isone in the prevention of syncope remains unclear.
To assess its effectiveness, we are conducting the second revention of Syncope Trial (POST II), a multinational, andomized, controlled clinical trial.20 Patients with recur- ent vasovagal syncope are receiving either fludrocortisone r placebo for 1 year; the primary outcome is the proportion f patients with at least one syncope recurrence. Enrollment s underway in both North and South America, and the trial hould conclude in 2010.
Recommendation: In the absence of contraindications, requently symptomatic patients might be prescribed fludro-
ortisone. Debatable effect, weak evidence.
P I v l s p I p o d u S d t t r t n a a p t t p t
w s t u a s r c
a e f r p r s e p t d i p s p c i i i
t e d d f
T A a h o p t i p fi o o m b 4 r u fl l i
u w f t r m d
R
F d t r f R S R A c
1613Kuriachan et al Treatment of Vasovagal Syncope
ermanent pacemakers nitial studies reported a benefit from pacing in patients with asovagal syncope. Three observational and three open- abel randomized studies showed impressive and highly ignificant benefits of 80%–87% relative risk reduction with acing.5 However, the second Vasovagal Pacemaker Study I (VPS II), a double blind, placebo-controlled, multicenter, rospective trial randomly allocated 100 patients with a history f recurrent vasovagal syncope and a positive tilt table test to ual-chamber pacing or sensing only. Over a 6-month follow- p, no significant benefit was seen21 (Figure 2). The Vasovagal yncope and Pacing trial (SYNPACE), a similar study, ran- omized 29 patients with recurrent syncope and a positive ilt table test to DDD or OOO mode.22 This study was erminated early because of the first interim analysis and the esults of VPS II. No significant difference was seen be- ween the two groups. Hence, the double-blind studies did ot…
Related Documents
