2015 Heart Rhythm Society Expert Consensus Statement on the Diagnosis and Treatment of Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia, and Vasovagal Syncope

In the paper

“None of the studies were conventional, placebo-controlled, randomized clinical trials of moderately to severely symptomatic patients.125–128”

What the sources say

• ?Not checked — no full text of the sourcecites [125] Samniah, 2001, Efficacy and safety of midodrine hydrochloride in patients with refractory vasovagal syncope, Am J Cardiol source
• Supported

  The Methods describe randomizing patients with at least monthly syncope to midodrine or fluid therapy, salt tablets, and counseling—not to a placebo. Thus, although this was a randomized study of severely symptomatic patients, it was not a conventional placebo-controlled trial. The Results occasionally call the comparison group a “placebo arm,” but describe its treatment as fluid and salt therapy. (LLM, conf=0.90)

  cites [126] Perez-Lugones, 2001, Usefulness of midodrine in patients with severely symptomatic neurocardiogenic syncope: a randomized control study, J Cardiovasc Electrophysiol source
• Disputed

  The Patients and methods section describes a randomized, double-blind, placebo-controlled midodrine trial, contrary to the claim that none of the cited studies had those features. The Abstract describes participants with frequent symptoms—more than two syncopal episodes and fewer than 20 symptom-free days per month. The trial used a crossover design, so it was not a conventional parallel-group trial, but the source does not support the blanket characterization. (LLM, conf=0.84)

  Checked by a reasoning model — may be wrong.

  cites [127] Ward, 1998, Midodrine: a role in the management of neurocardiogenic syncope, Heart sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [128] Qingyou, 2006, The efficacy of midodrine hydrochloride in the treatment of children with vasovagal syncope, J Pediatr source

In the paper

“A small and underpowered crossover study reported the efficacy of low-dose midodrine in participants who had previously been trained in physical counterpressure man-euevres.124”

What the sources say

• Disputed

  The Methods describe a small crossover trial using 5 mg of midodrine twice daily in patients who had received non-pharmacological treatment, including physical counterpressure manoeuvres. But the Discussion explicitly says the trial was unable to demonstrate midodrine’s effectiveness in these patients—the opposite of the claimed efficacy. Page numbers were not available in our copy. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  cites [124] Romme, 2011, Effectiveness of midodrine treatment in patients with recurrent vasovagal syncope not responding to non-pharmacological treatment (STAND-trial), Europace sourceExperimental — accuracy not yet measured

In the paper

“The standing (or orthostatic) heart rate of individuals with POTS is often ≥120 bpm,8–13”

What the sources say

• ?Not checked — no full text of the sourcecites [8] Schondorf, 1993, Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia?, Neurology source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [9] Low, 1995, Postural tachycardia syndrome (POTS), Neurology
• ?Not checked — no full text of the sourcecites [10] Freeman, 2011, Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome, Auton Neurosci source
• Supported

  The paper’s introductory passage states that most authors include an absolute orthostatic heart rate of at least 120 bpm in POTS diagnostic criteria. The Discussion’s proposed pediatric criteria set a threshold of at least 120 bpm for ages 14 and older and at least 130 bpm for younger children. (LLM, conf=0.88)

  cites [11] Singer, 2012, Postural tachycardia in children and adolescents: what is abnormal?, J Pediatr source
• ?Not checked — no full text of the sourcecites [12] Garland, 2007, The hemodynamic and neurohumoral phenotype of postural tachycardia syndrome, Neurology source
• Supported

  The Abstract’s Introduction defines POTS as an orthostatic heart-rate increase usually reaching at least 120 bpm. This supports the citing sentence’s description of the standing heart rate as often ≥120 bpm; no page number is provided in our copy. (LLM, conf=0.94)

  cites [13] Low, 2009, Postural tachycardia syndrome (POTS), J Cardiovasc Electrophysiol source

In the paper

“It is believed that impaired sympathetic tone (as measured by norepinephrine spillover) reduces venoconstriction, leading to venous pooling in the lower limbs and splanchnic beds.24”

What the sources say

• Partly supported

  The discussion (section 2.0; page unavailable) links impaired norepinephrine spillover to noradrenergic dysfunction in the legs and discusses minimizing orthostatic blood pooling in the lower body. It does not establish reduced venoconstriction or pooling in splanchnic beds; instead, it suggests that sympathetic neurons in organs such as the mesentery remain intact. (LLM, conf=0.86)

  cites [24] Jacob, 2000, The neuropathic postural tachycardia syndrome, N Engl J Med sourceExperimental — accuracy not yet measured

In the paper

“During a vasovagal syncope episode, an ineffective reflex response causes venous pooling in the periphery and/or splanchnic regions.73–76”

What the sources say

• Partly supported

  In “Pathophysiological Mechanisms in Postural NMS” (page unavailable), the review describes evidence suggesting increased peripheral pooling in people prone to syncope and reports a failure of reflex venoconstriction during exercise. It also cites evidence against exaggerated pooling. The paper does not establish that an ineffective reflex causes peripheral or splanchnic pooling during a syncope episode; the claim states a proposed, contested mechanism as fact. (LLM, conf=0.86)

  cites [73] Mosqueda-Garcia, 2000, The elusive pathophysiology of neurally mediated syncope, Circulation sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [74] Glick, 1963, Hemodynamic changes during spontaneous vasovagal reactions, Am J Med source
• Partly supported

  The Abstract and Discussion report greater calf venous blood volume and less variable venous tone during head-up tilt in patients who fainted. The authors propose that an inadequate peripheral venous response may help trigger syncope, but they do not establish it as a cause or assess splanchnic pooling. They also distinguish this proposed venous abnormality from generalized autonomic dysfunction. (LLM, conf=0.85)

  cites [75] Hargreaves, 1992, Lack of variation in venous tone potentiates vasovagal syncope, Br Heart J sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion reports greater calf venous pooling during tilt-induced syncope and suggests that reduced venous responsiveness to sympathetic stimulation may explain it. The paper’s own forearm measurements were taken during mental stress, not a syncopal episode; it does not establish the proposed reflex mechanism as a cause or address splanchnic pooling. No page number is available in our copy. (LLM, conf=0.84)

  cites [76] Manyari, 1996, Abnormal reflex venous function in patients with neuromediated syncope, J Am Coll Cardiol sourceExperimental — accuracy not yet measured

In the paper

“Approximately 60% of patients with POTS treated with ivabradine in an open-label study had symptom improvement.44”

What the sources say

• Supported

  The Conclusion states that 60% of patients treated with ivabradine reported symptomatic improvement. The Methods describe a retrospective, self-reported assessment rather than a blinded trial, consistent with the citing sentence’s open-label description. (LLM, conf=0.92)

  cites [44] McDonald, 2011, Single centre experience of ivabradine in postural orthostatic tachycardia syndrome, Europace source

In the paper

“Paradoxically, some of these patients have low plasma renin activity and aldosterone levels compared with healthy subjects.32”

What the sources say

• Partly supported

  The Renin and Aldosterone results report significantly lower aldosterone in patients with POTS than in healthy controls, both supine and upright. They report no difference in plasma renin activity in either position. The paper calls renin inappropriately low relative to the patients’ reduced plasma volume, not lower than the controls’ renin activity. (LLM, conf=0.94)

  cites [32] Raj, 2005, Renin-aldosterone paradox and perturbed blood volume regulation underlying postural tachycardia syndrome, Circulation sourceExperimental — accuracy not yet measured

In the paper

“The strongest evidence to date comes from a small, randomized crossover study in which 21 patients with IST were randomized to placebo or ivabradine 5 mg twice daily for a total of 12 weeks.63”

What the sources say

• Partly supported

  The Results report 21 enrolled patients, and Study design describes a randomized placebo-controlled crossover trial with two six-week treatment phases separated by a seven-day washout. Ivabradine started at 5 mg twice daily, but Effects of ivabradine on symptoms and HR reports that the dose was increased in 11 patients and decreased in two; 5 mg twice daily was therefore not the fixed dose throughout. (LLM, conf=0.88)

  cites [63] Cappato, 2012, Clinical efficacy of ivabradine in patients with inappropriate sinus tachycardia: a prospective, randomized, placebo-controlled, double-blind, crossover evaluation, J oAm Coll Cardiol sourceExperimental — accuracy not yet measured

In the paper

“Long-acting propranolol does not improve the quality of life of patients with POTS,43”

What the sources say

• Supported

  The Discussion (‘Effects of Propranolol in POTS’) states that after four weeks of long-acting propranolol, patient quality of life remained unchanged. The Results (‘Propranolol Treatment’) report the same finding in POTS patients. (LLM, conf=0.94)

  cites [43] Fu, 2011, Exercise training versus propranolol in the treatment of the postural orthostatic tachycardia syndrome, Hypertension source

In the paper

“Most patients stop fainting after assessment and in the absence of specific therapy.”

What the sources say

• ?Not checked — no full text of the sourcecites [69] Chen, 2003, Prevalence and clinical outcomes of patients with multiple potential causes of syncope, Mayo Clin Proc source
• ?Could not verify

  The Diagnosis section (p. 3) reports how often vasovagal syncope was identified, but not whether patients subsequently stopped fainting. The Discussion (p. 6) says the study did not collect follow-up or prognosis data, so our copy cannot verify the claimed outcome after assessment without specific therapy. (LLM, conf=0.79)

  cites [70] Brignole, 2006, A new management of syncope: prospective systematic guideline-based evaluation of patients referred urgently to general hospitals, Eur Heart J sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Discussion says situational, orthostatic or vasovagal causes accounted for up to one third of cases, and Table 5 reports how many patients were discharged home. Neither reports whether most patients stopped fainting after assessment or did so without specific therapy. Searches for that wording and for recurrence without treatment found no passage addressing the claim. (LLM, conf=0.76)

  cites [71] D’Ascenzo, 2013, Incidence, etiology and predictors of adverse outcomes in 43,315 patients presenting to the Emergency Department with syncope: an international meta-analysis, Int J Cardiol sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [72] Barón-Esquivias, 2004, Long-term outcome of patients with vasovagal syncope, Am Heart J source

In the paper

“Reports from tertiary care centers have indicated that up to 50% of patients with POTS have a restricted autonomic neuropathy of small and distal postganglionic sudomotor fibers,19,20 predominantly of the feet and toes.21–23”

What the sources say

• Partly supported

  The Results report abnormal QSART in 17 of 30 women with POTS (57%), most often at the foot or proximal leg, and the Discussion identifies QSART as a test of postganglionic sudomotor fibers. But the Discussion describes the deficits as patchy and less suggestive of a distal-predominant neuropathy. The paper therefore supports frequent lower-extremity sudomotor abnormalities, not the claim that up to half of POTS patients have the stated restricted neuropathy, predominantly in the feet and toes. (LLM, conf=0.88)

  cites [19] Peltier, 2010, Distal sudomotor findings in postural tachycardia syndrome, Clin Auton Res sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [20] Singer, 2004, Prospective evaluation of somatic and autonomic small fibers in selected autonomic neuropathies, Neurology source
• ?Not checked — no full text of the sourcecites [21] Low, 1994, Comparison of the postural tachycardia syndrome (POTS) with orthostatic hypotension due to autonomic failure, J Auton Nerv Syst source
• ?Not checked — no full text of the sourcecites [22] Vogel, 2005, Blood pressure recovery from Valsalva maneuver in patients with autonomic failure, Neurology source
• ?Not checked — no full text of the sourcecites [23] Sandroni, 2000, Mechanisms of blood pressure alterations in response to the Valsalva maneuver in postural tachycardia syndrome, Clin Auton Res source

In the paper

“This neuropathic manifestation of POTS requires a high cardiac output to compensate for reduced splanchnic and peripheral resistance and venous pooling.25–28”

What the sources say

• ?Not checked — no full text of the sourcecites [25] Stewart, 2004, Decreased skeletal muscle pump activity in patients with postural tachycardia syndrome and low peripheral blood flow, Am J Physiol Heart Circ Physiol source
• Partly supported

  The Results (page unavailable) report increased cardiac index and decreased total peripheral resistance in high-flow POTS. The Discussion (page unavailable) reports splanchnic pooling in normal-flow POTS, but describes peripheral vasoconstriction—not reduced peripheral resistance—in that group. The paper does not establish that neuropathic POTS requires high cardiac output to compensate for both reduced splanchnic and peripheral resistance and venous pooling. (LLM, conf=0.85)

  cites [26] Stewart, 2006, Persistent splanchnic hyperemia during upright tilt in postural tachycardia syndrome, Am J Physiol Heart Circ Physiol sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion (page unavailable) describes high-flow POTS as neuropathic and associates reduced peripheral resistance with increased cardiac output and lower-extremity fluid collection. It does not establish reduced splanchnic resistance or say that high cardiac output is required to compensate for venous pooling; it identifies splanchnic pooling with normal-flow POTS. (LLM, conf=0.88)

  cites [27] Stewart, 2004, Regional blood volume and peripheral blood flow in postural tachycardia syndrome, Am J Physiol Heart Circ Physiol sourceExperimental — accuracy not yet measured
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [28] Tani, 1999, Splanchnic and systemic circulation in the postural tachycardia syndrome, Clin Auton Res

In the paper

“In contrast, the normal blood pressure phenotype features increased norepinephrine transporter levels consistent with augmented norepinephrine reuptake.”

What the sources say

• Supported

  The Abstract reports increased norepinephrine transporter levels in the normal blood pressure phenotype and describes them as augmenting transmitter reuptake. The Cellular: SNPs section likewise reports elevated transporter levels, while presenting increased reuptake as the probable mechanism rather than a directly measured effect. (LLM, conf=0.94)

  cites [87] Vaddadi, 2011, Recurrent postural vasovagal syncope: sympathetic nervous system phenotypes, Circ Arrhythm Electrophysiol source

In the paper

“Diagnostic scores have been developed based on patients with rigorously defined diagnoses.90–93”

What the sources say

• ?Not checked — no full text of the sourcecites [90] Sheldon, 2010, Syncope and structural heart disease: historical criteria for vasovagal syncope and ventricular tachycardia, J Cardiovasc Electrophysiol source
• ?Not checked — no full text of the sourcecites [91] Sheldon, 2006, Diagnostic criteria for vasovagal syncope based on a quantitative history, Eur Heart J source
• Partly supported

  The Patient selection section says participants had diagnoses established by preset criteria without reasonable diagnostic confusion; vasovagal syncope required a positive tilt test. The Discussion says the resulting point score distinguished syncope from seizures, not vasovagal syncope specifically, and that schemes for distinguishing causes of syncope were still being developed. Page numbers were not supplied for these passages. (LLM, conf=0.87)

  cites [92] Sheldon, 2002, Historical criteria that distinguish syncope from seizures, J Am Coll Cardiol sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [93] Sheldon, 1998, Electroencephalographic findings during presyncope and syncope induced by tilt table testing, Can J Cardiol

In the paper

“NE spillover was below normal during tilt in both phenotypes.”

What the sources say

• Supported

  The Abstract reports a subnormal norepinephrine spillover response during head-up tilt in both patient groups. The Figure 4 description says spillover was lower than in controls in both phenotypes, although the difference for the normal-blood-pressure group was not statistically significant (P=0.126). (LLM, conf=0.90)

  cites [87] Vaddadi, 2011, Recurrent postural vasovagal syncope: sympathetic nervous system phenotypes, Circ Arrhythm Electrophysiol source

In the paper

“Generally, attempts at validation have not been conducted with patients as rigorously defined as in the derivation studies.94,95”

What the sources say

• ?Not checked — no full text of the sourcecites [94] Romme, 2009, Diagnosing vasovagal syncope based on quantitative history-taking: validation of the Calgary Syncope Symptom Score, Eur Heart J source
• Partly supported

  The Discussion (page not provided) says one validation study included patients with other causes of loss of consciousness, which it identifies as a methodological issue. It also contrasts this study’s elderly patients with the original score’s population without structural heart disease. These examples support the concern, but the paper does not establish that validation attempts generally used less rigorously defined patients. (LLM, conf=0.84)

  cites [95] Exposito, 2013, Usefulness of the Calgary Syncope Symptom Score for the diagnosis of vasovagal syncope in the elderly, Europace sourceExperimental — accuracy not yet measured

In the paper

“NE spillover in the low-pressure phenotype was associated with low tyrosine hydroxylase levels, which probably reduced NE synthesis.”

What the sources say

• Supported

  The Cellular: SNPs section reports low tyrosine hydroxylase levels and low norepinephrine spillover in the low-blood-pressure phenotype, with reduced norepinephrine synthesis offered as the presumed explanation. The Conclusions likewise attribute subnormal spillover in that phenotype most likely to low levels of tyrosine hydroxylase. (LLM, conf=0.94)

  cites [87] Vaddadi, 2011, Recurrent postural vasovagal syncope: sympathetic nervous system phenotypes, Circ Arrhythm Electrophysiol source

In the paper

“Patients with recurrent postural vasovagal syncope might have sympathetic nervous system phenotypes.87”

What the sources say

• Supported

  The Conclusions state that patients with recurrent vasovagal syncope can be divided into two clinical groups based on supine blood pressure, with different mechanisms affecting norepinephrine availability. The Abstract explicitly says the groups show unique sympathetic nervous system abnormalities. (LLM, conf=0.94)

  cites [87] Vaddadi, 2011, Recurrent postural vasovagal syncope: sympathetic nervous system phenotypes, Circ Arrhythm Electrophysiol source

In the paper

“Two clinical studies have reported that isometric exercise of the large muscles induces a significant blood pressure increase during the phase of impending reflex syncope on tilt tests, enabling the patient to avoid or delay losing consciousness.118,119”

What the sources say

• ?Not checked — no full text of the sourcecites [118] Krediet, 2002, Management of vasovagal syncope: controlling or aborting faints by leg crossing and muscle tensing, Circulation source
• Supported

  The Results report that handgrip during impending tilt-induced vasovagal syncope raised systolic blood pressure relative to control and reduced the proportion of patients who fainted. The Discussion states that arm contraction can abort syncope in some cases and delay it in others. This paper supports the claim as one of the two cited clinical studies. (LLM, conf=0.93)

  cites [119] Brignole, 2002, Isometric arm counter-pressure maneuvers to abort impending vasovagal syncope, J Am Coll Cardiol source

In the paper

“Four randomized trials on midodrine have shown a consistent risk reduction of approximately 70%.”

What the sources say

• ?Not checked — no full text of the sourcecites [125] Samniah, 2001, Efficacy and safety of midodrine hydrochloride in patients with refractory vasovagal syncope, Am J Cardiol source
• Partly supported

  The Results report a 78% risk reduction in this randomized trial, broadly consistent with the claimed approximate 70%. This paper reports one trial; its Results and Present Study sections do not establish that four randomized trials found a consistent reduction. (LLM, conf=0.88)

  cites [126] Perez-Lugones, 2001, Usefulness of midodrine in patients with severely symptomatic neurocardiogenic syncope: a randomized control study, J Cardiovasc Electrophysiol sourceExperimental — accuracy not yet measured
• Partly supported

  The Patients and methods section describes one randomized crossover trial, not four trials. The Results report fewer tilt-induced syncopal episodes with midodrine; the reported counts of 14 on placebo versus 6 on midodrine correspond to an approximately 57% reduction, not a consistent reduction of approximately 70% across trials. Page numbers are unavailable in our copy. (LLM, conf=0.91)

  cites [127] Ward, 1998, Midodrine: a role in the management of neurocardiogenic syncope, Heart sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [128] Qingyou, 2006, The efficacy of midodrine hydrochloride in the treatment of children with vasovagal syncope, J Pediatr source

In the paper

“In this 23-patient trial, there was only an insignificant trend to benefit from midodrine in the exposure arms limited to 3 months.”

What the sources say

• Supported

  The Recurrences section reports fewer syncopal recurrences during midodrine than placebo treatment (48% vs. 65%), but the difference was not statistically significant (P = 0.22). The trial design specifies 3-month treatment periods, and Table 2 identifies 23 patients in the analysis. Page numbers are not provided in our copy. (LLM, conf=0.93)

  cites [124] Romme, 2011, Effectiveness of midodrine treatment in patients with recurrent vasovagal syncope not responding to non-pharmacological treatment (STAND-trial), Europace source

In the paper

“However, in a meta analysis of a prespecified, prestratified substudy of POST 1 and a large earlier observational study, there was evidence of benefit in patients older than 40 years.122”

What the sources say

• Partly supported

  The paper’s Abstract and Combined Populations section describe a meta-analysis of POST and an earlier observational cohort, with a pooled estimate suggesting benefit in older patients. However, the analysis used an age cutoff of ≥42 years, not older than 40; the pooled 95% confidence interval also included no effect. No page number is available in our copy. (LLM, conf=0.85)

  cites [122] Sheldon, 2012, Age-dependent effect of beta-blockers in preventing vasovagal syncope, Circ Arrhythm Electrophysiol sourceExperimental — accuracy not yet measured

In the paper

“It is important to note that there have been randomized controlled trials of the devices’ clinical effectiveness, and the results consistently show that for older patients with unexplained syncope, recorders should be used earlier in the investigation rather than later.102–104”

What the sources say

• ?Not checked — no full text of the sourcecites [102] Farwell, 2006, The clinical impact of implantable loop recorders in patients with syncope, Eur Heart J source
• Partly supported

  The Patients and Discussion sections describe a randomized comparison and report that using an implantable loop recorder as the primary monitoring strategy yielded more diagnoses than conventional testing in patients with unexplained syncope. But this paper reports one trial, not consistent results across multiple trials; it also advises trying an external loop recorder first when the patient can use one and cautions against generalizing its findings to all patients with syncope. (LLM, conf=0.86)

  cites [103] Krahn, 2003, Cost implications of testing strategy in patients with syncope: randomized assessment of syncope trial, J Am Coll Cardiol sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [104] Krahn, 1998, Final results from a pilot study with an implantable loop recorder to determine the etiology of syncope in patients with negative noninvasive and invasive testing, Am J Cardiol source

In the paper

“These patients appear to benefit from permanent pacing.105–112”

What the sources say

• ?Not checked — no full text of the sourcecites [105] Krahn, 1995, The etiology of syncope in patients with negative tilt table and electrophysiological testing, Circulation source
• Partly supported

  The Symptom-Rhythm Correlation section reports that 12 of 18 patients with bradycardia during recurrent symptoms received pacemakers. It does not report whether pacing reduced subsequent syncope or otherwise benefited those patients; the study evaluated prolonged monitoring, not pacing outcomes. No page number is available in our copy. (LLM, conf=0.84)

  cites [106] Krahn, 1999, Use of an extended monitoring strategy in patients with problematic syncope. Reveal Investigators, Circulation sourceExperimental — accuracy not yet measured
• Partly supported

  The Clinical Events section (page unavailable) reports that 14 patients received permanent pacemakers based on loop-recorder findings. But the Clinical Implications section (page unavailable) says the efficacy of therapy in preventing further syncope remains to be proved; this study does not establish that those patients benefited from pacing. (LLM, conf=0.84)

  cites [107] Moya, 2001, International Study on Syncope of Uncertain Etiology (ISSUE) Investigators. Mechanism of syncope in patients with isolated syncope and in patients with tilt-positive syncope, Circulation sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [108] Moya, 2008, Reproducibility of electrocardiographic findings in patients with suspected reflex neurally-mediated syncope, Am J Cardiol source
• ?Not checked — no full text of the sourcecites [109] Solano, 2004, Incidence, diagnostic yield and safety of the implantable loop-recorder to detect the mechanism of syncope in patients with and without structural heart disease, Eur Heart J source
• ?Not checked — no full text of the sourcecites [110] Brignole, 2006, International Study on Syncope of Uncertain Etiology (ISSUE) 2 Group. Early application of an implantable loop recorder allows effective specific therapy in patients with recurrent suspected neurally mediated syncope, Eur Heart J source
• ?Not checked — no full text of the sourcecites [111] Brignole, 2012, Pacemaker therapy in patients with neurally mediated syncope and documented asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial, Circulation source
• Partly supported

  The Abstract says permanent pacing reduced recurrent syncope in patients with documented asystole. However, the Discussion reports no observed benefit in the tilt-test-positive subgroup; the apparent benefit was greatest in tilt-test-negative patients. The unqualified reference to “these patients” therefore extends beyond the subgroup for which this analysis found benefit. (LLM, conf=0.84)

  cites [112] Brignole, 2014, Benefit of pacemaker therapy in patients with presumed neurally mediated syncope and documented asystole is greater when tilt test is negative: an analysis from the third International Study on Syncope of Uncertain Etiology (ISSUE-3), Circ Arrhythm Electrophysiol sourceExperimental — accuracy not yet measured

In the paper

“In a randomized, prospective parallel clinical trial, a physical counterpressure maneuver was superior to controls, with a relative risk reduction of 39%.120”

What the sources say

• Partly supported

  The Methods describe a prospective randomized trial, and the Results (Population section) report fewer syncopal recurrences with physical counterpressure maneuvers than with conventional therapy. However, that Results passage gives a relative risk reduction of 0.36 (36%), not the claimed 39%. (LLM, conf=0.86)

  cites [120] van Dijk, 2006, PC-Trial Investigators. Effectiveness of physical counter pressure maneuvers in preventing vasovagal syncope: the Physical Counter pressure Manoeuvres Trial (PC-Trial), J Am Coll Cardiol sourceExperimental — accuracy not yet measured

In the paper

“Cardiac pacing effectively prevents syncopal recurrences.112,139,140”

What the sources say

• Partly supported

  The Discussion (page not specified in our copy) concludes that pacing is very effective in patients with a negative tilt test, but says syncope can frequently recur when the test is positive. The unqualified claim omits that distinction and overstates the effectiveness reported for the full study population. (LLM, conf=0.88)

  cites [112] Brignole, 2014, Benefit of pacemaker therapy in patients with presumed neurally mediated syncope and documented asystole is greater when tilt test is negative: an analysis from the third International Study on Syncope of Uncertain Etiology (ISSUE-3), Circ Arrhythm Electrophysiol sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Methods and Results describe adenosine levels and diagnostic testing, not treatment or recurrence after pacing. The Discussion discusses a possible mechanism and an ongoing study, but does not establish that cardiac pacing prevents syncopal recurrences (searched: pacing, pacemaker, recurrence, and treatment). (LLM, conf=0.76)

  cites [139] Deharo, 2013, Syncope without prodromes in patients with normal heart and normal electrocardiogram: a distinct entity, J Am Coll Cardiol sourceExperimental — accuracy not yet measured
• Supported

  The Results report that 17 patients received permanent dual-chamber pacing and none had recurrent syncope during follow-up. The Discussion states that pacing was completely successful in preventing syncopal recurrences in these patients with idiopathic paroxysmal AV block (article pp. 167–173). (LLM, conf=0.94)

  cites [140] Brignole, 2011, Syncope due to idiopathic paroxysmal atrioventricular block: long-term follow-up of a distinct form of atrioventricular block, J Am Coll Cardiol source

In the paper

“Finally, a small, double-blind study reported that pacing improved symptoms in very young patients with frequent vasovagal syncope.142”

What the sources say

• Partly supported

  The Abstract describes a small blinded study of 12 children (median age 2.8 years) in which pacing significantly reduced syncope compared with sensing only. However, the children had frequent, severe neurally mediated syncope with reflex anoxic seizures; the paper does not describe the study population simply as having vasovagal syncope. (LLM, conf=0.84)

  cites [142] McLeod, 1999, Cardiac pacing for severe childhood neurally mediated syncope with reflex anoxic seizures, Heart sourceExperimental — accuracy not yet measured

In the paper

“A small, single-blind randomized trial reported that permanent cardiac pacing greatly reduced syncope burden in young children, with frequent syncope associated with documented asystole.142”

What the sources say

• Partly supported

  The Abstract reports a study of 12 children with frequent attacks and recorded asystole; both pacing modes significantly reduced syncope compared with sensing only. However, the Methods describe allocation by chronological order of implantation, not randomization, and say the parent, patient, and doctor analyzing results were blinded—not a single-blind design. Page numbers are unavailable in our copy. (LLM, conf=0.91)

  cites [142] McLeod, 1999, Cardiac pacing for severe childhood neurally mediated syncope with reflex anoxic seizures, Heart sourceExperimental — accuracy not yet measured

In the paper

“Patients with an asystolic response during tilt testing fared no better than those with nonasystolic responses.”

What the sources say

• Supported

  The Supplemental table W3 passage reports that patients with an asystolic tilt-test response had syncope recurrence rates similar to those with a nonasystolic positive response (p=0.53). This supports the comparison in the claim, with “fared no better” referring to syncope recurrence. (LLM, conf=0.93)

  cites [112] Brignole, 2014, Benefit of pacemaker therapy in patients with presumed neurally mediated syncope and documented asystole is greater when tilt test is negative: an analysis from the third International Study on Syncope of Uncertain Etiology (ISSUE-3), Circ Arrhythm Electrophysiol source

In the paper

“Two randomized clinical trials reported that midodrine improved either hemodynamic changes to orthostasis or clinical symptoms in patients with POTS.145,146”

What the sources say

• Partly supported

  The Results (Pharmacological interventions; page unavailable) report that 45% of respondents who evaluated midodrine said it improved brain fog, a symptom in patients with POTS. The Methods (Study questionnaire; page unavailable) describe a patient survey, not a randomized clinical trial, and the paper does not report that midodrine improved hemodynamic responses to orthostasis. (LLM, conf=0.88)

  cites [145] Ross, 2013, What is brain fog? An evaluation of the symptom in postural tachycardia syndrome, Clin Auton Res sourceExperimental — accuracy not yet measured
• Supported

  The Discussion identifies this as a randomized controlled study in children with POTS. The Abstract reports significantly better symptom scores and treatment outcomes with midodrine than with the comparison treatments. This source supports the clinical-symptoms part of the sentence; the sentence's other trial is cited separately. Page numbers are not available in our copy. (LLM, conf=0.92)

  cites [146] Chen, 2011, Midodrine hydrochloride is effective in the treatment of children with postural orthostatic tachycardia syndrome, Circ J source

In the paper

“These tests should not be performed routinely as there is no evidence that they improve the care or the process of care in the majority of patients.”

In the paper

“Although a number of patients with POTS have been found to have herniation of their cerebellar tonsils (Chiari I), there is no association between cerebellar tonsil herniation and POTS.51”

What the sources say

• ?Not checked — no full text of the sourcecites [51] Garland, 2001, Chiari I malformation as a cause of orthostatic intolerance symptoms: a media myth?, Am J Med source

In the paper

“There are no long-term, prospective, placebo-controlled clinical trials of any therapeutic intervention that have demonstrated a substantial improvement in outcomes”

In the paper

“Blood volume is reduced in up to 70% of patients with POTS.”

In the paper

“POTS is also common in patients with chronic fatigue syndrome.17”

What the sources say

• ?Not checked — no full text of the sourcecites [17] Lewis, 2013, Clinical characteristics of a novel subgroup of chronic fatigue syndrome patients with postural orthostatic tachycardia syndrome, J Intern Med source

In the paper

“IST is rarely associated with tachycardia-mediated cardiomyopathy.55,56”

What the sources say

• ?Not checked — no full text of the sourcecites [55] Winum, 2009, A case of cardiomyopathy induced by inappropriate sinus tachycardia and cured by ivabradine, Pacing Clin Electrophysiol source
• ?Not checked — no full text of the sourcecites [56] Romeo, 2011, A pediatric case of cardiomyopathy induced by inappropriate sinus tachycardia: efficacy of ivabradine, Pediatr Cardiol source

In the paper

“Rising to an upright position increases gravitational forces and leads to the pooling of 500 to 800 mL of blood in the venous system, in the pelvic and splanchnic circulation, and in the lower limbs.”

In the paper

“Few treatments have been tested with the usual rigor of randomized clinical trials”

In the paper

“This outcome suggests that vasovagal syncope can have 2 distinct physiologic groups that can be clinically detected based on supine blood pressure.”

In the paper

“Tilt-table tests feature prolonged passive postural stress to determine whether patients have the autonomic substrate for vasovagal syncope.”

In the paper

“A syncopal episode with suppression of both AV and sinus node activity is very likely the result of vasovagal syncope.”

In the paper

“Ultimately, paradoxical vasodilation can occur, leading to further hypotension and loss of consciousness.77”

What the sources say

• ?Not checked — no full text of the sourcecites [77] Thomson, 1996, Failure of reflex venoconstriction during exercise in patients with vasovagal syncope, Circulation source

In the paper

“In addition, there is no “ideal” protocol, given that there is an inexorable trade-off between sensitivity and specificity.”

In the paper

“While unconscious, the patient is usually motionless.”

In the paper

“The tilt test has not been prospectively validated with populations with rigorously defined vasovagal syncope.”

In the paper

“However, with increasingly aggressive protocols comes the likelihood of decreased specificity.”

In the paper

“These studies challenge the hypothesis that abrupt sympathetic nerve activity withdrawal causes the vasovagal syncope response.”

In the paper

“- establishing a diagnosis of pseudosyncope.”

In the paper

“Diagnostic accuracy is approximately 10%–25% after 1 month of monitoring.”

In the paper

“- differentiating convulsive syncope from true seizure activity”

In the paper

“A careful and focused medical history review will often determine the diagnosis, with no further investigation needed.89”

What the sources say

• ?Not checked — no full text of the sourcecites [89] van Dijk, 2008, High diagnostic yield and accuracy of history, physical examination, and ECG in patients with transient loss of consciousness in FAST: the Fainting Assessment study, J Cardiovasc Electrophysiol source

In the paper

“The use of high doses of isoproterenol during tilts exceeding 10 minutes at 80° head-up tilt is accompanied by reduced specificity.98”

What the sources say

• ?Not checked — no full text of the sourcecites [98] Natale, 1995, Provocation of hypotension during head-up tilt testing in subjects with no history of syncope or presyncope, Circulation source

In the paper

“In general, cardiac pacing has a very limited role in patients with typical vasovagal syncope.”

In the paper

“Adequately designed and controlled randomized studies have found that beta-blockers are not effective for treating vasovagal syncope.”

What the sources say

• ?Not checked — no full text of the sourcecites [91] Sheldon, 2006, Diagnostic criteria for vasovagal syncope based on a quantitative history, Eur Heart J source
• ?Not checked — no full text of the sourcecites [121] Madrid, 2001, Lack of efficacy of atenolol for the prevention of neurally mediated syncope in a highly symptomatic population: a prospective, double-blind, randomized and placebo-controlled study, J Am Coll Cardiol source

In the paper

“However, due to selection or design issues, none of the trials provided high-level evidence for adults.”

In the paper

“The maneuvers do not work for patients with a minimal or absent prodrome.”

In the paper

“There remains considerable uncertainty about the efficacy of serotonin transport inhibitors in preventing syncope.”

In the paper

“Numerous observational studies have shown that ILRs can deliver diagnoses for approximately 35% of patients during the devices’ lifetime.”

In the paper

“Despite the apparently benign profile of vasovagal syncope, patients with frequent episodes occasionally need treatment.”

In the paper

“The study populations of these trials were predominantly composed of patients in their 70s and 80s.”

In the paper

“Atenolol was no more effective than placebo in preventing recurrent syncope in another double-blind randomized clinical trial.121”

What the sources say

• ?Not checked — no full text of the sourcecites [121] Madrid, 2001, Lack of efficacy of atenolol for the prevention of neurally mediated syncope in a highly symptomatic population: a prospective, double-blind, randomized and placebo-controlled study, J Am Coll Cardiol source

In the paper

“The largest prospective, placebo-controlled, randomized critical trial of beta-blocker therapy was the POST I trial, which analyzed the use of metoprolol for patients with tilt-positive presumed vasovagal syncope.91”

What the sources say

• ?Not checked — no full text of the sourcecites [91] Sheldon, 2006, Diagnostic criteria for vasovagal syncope based on a quantitative history, Eur Heart J source

In the paper

“There is ample evidence for the involvement of serotonin in the midbrain regulation of heart rate and blood pressure.”

In the paper

“The likelihood of a patient fainting after specialist assessment can be predicted from the number of syncopes in the preceding year.”

What the sources say

• ?Not checked — no full text of the sourcecites [91] Sheldon, 2006, Diagnostic criteria for vasovagal syncope based on a quantitative history, Eur Heart J source
• ?Not checked — no full text of the sourcecites [68] Sumner, 2010, Prevention of Syncope Trial I. Recent history of vasovagal syncope in a young, referral-based population is a stronger predictor of recurrent syncope than lifetime syncope burden, J Cardiovasc Electrophysiol source

In the paper

“Most of the studies on tilt-training were poorly controlled.”

In the paper

“A small pediatric trial showed that children who took placebo had a better long-term outcome with respect to presyncope and syncope than those who took fludrocortisone.123”

What the sources say

• ?Not checked — no full text of the sourcecites [123] Salim, 2005, Effectiveness of fludrocortisone and salt in preventing syncope recurrence in children: a double-blind, placebo-controlled, randomized trial, J Am Coll Cardiol source

In the paper

“There are no quantitative data on the outcome of pediatric patients with vasovagal syncope or POTS.”

In the paper

“In a small multicenter trial performed on 80 selected elderly patients with unexplained syncope, dual-chamber cardiac pacing significantly reduced 2-year syncopal recurrence from 69% in the control group to 23% in the active group.141”

What the sources say

• ?Not checked — no full text of the sourcecites [141] Flammang, 2012, Treatment of unexplained syncope: a multicenter, randomized trial of cardiac pacing guided by adenosine 5’-triphosphate testing, Circulation source

In the paper

“A small randomized trial reported that midodrine was effective in preventing recurrent syncope.128”

What the sources say

• ?Not checked — no full text of the sourcecites [128] Qingyou, 2006, The efficacy of midodrine hydrochloride in the treatment of children with vasovagal syncope, J Pediatr source

In the paper

“and placebo more effective than metoprolol in preventing syncope.147”

What the sources say

• ?Not checked — no full text of the sourcecites [147] Zhang, 2008, Randomized comparison of metoprolol versus conventional treatment in preventing recurrence of vasovagal syncope in children and adolescents, Med Science Monitor

In the paper

“By showing that patients with prolonged pauses during syncope but negative tilt test results benefit most from cardiac pacing, ISSUE-3 suggested that a positive tilt test result could be used to select patients who should not undergo permanent cardiac pacing.”

In the paper

“During clinical syncope, paroxysmal AV block occurs with 1 or multiple consecutive pauses but with no preceding or accompanying changes in sinus or AV node function.”

In the paper

“To date, there are no effective therapies that have passed the scrutiny of even moderately sized, randomized clinical trials for any of these syndromes.”

In the paper

“This outcome occurs without sinus node slowing or progressive atrioventricular conduction delay.”

In the paper

“A 24-hour Holter monitor can be performed to distinguish POTS from IST.”

In the paper

“In the Third International Study on Syncope of Uncertain Etiology (ISSUE-3; a randomized, double-blind trial), 511 patients aged 40 years and older with recurrent reflex syncope were given an ILR.111”

What the sources say

• ?Not checked — no full text of the sourcecites [111] Brignole, 2012, Pacemaker therapy in patients with neurally mediated syncope and documented asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial, Circulation source

In the paper

“Two randomized studies of children with syncope found placebo more effective than fludrocortisone and salt in preventing syncope123”

What the sources say

• ?Not checked — no full text of the sourcecites [123] Salim, 2005, Effectiveness of fludrocortisone and salt in preventing syncope recurrence in children: a double-blind, placebo-controlled, randomized trial, J Am Coll Cardiol source

In the paper

“Most of these patients were randomly assigned to dual-chamber pacing with rate-drop response or to sensing only.”

What the sources say

• ?Not checked — no full text of the sourcecites [111] Brignole, 2012, Pacemaker therapy in patients with neurally mediated syncope and documented asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial, Circulation source

In the paper

“Only 17% of the patients had syncope with documented asystole, or ≥6 seconds of asystole without syncope.”

What the sources say

• ?Not checked — no full text of the sourcecites [111] Brignole, 2012, Pacemaker therapy in patients with neurally mediated syncope and documented asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial, Circulation source

In the paper

“There are currently no positive placebo-controlled studies on pacemakers with patients younger than 40 years with vasovagal syncope; for these patients, cardiac pacing should be the last choice.”

In the paper

“A syncope syndrome with low plasma adenosine levels has been described in patients with unexplained syncope, sudden onset and no prodrome, and a normal heart and normal ECG.”