Canadian Cardiovascular Society and Canadian Pediatric Cardiology Association Position Statement on the Approach to Syncope in the Pediatric Patient

Accepted Manuscript Canadian Cardiovascular Society and Canadian Pediatric Cardiology Association Position Statement on the Approach to Syncope in the Pediatric Patient Shubhayan Sanatani, MD FRCPC (Chair), Vann Chau, MD FRCPC (Co-Chair), Anne Fournier, MD FRCPC, Andrew Dixon, MD FRCPC, Renee Blondin, MD, Robert S. Sheldon, MD FRCPC PII:

S0828-282X(16)30978-3

DOI:

10.1016/j.cjca.2016.09.006

Reference:

CJCA 2260

To appear in:

Canadian Journal of Cardiology

Received Date: 13 September 2016 Revised Date:

28 September 2016

Accepted Date: 28 September 2016

Please cite this article as: Sanatani S, Chau V, Fournier A, Dixon A, Blondin R, Sheldon RS, Canadian Cardiovascular Society and Canadian Pediatric Cardiology Association Position Statement on the Approach to Syncope in the Pediatric Patient, Canadian Journal of Cardiology (2016), doi: 10.1016/ j.cjca.2016.09.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

Title: Canadian Cardiovascular Society and Canadian Pediatric Cardiology Association Position Statement on the Approach to Syncope in the Pediatric Patient

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Shubhayan Sanatani MD FRCPC (Chair),1 Vann Chau MD FRCPC (Co-Chair),2 Anne Fournier MD FRCPC,3 Andrew Dixon MD FRCPC,4 Renee Blondin MD,3 Robert S Sheldon MD FRCPC 5

For a complete list of panelists and collaborators, please see Appendix A.

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Affiliations: BC Children’s Hospital and University of British Columbia, Vancouver, British Columbia, Canada. 2 The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada. 3 Centre Hospitalier Universitaire Sainte-Justine and University of Montreal, Montreal, Quebec, Canada. 4 Stollery Children’s Hospital and University of Alberta, Edmonton, Alberta, Canada. 5 Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.

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Corresponding Author: Shubhayan Sanatani, MD FRCPC BC Children’s Hospital 4480 Oak Street, Room 1F9 Vancouver, British Columbia CANADA Telephone: (604) 875-3619/ Fax: (604) 875-3463 E-mail address: [email protected]

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Disclosures: The disclosure information of the authors and reviewers is available from the CCS on their guidelines library at www.ccs.ca.

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Summary: Syncope is a common problem in young patients and is usually vasovagal in origin. Most patients with transient loss of consciousness do not require investigations beyond a comprehensive history and physical. This position paper promotes an evidencebased clinical approach, while highlighting when referral and further investigation are

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warranted. Routine electrocardiograms are not usually required for typical vasovagal

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syncope. Management strategies for vasovagal syncope are provided.

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Abstract: Pediatric syncope is a common problem peaking in adolescence, for which there is little data or evidence-based consensus on investigation and management. This document offers guidance for practical evaluation/management of pediatric patients (age<19 years) with syncope encountered in the acute or primary care setting. The

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writing committee utilized the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Most syncope is vasovagal, which is benign and does not require extensive investigation. This position paper presents recommendations to encourage an efficient and cost-effective disposition for the many patients with a

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benign cause of syncope, while highlighting atypical or concerning clinical findings

associated with other causes of transient loss of consciousness. The prodrome and the

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circumstances around which the event occurred are the most important aspects of the history. Syncope occurring mid-exertion suggests a cardiac etiology. A family history which includes sudden death from unknown or suspicious natural causes can be a red flag. The electrocardiogram (EKG) is the most frequently ordered test, but the yield is low and the test is not cost-effective when applied broadly to a population of patients with syncope. We recommend an EKG when the history is not suggestive of vasovagal

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syncope and there are features suggesting a cardiac cause like absence of a prodrome, mid-exertional event, family history of early-life sudden death or heart disease, abnormal physical exam or new medication with potential cardiotoxicity. For most patients with syncope, medical testing is not required and lifestyle modifications without medications

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suffice to prevent recurrences.

ACCEPTED MANUSCRIPT Sanatani et al/ 4 INTRODUCTION This document serves as a clinical guideline for the evaluation and management of pediatric patients, typically those younger than 19 years, with syncope encountered in

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the acute or primary care setting. It was developed following a thorough consideration of the best available evidence and clinical experience, and represents the consensus of a Canadian panel comprised of multidisciplinary experts with a mandate to formulate

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disease-specific recommendations. The purpose of this statement is to ensure that

practitioners who encounter pediatric patients with syncope may readily recognize

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syncope due to an etiology other than transient autonomic nervous system dysfunction, and to encourage an efficient and cost-effective disposition for those with evidence of a benign cause. A systematic and directed approach (Figure 1) will prevent missing potentially dangerous diagnoses, the most common of which are cardiovascular and

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neurologic abnormalities (Table 1). With the exception of vasovagal syncope (VVS), the most common cause of syncope in children, this document does not discuss the

METHODS

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management of the various conditions that can present with syncope.

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The CCS appointed co-chairs, a primary panel, and a secondary panel to develop

this statement. The primary panel developed the scope of the document, identified topics for review, performed the literature review and critical appraisal of the identified literature using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology, drafted the recommendations, and voted on the recommendations. Peer review was provided by both the secondary panel and the CCS

Pediatric syncope

ACCEPTED MANUSCRIPT Sanatani et al/ 5 Guidelines committee. The final draft was presented and approved by the CCS Executive Committee. Using a validation set of relevant articles identified by the authors, a librarian

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drafted a search strategy for Medline that was adapted and run in Embase, Cinahl and

PubMed. The strategy consisted of two blocks of search terms (subject heading and freetext), combined using the AND operator. The first block contained the condition

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“syncope” and the terms in the second block were related to the diagnostic concept of

syncope (e.g., tilt-table test, electrocardiogram (EKG), differential diagnosis). The set of

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articles retrieved by these two search blocks was further restricted to pediatric studies in English or French, and a filter to exclude review papers was applied. The search covered the time from the inception of each database through December 2015. A complete description of this strategy is available in the Appendix B. The search retrieved 5997

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references. After duplicates were removed, 4307 references were screened using Covidence. These were reviewed by the panel members to ensure they were pediatric, English or French, and original articles. Case reports were excluded, leaving 296 papers

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for full text review and 231 that were included. The primary panel built the evidence for the recommendations based on selected relevant articles (See Evidence Tables, Appendix

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B).

Terminology

Syncope is a transient loss of consciousness, associated with an inability to

maintain postural tone, followed by rapid and spontaneous recovery with the absence of clinical features specific for another form of transient loss of consciousness such as

Pediatric syncope

ACCEPTED MANUSCRIPT Sanatani et al/ 6 epileptic seizure.1 It is caused by global cerebral hypoperfusion, secondary to a myriad of etiologies (Table 1). Unlike in the adult population, the distinction between syncope and transient loss of consciousness has not been applied systematically to children. In this

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document, we attempt to align with the international and adult communities in using the term “transient loss of consciousness” when the etiology may not be cerebral

hypoperfusion, with the most notable example being seizures. There are many terms to

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describe the syncope due to a transient dysfunction of the autonomic nervous system, including “fainting”, “vasovagal syncope”, “reflex syncope” or “neurocardiogenic

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syncope”. In this document, we will use the term vasovagal syncope (VVS), which is defined as a syncope syndrome that typically (1) occurs with upright posture held for more than 30 seconds or with exposure to emotional stress, pain, or medical settings; (2) features diaphoresis, warmth, nausea, and pallor; (3) is associated with hypotension and

Epidemiology

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relative bradycardia, when known; and (4) is followed by fatigue.1

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Syncope is common, with a cumulative incidence of 30-40% by age 60,1 and accounts for about 1% of pediatric emergency-room visits. Many patients with syncope

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do not seek medical attention.2 The incidence peaks in adolescence, with a lesser peak between 6-18 months, related to breath-holding spells.3 In breath-holding spells, the child experiences an emotional or minor physical trauma, resulting in a breath-hold and a brief loss of consciousness. The episodes are often associated with facial cyanosis or progressive pallor with an appearance of being disoriented, and can involve involuntary muscle twitching, all of which can be quite dramatic to the observer. However, these are

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ACCEPTED MANUSCRIPT Sanatani et al/ 7 benign self-limited episodes and do not require further investigation or treatment. Some

HISTORY AND PHYSICAL (Table 2)

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infants with breath-holding spells will have VVS later in life.4

Symptoms: The prodrome is the most important aspect of the history. A warm or clammy sensation, nausea, light-headedness, or visual changes (e.g., seeing spots, gray out,

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tunneling) are strongly suggestive of VVS. Other symptoms include irritability, confusion, auditory changes, dyspnea, or abdominal symptoms. The absence of a prodrome raises

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suspicion of a possible cardiac cause.2, 5 In 154 children with syncope, 85% of children with VVS had a prodrome, while only 40% of those with cardiac conditions had prodromal symptoms.6

Palpitations and chest pain have been related to pediatric cardiac causes of

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syncope on the basis of very little data. Massin et al found that 9/25 patients with cardiac syncope had palpitations and/or chest pain; however, this study did not report the rates of such symptoms in patients with VVS.5 Hurst et al reported that the combination of the

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following features had 98% specificity for cardiac disease: absence of a prodrome, a midexertional event and chest pain or palpitations preceding the event.2 However, there were

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very few (3/3445, <0.1%) cardiac syncope patients in the study. In the adult literature7 and in the experience of the authors, palpitations are a relatively common finding in patients with VVS, often attributed to the adrenergic surge preceding the vagal response. Circumstances: The circumstances under which the syncope occurred often inform the diagnosis. Syncope occurring mid-exertion, before the child has a chance to stop the activity, suggests a cardiac etiology.8 While post-exertional syncope is typically benign,

Pediatric syncope

ACCEPTED MANUSCRIPT Sanatani et al/ 8 in Miyake’s review of 60 patients with mid-exertional syncope 32 patients had cardiac causes.9 There were no other risk factors from the history that differentiated the cardiac from non-cardiac exertional syncope groups. The distinction between cardiac syncope

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and postural orthostatic tachycardia syndrome-associated syncope could be helped with the use of the modified Calgary score for the pediatric population.10 The median of

modified Calgary scores for cardiac syncope was -5.0, which significantly differs from

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that of postural orthostatic tachycardia syndrome. The sensitivity and specificity of a differentiation score of less than -2.5 are 96.3% and 72.7%, respectively (Table 3).10

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Syncope associated with recent change of position, poor hydration or nutritional status, or a warm environment is usually VVS. The most common position in which VVS occurs is standing, although syncope when seated has also been observed. Syncope when supine suggests neurologic or psychologic causes. In 268 syncopal children, no VVS

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occurred when supine.11 Other common precipitating factors for VVS include phlebotomy, the sight of blood or disfiguring injury (e.g., fractures or soft tissue injuries), hair grooming, micturition/defecation, emotional upset, mild physical trauma or pain,

conditions.

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intercurrent illness, especially those with gastrointestinal symptoms, and hot or crowded

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Collateral history: Interviewing persons that witnessed the syncope may be helpful. Details like duration of the loss of consciousness and required degree of intervention, should be solicited whenever possible. Pallor or loss of colour are frequently seen in VVS. Some involuntary movement is also common in VVS, leading to a suspicion of seizure (Table 4). Twelve percent of prospectively studied pediatric patients have been reported to be affected by the myoclonic variant of VVS.12 Syncopal myoclonus may manifest as

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ACCEPTED MANUSCRIPT Sanatani et al/ 9 anything from a single muscle twitch to violent jerks affecting the entire body. Muscle jerks are often asynchronous in different parts of the body. Proximal and distal muscles are equally affected and facial involvement is common. In contrast to epileptic activity,

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syncopal myoclonus is not rhythmic and is only rarely sustained for more than half a minute.13 VVS may also produce more complex movements, raising a suspicion of

epilepsy.14 After evaluation with simultaneous tilt-test and video-electroencephalogram

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(EEG) recordings, the majority of patients initially treated for epilepsy was subsequently diagnosed with VVS.14

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In general, loss of consciousness occurs with the onset of movements in seizures, but loss of consciousness precedes movements in most cases of true syncope. Loss of consciousness from VVS frequently lasts <1 minute. Prolonged events may be noncardiac (e.g., seizures, stroke) or represent somatization. One study found that almost

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90% of those with eventual psychiatric diagnoses had loss of consciousness lasting over 5 minutes.6 Inadequate history taking and overemphasis on positive family history for seizures were important causes of misdiagnosis of epilepsy.15

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Medications, past medical history, and family history: Medications that alter vascular tone or heart rate, like β-blockers, calcium-channel blockers, and diuretics, may

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contribute to syncope. The past medical history must include previous syncopal events, cardiac disease, diabetes, seizures, medication or drug use, and psychiatric or psychological problems. The family history is important. A family history of sudden death from unknown or suspicious natural causes, such as a “heart attack” in an apparently healthy person, drowning in a capable swimmer, or unexplained motor vehicle accidents, should prompt evaluation for cardiac causes. Although arrhythmias and

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ACCEPTED MANUSCRIPT Sanatani et al/ 10 inherited arrhythmia conditions are much less common than benign causes of syncope, many initially present with syncope. Any family history of structural cardiac disease, arrhythmias, migraine, or seizures is also relevant.

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Suggested approach: The history should focus on the symptoms and context in which syncope occurred (Table 2). The most useful information is obtained from the patient

directly, even if they are young. The history should be taken before repetitive questions

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provide leading suggestions. As indicated above, the prodrome is the most important

aspect of the history. The historian must determine whether the patient had stopped their

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activity and had any prodromal symptoms, or whether the event occurred without any warning. Syncope during exertion can be secondary to peripheral vasodilatation and hypotension: this should be verified with a stress test.16 The presence of palpitations is of unclear significance and should be considered in the clinical context, rather than as an

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isolated finding indicating underlying cardiac disease. Mid-exertional syncope should prompt an urgent cardiac evaluation. New medications or recent dosage adjustments,

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particularly of antihypertensives or beta-blockers, should prompt review by the prescriber.

Recommendation #1 We recommend a detailed history in all cases (see Table 2).

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(Strong recommendation, Moderate Quality Evidence) Values and Preferences: Given the unique diagnostic information obtained from the history, the committee placed emphasis on an accurate and detailed history, as supported by all of the available data. The history is the diagnostic test of most utility in managing pediatric syncope. Practical Tip #1: The history should focus on accompanying symptoms and the context

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ACCEPTED MANUSCRIPT Sanatani et al/ 11 in which syncope occurred. The prodrome and timing of syncope in relation to exercise are particularly important. The most informative aspects are obtained from the patient

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directly.

Physical Examination: The physical examination is rarely helpful. Evidence of trauma

related to the syncopal event, as well as potential diagnostic clues for the cause, should be

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sought. Complete cardiac and neurologic examinations should be performed to identify the rare occurrence of occult structural cardiac or neurological disease.17 Assessing the

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heart rate and blood pressure responses to standing – postural vital signs – are helpful in assessing hydration and demonstrating dysautonomic responses to orthostatic stress. Pulse rate and regularity at the time of syncope are useful. An irregular pulse is usually due to sinus arrhythmia, which is common in children and of no significance. Innocent

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murmurs are common and should not cause alarm. In contrast, cyanosis, a pathologic murmur, diminished pulse volume, or a sternotomy scar point to underlying structural cardiac disease.5, 6, 18 Persistent neurologic deficits should raise concern for underlying

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neurologic conditions like stroke, seizure or complex migraine.

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Recommendation #2 A focused physical examination should always be performed. (Strong recommendation, Low Quality Evidence) Practical Tip #2: Postural vital signs are helpful in assessing hydration. An abnormal cardiac or neurologic examination warrants further investigation.

INVESTIGATIONS

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ACCEPTED MANUSCRIPT Sanatani et al/ 12 In a review of costs associated with diagnostic testing in a tertiary center, not including hospital costs and physician fees, the mean cost per patient was over $1000 in the 1990s.19 Considering that between 15 and 50% of children have at least one syncopal

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event, the consequences and costs of over-investigation are significant.19 Any further

testing should be guided by the history and physical examination. In typical VVS, no

further investigations are needed. Otherwise, investigations are guided by the history and

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physical exam to detect life-threatening arrhythmias and causes of syncope. Bloodwork is not required in cases of typical VVS. Hypoglycemia is a rare cause of syncope and is

tremor, nervousness and hunger.

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typically associated with autonomic symptoms like sweating, weakness, tachycardia,

The EKG is the most frequently-ordered test, accounting for more than one-third of all tests in a study of 169 pediatric patients with new-onset syncope.19 Of these, only 1

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EKG was of diagnostic utility, rendering it the least cost-effective test of those performed. A combination of history, physical examination and EKG had 96% sensitivity for cardiac syncope, with exertional syncope being the most consistent factor.20 The EKG

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was the only indicator of cardiac disease in 5 of the 480 patients (1%), and causality could not be determined.

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Despite the fear of missing a cardiac cause of syncope, the low yield and

specificity do not support routine use of the EKG in the acute setting. For cases in which an EKG is indicated (Table 5), the features that should raise concern are listed in Table 6. Long QT syndrome (LQTS), due to abnormalities in the function of ion channels controlling repolarization (“ion channelopathy”) can cause syncope and sudden death in otherwise healthy individuals. LQTS is the most common ion channelopathy, occurring

Pediatric syncope

ACCEPTED MANUSCRIPT Sanatani et al/ 13 in 1 in 2500 individuals.21 The QT interval should be verified and corrected for heart rate according to Bazett’s formula (Figure 2). An EKG done acutely may not be optimal. In the emergency department, approximately one-third of pediatric patients had a QTc

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interval ≥440 msec and normalization of QTc values on follow-up.21 Thus, first-time

EKGs obtained after a syncopal episode must be interpreted with caution to avoid overdiagnosis of a LQTS. Wolff-Parkinson-White syndrome is due to an accessory pathway

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connecting the atria and the ventricles. It never causes syncope in the absence of

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arrhythmia.

Recommendation #3 For all children with atypical syncope or who have additional risk factors (see Table 5), we recommend a 12-lead electrocardiogram. (Strong recommendation, Low Quality Evidence)

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Values and Preferences: While the EKG is the most often ordered test in children with syncope, the data does not support its routine use. The yield is very low (1%), the cost is significant, and abnormal EKGs at the acute event are often false-positives subject to

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misinterpretation. Therefore, the committee deliberately emphasizes that EKGs are not required in typical syncope and should be obtained only when there is a particular

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indication, such as those provided in Table 5.

When the history, physical examination or EKG suggests the possibility of

cardiac disease, further testing is warranted. This should be directed by a pediatric cardiologist with expertise in syncope, and will often include an echocardiogram. In one study, echocardiograms were obtained in 67% of patients and none revealed a pertinent

Pediatric syncope

ACCEPTED MANUSCRIPT Sanatani et al/ 14 abnormality not already suspected on the basis of the history, physical findings, or EKG.20 A treadmill test should be done when patients have exertional symptoms. In those too young for structured exercise testing, a Holter monitor during active play can be

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useful. Longer-term monitoring strategies and event monitors are reserved for patients with associated palpitations or recurrent unexplained syncope. Recent attention has

focused on implantable cardiac monitors, due to their small size and ease of deployment.

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These can be useful for complex cases in which extensive investigations have not

confirmed a cause of syncope. Their greatest utility may be in patients with established

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heart disease and new paroxysmal symptoms.

Reports on the specificity of tilt-tests in children vary tremendously and results are difficult to interpret.22 A positive tilt-test may not reliably exclude other conditions and this test is of limited utility.23 Tilt-testing should not be used to establish a diagnosis

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of VVS. It may be useful to explore episodes of psychogenic syncope.

Recommendation #4 For children with a history typical of vasovagal syncope, no

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family history of arrhythmia, and normal physical exam, we suggest that further cardiac investigations not be performed.

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(Strong recommendation, Low Quality of Evidence) Values and Preferences: The echocardiogram, treadmill test, Holter monitor, long-term monitoring strategies and tilt-test do not help to establish a diagnosis of VVS. They should generally be prescribed only by specialists with expertise in pediatric syncope in specific situations (e.g., treadmill test for exertional syncope).

Pediatric syncope

ACCEPTED MANUSCRIPT Sanatani et al/ 15 Atypical presentations like onset in the supine position, a preceding aura, or subsequent significant confusion or amnesia suggest an epileptic cause. In this case, a sleep-deprived EEG or ambulatory EEG (if the episodes of syncope are frequent enough)

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may be useful. Standard EEG should include concomitant EKG. Focal slowing or

interictal discharges on the EEG, or neurological deficits such as diplopia, dysarthria, and

signs or deficits, neuroimaging is of very low yield.

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paresis, should be investigated further with brain imaging. In the absence of such focal

It is important to remember that other causes of syncope and epilepsy can co-exist.

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If doubts persist after initial investigations, simultaneous tilt-testing and video-EEG monitoring can help distinguish other forms of syncope from epilepsy in patients with recurrent loss of consciousness.14

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Recommendation #5 For children presenting with a history typical of vasovagal syncope, no family history of epilepsy, and normal physical examination, we suggest that an EEG or neuroimaging not be performed.

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(Strong recommendation, Low Quality of Evidence) Practical Tip: Sleep-deprived EEG, ambulatory EEG, and neuroimaging should be

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reserved for specific situations like syncope in a supine position, with a preceding aura, or with subsequent significant confusion or amnesia.

TREATMENT OF VASOVAGAL SYNCOPE IN CHILDREN Children with VVS generally do well, with few recurrences, and do not require hospitalization or intervention. The evidence that specific treatments help is sparse, and

Pediatric syncope

ACCEPTED MANUSCRIPT Sanatani et al/ 16 most recommendations are adopted from the adult literature. Management should begin with explanation and reassurance. Patients can look alarmingly ill when unconscious, so family members and witnesses may benefit from this education. It is crucial to educate

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the patient about the importance of recognizing and reacting to presyncopal prodromes.

Avoidance of precipitating factors like prolonged standing, dehydration, and hot crowded environments is beneficial in preventing recurrences.

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An increase in dietary salt and fluid intake should be encouraged. In a randomized trial of 166 children and adolescents oral rehydration salts (a mixture of NaCl, KCl and

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NaHCO3) decreased syncope recurrences for up to 6 months (56 % vs 39%, p=0.029).24 Both groups also received education and tilt training consisting of periods of standing upright. In adults, physical techniques like squatting, crossing legs or butt clenching while upright prevent syncope in randomized open-label trials.1 These maneuvers are safe

VVS.

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and, even in the absence of specific pediatric data, should be taught to all children with

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Recommendation #6 For children with typical vasovagal syncope, we recommend a conservative strategy including education, avoidance of provoking factors, increase

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in salt and fluid intake, and teaching physical maneuvers as a preventative and rescue strategy. For most patients with VVS, education and hydration strategies suffice.

(Strong recommendation, Low Quality Evidence)

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ACCEPTED MANUSCRIPT Sanatani et al/ 17 Medication is rarely required to treat VVS. A small prospective randomized study showed that midodrine prevents recurrent VVS in children who are refractory to conservative management for up to 6 months (recurrence rates in placebo and midodrine

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groups 80% and 22%, respectively).25 Side effects from midodrine (principally supine

hypertension) are rare. The evidence for benefit from fludrocortisone or beta-blockers is weak. A small randomized clinical trial showed that outcomes with placebo were better

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than with fludrocortisone, and that most of the outcomes in the placebo arm occurred

after the placebo was stopped.26 Similarly in a prospective, randomized trial, treatment

conventional treatment (29%).27

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with metoprolol was associated with a higher recurrence rate (43%) compared to

In patients who undergo tilt-testing and other cardiac monitoring strategies, sinus arrest, transient heart block, and asystole can accompany VVS. These findings raise the

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possibility of treatment with a permanent pacemaker. Although a small double-blind study reported improvement with pacing in very young patients with frequent vasovagal syncope28, this is a highly invasive treatment for a generally benign condition, and should

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be undertaken only in exceptional cases, and only in consultation with a pediatric

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arrhythmia specialist.

Recommendation #7 For children with highly symptomatic vasovagal syncope resistant to conservative measures, we suggest treatment with midodrine during active hours.

(Strong recommendation, Low Quality Evidence)

Pediatric syncope

ACCEPTED MANUSCRIPT Sanatani et al/ 18 PROGNOSIS AND DISPOSITION In children presenting with syncope, it is critical to identify the rare patients at risk of sudden death. A careful history as outlined above, as well as a detailed family

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history, will identify most at-risk patients.2, 29 Atypical features, such as syncope without a prodrome, syncope while supine or during exercise, a family history of early or sudden death, or an EKG suggesting electrical or structural heart disease, should prompt an

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urgent referral to a specialist. The prognosis for these patients depends on recognition and treatment of the underlying cause.

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There are few data about the prognosis of young patients with VVS. Although there are no prospective long-term studies, there is a general sense that pediatric VVS resolves, but that before this, it can be recurrent and troublesome. The only predictor of recurrence is the recent syncope frequency.30 The likelihood of recurrence drops

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markedly after a proper assessment and reassurance, and the recurrence rate is proportional to syncope frequency in the preceding year. Generally, patients have a 2050% likelihood of having at least one more syncopal spell in the year after assessment.

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Routine follow-up in 3-6 months is reasonable. Young people with a classic history of VVS should best be managed by their

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primary care physician. For patients with significant issues around quality of life, return to activity, anxiety, referral to a clinic with expertise in syncope is warranted, with concurrent initiation of education and preventative measures.

Recommendation #8 For children with syncope and a history atypical for vasovagal syncope, a family history of arrhythmia or epilepsy, relevant

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ACCEPTED MANUSCRIPT Sanatani et al/ 19 abnormalities on physical exam, or an abnormal EKG, we recommend referral to a specialist with expertise in syncope.

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(Strong recommendation, Low Quality Evidence)

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ACCEPTED MANUSCRIPT Sanatani et al/ 20 REFERENCES

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1. Sheldon RS, Grubb BP, 2nd, Olshansky B, et al. 2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm 2015;12:e41-63. 2. Hurst D, Hirsh DA, Oster ME, et al. Syncope in the Pediatric Emergency Department - Can We Predict Cardiac Disease Based on History Alone? J Emerg Med 2015;49:1-7. 3. Wieling W, Ganzeboom KS, Saul JP. Reflex syncope in children and adolescents. Heart 2004;90:1094-100. 4. Camfield PR, Camfield CS. Syncope in childhood: a case control clinical study of the familial tendency to faint. Can J Neurol Sci 1990;17:306-8. 5. Massin MM, Malekzadeh-Milani S, Benatar A. Cardiac syncope in pediatric patients. Clin Cardiol 2007;30:81-5. 6. Chen L, Zhang Q, Ingrid S, Chen J, Qin J, Du J. Aetiologic and clinical characteristics of syncope in Chinese children. Acta Paediatr 2007;96:1505-10. 7. Calkins H, Shyr Y, Frumin H, Schork A, Morady F. The value of the clinical history in the differentiation of syncope due to ventricular tachycardia, atrioventricular block, and neurocardiogenic syncope. Am J Med 1995;98:365-73. 8. Colivicchi F, Ammirati F, Santini M. Epidemiology and prognostic implications of syncope in young competing athletes. Eur Heart J 2004;25:1749-53. 9. Miyake CY, Motonaga KS, Fischer-Colbrie ME, et al. Risk of cardiac disease and observations on lack of potential predictors by clinical history among children presenting for cardiac evaluation of mid-exertional syncope. Cardiol Young 2015:1-7. 10. Yang J, Zhu L, Chen S, et al. Modified Calgary score in differential diagnosis between cardiac syncope and postural orthostatic tachycardia syndrome-associated syncope in children. Cardiol Young 2013;23:400-4. 11. Ikiz MA, Cetin, II, Ekici F, Guven A, Degerliyurt A, Kose G. Pediatric syncope: is detailed medical history the key point for differential diagnosis? Pediatr Emerg Care 2014;30:331-4. 12. Fernandez Sanmartin M, Rodriguez Nunez A, Martinon-Torres F, Eiris Punal J, Martinon Sanchez JM. [Convulsive syncope: characteristics and reproducibility using the tilt test]. An Pediatr (Barc) 2003;59:441-7. 13. Lempert T, Bauer M, Schmidt D. Syncope: a videometric analysis of 56 episodes of transient cerebral hypoxia. Ann Neurol 1994;36:233-7. 14. Yilmaz S, Gokben S, Levent E, Serdaroglu G, Ozyurek R. Syncope or seizure? The diagnostic value of synchronous tilt testing and video-EEG monitoring in children with transient loss of consciousness. Epilepsy Behav 2012;24:93-6. 15. Sabri MR, Mahmodian T, Sadri H. Usefulness of the head-up tilt test in distinguishing neurally mediated syncope and epilepsy in children aged 5-20 years old. Pediatr Cardiol 2006;27:600-3. 16. Kosinski D, Grubb BP, Karas BJ, Frederick S. Exercise-induced neurocardiogenic syncope: clinical data, pathophysiological aspects, and potential role of tilt table testing. Europace 2000;2:77-82.

Pediatric syncope

ACCEPTED MANUSCRIPT Sanatani et al/ 21

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17. Massin MM, Bourguignont A, Coremans C, Comte L, Lepage P, Gerard P. Syncope in pediatric patients presenting to an emergency department. J Pediatr 2004;145:223-8. 18. Tretter JT, Kavey RE. Distinguishing cardiac syncope from vasovagal syncope in a referral population. J Pediatr 2013;163:1618-23 e1. 19. Steinberg LA, Knilans TK. Syncope in children: diagnostic tests have a high cost and low yield. J Pediatr 2005;146:355-8. 20. Ritter S, Tani LY, Etheridge SP, Williams RV, Craig JE, Minich LL. What is the yield of screening echocardiography in pediatric syncope? Pediatrics 2000;105:E58. 21. Van Dorn CS, Johnson JN, Taggart NW, Thorkelson L, Ackerman MJ. QTc values among children and adolescents presenting to the emergency department. Pediatrics 2011;128:e1395-401. 22. Boysen A, Lewin MA, Uhlemann F. Common patterns of response to the head-up tilt test in children and adolescents. Cardiol Young 2006;16:537-9. 23. Batra AS, Balaji S. Usefulness of tilt testing in children with syncope: a survey of pediatric electrophysiologists. Indian Pacing Electrophysiol J 2008;8:242-6. 24. Chu W, Wang C, Wu L, Lin P, Li F, Zou R. Oral rehydration salts: an effective choice for the treatment of children with vasovagal syncope. Pediatr Cardiol 2015;36:867-72. 25. Qingyou Z, Junbao D, Chaoshu T. The efficacy of midodrine hydrochloride in the treatment of children with vasovagal syncope. J Pediatr 2006;149:777-80. 26. Salim MA, Di Sessa TG. Effectiveness of fludrocortisone and salt in preventing syncope recurrence in children: a double-blind, placebo-controlled, randomized trial. J Am Coll Cardiol 2005;45:484-8. 27. Zhang Q, Jin H, Wang L, Chen J, Tang C, Du J. Randomized comparison of metoprolol versus conventional treatment in preventing recurrence of vasovagal syncope in children and adolescents. Med Sci Monit 2008;14:CR199-203. 28. McLeod KA, Wilson N, Hewitt J, Norrie J, Stephenson JB. Cardiac pacing for severe childhood neurally mediated syncope with reflex anoxic seizures. Heart 1999;82:721-5. 29. Krahn AD, Healey JS, Simpson CS, et al. Sentinel symptoms in patients with unexplained cardiac arrest: from the cardiac arrest survivors with preserved ejection fraction registry (CASPER). J Cardiovasc Electrophysiol 2012;23:60-6. 30. Kouakam C, Vaksmann G, Pachy E, Lacroix D, Rey C, Kacet S. Long-term follow-up of children and adolescents with syncope; predictor of syncope recurrence. Eur Heart J 2001;22:1618-25. 31. Zhang Q, Du J, Wang C, Du Z, Wang L, Tang C. The diagnostic protocol in children and adolescents with syncope: a multi-centre prospective study. Acta Paediatr 2009;98:879-84. 32. Raucci U, Scateni S, Tozzi AE, et al. The availability and the adherence to pediatric guidelines for the management of syncope in the Emergency Department. J Pediatr 2014;165:967-72 e1. 33. Postema PG, De Jong JS, Van der Bilt IA, Wilde AA. Accurate electrocardiographic assessment of the QT interval: teach the tangent. Heart Rhythm 2008;5:1015-8.

Pediatric syncope

ACCEPTED MANUSCRIPT Sanatani et al/ 22 Table 1. Common Causes of Transient Loss of Consciousness in Children31, 32 Incidence (%)

Vasovagal syncope

64 -73

Breath holding spell

6.4

Cardiac

2.9 - 4.8

Examples

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Causes

Primary electrical disturbances: •

Long QT syndrome, Brugada

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syndrome, Catecholaminergic

Polymorphic Ventricular Tachycardia,

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Short QT syndrome, Wolff-ParkinsonWhite syndrome

Structural heart disease •

Hypertrophic cardiomyopathy, coronary

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artery anomalies, Arrhythmogenic Right Ventricular Cardiomyopathy, valvular aortic stenosis, dilated

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cardiomyopathy, pulmonary

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Neurologic

2.1 - 4.6

hypertension, acute myocarditis Seizures •

Panayiotopouolos syndrome

Vascular events •

Subclavian steal phenomenon, vertebrobasilar insuffficiency

Disrupted cerebrospinal fluid circulation

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Colloid cyst of the third ventricle, posterior fossa tumor

Basilar migraine

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Vertiginous drop attack

Narcolepsia/cataplexia Metabolic

0.8

Bleeding, dehydration, hypoglycemia,

Psychiatric

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electrolyte disturbances 2.2 - 2.3

Conversion disorder, somatization,

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Munchausen syndrome/malingering, anxiety and hyperventilation syndrome

8.2 - 18.9

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Unknown

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Activity preceding the syncopal event

Position of child preceding event Duration of loss of consciousness

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No prodrome (concerning for arrhythmia)

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Other Symptoms

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Syncope triggered by loud noise-look for long QT-refer if EKG positive Mid-exertional syncope (consider cardiac causes) Syncope while swimming (may be associated with LQTS)

Use of drugs and medications

Prodrome

Yellow Light Consider further investigations or semi-urgent referral to syncope specialist

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Hydration status and timing of last meal Environmental conditions

Red Light Recommend Urgent Referral to Syncope Specialist

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Table 2. History and Physical History and Physical Findings

Medications that may prolong QT (refer if EKG abnormal) Short or atypical prodrome

Acute chest pain followed by syncope Palpitations just prior to syncope Supine (consider seizure) Prolonged >5 minutes (consider seizure or

Pediatric syncope

Green Light reassuring for non-serious cause not further investigation required Missed meals, poor fluid intake Painful stimulus, sight of blood, very warm environment Post-exertion syncope Prolonged standing

No medications

Warmth, nausea, lightheadedness, and a visual gray out or tunneling of vision

Prolonged or recent standing Position change from seated or lying to standing Short-less than 1-2 minutes

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Diabetes Psychiatric disorder or medications Significant Co-morbidities

No relevant medical history Previous events consistent with vasovagal syncope or breath-holding spells

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Myoclonic jerks after loss of consciousness

Sudden death Arrhythmias

Seizures Structural Heart Disease

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Pathologic Murmur Sternotomy Scar Persistent neurologic deficits (consider stroke, seizure, migraine)

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Past history (previous syncopal events, cardiac disease, diabetes, seizures, and psychiatric or psychological problems) Family history (structural cardiac disease, arrhythmias, sudden death, migraines, or seizures) Focused Cardiac and Neurologic Examinations

Tonic-clonic movements- or motor activity preceding LOC (consider seizure) Arrhythmia, structural heart disease Seizures

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Movement during event

somatization) Exaggerated or flailing movements (consider somatization)

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Vasovagal syncope Migraines

Normal examination Typical flow murmur

ACCEPTED MANUSCRIPT Sanatani et al/ 26 Table 3. Individual Items of the Modified Calgary Score10 Question

Point (if yes)

tachycardia?

-5

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1. Is there a history of bifascicular block, asystole, or supraventricular

-4

3. Did your syncope start when you were 5 years of age or younger?

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4. Do you remember anything about being unconscious?

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2. At times have bystanders noted that you turn blue during your faint?

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6. Do you sweat before a faint?

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5. Do you feel faint with prolonged sitting or standing?

7. Do you feel faint with pain or in medical settings?

3

The modified Calgary score is derived from the Calgary score, originally developed to make differential diagnoses between adult vasovagal syncope and other types of syncope.

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Based on a cohort of 213 children, this modified score consisted of 7 diagnostic questions relating to medical history, triggers, circumstances as well as signs and symptoms of transient loss of consciousness. All questions were answered with “yes” or “no”, and then

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summarized to obtain a total score, ranging from -14 to +6 points. A score of less than 3.0 suggests a diagnosis of cardiac syncope, as opposed to postural orthostatic

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tachycardia syndrome-associated syncope.

Pediatric syncope

ACCEPTED MANUSCRIPT Sanatani et al/ 27 Table 4. Events Easily Mistaken for Cardiovascular Syncope Distinguishing Characteristics

Basilar migraine

Headache, rarely loss of consciousness, other neurologic symptoms such as dysarthria, ataxia and paresthesia

Seizure

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Condition

Loss of consciousness simultaneous with motor event, prolonged

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postictal phase (e.g. bladder and bowel incontinence, tongue biting) Rotation or spinning sensation, no loss of consciousness

Hyperventilation

Inciting event, paresthesias or carpopedal spasm, tachypnea

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Vertigo

Psychosocial causes No loss of consciousness, indifference to event Hypoglycemia

Confusion progressing to loss of consciousness, with adrenergic manifestations (sweating, pallor, shivering), requires glucose

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administration to terminate

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ACCEPTED MANUSCRIPT Sanatani et al/ 28 Table 5. When to Do an EKG in Syncope History is not diagnostic of VVS.

Mid-exertional event (e.g., swimming). Syncope triggered by loud noise or startle

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No prodrome before syncope.

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Family history of sudden death or heart disease in young individuals. Abnormal cardiac exam

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New medication with potential cardiac side effects (e.g., https://crediblemeds.org/)

Pediatric syncope

ACCEPTED MANUSCRIPT Sanatani et al/ 29 Table 6. EKG Findings in Syncope EKG FINDINGS Abnormal QT interval*




Long QT interval (QTc > 470 msec)




Short QT interval (QTc ≤ 330 msec)




Type 1 Brugada pattern




Delta wave (ventricular pre-excitation or Wolff-

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RED LIGHT

Parkinson-White syndrome)

Signs of myocardial ischemia (ST-T wave changes, Q

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waves >1mm wide)

PVCs, polymorphic




3rd degree AV block




Left ventricular hypertrophy (including left axis

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deviation, tall R wave in V6, tall S wave in V1, deep Q waves in II, III and aVF and ST-T wave changes)




PVCs, monomorphic




2nd degree AV block




Heart rate <40bpm in normally nourished, non-athletic

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YELLOW LIGHT

individual


Sinus arrhythmia




Wandering atrial pacemaker - Atrial or junctional

GREEN LIGHT rhythm


1st degree AV block

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Negative T waves in right precordial lead




Early repolarisation




Incomplete right bundle branch block

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Red light: May suggest malignant arrhythmia in certain contexts. Yellow light: May require a non-urgent evaluation in cardiology.

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*Manual measurement using tangent, see figure 2.

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Green light: Normal variants – no further management needed.

Pediatric syncope

ACCEPTED MANUSCRIPT Sanatani et al/ 31 Figure Legends

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Figure 1. Clinical pathway for pediatric syncope patients.

Figure 2. Measuring the QT Interval. Image modified from Postema et al.33 QTc is the heart rate corrected with Bazett’s formula with use of the preceding RR interval. To

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determine QT, a tangent is drawn to the steepest slope of the last limb of the T wave in

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lead II or V5. The end of the T wave is the intersection of the tangent with the baseline.

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CCS/CPCA Position Statement on the approach to syncope in the pediatric patient - Framework for Application of GRADE and Evidence Tables

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There is a growing expectation that guideline/position statement developers document their approach to systematic reviews of evidence and development of recommendations. Now it is preferred that guideline/position statement writing panels apply GRADE with more rigour and document the "evidence review to recommendation" process. The goal is to have writing panels follow a systematic approach to the development of recommendations based on evidence and produce documentation that provides transparency of process to readers and stakeholders. This supplement explains the new application of GRADE and the steps the Pediatric Syncope writing groups followed throughout the guideline/position statement development process:

 

ALL recommendations will begin with we recommend (where strength and quality of evidence are strong) and we suggest (where strength and quality of evidence is not strong). For strength of recommendations, we will use strong and conditional / weak as qualifiers. For quality of evidence, we will use the words very low, low, moderate, or high.

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1. Develop your health care questions in PICO format. 2. Conduct an evidence search and document the search strategy; databases, timeframe, inclusion, exclusion criteria, etc. 3. Review the studies to assess high level risk of bias and rate the evidence and document in table format. 4. Map the "evidence review to recommendation" process and document in an evidence table (see pages that follow). 5. Develop recommendations based on review of evidence and GRADE the recommendations in CCS format:

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For more information on the framework for application of GRADE, please visit ccs.ca.

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Study

Study Design

Patient Population

Primary Endpoint and Results Primary endpoint: Sensitivity(S) and Specificity(SP) of historical features to predict cardiac cause of syncope

Hurst D, Hirsh DA, Oster ME, et al. Syncope Study type: Retrospective chart review in the Pediatric Emergency Department Can We Predict Cardiac Disease Based on Size: 3445 syncope patients History Alone? J Emerg Med 2015;49:1-7.

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Inclusion criteria: Presented to Emergency Results: Department with Syncope or near-Syncope During Exercise S-67% SP-100% Chest Pain S-67% SP-100% No Prodrome S-67% SP-70% Palpitations S-100% SP-98%

Summary/Conclusions/Comments

Only 3 patients in entire cohort had significant undiagnosed cardiac disease presenting as syncope, which limits the generalizability of the results

Primary endpoint: Features on history and physical associated with cardiac syncope

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Study type: prospective cohort Massin MM, Malekzadeh-Milani S, Benatar A. Cardiac syncope in pediatric patients. Size: 25 patients Clin Cardiol 2007;30:81-85.

Calkins H, Shyr Y, Frumin H, Schork A, Morady F. The value of the clinical history Study type: Prospective Cohort in the differentiation of syncope due to ventricular tachycardia, atrioventricular Size: 80 adult syncope patients block, and neurocardiogenic syncope. Am J Med 1995;98:365-373.

Inclusion criteria: Presented to Cardiac Clinic in 1 year period Results: and diagnosed with VVS Screening tool including exertional Cardiac syncope diagnoses from past 10 syncope, concerning family history, years abnormal physical exam and abnormal ekg (any feature positive meant a positive screen) S-100% Sp-60%

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Study type: Chen L, Zhang Q, Ingrid S, Chen J, Qin J, Du Retrospective Cohort J. Aetiologic and clinical characteristics of syncope in Chinese children. Acta Paediatr Size: 154 syncope patients 2007;96:1505-1510.

Descriptive cohort with no control group to determine prevalence of same symptoms in non-cardiac syncope

1˚ endpoint: Sensitivity(S) and Specificity(SP) of historical features to predict cardiac cause of syncope

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Study type: Retrospective cohort Tretter JT, Kavey RW. Distinguishing Cardiac Syncope from Vasovagal Syncope in Size: 89 Patients diagnosed with VVS a Referral Population J Pediatr compared to 17 patients with known 2013;163:1618-23 cardiac syncope

Results: Cardiac Family History 3/25 Known Heart Disease 14/25 During Exercise 11/25 Palpitations or Chest Pain 9/25 No Prodrome 15/25

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Inclusion criteria: Diagnosis with cardiac cause of syncope

Inclusion criteria: Transient loss of consciousness

10/17 patients with cardiac syncope presented in pulseless arrest so may represent only a subset of severe cardiac syncope etiologies.

Primary endpoint: Description of final diagnoses and investigations performed Results: VVS 64.3% Cardiac 10% No diagnosis 16.2%

Investigations were rarely helpful including electrolytes, CT, EEG and echocardiography.

Primary endpoint: Odds ratio(OR) of historical features for predicting cardiac syncope Inclusion criteria: Syncope patients in whom a diagnosis of VVS, VTach or AV block were established

Results: ≤2 episodes OR 24 Prodrome <5s OR 8.3 Palpitations OR 0.1 Warmth OR 0.2 Diaphoresis OR 0.1

Fully 34% had CT, but only 1 (3% of ordered) was of even dubious relevance

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Patient Population

Study type: Retrospective questionnaire and prospective observational cohort Inclusion criteria: Athletes (mean age around 16yo) pre participation cardiovascular evaluation

Size: 7568 athletes – pre participation questionnaire (history of syncope in the 5 years preceding), follow-up duration 6.3 years

Miyake CY, Motonaga KS, Fischer-Colbrie MD, Chen L, Hanisch DG, Balise RR, Kim JJ, Dubin AM. 2016. Study type: Retrospective cohort review Risk of cardiac disease and observations on lack of potential Size: predictors by clinical history among 60 patients children presenting for cardiac evaluation of mid-exertional syncope Cardiology in the Young 26 : 894–900

Ikiz MA, Çetin II, Ekici F, Güven A, Degerliyurt A, Köse G. 2014. Pediatric Syncope Is Detailed Medical History the Key Point for Differential Diagnosis? Pediatr Emerg Care 30 :331-334

Study type: Prospective observational cohort Size: 268 children (1 – 18 years)

Inclusion criteria: Patients presenting to pediatric polyclinics as well as cardiology and neurology departments with a primary complaint of syncope

Summary/Conclusions/Comments

Primary endpoint: History of syncope in the 5 years preceding the pre-participation Syncope is rather common in young evaluation athletes and has a neurally-mediated origin in most cases. This study confirms that Results: Overall incidence of syncope of syncopal spells occurring during exercise 6.2%, exertional syncope in 6 (1.3%), 1 tend to be more ominous than those in the hypertrophic cardiomyopathy, 1 RVOT VT, post-exertional state or during ordinary 4 positive tilt test. Disqualification in only 2 daily activities. (0.4%). No major adverse cardiovascular event of any kind was noted during the follow up period in the study population.

Results: 32 (53%) were diagnosed with cardiac syncope and 28 with non-cardiac syncope. A majority of cardiac patients were diagnosed with an electrical myopathy, the most common being Long QT syndrome

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Inclusion criteria: Cardiac syncope diagnosed with appropriate tests or POTS diagnosed with tilt table testing

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Size: 213 children (22 cardiac syncope, 191 POTS)

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Study type: Retrospective cohort study

Inclusion criteria: mid-exertional syncope; age ⩽18 years; mid-exertional syncope; electrocardiogram, echocardiogram and an exercise stress test, electrophysiology study, or tilt test, with exception of long QT, which did not require additional testing; and evaluation by a paediatric cardiologist.

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Yang J, Zhu L, Chen S, LI X, Zhnag Q, Zhnag F, Chen L, Tang C, Du J, Jin H. 2013. Modified Calgary score in differential diagnosis between cardiac syncope and postural orthostatic tachycardia syndrome-associated syncope in children Cardiology in the Young 23 : 400–404

Primary Endpoint and Results

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Colivicchi F, Ammirati F, Santini M. 2004. Epidemiology and prognostic implications of syncope in young competing athletes Eur Heart J 25:1749-1753

Study Design

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Children with mid-exertional syncope are at risk for cardiac disease and warrant evaluation. Reported symptoms may not differentiate benign causes from life-threatening disease.

Primary endpoint: Measurement of the modified Calgary score (question on age modified from the original Calgaray score)

The modified Calgary score could be used to make an initial differential diagnosis between cardiac syncope and postural Results: orthostatic tachycardia syndrome The median of modified Calgary associated syncope in pediatric the scores for cardiac syncope was - 5.0, which population. significantly differed from that of postural orthostatic tachycardia syndrome (0.0; p,0.01). Primary endpoint: Determine a cause of syncope Results: Neurocardiogenic syncope was the most common diagnosis (n = 232, 86.5 %). Cardiologic problems were identified in 12 (4.4%) patients. The remaining 9 (3.3%) patients were classified in the neurologic syncope group; 9 (3.3%), in the psychiatric syncope group; 4 (1.5%) patients, in the situational; and 2 (0.7%), benign paroxysmal positional vertigo group.

An ECG and a medical history including the event details, chronic and familial diseases are an important step in accurate diagnosis and prognosis.

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Study

Study Design

Patient Population

Primary Endpoint and Results

Study type: Retrospective chart review

Inclusion criteria: 4-18 y.o with new syncope. No previous diagnosis of seizure or syncope

Size: 169 pediatric patients with syncope

Results: 3.9 tests per patient. 116/128 diagnosed with VVS, 24% diagnosis unknown or disputed. 3.9% of tests were diagnostic and done in 24 patients. A positive test correlated with clinical diagnosis in 23/663 tests and 21/169 pts. ECG had lowest diagnostic yield (0.4%) and highest cost per diagnostic test.

Testing is common and costly and does not contribute to diagnosis in majority of cases. EKG is most common and costly with lowest yield. Negative testing can be reassuring in some cases.

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Steinberg LA, Knilans TK. Syncope in children: diagnostic tests have a high cost and low yield. J Pediatr 2005;146:355-8

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Primary endpoint: Tests obtained as part of evaluation, and hospital cost for testing only Secondary endpoint: Diagnostic yield of tests

Summary/Conclusions/Comments

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Primary endpoint: Echocardiogram use and yield

Echo findings in 12% but significant in 1% and causally relevant in 0.5%. The issue Results: 71% VVS. Echoes in 322/480 and with this retrospective approach is that Inclusion criteria: Patients diagnosed with abnormal in 12%. Abnormalities were trivial syncope more likely to be attributed to a syncope, initial encounter in 89% of these and 2/4 abnormal echoes cardiac cause if the EKG or Echo is had abnormal EKGs. Of 22 with a [potential] abnormal. However, it is possible to have cardiac cause, 16 exertional/positive family VVS and an unrelated abnormality on EKG, history/abnormal exam. EKG abnormal in such as WPW. 5/6 patients.

Inclusion criteria: Electronic chart review of 626 consecutive patients < 22 y.o. who had an EKG in Emergency Dept

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Size: 403 patients

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Study type: Retrospective chart review Van Dorn CS, Johnson JN, Taggart NW, Thorkelson L, Ackerman MJ.

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Ritter S, Tani LY, Etheridge SP, Williams RV, Study type: Retrospective chart review Craig JE, Minich LL. What is the Yield of Screening Echocardiography in Pediatric Size: 480 patients Syncope? Pediatrics 2000;105;e58.

Petramfar P, Yaghoobi E, Nemati R, AsadiPooya AA. Serum creatine phosphokinase is Study type: Prospective observational helpful in distinguishing generalized tonic- cohort clonic seizures from psychogenic nonepileptic seizures and vasovagal Size: 20 patients syncope. Epilepsy & Behavior 2009;15:3302.

Primary endpoint: EKG findings and diagnosis Results: 26% EKGs for pre- or syncope. 1 in 4 pts with pre-or syncope had QTc > 440 msec but no one received a diagnosis of Long QT. 14/104 pts with pre- or syncope had follow-up EKGs. These demonstrated a decrease in QTc of 33msec from initial EKG. Most patients, including those with QTc > 440 did not get a follow-up EKG.

EKGs are commonly done in Emergency. Many show a QTc > 440 msec. For those which are repeated, there is a significant decrease in QTc interval at follow-up EKG. Autonomic tone and diurnal factors contribute to QT interval. Finding of a borderline EKG following syncope is common and not usually actionable.

Primary endpoint: CPK concentration 1215 h post-event compared to control group Inclusion criteria: Adult patients admitted to Neurology ward with witnessed loss of consciousness and abnormal movements

Not a pediatric study. Findings may not be Results: Higher CPK in generalized tonicgeneralizable. Small group. However, clonic seizures (GTCS) compared to VVS and persistent elevation of CPK may provide an psychogenic causes. Sensitivity of 75% and opportunity for post-event investigation. specificity of 86% diagnosing GTCS. Negative predictive value in excluding GTCS 91.4%

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Study

Study Design

Patient Population

Primary Endpoint and Results

Summary/Conclusions/Comments

Primary endpoint: Effectiveness of 500ml of oral rehydration salts (ORS) daily in the treatment of children with VVS after 6 months follow-up Inclusion criteria: Children with 2 or more syncopes since 6 months, VVS highly suspected, HUTT positive

Size: 166 syncope patients, Gr I:87 tx with ORS, Gr II:79 controls

Results: Gr I: 49 (56,3%) no recurrence 34 (39,1%) improved 4 (4,6%) no better HUTT at 6 months: 57 (65,5%) Neg 30 (34,5%) positive Gr II: 31 (39,2%) no recurrence 37 (46,8%) improved 11 (14%) no better HUTT at 6 months: 28 (35,4%) Neg 51 (64,6%) positive

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Study type: Prospective Randomized-controlled trial

ORS is a simple and effective treatment for VVS. Both groups studied had health education, the control group had no other tx, it would be interesting to compare with 500 ml of water daily.

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Chu W, Wang C, Wu L, Lin P, Li F, Zou R. Oral rehydration salts: an effective choice for the treatment of children with vasovagal syncope. Pediatr Cardiol 2015;36:867-872.

Size: 26 syncope patients, Gr I:13 tx with midodrine, Gr II: 13 controls

Inclusion criteria: Children with 3 or more syncope per year, investigation neg with etiology of syncope undetermined but VVS highly suspected, HUTT positive

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Study type: Prospective Randomized-controlled trial

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Qingyou Z, Junbao D, Chaoshu T. The efficacy of midodrine hydrochloride in the treatment of children with vasovagal syncope. J Pediatr 2006;149:777-780

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Primary endpoint: Effectiveness of midodrine treatment at one week in preventing VVS in children measured with HUTT Secondary endpoint: Effectiveness of midodrine treatment after 6 months followup A small trial but shows efficacy of midodrine from 1,25 mg to 2,5 mg BID with Results: Gr I:midodrine 1,25 mg BID 3/12 few side effects. HUTT neg , the 9 positive responders Both groups had health education, the increased midodrine at 2,5 mg BID and controlled group didn’t take a placebo repeat HUTT at one week again then 6/9 HUTT neg. 1 patient is excluded, he didn’t repeat the HUTT. Gr II: 2/10 HUTT neg. 3 patients excluded who didn’t complete the repeat HUTT. P= 0,03 At 6 months; Gr I: recurrence of syncope in 2/9 (22%), Gr II: 8/10 (80%) P= 0,023

Primary endpoint: Effectiveness of fludrocortisone 0,1mg and NaCl 1g daily in Study type: Prospective randomized doublepreventing syncope recurrence in children Salim MA, Di Sessa TG. Effectiveness of blinded placebo-controlled trial Inclusion criteria: Fludrocortisone plus salt is ineffective to after one year fludrocortisone and salt in preventing Children with 1 or more syncope or severe prevent recurrence of syncope in children. syncope recurrence in children: a double- Size: 33 syncope or pre-syncope patients, pre-syncope, investigation neg for other Both group had health education. This Results: blind, placebo-controlled, randomized trial. 18 tx with fludrocortisone and salt, 15 causes of syncope, HUTT positive study highlight the effect of placebo. Gr Tx: 10/18 recurrence J Am Coll Cardiol 2005;45:484-488 controls minus 1 lost after randomization Gr placebo: 5/10 recurrence, all after the placebo has been discontinued P< 0,04

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Patient Population

Primary Endpoint and Results

Inclusion criteria: Children with 3 or more syncope per year, investigation neg for other cause of syncope, HUTT positive, no CI for beta blockers

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Size: 28 VVS patients, 14 tx with metoprolol, 14 conventional tx

Summary/Conclusions/Comments

Primary endpoint: Recurrence of syncope after 2 weeks of therapy of metoprolol up Metoprolol is ineffective in preventing the to 1,5 mg/kg BID, max 100mg BID and recurrence of syncope in children. Their recurrence after one year. control group had health education but it seems that the treated group didn’t, so Results: there’s a bias in the comparison. Gr Tx: 6/14 recurrence (43%) Gr conventional tx: 4/14 (29%)

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Study type: Prospective Randomized trial

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Zhang Q, Jin H, Wang L, Chen J, Tang C, Du J. Randomized comparison of metoprolol versus conventional treatment in preventing recurrence of vasovagal syncope in children and adolescents. Med Sci Monit 2008;14:CR199-203

Study Design

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Study Design

Patient Population

Zhang Q, Jin H, Wang L, Chen J, Tang C, Du Study type: Probably open label RCT of J. Randomized comparison of metoprolol metoprolol vs conventional treatment versus conventional treatment in preventing recurrence of vasovagal Size: 28 patients syncope in children and adolescents. Med Sci Monit 2008;14:CR199-203.

Inclusion criteria: age 8-17 years, positive tilt test, >2 faints in prior year

Study type: Single blind multiple crossovers of single, dual and no chamber pacing. Adjudication blinded but probable big Inclusion criteria: typical VVS history in placebo effect due to expectancy. mainly toddlers (2-14 years) and >4sec pause during syncope Size: 12 patients

Results: 6/14 and 4/14 outcomes in metoprolol and control arms; p=0.39 log rank

Primary endpoint: total syncope count during each 4-month epoch Results: DDD and VVI superior to ODO in preventing syncope

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Krahn AD, Healey JS, Simpson CS, et al. Sentinel symptoms in patients with unexplained cardiac arrest: from the cardiac arrest survivors with preserved ejection fraction registry (CASPER). J Cardiovasc Electrophysiol 2012;23:60-66.

Summary/Conclusions/Comments

Primary endpoint: first recurrence of syncope, actuarial analysis, up to 3 years

Primary endpoint: Registry. Does syncope predict sudden death? Results: Syncope present in only a minority. Study not designed to detect predictive values

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McLeod KA, Wilson N, Hewitt J, Norrie J, Stephenson JB. Cardiac pacing for severe childhood neurally mediated syncope with reflex anoxic seizures. Heart 1999;82:721725.

Primary Endpoint and Results

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Study

Study type: prospective registry of 100 Inclusion criteria: unexplained sudden death survivors and 63 Adult cardiac arrest survivors NYD and 1st degree family members. Examined family members. effect of a history of syncope

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Kouakam C, Vaksmann G, Pachy E, Lacroix Study type: Observational cohort study, ad D, Rey C, Kacet S. Long-term follow-up of Inclusion criteria: Recurrent syncope (91) hoc treatment including beta blocker children and adolescents with syncope; or presyncope (10). Median 3 historical predictor of syncope recurrence. Eur Heart faints. Tilt test result noted Size: 101 patients ages 7-18 J 2001;22:1618-1625.

Primary endpoint: Syncope Results: 32% had at least 1 faint in mean 46 months. Not actuarial

Under powered, open label, no hint of a signal

Small, underpowered for multiple comparisons, potential for large observer expectancy effect

Adult study of sudden death survivors. Not relevant to CCS document

Poorly defined inclusion criteria and analysis. Syncope recurs in children with recurrent syncope, and many were on beta blockers