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Canadian Journal of Cardiology

Canadian Cardiovascular Society Position Statement on Postural Orthostatic Tachycardia Syndrome (POTS) and Related Disorders of Chronic Orthostatic Intolerance

      Abstract

      The current definition of postural orthostatic tachycardia syndrome (POTS) dates back to a small case series of patients with a subacute illness who presented with excessive orthostatic tachycardia and orthostatic intolerance, in the absence of another recognized disease. Conventional POTS criteria require an excessive orthostatic tachycardia in the absence of substantial orthostatic hypotension, and predominant symptoms of orthostatic intolerance, worse with upright posture and better with recumbence. POTS is a heterogeneous syndrome with likely several underlying pathophysiological processes, and not a specific disease. The primary panel for this Canadian Cardiovascular Society position statement sought to provide a contemporary update of the best evidence for the evaluation and treatment of POTS. We performed a systemic review of evidence for the evaluation of treatment of POTS using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology, and developed recommendations on the basis of the Canadian Cardiovascular Society approach to position statements. One identified problem was that numerous patients who did not meet criteria for POTS would still be given that diagnoses by providers to validate the illness even though this diagnosis is incorrect. This includes patients with postural symptoms without tachycardia, orthostatic tachycardia without symptoms, and those with orthostatic tachycardia but another overt cause for excessive tachycardia. We developed a novel nomenclature ecosystem for orthostatic intolerance syndromes to increase clarity. We also provide more clarity on how to interpret the orthostatic vital signs. These concepts will need to be prospectively assessed.

      Résumé

      La définition actuelle du syndrome de tachycardie orthostatique posturale (STOP) remonte à une petite série de cas de patients atteints d’une maladie subaiguë qui présentaient une tachycardie orthostatique excessive et une intolérance orthostatique, en l’absence d’une autre maladie reconnue. Selon les critères classiques, le STOP implique une tachycardie orthostatique excessive en l’absence d’hypotension orthostatique marquée, ainsi que des symptômes prédominants d’intolérance orthostatique, s’aggravant en position verticale et s’atténuant en position allongée. Le STOP est une entité hétérogène où interviennent probablement plusieurs processus physiopathologiques sous-jacents; il ne s’agit pas d’une maladie en tant que telle. Le principal groupe d’experts à l’origine de cet énoncé de position de la Société canadienne de cardiologie a cherché à présenter les données probantes les plus récentes et les meilleures en matière d’évaluation et de traitement du STOP. Nous avons effectué un examen systématique des données probantes aux fins d’évaluation du traitement du STOP conformément à la méthodologie GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) et formulé des recommandations fondées sur le cadre de référence relatif aux énoncés de position de la Société canadienne de cardiologie. Notre démarche a notamment fait ressortir une problématique, où un diagnostic de STOP avait été posé chez de nombreux patients malgré l’incongruence de leur état et des critères définissant le syndrome. Un tel diagnostic erroné avait notamment été prononcé chez des patients présentant des symptômes posturaux en l’absence de tachycardie, une tachycardie orthostatique asymptomatique ou encore une tachycardie orthostatique en présence d’une autre cause manifeste de tachycardie excessive. Par souci de clarté, nous avons élaboré un nouvel écosystème de classification des syndromes d’intolérance orthostatique. Dans la même optique, nous avons également précisé les critères d’interprétation des signes vitaux orthostatiques. Ces concepts devront être l’objet d’une évaluation prospective.

      1. Introduction and Rationale

      The current definition of postural orthostatic tachycardia syndrome (POTS) dates back to 1993.
      • Schondorf R.
      • Low P.A.
      Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia?.
      This initial report was a small case series of patients with a subacute onset illness who presented with an excessive orthostatic tachycardia and orthostatic intolerance, in the absence of another recognized disease.
      The conventional criteria for POTS (Table 1) require excessive orthostatic tachycardia in the absence of substantial orthostatic hypotension. In addition to the hemodynamic criteria, POTS requires predominant symptoms of orthostatic intolerance, with symptoms that are worse with upright posture and better with recumbence. POTS is a syndrome, and not a specific disease. It is also a heterogeneous disorder with likely several underlying pathophysiological processes. The hope is that discrete subtypes will be identified over time, each with a specific underlying pathophysiology and targeted treatment.
      Table 1Chronic orthostatic intolerance syndromes: diagnostic hemodynamic and symptom criteria
      ConditionHemodynamic criteriaClinical criteriaAssociated comorbiditiesDuration of symptoms
      POTSSustained increase in heart rate ≥ 30 bpm in adults (older than 19 years) or 40 bpm in children/adolescents (younger than 19 years), from supine position to upright within 10 minutes of standing, and absence of orthostatic hypotension (decrease in systolic blood pressure > 20 mm Hg or diastolic blood pressure > 10 mm HgOrthostatic intolerance symptoms:
      • Lightheadedness
      • Palpitation (“heart racing”)
      • Tremulousness
      • Atypical chest discomfort
      Other symptoms not associated with changes in position:
      • Sleep disturbance
      • Headaches
      • Chronic fatigue
      • Exercise intolerance and deconditioning
      • Perceived cognitive impairment (“brain fog”)
      • Peripheral acrocyanosis (“POTS feet”)
      • Frequent nausea
      • Mild diarrhea, constipation, bloating, unspecific abdominal pain (“irritable bowel syndrome”)
      None> 3 Months
      POTS plusSame as POTSSame as POTS and 1 or more:
      • Gastric emptying problems
      • Intractable vomiting
      • Severe constipation
      • Neurogenic bladder
      • Severe chronic pain
      • Intractable headaches
      • Significant flushing anaphylaxis symptoms
      • Severe food intolerances
      • Hypermobile Ehlers-Danlos syndrome
      • Hypermobile spectrum disorder
      • Mast cell activation disorder
      • Chronic fatigue syndrome/ME
      • Celiac disease
      • Autoimmune disorder
      • Chronic migraines
      • Cerebrospinal fluid leak
      • Mitochondrial mutations disorders
      • Multiple sclerosis
      Same as POTS
      PSWTNo evidence of orthostatic tachycardia and orthostatic hypotension
      • Orthostatic intolerance symptoms as with POTS and 1 or more:
      • Gastric emptying problems
      • Intractable vomiting
      • Severe constipation
      • Neurogenic bladder
      • Severe chronic pain
      • Intractable headaches
      • Significant flushing anaphylaxis symptoms
      • Severe food intolerances
      NoneSame as POTS
      PSWT plusNo evidence of orthostatic tachycardia and orthostatic hypotension
      • Orthostatic intolerance symptoms as with POTS and 1 or more:
      • Gastric emptying problems
      • Intractable vomiting
      • Severe constipation
      • Neurogenic bladder
      • Severe chronic pain
      • Intractable headaches
      • Significant flushing anaphylaxis symptoms
      • Severe food intolerances
      • Hypermobile Ehlers-Danlos syndrome
      • Hypermobile spectrum disorder
      • Mast cell activation disorder
      • Chronic fatigue syndrome/ME
      • Celiac disease
      • Autoimmune disorder
      • Chronic migraines
      • Cerebrospinal fluid leak
      • Mitochondrial mutations disorders
      • Multiple sclerosis
      Same as POTS
      PTOCSame as POTSSame as POTSSecondary identifiable cause:
      • Acute hypovolemia
      • Endocrinopathy
      • Anemia
      • Anxiety and panic attacks
      • Medication side effects
      • Recreational drugs effects
      • Prolonged or sustained bed rest
      Transient
      bpm, beats per minute; ME, myalgic encephalomyelitis; POTS, postural orthostatic tachycardia syndrome; PSWT, postural symptoms without tachycardia; PTOC, postural tachycardia of other cause.
      The primary panel for this Canadian Cardiovascular Society (CCS) position statement sought to provide a contemporary update of the best evidence for the evaluation and treatment of POTS. We performed a systemic review of evidence for the evaluation of treatment of POTS, and developed recommendations on the basis of the CCS approach to position statements.
      As our discussions progressed, a larger problem of nomenclature that inhibited effective communication became apparent, and this contributed to mistaken diagnoses of POTS. One issue was that even within the expert panel, there was disagreement about whether POTS was a purely cardiovascular and hemodynamic disorder, or one that could be associated with other disorders with systemic (and nonhemodynamic) presentations. Some believed that if a patient had another condition (eg, Ehlers-Danlos syndrome) that they should not be diagnosed with POTS because they would not have been included in the original report.
      • Schondorf R.
      • Low P.A.
      Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia?.
      However, this group with comorbid conditions comprise a significant population in our clinics diagnosed with POTS. It is likely that the natural history, prognosis, and response to treatment are different between this “pure” group and that with the comorbid conditions, and therefore it was important to develop a language that conveys those differences.
      Another problem that surfaced was that numerous patients who did not meet criteria for POTS would arrive at our clinics diagnosed with POTS. This might be because of a misunderstanding of the POTS criteria in the broader medical community. Another issue is that for a patient who is unwell, the diagnosis of POTS can provide hope and validation of illness. These include patients with severe symptoms of orthostatic intolerance, but who did not meet the excessive orthostatic tachycardia criterion. This group also includes patients who suffered from symptoms of orthostatic intolerance and from excessive orthostatic tachycardia, and who have a condition that precludes the diagnosis of POTS (eg, prolonged bedrest or medications that exacerbate orthostatic tachycardia).
      The primary panel sought to describe the ecosystem of chronic orthostatic intolerance that included POTS, and also the related disorders that did not meet POTS criteria. Some of these related disorders require treatment, similar to POTS, whereas others (eg, asymptomatic postural tachycardia) might not require treatment. Importantly, we did not expand the definition of POTS beyond the American Autonomic Society statement, although we did try to provide clarity to specific aspects of that definition. These newly described disorders were created on the basis of expert opinion of the primary panel and will need to be evaluated to determine if further modifications are required. It was clear to the primary panel that something was required, and this was its attempt to address the issue.

      2. Methods

      The CCS appointed co-chairs, a primary panel, and a secondary panel to develop this position 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,
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE Working Group
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      drafted the recommendations for treatment and evaluation, and voted on the recommendations. The search strategy and evidence tables are presented in the Supplemental Appendix S1 and Supplemental Table S1, respectively.
      The strength of recommendation could be either “strong” or “weak.” The recommendations are to begin with “we recommend” (where strength is strong) and “we suggest” (where strength is weak). The quality of the evidence (QOE) was rated as “high,” “moderate,” “low,” and “very low” on the basis of the likelihood that further research would change our confidence in the estimate of effect. A QOE of “high” is one in which such a change is very unlikely, a QOE of “moderate” is one in which such a change is likely, a QOE of “low” is one in which such a change is very likely, and a QOE of “very low” suggests that any estimate of effect is very uncertain.
      The newly suggested nomenclature and definitions for the disorders “related to POTS” (but that are not POTS) in the chronic orthostatic intolerance ecosystem were developed on the basis of expert consensus opinion of the primary panel after lengthy and detailed discussion. Peer review was provided by the secondary panel and the CCS Guidelines Committee. The final draft was presented and approved by the CCS Executive Committee.

      3. Definitions and Diagnostic Criteria

      Current guidelines define POTS as a heterogeneous clinical syndrome that is characterized by sustained and excessive sinus tachycardia upon standing, in the absence of orthostatic hypotension and with chronic symptoms of orthostatic intolerance.
      • Freeman R.
      • Wieling W.
      • Axelrod F.B.
      • et al.
      Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome.
      ,
      • Sheldon R.S.
      • Grubb B.P.
      • 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.
      However, the term “POTS” is now commonly used to speak about a spectrum of disorders, some of which fit into the original definition
      • Schondorf R.
      • Low P.A.
      Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia?.
      of POTS, but much of which does not fit that original definition. For that reason, we propose a new classification framework with specific hemodynamic and clinical diagnostic criteria to better characterize this disorder (Fig. 1).
      Figure thumbnail gr1
      Figure 1Proposed framework for postural orthostatic tachycardia syndrome (POTS) and related disorders. This newly proposed framework defines a novel framework for defining POTS and related disorders on a grid of orthostatic tachycardia and orthostatic symptoms. PSWT, postural symptoms without tachycardia.
      This novel classification is on the basis of expert opinion of the Writing Committee on the basis of limitations with the current nomenclature. Suggested diagnostic terms in the spectrum of orthostatic tachycardia and orthostatic intolerance include POTS, POTS plus, postural symptoms without orthostatic tachycardia (PSWT), PSWT plus, and postural tachycardia of other cause (PTOC). The details of these newly defined diagnoses are described in the following sections and summarized enumerated in Table 1. Figure 2 provides a diagnostic flow algorithm.
      Figure thumbnail gr2
      Figure 2Postural orthostatic tachycardia syndrome (POTS) diagnostic criteria algorithm: a flow algorithm to help clinicians navigate the diagnosis of POTS and related disorders of orthostatic intolerance and orthostatic tachycardia. bpm, beats per minute; EDS, Ehlers-Danlos syndrome; HR, heart rate; IST, inappropriate sinus tachycardia; MCAS, mast cell activation syndrome; PSWT, postural symptoms without tachycardia.

      3.1 Chronic orthostatic intolerance syndromes

      All of the following classifications (POTS, POTS plus, PSWT, PSWT plus, and PTOC) are forms of “chronic orthostatic intolerance.”

      3.2 POTS

      Primary POTS criteria fulfil the American Autonomic Society consensus definition
      • Freeman R.
      • Wieling W.
      • Axelrod F.B.
      • et al.
      Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome.
      (Table 1), with some specific hemodynamic and symptom criteria clarifications.
      • Shen W.K.
      • Sheldon R.S.
      • Benditt D.G.
      • et al.
      2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.
      ,
      • Singer W.
      • Sletten D.M.
      • Opfer-Gehrking T.L.
      • et al.
      Postural tachycardia in children and adolescents: what is abnormal?.
      We have not expanded the definition of POTS. Hemodynamics and symptoms must be chronic, persisting for at least 3 months. Differential diagnosis includes inappropriate sinus tachycardia (IST; see section 3.8 for more details), which has a different hemodynamic pattern than POTS, but can share many symptoms.

      3.2.1 POTS hemodynamic criteria

      • There must be excessive orthostatic tachycardia, defined as a sustained increase in heart rate from the supine position to upright ≥ 30 beats per minute (bpm) within 10 minutes of standing if older than 19 years (and ≥ 40 bpm if 12-19 years of age).
      • The American Autonomic Society criteria included a heart rate > 120 bpm even without orthostatic tachycardia. This is not included in current CCS POTS criteria, because most of these patients already meet the excessive orthostatic tachycardia criteria, and many of the remaining patients might fit better within a diagnosis of IST.
      • To be sustained, the heart rate above threshold should be seen on at least 2 measurements at least 1 minute apart. If only seen on the last measurement, this should be repeated 1 minute later to document that the heart rate increase is sustained and not spurious.
      • In patients with low supine resting heart rates (< 60 bpm), the threshold will be on the basis of an increase from a resting heart rate of 60 bpm.
      • Diagnostic orthostatic tachycardia must occur in the absence of sustained orthostatic hypotension (decrease in systolic blood pressure > 20 mm Hg or diastolic blood pressure > 10 mm Hg within 3 minutes of standing). Transient initial orthostatic hypotension (lasting < 1 minute) does not preclude the diagnosis of POTS.
      • These hemodynamic criteria do not need to be met at every visit (ie, the POTS status should not change from visit to visit if the heart rate increase decreases to < 30 bpm for a single visit).

      3.2.2 POTS symptoms criteria

      • Predominant and bothersome orthostatic symptoms, many of which, if not all, get better with recumbence; these symptoms have to be dominant in the clinical presentation. Common POTS symptoms are enumerated in Table 2. Presentations can vary with different symptom clusters in different patients. There is not a specific cardinal symptom, nor a critical number of symptoms, required.
        Table 2Symptoms associated with POTS
        Common orthostatic intolerance symptoms
        • Lightheadedness
        • Palpitation (“heart racing”)
        • Tremulousness
        • Atypical chest discomfort
        Other commonly reported symptoms not necessarily associated with particular postures
        • Sleep disturbances
        • Headaches
        • Chronic fatigue
        • Chronic pain
        • Exercise intolerance and deconditioning
        • Perceived Cognitive impairment (“brain fog”)
        • Peripheral acrocyanosis (“POTS feet”)
        • Frequent nausea
        • Mild diarrhea/constipation/bloating/unspecific abdominal pain (“irritable bowel syndrome”)
        POTS, postural orthostatic tachycardia syndrome.

      3.3 POTS plus

      • Meets all hemodynamic and orthostatic intolerance symptoms criteria for POTS.
      • In addition, these patients can have one or more additional noncardiovascular symptom(s) that can be debilitating and, in some cases, more debilitating than the orthostatic symptoms (Table 3).
        Table 3Noncardiovascular debilitating symptoms
        • Gastric emptying problems (too fast or too slow) that can present with intractable nausea and sometimes cycling vomiting
        • Severe constipation and diarrhea
        • Neurogenic bladder/incontinence/urinary retention
        • Severe chronic pain
        • Joint hypermobility
        • Intractable headaches
        • Significant flushing/anaphylaxis symptoms
        • Severe food intolerances
        • Neurological symptoms (eg, paresthesia, numbness, and neuropathic pain)
      • Patients with POTS plus might have additional comorbid diagnoses (Table 4). These conditions and the POTS presentation might or might not have a common underlying cause.
        Table 4Associated comorbid conditions seen in POTS plus
        • Comorbid condition
        Prevalence
        • Chronic migraine/cerebrospinal fluid leak
        40%
        • Hypermobile Ehlers-Danlos syndrome and hypermobile spectrum
        25%
        • Chronic fatigue syndrome/myalgic encephalomyelitis
        21%
        • Fibromyalgia
        20%
        • Autoimmune disorders
        16%
        • Mast cell activation disorder
        9%
        • Celiac disease
        3%
        Reproduced from Shaw et al.
        • Shaw B.H.
        • Stiles L.E.
        • Bourne K.
        • et al.
        The face of postural tachycardia syndrome – insights from a large cross-sectional online community-based survey.
        by Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0).

      3.4 PSWT

      • These patients meet the symptoms criteria for POTS but do not meet the hemodynamic criteria for POTS. Although these patients might have orthostatic intolerance, they should not be diagnosed with POTS.
      • A patient might be in this category during an initial visit in which the patient does not meet the hemodynamic criteria, and later clearly meet the hemodynamic criteria and switch to a diagnosis of POTS.
      • There are numerous potential causes for these symptoms. In some cases, the treatment approaches used for patients with POTS also might be appropriate for these patients.

      3.5 PSWT plus

      • These patients meet the orthostatic intolerance symptoms criteria for POTS plus but do not meet the hemodynamic criteria for POTS.
      • In addition, these patients can have one or more additional noncardiovascular symptoms that can be debilitating and, in some cases, more debilitating than the orthostatic symptoms (Table 3).
      • Patients with PSWT plus might have additional comorbid diagnoses (Table 4). These conditions and the POTS presentation might or might not have a common underlying cause.

      3.6 PTOC

      • These patients meet hemodynamic criteria for POTS, but there is a clear secondary and underlying cause for the excessive orthostatic tachycardia that should be addressed (Table 5), and that precludes the diagnosis of POTS.
        Table 5Underlying conditions associated with PTOC
        • Acute hypovolemia (dehydration or blood loss)
        • Endocrinopathy (carcinoid, adrenal insufficiency, Cushing syndrome, hyperthyroidism, pheochromocytoma, etc)
        • Anemia
        • Anxiety and panic attacks
        • Medication side effects
        • Recreational drugs effects
        • Prolonged or sustained bed rest
        PTOC, postural tachycardia of other cause.
      • These conditions could include (but are not limited to) prolonged bedrest, severe hypovolemia, or medications that could cause tachycardia.
      • These patients should not be diagnosed with POTS.
      • The excessive orthostatic tachycardia would be expected to resolve with treatment of the underlying condition (“other cause”).

      3.7 Asymptomatic orthostatic tachycardia

      • Despite meeting the hemodynamic criteria for POTS, these patients are asymptomatic or minimally symptomatic. These patients should not be diagnosed with POTS.
      • Patients might increasingly present with asymptomatic tachycardia because of the increasing prevalence of wearable heart rate monitors.
      • These patients often will not require specific medical follow-up or treatment aside from reassurance.
      • This etiology of this tachycardia can be multifactorial and can sometimes be intermittent.

      3.8 IST

      IST is defined as sinus heart rate > 100 bpm at rest (with a mean 24-hour heart rate > 90 bpm) not due to a primary underlying cause, and that is associated with distressing symptoms of palpitations. A detailed approach to the diagnosis and management of IST can be found elsewhere.
      • Sheldon R.S.
      • Grubb B.P.
      • 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.
      • 1.
        We recommend using specific hemodynamic and symptom criteria definitions for the diagnosis of POTS in adolescents and adults, to avoid misdiagnosis (Strong Recommendation, Low-Quality Evidence).
      Practical tip. Sustained excessive heart rate increase in the upright position. Heart rate can transiently increase in many people on initial standing, and this can be a manifestation of initial orthostatic hypotension.
      • Freeman R.
      • Wieling W.
      • Axelrod F.B.
      • et al.
      Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome.
      ,
      • Sheldon R.S.
      • Grubb B.P.
      • 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.
      This is not a part of the diagnosis of POTS. POTS requires the heart rate increase to be sustained and persistent, and this will usually become more pronounced during the first 10 minutes upright. The diagnosis of POTS requires an increase in heart rate from supine to upright of ≥ 30 bpm within 10 minutes of standing (≥ 40 bpm in patients between 12 and 19 years of age). The excessive orthostatic tachycardia should not be transient and should be present during a continuous recording or on multiple recordings during the 10-minute upright test.
      Practical tip. Resting heart rate. POTS is a disorder of excessive upright tachycardia. Some people have a very low resting heart rate that climbs to the normal range with standing. This is not considered to warrant a POTS diagnosis. We therefore propose that a minimum heart rate while standing of 90 bpm in adults (100 bpm in teenagers) be required for a POTS diagnosis. In other words, if the supine resting heart rate is < 60 bpm, then 60 bpm will be used as the reference supine heart rate to make the diagnosis.
      For example, an adult with a resting heart rate of 55 bpm would need to reach an upright heart rate of 90 bpm (60 bpm + 30 bpm) to meet the orthostatic tachycardia criteria, whereas an adult with a resting heart rate of 65 bpm would need to reach an upright heart rate of 95 bpm (65 bpm + 30 bpm).

      4. Epidemiology and Natural History

      The prevalence of POTS in Canada is unknown. Data from the United States suggest a prevalence of up to 0.1%-1.0% in the general population.
      • Freeman R.
      • Wieling W.
      • Axelrod F.B.
      • et al.
      Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome.
      ,
      • Sheldon R.S.
      • Grubb B.P.
      • 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.
      Anecdotally, most patients present with POTS between 13 to 40 years, and more than 90% are female. If not adequately treated, POTS can become a debilitating disorder that can lead to impairment in quality of life and disability,
      • Shaw B.H.
      • Stiles L.E.
      • Bourne K.
      • et al.
      The face of postural tachycardia syndrome – insights from a large cross-sectional online community-based survey.
      although mortality has rarely been directly attributable to POTS. Although prognosis in POTS can be quite variable, many POTS patients can improve with appropriate treatment.
      • Shaw B.H.
      • Stiles L.E.
      • Bourne K.
      • et al.
      The face of postural tachycardia syndrome – insights from a large cross-sectional online community-based survey.
      A better definition and diagnostic criteria would help to better clarify the prevalence of POTS and allow for well designed prospective studies that could better define the natural history of POTS.

      5. Pathophysiology

      A number of pathophysiological mechanisms have been described in patients with primary POTS including, but not limited to, autonomic denervation,
      • Li H.
      • Yu X.
      • Liles C.
      • et al.
      Autoimmune basis for postural tachycardia syndrome.
      hypovolemia,
      • Raj S.R.
      • Biaggioni I.
      • Yamhure P.C.
      • et al.
      Renin-aldosterone paradox and perturbed blood volume regulation underlying postural tachycardia syndrome.
      hyperadrenergic stimulation,
      • Garland E.M.
      • Raj S.R.
      • Black B.K.
      • Harris P.A.
      • Robertson D.
      The hemodynamic and neurohumoral phenotype of postural tachycardia syndrome.
      and deconditioning
      • Fu Q.
      • Vangundy T.B.
      • Galbreath M.M.
      • et al.
      Cardiac origins of the postural orthostatic tachycardia syndrome.
      (Table 6). These mechanisms often appear to coexist within individual patients with POTS.
      • 2.
        We do not recommend pathophysiological subtyping during the initial screening and diagnosis of POTS because of the lack of tools to provide such characterization (Strong Recommendation, Low-Quality Evidence).
      Table 6POTS pathophysiological subtypes
      TypeMechanismClinical findings
      Peripheral autonomic denervation
      • Restricted autonomic neuropathy of small and distal postganglionic autonomic fibres
      • Sympathetic tone impairment
      • Reduce vasoconstriction
      • Compensatory tachycardia
      • Autonomic dysfunction
      • Autoimmune markers
      • Severe deconditioning
      Hypovolemia
      • Reduced blood volume
      • Plasma renin activity and aldosterone levels can be reduced in those patients
      • Decrease 24-hour urine sodium excretion (< 170 mmol per 24 hours)
      Hyperadrenergic
      • Norepinephrine transporter deficiency
      • Plasma norepinephrine levels ≥ 600 pg/mL while standing
      • Systolic blood pressure increase ≥ 10 mm Hg
      • Excessive phase IV overshoot on the Valsalva manoeuvre
      Deconditioning
      • Reduced left ventricular mass, stroke volume, and blood volume
      • Objective cardiovascular deconditioning on stress test
      POTS, postural orthostatic tachycardia syndrome.

      6. Diagnosis and Evaluation

      The basic evaluation of a patient suspected of having POTS should include a complete clinical history, physical examination (including orthostatic vital signs), and a 12-lead electrocardiogram (ECG) to assess for persistent underlying arrhythmias.
      • Thieben M.J.
      • Sandroni P.
      • Sletten D.M.
      • et al.
      Postural orthostatic tachycardia syndrome: the Mayo clinic experience.
      For most patients, this minimal approach is sufficient to establish a diagnosis and initiate treatment. However, because of the heterogeneity of the clinical features associated with POTS, an individualized approach to the diagnostic evaluation is warranted. A POTS diagnostic approach algorithm is presented in Figure 3.
      Figure thumbnail gr3
      Figure 3Postural orthostatic tachycardia syndrome (POTS) diagnostic approach algorithm: a flow algorithm that includes a diagnostic approach for POTS, relevant investigations, and indications for referral to a specialist. ECG, electrocardiography; EEG, electroencephalography; EMG, electromyography

      6.1 Clinical history

      The clinical history should focus on identifying possible primary causes and associated disorders (Table 4), potential triggers and precipitating events (which might be present in up to 50% of patients, and most commonly include infections, surgery, and pregnancy),
      • Shaw B.H.
      • Stiles L.E.
      • Bourne K.
      • et al.
      The face of postural tachycardia syndrome – insights from a large cross-sectional online community-based survey.
      ,
      • Thieben M.J.
      • Sandroni P.
      • Sletten D.M.
      • et al.
      Postural orthostatic tachycardia syndrome: the Mayo clinic experience.
      severity of symptoms and effect on quality of life, as well as mitigating factors. Special attention should be given to diet (salt and water intake), exercise (functional capacity), as well as features of autonomic neuropathy, and a detailed autonomic review of systems
      • Goodman B.P.
      Evaluation of postural tachycardia syndrome (POTS).
      (Table 7). A careful medication history is also critical, because certain medications might mimic symptoms or result in symptom exacerbation. Examples of medications and substances that might mimic or exacerbate POTS include stimulants (eg, attention deficit disorder medications), α-adrenergic blockers, excessive β-adrenergic blockers (whereas low dose β-blockers can be beneficial), calcium channel blockers, serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, and phenothiazine. Symptoms might develop acutely (< 1 month), subacutely (1-3 months), or more insidiously (> 3 months).
      Table 7Autonomic review of systems
      Sudomotor
      • Hyperhidrosis
      • Hypohidrosis
      • Anhidrosis
      • Heat intolerance
      Secretomotor
      • Dry eyes
      • Dry mouth
      Cardiovascular
      • Postural lightheadedness
      • Near-syncope
      • Syncope
      Gastrointestinal
      • Nausea
      • Dysphagia
      • Early satiety
      • Gastroparesis
      • Abdominal bloating
      • Constipation
      • Diarrhea
      Genitourinary
      • Nocturia
      • Incomplete bladder emptying
      • Urinary retention
      • Impotence
      • Dyspareunia
      Reproduced from Goodman
      • Goodman B.P.
      Evaluation of postural tachycardia syndrome (POTS).
      with permission from Elsevier.

      6.2 Physical examination

      The general physical examination is a critical component of the evaluation of a patient with suspected POTS. This should include orthostatic vital signs, as well as a complete cardiac and neurological examination. During the stand test for orthostatic vital signs, close attention should be paid to the correlation between heart rate increments or the other indices of orthostatic intolerance, and patient symptoms.
      • Goodman B.P.
      Evaluation of postural tachycardia syndrome (POTS).

      6.3 Investigations

      The use of investigations should be limited to determine the underlying cause or associated conditions. The decision about additional investigations should be influenced by the duration, severity, and treatment responsiveness of the patient’s condition.

      6.3.1 Blood work

      Routine blood tests including complete blood count, electrolytes (Na+, K+, and Cl), renal function (creatinine, and urea), ferritin, thyroid stimulating hormone, and morning cortisol level should be performed during the initial assessment of POTS to identify secondary causes of orthostatic tachycardia.
      • Garland E.M.
      • Raj S.R.
      • Black B.K.
      • Harris P.A.
      • Robertson D.
      The hemodynamic and neurohumoral phenotype of postural tachycardia syndrome.

      6.3.2 Cardiovascular testing

      Cardiac testing, including external ECG monitoring, echocardiogram, and exercise stress test should not be ordered as a routine. Strong consideration should be given to more detailed cardiovascular testing when there is a concern or suspicion about structural heart disease (eg, cardiomyopathy, valvulopathy) or clinical suspicion of an arrhythmia not coming from the sinus node.

      6.3.3 Neurological investigations and autonomic testing

      Neuroimaging, electroencephalography, or electromyography studies should be considered only in patients with clear neurological deficits. If patients’ symptoms do not resolve or markedly improve with initial conventional therapy, and there is a suspicion of autonomic neuropathy, then a more extensive evaluation by an autonomic specialist might be required. Detailed autonomic testing (including tilt table test, plasma norepinephrine levels determination during orthostatic stress, Valsalva manoeuvre, deep breathing test, thermoregulatory sweat test, and quantitative sudomotor axonal reflex test), 24-hour urine sodium, blood volume measurement, and antinicotinic ganglionic antibodies should be considered only in those specific cases. Most patients with POTS will not need these tests.
      • 3.
        We recommend that patients with a presumptive diagnosis of POTS have a detailed history and physical examination during the initial assessment. For most patients this minimal approach is sufficient to establish a diagnosis and to initiate treatment (Strong Recommendation, High-Quality Evidence).
      • 4.
        We recommend that heart rate and blood pressure be measured while the patient is in the supine position for at least 5 minutes, and then while the patient is in the standing position for up to 10 minutes. For a diagnosis of POTS, the orthostatic tachycardia must be sustained for at least 2 consecutive recordings (separated by at least 1 minute) after the first minute (Strong Recommendation, Moderate-Quality Evidence).
      Practical tip. We suggest measuring the orthostatic vital signs with intermittent (automated or manual) blood pressure brachial cuff and/or continuous noninvasive heart rate measurement (ECG, optical/photoplethysmographic sensors, smart watches, or fitness wearable monitors).
      • 5.
        We recommend screening for comorbid or underlying conditions that can cause POTS plus because these might alter the response to treatment and the patient’s prognosis over time (Strong Recommendation, Moderate-Quality Evidence).
      • 6.
        We recommend performing a 12-lead ECG and routine blood tests including complete blood count, electrolytes (Na+, K+, and Cl), renal function (creatinine, and urea), ferritin, thyroid stimulating hormone, and morning cortisol level to identify secondary causes of orthostatic tachycardia (Strong Recommendation, Moderate-Quality Evidence).
      • 7.
        We do not recommend the routine use of ancillary cardiac testing (eg, echocardiogram, external ECG loop monitoring) although these might be considered to rule out conditions that can mimic POTS (Strong Recommendation, Moderate-Quality Evidence).
      Practical tip. Although not routinely required, cardiac testing should be ordered when there is clinical evidence of structural heart disease, clinical suspicion of reentrant or other symptomatic arrhythmia not coming from the sinus node, or cardiac deconditioning. For example, a patient with peripartum cardiomyopathy can present with orthostatic tachycardia and orthostatic intolerance symptoms, but she does not have POTS and many POTS treatments could be harmful in that condition.
      • 8.
        We do not recommend routinely performing tilt table testing, autonomic nervous system testing, plasma catecholamine testing, autoimmune workup, blood volume assessment, neuroimaging, and neurological studies (Weak Recommendation, Low-Quality Evidence).
      • 9.
        We do recommend additional testing in select patients with POTS for diagnostic clarification or targeted therapy (Strong Recommendation, Moderate-Quality Evidence).
      Practical tip. Neuroimaging and neurological studies should be considered only for patients with clear focal neurological deficits.
      Practical tip. Autonomic testing should not be performed routinely but can be used at specialist centres for the management of complicated patients or patients who might be refectory to initial therapy.

      7. Treatment and Management

      POTS is a chronic condition with multiple proposed pathophysiologic mechanisms that contribute to the constellation of symptoms. There are currently no “cures” for POTS. The overarching goals of treatment should be to provide patient education, reduce symptoms, enhance quality of life, improve physical conditioning, and if possible, to achieve symptom remission. Treatment usually requires a combination of strategies starting with nonpharmacological interventions either alone or in combination with additional pharmacological therapies, depending on the severity of the initial presentation. There have been no robust multicentre randomized controlled trials of treatment modalities and no single treatment has been shown to be effective in all patients. Further, no pharmacologic therapies are currently approved for the treatment of POTS in Canada.
      This section describes a general approach to management. For therapies considered beyond first- or second-line, the patient might need to be referred to a centre with special expertise in POTS. We propose a POTS treatment algorithm that includes a 2-step approach for nonpharmacological and pharmacological interventions (Fig. 4). The current therapeutic strategies for the treatment and management of POTS and their grade of evidence are summarized in Table 8. These lists are not exhaustive, and there might be emerging treatments not listed.
      Figure thumbnail gr4
      Figure 4Postural orthostatic tachycardia syndrome treatment algorithm: a suggested treatment algorithm for patients with postural orthostatic tachycardia syndrome.
      Table 8Summary of treatment and management of POTS
      InterventionStrength of recommendationQuality of evidenceSpecial dose range
      Multidisciplinary ApproachWeak (suggest)Low
      Nonpharmacological
       Withdraw exacerbating medicationsStrong (recommend)Low
       Salt and water POStrong (recommend)Low-moderateWater: 3 L/d; NaCl: 10 g/d
       Lower body compression garmentsWeak (suggest)LowWaist high; 20-30 mm Hg or 30-40 mm Hg compression
       Exercise trainingStrong (recommend)ModerateEvery other day; ≥ 30-minute sessions; nonupright; focus on aerobic reconditioning
      Pharmacologic (first-line)
       MidodrineStrong (recommend)Moderate2.5-15 mg PO every 4 hours 2-3 times per day (eg, 8 AM, noon, 4 PM
       Propranolol (nonselective β-blocker)Strong (recommend)Moderate10-20 mg PO QID (PRN)
       PyridostigmineWeak (suggest)Low30-60 mg PO TID
       FludrocortisoneWeak (suggest)Low0.1-0.3 mg PO daily
       IvabradineWeak (suggest)Low2.5-7.5 mg PO BID
       MethyldopaWeak (suggest)Low125-250 mg QHS-BID
       ClonidineWeak (suggest)Low0.1-0.2 mg PO TID
       I.V. NS bolus; occasional as rescue medicationWeak (suggest)Low1-2 L over 1-2 hours
       I.V. NS; regular long-term useStrong (against)Low (harm)
      Devices
       Radiofrequency ablation of sinus nodeStrong (against)Very low (harm)
       Surgical decompression of Chiari malformationStrong (against)Very low (harm)Unless there is another specific neurological indication
       Balloon dilation of superior jugular veinStrong (against)Low (harm)
      BID, twice per day; I.V., intravenous; NS, normal saline; PO, orally; POTS, postural orthostatic tachycardia syndrome; PRN, as needed; QHS, every night at bedtime; QID, 4 times per day; TID, 3 times per day.

      7.1 Multidisciplinary approach to the management of POTS

      The only published study of a multidisciplinary approach to management of POTS was in a pediatric population.
      • Bruce B.K.
      • Harrison T.E.
      • Bee S.M.
      • et al.
      Improvement in functioning and psychological distress in adolescents with postural orthostatic tachycardia syndrome following interdisciplinary treatment.
      There have been no studies in adult patients. The specific patient populations most likely to benefit from this approach are unclear. On the basis of expert opinion, patients with the most disabling symptoms might be the most likely to benefit from a team-based intervention.
      • 10.
        We suggest treatment be provided by a collaborative multidisciplinary team that includes physicians and allied health professionals (Weak Recommendation, Low-Quality Evidence).
      Practical tip. Allied health care professionals include: physiotherapist, exercise physiologist, kinesiologist, occupational therapist, dietician, and psychologist and/or social worker.

      7.2 Nonpharmacological management of POTS

      The treatment of POTS should always include nonpharmacologic strategies as a first line of therapy. This includes withdrawal of medications that can exacerbate orthostatic tachycardia, increase blood volume with dietary interventions,
      • Raj S.R.
      • Biaggioni I.
      • Yamhure P.C.
      • et al.
      Renin-aldosterone paradox and perturbed blood volume regulation underlying postural tachycardia syndrome.
      ,
      • George S.A.
      • Bivens T.B.
      • Howden E.J.
      • et al.
      The international POTS registry: evaluating the efficacy of an exercise training intervention in a community setting.
      ,
      • Z’Graggen W.J.
      • Hess C.W.
      • Humm A.M.
      Acute fluid ingestion in the treatment of orthostatic intolerance - important implications for daily practice.
      use of lower body compression garments, and semirecumbent exercise.
      • George S.A.
      • Bivens T.B.
      • Howden E.J.
      • et al.
      The international POTS registry: evaluating the efficacy of an exercise training intervention in a community setting.
      ,
      • Fu Q.
      • Vangundy T.B.
      • Shibata S.
      • et al.
      Exercise training versus propranolol in the treatment of the postural orthostatic tachycardia syndrome.
      ,
      • Shibata S.
      • Fu Q.
      • Bivens T.B.
      • et al.
      Short-term exercise training improves the cardiovascular response to exercise in the postural orthostatic tachycardia syndrome.
      • 11.
        We recommend the first therapeutic step should include, when possible, the withdrawal of any medications or substances that might exacerbate orthostatic tachycardia or orthostatic symptoms (Strong Recommendation, Low-Quality Evidence).
      Practical tip. Patients should be encouraged to sleep in the head-up tilt position (> 10°) to promote volume expansion and reduce nocturnal diuresis.
      • 12.
        We recommend patients be encouraged to increase blood volume through dietary interventions that include daily oral fluid intake of at least 3 L and daily oral NaCl intake of 10 g via high-salt foods, NaCl sachets, salt sticks, or salt tablets (Strong Recommendation, Low-Quality Evidence).
      Practical tip. If the patient is not responding to treatment or supplemental salt intake is suspected to be suboptimal, 24-hour urine sodium excretion may be measured as a surrogate estimate of dietary salt intake and as a means to optimize therapy. Currently recommended target for 24-hour urinary sodium is > 170 mmol/d.
      • 13.
        We suggest the use of lower body compression garments such as waist high-compression stockings or abdominal binders to reduce venous pooling (Weak Recommendation, Low-Quality Evidence).
      Practical tip. Patients might benefit from instruction in counter-pressure manoeuvres to avoid venous pooling and enhance venous return when acutely symptomatic. They might also be advised to avoid provocative stimuli such as warm environments and prolonged standing.
      Practical tip. Tailor the height and type of compression garments to the individual. Patients might have difficulty tolerating the compression garments for a variety of reasons. Examples include exacerbation of gastrointestinal symptoms, tendency to easy bruising, and heat intolerance. Start with a compression of 20-30 mm Hg and increase pressure to symptomatic response and as tolerated. Compression below the thighs are unlikely to be effective.
      • 14.
        We recommend exercise training (done at least initially in the semirecumbent position) in all treatment strategies because it might alleviate symptoms, improve quality of life, and might achieve remission in a proportion of patients (Strong Recommendation, Moderate-Quality Evidence).
      Practical tip. An exercise program featuring aerobic training, with some additional leg resistance training, has been shown to improve symptoms and physiology in patients with POTS.
      • Fu Q.
      • Vangundy T.B.
      • Galbreath M.M.
      • et al.
      Cardiac origins of the postural orthostatic tachycardia syndrome.
      Regular exercise frequency (at least 4 days per week) with a session duration of at least 30 minutes is critical to success. It can take 4-6 weeks for some patients to start to notice improvements.
      • Raj S.R.
      Row, row, row your way to treating postural tachycardia syndrome.
      Practical tip. An exercise program using rowing machines, recumbent cycles, or swimming are often better tolerated than upright exercises in patients with POTS.
      • Raj S.R.
      Row, row, row your way to treating postural tachycardia syndrome.
      Practical tip. Although the exercise program can be completed independently, some patients do benefit from the structure of working with a trainer or a formal cardiac rehabilitation program.

      7.3 Pharmacological management of POTS

      If patients have disabling symptoms at the time of presentation and/or continue to experience symptoms after implementation of nonpharmacologic strategies, then pharmacologic treatments should be considered. These treatments might also be helpful to support patients, especially during the early stages of the exercise program. Drug therapy is aimed at ameliorating symptoms by improving central blood volume, enhancing vasoconstriction, and reducing sinus tachycardia. Drug therapies might be synergistic, with varied but complementary mechanisms of action. Most common medications used in the management of POTS include midodrine,
      • Ross A.J.
      • Ocon A.J.
      • Medow M.S.
      • Stewart J.M.
      A double-blind placebo-controlled cross-over study of the vascular effects of midodrine in neuropathic compared with hyperadrenergic postural tachycardia syndrome.
      • Chen L.
      • Wang L.
      • Sun J.
      • et al.
      Midodrine hydrochloride is effective in the treatment of children with postural orthostatic tachycardia syndrome.
      • Lai C.C.
      • Fischer P.R.
      • Brands C.K.
      • et al.
      Outcomes in adolescents with postural orthostatic tachycardia syndrome treated with midodrine and beta-blockers.
      propranolol,
      • Fu Q.
      • Vangundy T.B.
      • Shibata S.
      • et al.
      Exercise training versus propranolol in the treatment of the postural orthostatic tachycardia syndrome.
      ,
      • Raj S.R.
      • Black B.K.
      • Biaggioni I.
      • et al.
      Propranolol decreases tachycardia and improves symptoms in the postural tachycardia syndrome: less is more.
      ,
      • Arnold A.C.
      • Okamoto L.E.
      • Diedrich A.
      • et al.
      Low-dose propranolol and exercise capacity in postural tachycardia syndrome: a randomized study.
      pyridostigmine,
      • Raj S.R.
      • Black B.K.
      • Biaggioni I.
      • Harris P.A.
      • Robertson D.
      Acetylcholinesterase inhibition improves tachycardia in postural tachycardia syndrome.
      ,
      • Kanjwal K.
      • Karabin B.
      • Sheikh M.
      • et al.
      Pyridostigmine in the treatment of postural orthostatic tachycardia: a single-center experience.
      fludrocortisone,
      • Rowe P.C.
      • Calkins H.
      • DeBusk K.
      • et al.
      Fludrocortisone acetate to treat neurally mediated hypotension in chronic fatigue syndrome: a randomized controlled trial.
      ,
      • Freitas J.
      • Santos R.
      • Azevedo E.
      • et al.
      Clinical improvement in patients with orthostatic intolerance after treatment with bisoprolol and fludrocortisone.
      ivabradine,
      • Gee M.E.
      • Watkins A.K.
      • Brown J.N.
      • Young E.J.A.
      Ivabradine for the treatment of postural orthostatic tachycardia syndrome: a systematic review.
      • Sutton R.
      • Salukhe T.V.
      • Franzen-McManus A.C.
      • et al.
      Ivabradine in treatment of sinus tachycardia mediated vasovagal syncope.
      • Ruzieh M.
      • Sirianni N.
      • Ammari Z.
      • et al.
      Ivabradine in the treatment of postural tachycardia syndrome (POTS), a single center experience.
      clonidine,
      • Shibao C.
      • Arzubiaga C.
      • Roberts L.J.
      • et al.
      Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders.
      and intermittent intravenous (I.V.) normal saline infusions.
      • Ruzieh M.
      • Baugh A.
      • Dasa O.
      • et al.
      Effects of intermittent intravenous saline infusions in patients with medication-refractory postural tachycardia syndrome.
      ,
      • Figueroa R.A.
      • Arnold A.C.
      • Nwazue V.C.
      • et al.
      Acute volume loading and exercise capacity in postural tachycardia syndrome.
      These data are from acute randomized, controlled trials, or retrospective noncontrolled series. There are no medium-term or long-term randomized controlled trials of pharmacological therapy for POTS.
      • 15.
        For patients with POTS, we recommend midodrine (2.5-15 mg every 4 hours up to 3 times per day) to improve symptom control (Strong Recommendation, Moderate-Quality Evidence).
      Practical tip. Midodrine enhances venous return, cardiac preload, and stroke volume. It is a prodrug metabolized to a short-acting peripheral α-1 adrenergic receptor agonist that requires frequent, often 3-4 times per day (2.5-15 mg per dose) dosing when given as maintenance therapy. A “pill in the pocket” approach for acute symptom management might be an alternative strategy and/or supplement to regular maintenance dosing. Dosing should be given before upright activities and not with the patient supine, because this could cause excessive hypertension.
      Practical tip. Midodrine is likely to be of most benefit in patients with a tendency to hypotension (or low blood pressure phenotype). Conversely, it might be of lesser benefit in patients with hyperadrenergic symptoms including tendency to hypertension.
      • 16.
        For patients with POTS, we recommend low-dose propranolol (10-20 mg 4 times per day), a nonselective β-blocker to reduce standing heart rate, improve exercise capacity, and improve symptom control (Strong Recommendation, Moderate-Quality Evidence).
      Practical tip. Patients with high heart rates on standing and with associated symptoms might benefit most from nonselective β-blocker therapy. Higher doses and long-acting formulations, although they might improve standing heart rate, are generally ineffective in controlling symptoms and therefore are not recommended.
      • Raj S.R.
      • Black B.K.
      • Biaggioni I.
      • et al.
      Propranolol decreases tachycardia and improves symptoms in the postural tachycardia syndrome: less is more.
      Side effects might include worsening of exercise tolerance and worsened fatigue. This might be particularly problematic when implementing a therapeutic exercise intervention as a treatment strategy.
      Practical tip. Less is known of the benefits of β1 cardioselective β-blockers and therefore nonselective β-blockade with propranolol is preferred.
      • 17.
        For patients with POTS, we suggest pyridostigmine (30-60 mg 3 times per day) be considered for symptom relief (Weak Recommendation, Low-Quality Evidence).
      Practical tip. Pyridostigmine is a peripheral acetylcholinesterase inhibitor that increases synaptic acetylcholine at autonomic ganglia and peripheral muscarinic receptors. It might be helpful when used in combination with a β-blocker to reduce orthostatic tachycardia and improve symptoms.
      Practical tip. Diarrhea is a common side effect of pyridostigmine and therefore, although often not well tolerated in patients with a history of frequent bowel actions, it might be well tolerated and beneficial in patients with a history of constipation. It can also contribute to bladder irritability and might not be well tolerated in patients with bladder dysfunction.
      • 18.
        For patients with POTS, we suggest the mineralocorticoid fludrocortisone (dose 0.1-0.3 mg daily) be considered to improve symptoms (Weak Recommendation, Low-Quality Evidence).
      Practical tip. Fludrocortisone might be helpful in patients who might benefit through volume expansion, for example, because of inability to optimize oral salt intake. Side effects might include edema and hypokalemia and possible risk of osteoporosis in young women. It is advisable to avoid fludrocortisone in patients with a history of migraines because of possible exacerbation of migraine frequency and/or symptoms.
      Practical tip. Plasma electrolyte concentrations, especially potassium, should be monitored when initiating, altering, and maintaining therapy with fludrocortisone.
      • 19.
        For patients with POTS, we suggest ivabradine (2.5-7.5 mg twice per day) be considered as a treatment option (Weak Recommendation, Low-Quality Evidence).
      Practical tip. Ivabradine might be an alternative to nonselective β-blocker therapy particularly when the patient has prominent symptomatic orthostatic tachycardia and is a nonresponder and/or has intolerance because of exacerbation of symptoms of fatigue, comorbid asthma, or a tendency to hypotension. Ivabradine may be teratogenic. Adequate contraception is required when using ivabradine in women with child-bearing potential.
      Practical tip. Availability of ivabradine might be limited for patients in Canada because of off-label use. There might also be consideration of expense and absence of evidence of proven efficacy.
      • 20.
        For patients with POTS, we suggest that patients with prominent hyperadrenergic symptoms may be treated with central sympatholytic agents (eg, clonidine 0.1-0.2 mg to a maximum of 3 times per day; methyldopa starting at 125 mg once at bedtime, which can be titrated up to 250 mg twice per day) (Weak Recommendation, Low-Quality Evidence).
      Practical tip. Central sympatholytic agents are used to improve palpitations, tremors, and significant orthostatic hypertension. They might not be tolerated in patients with relative supine hypotension or any degree of orthostatic hypotension. They might also be poorly tolerated because of other side effects including sedation and dry mouth.
      • 21.
        For patients with POTS, we suggest acute volume loading with intermittent I.V. normal saline bolus of 1-2 L over 1-2 hours be considered as second-line rescue therapy (Weak Recommendation, Low-Quality Evidence).
      Practical tip. Intermittent I.V. normal saline can be given for occasional short-term decompensation, bridging therapy while initiating, and to improve compliance with alternative therapies such as exercise regimens.
      • 22.
        We do not recommend routine I.V. normal saline for chronic treatment of POTS because there is potential for harm because of the risk of complications such as infections and thrombosis related to central I.V. access and in the absence of supporting evidence
        • Moak J.P.
        • Leong D.
        • Fabian R.
        • et al.
        Intravenous hydration for management of medication-resistant orthostatic intolerance in the adolescent and young adult.
        (Strong Recommendation, Low-Quality Evidence).
      Practical tip. Routine I.V. saline may be acceptable in exceptional cases where POTS symptoms are very chronic and disabling, including chronic vomiting, severe gastroparesis, or chronic diarrhea, and when the oral intake is limited, because of associated comorbidities, to prevent a chronic hypovolemic state.

      7.4 Procedural therapeutic strategies for the management of POTS

      In recent years, several procedural therapeutic strategies have been suggested in the literature for the management of POTS. Unfortunately, none of the reports have been conclusive and the evidence presented has been weak (lack of well designed randomized controlled trials). Many of these procedures can carry significant risk of adverse events.

      7.4.1 Radiofrequency ablation of the sinus node

      Radiofrequency modification of the sinus node has been performed in POTS patients. This can result in heart rate control without improvement in symptoms. Furthermore, this procedure might cause harm with a subsequent requirement for permanent pacemaker. It is not recommended because of risk of harm and lack of efficacy.
      • Shen W.K.
      • Low P.A.
      • Jahangir A.
      • et al.
      Is sinus node modification appropriate for inappropriate sinus tachycardia with features of postural orthostatic tachycardia syndrome?.
      • 23.
        We do not recommend radiofrequency modification of the sinus node for the management of POTS, because it might cause harm (Strong Recommendation, Very Low-Quality Evidence).

      7.4.2 Decompression of cerebral tonsils

      Surgical osteodural decompression of cerebral tonsils in patients with a Chiari type 1 malformation and POTS symptoms has been performed. Although there is anecdotal evidence of symptom improvement, this is an unproven intervention. Surgical decompression should not be considered for the treatment of POTS symptoms until there are more robust supportive data,
      • Straus D.
      • Foster K.
      • Zimmerman F.
      • Frim D.
      Chiari drop attacks: surgical decompression and the role of tilt table testing.
      ,
      • Garland E.M.
      • Anderson J.C.
      • Black B.K.
      • et al.
      No increased herniation of the cerebellar tonsils in a group of patients with orthostatic intolerance.
      Decompression might be appropriate for focal neurological findings.
      • 24.
        We do not recommend surgical decompression of a Chiari malformation for alleviation of primary symptoms of POTS because it might cause harm (Strong Recommendation, Very Low-Quality Evidence).

      7.4.3 Jugular venoplasty

      Balloon dilation and stenting of the jugular vein for presumed chronic cerebrospinal venous insufficiency, known as “liberation treatment,” has not been proven effective and can cause harm. This procedure should not be considered as a therapy for POTS patients.
      • Tsivgoulis G.
      • Faissner S.
      • Voumvourakis K.
      • et al.
      “Liberation treatment” for chronic cerebrospinal venous insufficiency in multiple sclerosis: the truth will set you free.
      • 25.
        We do not recommend balloon dilation and stenting of the superior jugular vein for POTS because it might cause harm (Strong Recommendation, Low-Quality Evidence).

      7.5 Treatment of non-POTS disorders of chronic orthostatic intolerance

      Symptomatic patients with other disorders of chronic orthostatic intolerance (not POTS) might also require nonpharmacological and pharmacological treatment. In most cases, asymptomatic sinus tachycardia does not require treatment. If there is another obvious cause for the postural tachycardia, then the underlying cause should be directly addressed. If there are no targeted treatments available, some strategies that are useful in POTS (see earlier sections) might be worth considering for these other disorders of chronic orthostatic intolerance. The additional noncardiovascular symptoms that are seen in POTS plus or PSWT plus might require targeted symptom-directed speciality treatment.

      8. Special Considerations

      8.1 Pediatric population

      POTS does occur in children or adolescents with a prevalence estimate of 1% with the median age of onset of 13 years.
      • Boris J.R.
      • Bernadzikowski T.
      Utilisation of medications to reduce symptoms in children with postural orthostatic tachycardia syndrome.
      Associated comorbidities including chronic fatigue, sleep disturbances, dizziness, syncope, migraines, functional gastrointestinal disorders, chronic nausea, fibromyalgia, and joint hypermobility are equally prevalent in this age group.
      • Chelimsky G.
      • Kovacic K.
      • Nugent M.
      • et al.
      Comorbid conditions do not differ in children and young adults with functional disorders with or without postural tachycardia syndrome.
      Normal adolescents might be capable of larger orthostatic increases in heart rate than adults, and a threshold heart rate increase of 40 bpm might be more realistic in defining POTS in the young. Adolescents should be treated primarily with nonpharmacological interventions. Patients who do not respond to nonpharmacological management should be offered pharmacological treatment. Two small randomized controlled trials of midodrine have been conducted in pediatric populations, and both reported significant benefit on the basis of improved orthostatic tolerance.
      • Ross A.J.
      • Ocon A.J.
      • Medow M.S.
      • Stewart J.M.
      A double-blind placebo-controlled cross-over study of the vascular effects of midodrine in neuropathic compared with hyperadrenergic postural tachycardia syndrome.
      ,
      • Chen L.
      • Wang L.
      • Sun J.
      • et al.
      Midodrine hydrochloride is effective in the treatment of children with postural orthostatic tachycardia syndrome.
      • 26.
        We recommend, in adolescents 12-19 years old, that the diagnostic heart rate increase criterion be at least 40 bpm from the resting supine position,
        • Singer W.
        • Sletten D.M.
        • Opfer-Gehrking T.L.
        • et al.
        Postural tachycardia in children and adolescents: what is abnormal?.
        with a standing heart rate of at least 100 bpm (Strong Recommendation, Moderate-Quality Evidence).
      • 27.
        We recommend that adolescents with POTS should be treated with nonpharmacological treatments, similar to adult patients (Strong Recommendation, Low-Quality Evidence).
      Practical tip. When treating adolescents with POTS, we suggest that exercise programs should take into account the child’s motor development, safety considerations, and access to equipment. Home-based programs are preferable, where possible.
      • 28.
        We suggest that in selected adolescents with POTS, when nonpharmacological interventions have proven inadequate, pharmacological treatments may be considered (Weak Recommendation, Very Low-Quality Evidence).
      • 29.
        We recommend assessing school performance and attendance when considering the need for, and response to, treatment in adolescents with POTS (Strong Recommendation, Low-Quality Evidence).
      Practical tip. Medications that can be used in adolescents include midodrine, fludrocortisone, β-adrenergic blockers, and ivabradine.

      8.2 When to refer to a specialist

      The primary care physicians in the community should offer care for patients with POTS. The primary care physician might consider referral to a POTS specialist for complicated patients, or those who do not respond to initial therapy. Referral for multidisciplinary management might be considered where those services are available. Patients can suffer from multiple symptoms spanning organ systems and including mental health. Concurrent management for these different disorders can be sought as needed.
      • 30.
        We recommend that patients with POTS be managed by a primary care physician for the diagnosis, appropriate exclusion of alternative diagnoses, and initial treatments (Strong Recommendation, Very-Low-Quality Evidence).
      • 31.
        We recommend that referral to a specialty clinic for POTS should be considered when there is diagnostic uncertainty, or a poor response to nonpharmacological and initial pharmacological treatments (Strong Recommendation, Very Low-Quality Evidence).

      Summary

      POTS can be a difficult disorder to manage, for providers and patients. Accurate diagnosis can lead to management that can improve the quality of life of POTS patients. These recommendations might guide health care providers in the treatment of a patient with POTS. These recommendations will require review in 5-10 years as new evidence appears regarding treatment in POTS. We have also attempted to address some lack of clarity with the diagnosis of POTS, and in particular in related disorders of orthostatic tolerance that are not POTS. This new ecosystem of disorders will need prospective evaluation over the next few years, and will likely undergo successive improvements.

      Supplementary Material

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