Pediatric Postural Orthostatic Tachycardia Syndrome: Where We Stand

Take-home points:

• Patients can have numerous symptoms across multiple body systems.

• POTS affects predominantly White females in the United States.

• Diagnostic criteria for pediatric POTS include symptoms of chronic orthostatic intolerance for ≥3 months, persistent symptomatic increase in heart rate by ≥40 beats per minute in the first 10 minutes of upright position after supine position without orthostatic hypotension, and the absence of other potential etiologies. The heart rate criteria may be disputed.

When considering clinical disorders spanning the pediatric and adult age range, it is tempting to contemplate similarities, consider overarching pathophysiologies, create global treatment approaches, and predict prognoses. Manifestations of POTS across ages are similar, with symptoms of chronic orthostatic intolerance,⁸  tachycardia without orthostatic hypotension, and multiple associated disabling symptoms across multiple body systems (Fig 1)(Table 1). In 1 study, 66% of patients reported at least 10 symptoms, 50% of patients reported ≥14 symptoms, and 30% of patients reported ≥26 symptoms.⁹  There also has been notable female (3.45:1) and White (94.1%) predominance,⁹  and association with previous infection or concussion.^9–11  Yet, on closer examination, there are important differences. In children aged 12 to 19, the diagnosis of POTS is, in part, defined from tilt table data as a heart rate increase of ≥40 beats per minute;¹²  it is unclear if this is valid for a 10-minute standing test. Diagnostic criteria also remain undefined at <12 years.

However, there are data that call a threshold heart rate criterion into question. A study by Boris in 2020 demonstrated that frequency of symptoms in children with a heart rate increase between 30 and 39 beats per minute on a 10-minute standing test was not statistically or significantly different from that of patients with a heart rate increase of ≥40 beats per minute¹³  (Table 2). Another study looking at joint hypermobility syndromes in pediatric patients demonstrated no significant difference in prevalence of joint hypermobility (hypermobile Ehlers-Danlos syndrome or hypermobility spectrum disorder) in children with a ≥40 beats per minute heart rate increase on a 10-minute standing test, children with a ≥30 beats per minute increase, or in comparable adult studies.¹⁴  Although the original article first documenting that the 95th percentile of heart rate increase in asymptomatic adolescents as 43 beats per minute was performed by tilt table testing,¹²  subsequently leading to recommendation of a 40 beats per minute threshold for diagnosis of pediatric POTS,¹⁵  a study in adults by Plash suggests that the mean increase in heart rate by tilt testing is 7 beats per minute higher than with a 10-minute standing test.¹⁶  Furthermore, Medow also showed that pediatric patients with vasovagal syncope had a mean increase in heart rate of 40 beats per minute in nearly half of patients, whereas controls only had a 20 beats per minute increase, despite affected patients not having POTS.¹⁷  At the present time, without a biological marker specific to POTS, the consensus is to continue utilizing the increase in heart rate as a major discriminating factor in the diagnosis.^15,18  However, paying attention to the multitude and diversity of symptoms in these patients may end up being more important as a discriminator. Once a biological marker is discovered, it may provide for better determination for the presence or absence of disease.

Take-home points:

• POTS can start after infection, concussion, growth spurt, or menarche.

• A small percentage of patients have spontaneous resolution of POTS, meaning that most patients remain at least somewhat affected.

• Many patients are high-achieving, either academically or athletically, before illness onset.

• The presence of parental care, plus ensuring that patients take responsibility for their own care, are both important to outcomes of symptomatic management.

Leveraging issues specifically seen in children and adolescents may help with understanding POTS pathophysiology, as the actual pathophysiology in POTS has yet to be defined. Although inadequate peripheral vasoconstriction with compensatory tachycardic response combined with inadequate systemic venous return has been offered a mechanism,⁶  why this occurs is unclear. POTS is noted to occur after growth spurt or menarche,¹⁹  and symptoms may abate after administration of testosterone,²⁰  suggesting a role for sex hormones. There is concern for association with immunization,²¹  although causation has not been demonstrated and population-based studies have not demonstrated an increase in disease frequency as adolescent vaccination rates have risen.^22,23  POTS-like findings have been seen in children with mitochondrial disorders.²⁴  We have anecdotally noted patients with chronic symptoms since infancy or toddlerhood (eg, dysmotility, headaches, or joint hypermobility) who eventually developed POTS later in childhood, with their parents feeling that there was always “something wrong” with them. A 2016 study of patients with POTS with onset during adolescence demonstrated spontaneous resolution of symptoms in up to 19% of patients by the time they reached adulthood.²⁵  However, in these patients, it was noted that POTS symptoms were still present in up to 33% of respondents who had “recovered.” A similar study of long-term outcomes in 2019 from China showed that 48% of pediatric patients with POTS were free of symptoms at 1-year follow-up, with >85% being symptom-free after 6 years,²⁶  although fewer symptoms were used for their assessment than those in other studies.⁹ 

Adolescence, when half of patients with POTS are diagnosed,¹  is an important time in which many changes occur in the body, demonstrating significant contrast to adults. During puberty, hormonal changes cause somatic growth, brain maturation, psychological maturation, and gonadal growth and maturation, although it is unclear how these affect the onset, pathophysiology, and outcomes. Children attend school and participate in athletics, whereas adults are more sedentary, and are often high-achieving in either academics and/or athletics.²⁷  Sleep hygiene can be difficult, especially with already recognized differences in adolescent sleep.²⁸  Anecdotally, we have noted patients’ symptoms improving when attending college. This may be because of increased time between classes, with more recovery time, increased neurologic maturity allowing for improved ability to recognize and avoid triggers, or being away from parents, forcing them to accept responsibility and own their disease management. Or it could be simply associated with the aforementioned improvement of symptoms with time.²⁵ 

A unique factor that pediatric patients have is parental involvement.²⁹  Parents can be strong advocates, getting these children to a knowledgeable and caring provider, especially when symptoms are ignored or misinterpreted by other providers.¹  They network with other parents to optimize their child’s care, and remind or push their children in routine care management. However, parents can generate hindrance to their child’s progress. They may expect rapid return of their (high-achieving) child to school or sports. They may have difficulties allowing their child to mature, or to fail.²⁹  Parents may have their own untreated medical and/or psychological issues influencing their child’s treatment, sometimes feeling compelled to maintain caregiver status as secondary gain.³⁰  They may also not recognize comorbid psychological issues in their children.

Take-home points:

• Patients with POTS demonstrate abnormal vascular responses, especially with upright position.

• There are abnormally elevated levels of compounds associated with vasodilation.

• Significant splanchnic and lower extremity venous pooling occurs in patients.

Research into specific abnormalities found in POTS in children and adolescents is limited because most studies are performed in either adults or a combination of adults and children, but interesting data do exist. Several studies have demonstrated abnormal neurohormonal levels and vascular findings, although these do not necessarily indicate a biological marker specific to POTS. Flow-mediated vasodilation in the brachial artery in children with POTS was found to be greater than that of healthy controls.³¹  In that same study, plasma concentrations of the vasodilator, nitric oxide, and activity of nitric oxide synthase were elevated. A Chinese study demonstrated that hydrogen sulfide, which can also induce vasodilation, was elevated in pediatric patients with POTS and in those with vasovagal syncope versus healthy controls.³²  Adolescents with POTS demonstrate elevated resting venous pressures and decreased arterial resistance.³³  Li et al showed that total peripheral vascular resistance and cardiac output were significantly reduced when upright, then normalized while supine, although these measures were unchanged in healthy controls in either position.³⁴  In that same study, C-natriuretic peptide levels were also greater in patients with POTS versus healthy controls. A separate study also confirmed elevated C-natriuretic peptide levels in pediatric patients with overcontrols.³⁵  Serum levels of resistin, a peptide hormone promoting vasoconstriction,³⁶  and copeptin, a glycopeptide closely correlated with vasopressin,³⁷  are noted to be elevated versus controls. Interestingly, supine resistin levels were also found to be inversely correlated with the degree of change of heart rate from supine to upright position.³⁶  Levels of antidiuretic hormone in children with POTS who have hypertension were noted to be higher than that of those without hypertension (397). Another Chinese study demonstrated that 24-hour urinary sodium excretion in children with POTS was significantly less than that of controls.³⁹  In that same study, they attempted to discern patients who would respond to subsequent increased sodium loading by demonstrating decreased symptom scores in patients with persistently low urinary sodium excretion; however, they did not assess this in their control group. Lastly, upright position has been found to induce splanchnic pooling and venous pooling, despite peripheral vasoconstriction.⁴⁰ 

Take-home points:

• Patients have abnormal cerebral blood flow with upright position.

• There is significant diurnal variability of upright heart rate response, with worsening morning response.

• Antroduodenal and anorectal manometry are the most frequently abnormal tests in patients with gastrointestinal (GI) symptoms.

• Patients with POTS have a higher prevalence of family members with orthostatic intolerance, joint hypermobility, and autoimmune disorders.

From a clinical standpoint, several studies have contributed to better understanding of pediatric POTS. Postconcussion syndrome is associated with pediatric POTS, with a high percentage of resolution of POTS-associated heart rate changes with tilt table as symptoms of postconcussion syndrome improve.¹¹  One finding seen in pediatric patients with POTS is initial orthostatic hypotension, occurring in 51% of patients versus 13% of controls,⁴¹  with greater severity and higher prevalence of altered cerebral blood flow and cardiorespiratory regulation. Corrected QT interval dispersion on electrocardiogram is noted to be longer in pediatric patients with POTS versus controls, serving as a marker of a risk factor for the presence of POTS, as well as lower likelihood of success with use of orthostatic training and other physical maneuvers.⁴²  An interesting study of ambulatory blood pressure monitoring in patients and controls showed that the rate pressure product (heart rate times systolic blood pressure) in patients was greater both before and after awakening versus controls,⁴³  with morning increase associated with worsening morning symptoms of orthostatic intolerance. They also demonstrated significant diurnal variability in heart rates of children with POTS, such that all patients met heart rate criteria for the diagnosis of POTS in the morning, but only 28% met those same criteria in the evening.⁴⁴  In patients evaluated for headaches and lightheadedness, those who met diagnostic criteria for POTS were more likely to have new-onset motion sickness, lightheadedness as a headache trigger, and orthostatic headaches, versus those not meeting heart rate criteria.⁴⁵ 

From a GI standpoint, antroduodenal manometry was found to be the most useful gastroenterologic evaluation versus gastric emptying studies and esophagogastroduodenoscopy, with abnormalities in 81% of pediatric patients demonstrating GI symptoms.⁴⁶  A retrospective case-control study of gastroenterologic symptoms in pediatric patients with POTS showed that anorectal manometry was also the most frequently abnormal test versus gastric emptying, colonic transit, and gastric accommodation.⁴⁷  Results from a study assessing electrogastrography in supine versus upright position revealed evidence of bradygastria and tachygastria in the antrum and fundus of patients with POTS when upright on a tilt table, whereas those without POTS but still with GI symptoms had a decrease in abnormal gastric electrical activity; both groups had baseline normal gastric activity while supine.⁴⁸ 

A study from the Mayo Clinic demonstrated that POTS symptoms in adolescents can improve with comprehensive interdisciplinary “pain rehabilitation,”⁴⁹  though greater symptom burden positively correlated with delayed clinical improvement.¹⁰  However, some data suggest that POTS may be a comorbid finding not related to other symptoms (eg, fatigue, pain, dysmotility, headache, or joint hypermobility).⁵⁰  Lastly, 14.2% of pediatric patients with POTS were found to have a family member with POTS, with 31.3% having a family member with orthostatic intolerance, 20.2% having a family member with joint hypermobility, and 45.1% having a family member with autoimmune disease.⁵¹ 

Take-home points:

• There are numerous medications that can be used to reduce symptoms of POTS.

• Parenteral saline can be used to reduce symptoms as a temporizing measure but is typically not recommended as prolonged therapy.

There is a notable paucity of prospective data related to medication management of pediatric patients with POTS. In fact, the first double-blind, prospective, crossover trial of a medication in POTS in adults, ivabradine, was just published in 2021.⁵²  The published studies addressing medication utilization in pediatric patients have been mostly retrospective and observational in nature, although there are a few small prospective studies. The 2 retrospective studies with the largest patient volumes were published by Boris et al.^53,54  Both assessed effectiveness of various medication therapies for specific symptoms using a threshold of at least 5 medication refills of the same medication at the same dose consecutively as a proxy measure for efficacy. Although overall therapeutic efficacy for symptoms of lightheadedness, headache, nausea, dysmotility, pain, and insomnia ranged from 39% to 53%,⁵³  efficacy for fatigue and cognitive dysfunction was greater, at nearly 70%.⁵⁴  In both studies, the efficacy of multiple medications was assessed both individually, as well as within symptom groupings.

Other smaller studies have been performed in the pediatric population. A retrospective analysis of 27 patients demonstrated that ivabradine improved symptoms in 67% of patients,⁵⁵  and another showed similar outcomes in 22 patients,⁵⁶  both with minimal side effects. A meta-analysis was performed evaluating studies in which β blockers were used in pediatric patients with POTS.⁵⁷  However, 7 of 8 studies reviewed were in Chinese and could not be assessed here. But the review stated that these 7 studies demonstrated significant concern for bias and were not considered to be of high enough quality. The eighth study, which was felt to be of adequate quality, was a prospective controlled study that was neither blinded nor randomized in evaluating groups receiving routine nonpharmacologic therapy, plus either a morning dose of 2.5 mg midodrine, twice daily metoprolol at 0.5 mg/kg per day, or no medications.⁵⁸  Both midodrine and metoprolol therapy reduced symptom scores in children versus untreated patients, with midodrine leading to a higher rate of overall resolution of symptoms of orthostatic intolerance. Lin, who demonstrated elevated C-natriuretic peptide levels in the study mentioned previously, also showed in that same study that metoprolol lowered symptom scores in pediatric patients.³⁵  Furthermore, a C-natriuretic peptide level greater than 32.55 pg/mL correlated with efficacy of metoprolol in lowering symptoms. Effectiveness of metoprolol was also assessed in a prospective trial, in which a threshold copeptin level of 10.225 pmol/L was predictive of efficacy.⁵⁹  A retrospective chart review analysis and survey of adolescent patients suggested that patients treated with midodrine or with β blockers both reported clinical improvement with addition of medication therapy, although those using β blockade felt that their medication had a more significant role in symptom reduction.⁶⁰  Lastly, in a prospective double-blind, placebo-controlled crossover study of midodrine in adolescents with neuropathic and hyperadrenergic POTS, midodrine was found to be effective in the treatment of those patients with neuropathic POTS, whereas no improvement or a placebo effect was seen in those with hyperadrenergic POTS.⁶¹ 

In patients who fail oral medication therapy, parenteral therapy may be an option. The only study in children with this therapy is a retrospective study that uses intravenous normal saline in patients with POTS, neurally mediated hypotension, or orthostatic intolerance.⁶²  Most patients reported an improved quality of life, although patients utilizing a permanent method of access, such as a peripherally inserted central catheter or central port, had a notable incidence of vascular thrombosis and infection.

Take-home points:

• A thorough history evaluating associated symptoms, as well as for comorbid disorders, is key to ensuring a comprehensive therapeutic approach.

• Except for clinical findings associated with comorbidities, physical examination findings may be completely normal.

• Management starts with nonpharmacologic interventions, with addition of medications, as indicated.

The general pediatrician’s approach to the care of children and adolescents with POTS, as with any clinical concern, starts with the evaluation. A thorough history is necessary to assess for the wide array of symptoms associated with POTS⁹  (Fig 1), as well as symptoms seen in associated disorders, including but not limited to joint hypermobility syndromes,¹⁴  mast cell activation syndrome,⁶³  craniocervical instability, median arcuate ligament syndrome,⁶⁴  and autoimmune disorders such as Sjögren syndrome and systemic lupus erythematosus.⁶⁵ 

Physical examination findings can include manifestations of the above disorders, such as an elevated Beighton score, dermatographia, urticaria, an epigastric/abdominal bruit, venous pooling, dilated pupils, etc. Often, except for upright tachycardia, clinical examination may be normal. Initial studies should include a baseline electrocardiogram, plus consideration of 24-hour Holter monitoring evaluating for arrhythmias. Suggested laboratory investigations include morning cortisol, thyroid function testing, vitamin D level, and ferritin because derangements in these can lead to orthostatic intolerance.⁶⁶ 

Evaluation for orthostatic intolerance includes a 10-minute standing test. Ideally, continuous blood pressure and heart rate monitoring are performed, but measurements at least once per minute should be obtained. The patient should rest in the supine position for 5 minutes, with heart rate and blood pressure obtained at the conclusion. Then, the patient should immediately stand for 10 minutes, with minimal stimulation and movement. A persistent heart rate increase of ≥40 beats per minute without orthostatic hypotension (decreased blood pressure of 20 mmHg systolic or 10 mmHg diastolic) with symptoms of orthostatic intolerance, plus a history of symptoms for ≥3 months, is diagnostic for POTS (after ruling out other diagnoses), although some sites use a 30 beats per minute threshold. Although tilt testing is utilized in a number of formal autonomic laboratories, the majority of clinics do not have access to these.

In the absence of finding other treatable etiologies for symptoms, therapeutic management starts with nonpharmacologic intervention, which is foundational. Increasing intravascular volume with daily fluid intake of 80 to 120 ounces daily, plus 8 to 10 g of sodium chloride,^8,67  is the most important initial treatment. Other therapies, including elevation of the head of the bed to reduce nocturnal diuresis,⁶⁸  appropriate sleep hygiene, use of compression garments,⁶⁹  and use of cooling vests to reduce heat intolerance are important adjunct measures. Initiation of an exercise protocol specifically for patients with POTS is important to help suppress symptoms. Fu and Levine developed a protocol utilizing initially recumbent aerobic exercises, plus isometric activities strengthening legs and core that produced important and lasting symptom reduction in adults with POTS.^70,71  A version of their protocol modified for adolescents can be found online.⁷²  However, basic principles of exercise for these patients include the following: utilizing both aerobic and isometric exercises, initially avoiding upright activities to prevent orthostatic intolerance, beginning with minimal duration of exercise, and ensuring consistent and progressive exercise. Patients with joint hypermobility are strongly advised to be evaluated by a physical therapist familiar with hypermobility to teach patients how to strengthen and protect their joints.⁷³ 

Often, nonpharmacologic therapy for POTS is insufficient to reduce symptoms, and patients are not able to resume their activities of daily living, much less incorporate exercise into their routine. Thus, use of medications to reduce symptoms of POTS can be beneficial. Although discussion of specific medication utilization is beyond the scope of this article, there are basic approaches that can be taken. One is to use medications targeted at specific symptoms.^53,54  Another is to take a general approach to use of medications, aiming at supporting blood pressure, with use of therapies such as fludrocortisone or midodrine, while gently slowing heart rate to improve cardiac output, such as with β blockade or ivabradine.⁷⁴  Many medications used in the management of POTS are already used in children and adolescents for medical disorders, allowing for familiarity. Certainly, these medications can have side effects, and patients may have persistent symptoms despite what seems to be appropriate therapy. Therefore, comfort using these medications takes practice, as well as communication with the patients and families. Patients may also require further referral to specialists, such as cardiologists, neurologists, gastroenterologists, allergist/immunologists, etc, depending upon specific persistent or abnormal clinical findings, or lack of response to therapy. In the United States, specialists in pediatric POTS include general pediatricians, pediatric cardiologists, pediatric gastroenterologists, and child neurologists. Caring for these patients and families is best achieved by providers with patience, perseverance, and creativity, and those who have time to validate, to explain details without using medical jargon, and to reassure these individuals.

Take-home points:

• There is increasing research interest in pathophysiology and management of POTS.

• Ensuring recognition of POTS in children and adolescents, including education and de-stigmatization, is important to allow patients to attain access to therapy.

Besides basic questions of underlying POTS pathophysiology, evaluation, and therapy, numerous questions pertaining to these patients remain, including whether pediatric POTS occurs with minimal symptoms, ascertainment of appropriate criteria for diagnosis (including orthostatic testing and heart rate cutoffs), how growth and hormonal changes influence POTS, roles of maladaptive psychiatric health of patients and parents, determination if POTS is 1 disease entity or multiple entities, the role of genetics, and the function of the immune response and inflammation on pathophysiology. These unanswered questions continue to limit the ability to more consistently diagnose and manage this diverse group of patients. As the adage “Children are not just small adults” rings true, so does another oft-repeated statement in multiple journal articles: “More research is required.” The NIH recently issued a notice of special interest to stimulate research on diagnosis, treatment, and mechanistic understanding of POTS.⁷⁵  As well, starting in 2021, the NIH listed funding for POTS in their annual categorical spending,⁷⁶  so that the amount of research dollars spent on this disorder can be better followed.

Yet, even basic recognition of POTS in adolescents remains limited. Diagnosis is typically delayed by a median of >3 years, especially with comorbid joint hypermobility.⁹  Patients may be recognized as having something wrong without ability of the provider to give further guidance,¹  or are incorrectly diagnosed as having a psychological or psychiatric disorder.¹ 

As knowledge and interest in this disorder, as well as research, continues to increase, the relative volume of pediatric research will also rise. Recognition of the unique aspects of pediatric POTS, specifically, will further augment greater understanding of this syndrome in general. But most importantly, improving understanding of pediatric and adolescent providers about its presence and diagnostic criteria will allow patients to receive a diagnosis and to access the care that they require to be able to return to their daily lives.

GI

gastrointestinal

NIH

National Institutes of Health

POTS

postural orthostatic tachycardia syndrome