Postural orthostatic tachycardia syndrome (POTS), a dysautonomia that affects multiple somatic systems in children and adults, causes significant disability.1,2
STPO has been increasingly recognized since its first report in 1992,3 with a steadily increasing number of publications since the late 1990s.4 Its relatively high morbidity, in addition to relatively low research funding, led the National Institutes of Health (NIH) of the United States to sponsor a seminar,5 where international experts in STPO met to discuss the state of the science and research priorities.6,7
As pediatric representatives at that meeting, JRB and JPM compiled an extensive review of the medical literature to discuss the pediatric aspects of STPO. However, as this symposium was not designed for a comprehensive discussion of the literature, it was felt that the ability to fully compare and contrast pediatric and adult STPO would be best addressed separately.
| Diagnostic criteria |
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When considering clinical disorders spanning the pediatric and adult age range, it is tempting to contemplate similarities, consider pathophysiologies, create comprehensive treatment approaches, and predict prognoses. The 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 (Table 1).
In one study, 66% of patients reported at least 10 symptoms, 50% ≥ 14 symptoms, and 30% ≥ 26 symptoms.9 There was also a notable predominance of the female sex (3.45:1) and the white race ( 94.1%),9 and association with previous infection or concussion.9-11 However, upon closer examination, there are important differences. In children aged 12 to 19 years, the diagnosis of POTS is defined, in part, from tilt table data as an increase in heart rate of ≥ 40 beats per minute;12 it is not clear if this is valid for the test. standing for 10 minutes. Diagnostic criteria also remain undefined in <12 years.
However, there are data that call into question the threshold heart rate criterion. A 2020 Boris study showed that the frequency of symptoms in children with an increase in heart rate between 30 and 39 beats per minute in the 10-minute standing test was not statistically or significantly different from that in patients with an increase heart rate of ≥ 40 beats per minute.13
Another study analyzing joint hypermobility syndromes in pediatric patients did not demonstrate significant differences in the prevalence of joint hypermobility (Ehlers-Danlos Syndrome or hypermobility spectrum disorder) in children with an increase in heart rate of ≥ 40 beats per minute in the 10-minute standing test, in children with an increase of ≥ 30 beats per minute, or in comparable studies of adults.14
Although the original article first documented that the 95th percentile for increased heart rate in asymptomatic adolescents as 43 beats per minute was determined using a tilt table test,12 subsequently leading to the recommendation of a threshold of 40 beats per minute for diagnosis of pediatric POTS,15 an adult study by Plash suggested that the mean increase in heart rate per tilt test is 7 beats per minute greater than with the 10-minute standing test.16 Additionally, Medow also showed that half of the patients with vasovagal syncope had a mean increase in heart rate of 40 beats per minute, while controls only had an increase of 20 beats per minute, even though affected patients did not have STPO. .17
Currently, without a specific biological marker for POTS, the consensus is to continue using increased heart rate as an important discriminating factor in diagnosis.15,18
However, paying attention to the multitude and diversity of these patients’ symptoms may end up being more important as a discriminator. Once a biological marker is discovered, it can provide a better determination of the presence or absence of disease
| Risk factors and outcomes |
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Taking advantage of problems observed specifically in children and adolescents may help understand the pathophysiology of POTS, as it has not yet been defined. Although a mechanism has been offered for inappropriate peripheral vasoconstriction with compensatory tachycardic response combined with inadequate systemic venous return,6 it is not clear why this occurs.
STPO is noted to occur after growth spurt or menarche,19 and symptoms may decrease after testosterone administration,20 suggesting a role for sex hormones. There is concern about the association with immunization,21 although causality has not been demonstrated and population-based studies have not shown an increase in the frequency of disease parallel to the increase in vaccination rates in adolescents.22,23
Findings similar to STPO have been observed in children with mitochondrial disorders.24 Anecdotally, patients with chronic symptoms from infancy or early childhood (e.g., dysmotility, headaches, or joint hypermobility) who eventually developed STPO have been reported. , with their parents feeling that there was always “something wrong” with them.
A 2016 study of patients with adolescent-onset POTS showed spontaneous resolution of symptoms in up to 19% of patients by adulthood.25 However, in these patients, POTS symptoms were still found to be present. present in up to 33% of respondents who had “recovered.” A similar 2019 long-term outcomes study in China showed that 48% of pediatric patients with POTS were symptom-free at 1-year follow-up, with >85% symptom-free after 6 years,26 although fewer symptoms were used to its evaluation than 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 a significant contrast with adults . During puberty, hormonal changes cause somatic growth, brain maturation, psychological maturation, and gonadal growth and maturation, although it is unclear how these changes affect onset, pathophysiology, and outcomes.
Children attend school and participate in sports activities, while adults are more sedentary and often high achievers in academic and/or athletic activities.27 Sleep hygiene can be difficult, especially with already recognized differences in adolescent sleep. .28 Anecdotally, patients’ symptoms have been observed to improve upon attending college. This may be due to increased time between classes, with more recovery time, increased neurological maturity that improves the ability to recognize and avoid triggers, or being away from parents, forcing them to accept responsibility and own the management of your disease. It could also simply be associated with the aforementioned improvement in symptoms over time.25
A unique factor that pediatric patients have is parental involvement.29 Parents can be strong advocates, bringing these children to an informed and caring professional, especially when symptoms are ignored or misinterpreted by other professionals.1 They connect with other parents to optimize their children’s attention and encourage their children in managing routine control. However, parents can create obstacles to their child’s progress. They can expect a quick return of their (high-achieving) child to school or sports. They may have difficulty allowing their child to mature or fail.29
Parents may have their own untreated psychological and/or medical problems that influence their treatment of the child, sometimes feeling obligated to maintain caregiver status as a secondary gain.30 They also sometimes fail to recognize comorbid psychological problems in their children. .
| Neuro-hormonal and hemodynamic alterations |
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Research into specific abnormalities found in the STPO of children and adolescents is limited because most studies are conducted in adults or a combination of adults and children, but there are interesting data.
Several studies have demonstrated abnormal neuro-hormonal levels and vascular findings, although these do not necessarily indicate a specific biological marker for STPO. Flow-mediated vasodilation in the brachial artery was found to be greater in children with POTS than in healthy controls.31 In that same study, plasma concentrations of the vasodilator nitric oxide and activity of the enzyme nitric oxide synthetase 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 show elevated resting venous pressures and decreased arterial resistance.33
Li et al. showed that total peripheral vascular resistance and cardiac output were significantly reduced in the upright position, with subsequent normalization in the supine position, although these measures were unchanged in healthy controls with any position.34 In that same study, C-peptide levels -natriuretic were also higher in patients with STPO than in healthy controls. A separate study also confirmed elevated C-natriuretic peptide levels in overcontrolled pediatric patients.35
Serum levels of resistin, a peptide hormone that promotes vasoconstriction,36 and copeptin, a glycopeptide closely correlated with vasopressin,37 were found to be elevated compared to controls. Interestingly, supine resistin levels were also found to be inversely correlated with the degree of heart rate change from supine to upright position.36
Antidiuretic hormone levels in children with POTS and hypertension were found to be higher than those without hypertension.39 Another Chinese study showed that 24-hour urinary sodium excretion in children with POTS was significantly lower than that of children with POTS. 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 evaluate this in their control group. Finally, it was found that the upright position induces splanchnic and venous stasis, despite peripheral vasoconstriction.40
| Clinical evaluation |
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From a clinical point of view, several studies have contributed to improving the understanding of pediatric STPO. Post-concussion syndrome is associated with pediatric POTS, with a high rate of resolution of heart rate changes associated with STPO on the tilt table as post-concussive syndrome symptoms improve.11
A finding seen in pediatric patients with POTS is initial orthostatic hypotension, which occurs in 51% of patients versus 13% of controls,41 with greater severity and greater prevalence of impaired cerebral blood flow and cardiorespiratory regulation.
It was observed that the dispersion of the corrected QT interval on the electrocardiogram is longer in pediatric patients with STPO compared to controls, serving as a marker of a risk factor for the presence of STPO, as well as a lower probability of success with the use orthostatic training and other physical maneuvers.42
An interesting study of ambulatory blood pressure monitoring in patients and controls showed that the pressure-rate product (heart rate times systolic blood pressure) in patients was higher both before and after awakening compared to controls,43 with an increase in the morning associated with worsening morning symptoms of orthostatic intolerance. Significant diurnal variability was also demonstrated in the heart rate of children with STPO, such that all patients met the heart rate criteria for the diagnosis of STPO in the morning, but only 28% met those same criteria for the morning. the night.44
In patients evaluated for headaches and dizziness , those who met diagnostic criteria for STPO were more likely to have new onset motion sickness , lightheadedness as a headache trigger, and orthostatic headaches, compared to those who did not meet heart rate criteria. Four. Five
From a GI perspective, antroduodenal manometry was found to be the most useful gastroenterological evaluation compared to gastric emptying studies and esophagogastroduodenoscopy, with abnormalities found in 81% of pediatric patients with GI symptoms.46
A retrospective case-control study of GI symptoms in pediatric patients with POTS showed that anorectal manometry was also the most frequently abnormal test vs. gastric emptying, colonic transit and gastric accommodation.47
Results of a study that evaluated electrogastrography in the supine position vs. Upright position revealed evidence of bradygastria and tachygastria in antrum and fundus of patients with STPO when they were upright on a tilting table, while those without STPO but still with GI symptoms had a decrease in abnormal gastric electrical activity; Both groups had normal basal gastric activity in the supine position.48
A Mayo Clinic study demonstrated that POTS symptoms in adolescents can improve with comprehensive interdisciplinary “pain rehabilitation,”49 although greater symptom burden is positively correlated with delayed clinical improvement.10 However, some data suggest that POTS may be a comorbid finding unrelated to other symptoms (e.g., fatigue, pain, dysmotility, headache, or joint hypermobility).50 Finally, 14.2% of pediatric patients with POTS were found to have a family member with STPO, 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
| Treatment |
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There is a notable paucity of prospective data related to medication management in pediatric patients with POTS. In fact, the first double-blind, prospective, crossover trial of a POTS medication in adults, ivabradine , was just published in 2021.52 Published studies addressing medication use in pediatric patients have been primarily retrospective and observational in nature, although there are some small prospective studies.
The 2 retrospective studies with the largest patient volumes were published by Boris et al.53,54 Both evaluated the effectiveness of various drug therapies for specific symptoms using a threshold of at least 5 refills of the same medication at the same dose consecutively as a indirect measure of effectiveness. 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 higher, at almost 70%.54 In In both studies, the effectiveness of multiple medications was evaluated on both group and individual symptoms.
Other smaller studies have been conducted in the pediatric population. A retrospective analysis of 27 patients showed that ivabradine improved symptoms in 67% of patients,55 and another showed similar results in 22 patients,56 both with minimal effects.
A meta-analysis was conducted 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 evaluated. But the review established that these 7 studies showed major concerns about bias and were not considered to be of high quality.
The eighth study, which was considered to be of adequate quality, was a prospective controlled study that was neither blinded nor randomized for the evaluation of groups receiving routine nonpharmacological therapy , plus a morning dose of 2.5 mg of midodrine, metoprolol twice daily at 0.5 mg/kg per day, or no medication.58 Both midodrine and metoprolol therapy reduced symptom scores in children versus untreated patients, with midodrine leading to a higher rate of resolution of symptoms of orthostatic intolerance.
Lin, who demonstrated increased levels of C-natriuretic peptide in the study mentioned above, also showed in that same study that metoprolol decreased symptom scores in pediatric patients.35 Additionally, a C-natriuretic peptide level greater than 32.55 pg/mL was correlated with the effectiveness of metoprolol in reducing symptoms.
The effectiveness of metoprolol was also evaluated in a prospective trial, in which a copeptin threshold level of 10,225 pmol/L was predictive of efficacy.59 A retrospective chart review analysis and a survey of adolescent patients suggested that patients treated with midodrine or β-blockers showed clinical improvement with the addition of drug therapy, although those who used β-blockers felt that their medication had a more significant effect in reducing symptoms.60
Finally, in a prospective, double-blind, placebo-controlled, crossover study of midodrine in adolescents with neuropathic and hyperadrenergic STPO, midodrine was found to be effective in the treatment of patients with neuropathic STPO, while no improvement was observed. or placebo effect in those with hyperadrenergic STPO.61
In patients who fail oral medication, parenteral therapy may be an option.
The only study in children with this therapy is a retrospective study that used intravenous normal saline in patients with POTS, neurally mediated hypotension, or orthostatic intolerance.62 Most patients reported an improvement in quality of life, although patients who used a permanent method of access, such as a peripherally inserted central catheter or a central port, had a notable incidence of vascular thrombosis and infection.
| Clinical management |
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The general pediatrician’s approach to the care of children and adolescents with POTS, as with any clinical problem, begins with evaluation. A complete clinical history is necessary to evaluate the broad set of symptoms associated with POTS,9 as well as symptoms seen in associated disorders, including, but not limited to, joint hypermobility syndromes,14 mast cell activation syndrome,63 craniocervical instability, medial arcuate ligament syndrome,64 and autoimmune disorders such as Sjôgren’s syndrome and systemic lupus erythematosus.65
Physical examination findings may include manifestations of the above disorders, such as an increased Beighton score, dermatography, urticaria, epigastric/abdominal sounds, venous stasis, dilated pupils, etc. Often, except for standing tachycardia, clinical examination may be normal. Initial studies should include a baseline electrocardiogram, plus consideration of 24-hour Holter monitoring to evaluate for arrhythmias. Suggested laboratory investigations include morning cortisol, thyroid function tests, vitamin D level and ferritin because disorders in these can lead to orthostatic intolerance.66
Evaluation for orthostatic intolerance includes the 10-minute standing test. Ideally, continuous monitoring of blood pressure and heart rate is performed, but measurements should be obtained at least once per minute. The patient should rest in a supine position for 5 minutes, obtaining heart rate and blood pressure at the end. The patient should then immediately stand for 10 minutes, with minimal stimulation and movement.
A persistent increase in heart rate of ≥40 beats per minute without orthostatic hypotension (decreased systolic blood pressure by 20 mmHg or diastolic blood pressure by 10 mmHg) with symptoms of orthostatic intolerance, plus a history of symptoms for ≥3 months, is diagnostic of POTS. (after ruling out other diagnoses), although some sites use a threshold of 30 beats per minute. Although the tilt test is used in several formal stand-alone laboratories, most clinics do not have access to it.
In the absence of other treatable etiologies, therapeutic management begins with non-pharmacological intervention, which is essential.
Increasing intravascular volume with daily fluid intake of 80 to 120 ounces, 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, the use of compression garments,69 and the use of cooling vests to reduce heat intolerance are important complementary measures.
Initiating a specific exercise protocol for patients with POTS is important to help suppress symptoms. Fu and Levine developed a protocol that initially uses aerobic exercises in the supine position, plus isometric activities that strengthen legs and trunk that often produce a significant and long-lasting reduction in symptoms in adults with POTS.70,71
A modified version of their protocol for adolescents can be found on the web.72 However, the basic principles of exercise for these patients include the following: use both aerobic and isometric exercises, initially avoiding upright activities to prevent orthostatic intolerance , starting with a minimum duration of exercise and guaranteeing a consistent and progressive increase. It is recommended that patients with joint hypermobility be evaluated by a physical therapist familiar with this condition to teach them how to strengthen and protect their joints.73
Often, non-pharmacological therapy for POTS is insufficient to reduce symptoms and patients are unable to return to their daily activities, much less incorporate exercise into their routine. Therefore, using medications to reduce STPO symptoms may be beneficial. Although discussion of the utilization of specific medications is beyond the scope of this article, there are basic approaches that can be considered. One is to use medications that target specific symptoms.53,54 Another is to take a general approach to medication use, with the goal of maintaining blood pressure, by using therapies such as fludrocortisone or midodrine, while gently slowing the heart rate. to improve cardiac output with β blockers or ivabradine.74
Many medications used in the management of POTS are already used in children and adolescents for other medical disorders, allowing for familiarity. Certainly, these medications can have side effects, and patients may have persistent symptoms even though they appear to have appropriate therapy. Therefore, comfort with using these medications also requires practice, as well as communication with patients and their families.
Patients may also require additional referral to specialists, such as cardiologists, neurologists, gastroenterologists, allergists/immunologists, etc. depending on specific persistent or abnormal clinical findings, or lack of response to therapy. In the United States, pediatric STPO specialists include general pediatricians, pediatric cardiologists, pediatric gastroenterologists, and pediatric neurologists. Caring for these patients and their families is best accomplished by professionals who have patience, perseverance, and creativity, and by those who have the time to validate and explain details without using medical jargon, and put these individuals at ease.
| Future steps |
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In addition to basic questions about the underlying pathophysiology, evaluation, and therapy of POTS, many questions remain related to these patients, including whether pediatric POTS occurs with minimal symptoms, determining appropriate criteria for diagnosis (including orthostatics and heart rate limits), how changes in growth and hormonal status influence STPO, the roles of maladaptive psychiatric health of patients and parents, determining whether STPO is a disease entity or multiple entities, the role of genetics, and the role of the immune response and inflammation in pathophysiology. These unanswered questions continue to limit the ability to more consistently diagnose and manage this diverse group of patients.
While the saying “Children are not just little adults” rings true, so does another statement often repeated in multiple journal articles: “More research is needed.” The NIH recently issued a notice of special interest to stimulate research on diagnosis, treatment, and mechanistic understanding of POTS.75 Additionally, beginning in 2021, the NIH included funding for POTS in its annual categorical spending,76 so that the number of research dollars spent on this disorder can be better tracked. .
However, even basic recognition of STPO 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 a problem without the provider being able to provide further guidance,1 or may be incorrectly diagnosed as having a disorder. psychological or psychiatric.1
As knowledge and interest in this disorder, as well as research, continues to increase, the relative volume of pediatric research will also increase. Recognition of the unique aspects of pediatric STPO, specifically, will further increase the understanding of this syndrome in general. But most importantly, improving professionals’ understanding of its presence and diagnostic criteria in children and adolescents will allow patients to receive a diagnosis and access the care they require to return to their daily lives.
Table 1. Diagnostic criteria for STPO.
1. Sustained increase in heart rate of not less than 30 beats per minute within 10 minutes of standing or tilting the head up. For people ages 12 to 19, the required heart rate increase is at least 40 beats per minute; and 2. Absence of orthostatic hypotension (ie, no sustained drop in systolic blood pressure of 20 mmHg or more); and 3. Frequent symptoms of orthostatic intolerance during standing, with rapid improvement upon returning to the supine position. Symptoms may include lightheadedness, palpitations, tremors, general weakness, blurred vision, and fatigue; and 4. Duration of symptoms for at least 3 months; and 5. Absence of other conditions that explain sinus tachycardia, such as anorexia nervosa, primary anxiety disorders, hyperventilation, anemia, fever, pain, infection, dehydration, hyperthyroidism, pheochromocytoma, use of cardioactive drugs (e.g., sympathomimetics, anticholinergics) or deconditioning caused by prolonged bed rest. |
Adapted from Vernino S et al, 2021.6
| Comment |
Postural orthostatic tachycardia syndrome is a dysautonomia that affects multiple somatic systems, causing significant disability.
Despite its relatively high morbidity, knowledge of the clinical, diagnostic, and therapeutic aspects of POTS in children and adolescents remains limited.
More research is required on this clinical condition, in order to promote its general understanding and help professionals in its identification and management, thus improving the quality of life of patients who suffer from it.
