Julian M. Stewart, MD, PhD,a Jeffrey R. Boris, MD,b Gisela Chelimsky, MD,c Phillip R. Fischer, MD,d PediatricJohn E. Fortunato, MD,e Blair P.Disorders Grubb, MD,f Geoffrey L. Heyer, MD,ofg Imad T. Jarjour, MD,h Marvin S. Medow, PhD,a Mohammed T. Numan, MD,i Paolo T. Pianosi, MD,d Wolfgang Singer, MD,d Sally Tarbell, PhD,j OrthostaticThomas C. Chelimsky, MD,c The Pediatric Intolerance Writing Group of the American Autonomic Society
abstract Orthostatic intolerance (OI), having difficulty tolerating an upright posture ∼ NIH because of symptoms or signs that abate when returned to supine, is common in pediatrics. For example, 40% of people faint during their lives, half of whom faint during adolescence, and the peak age for first faint is 15 years. Because of this, we describe the most common forms of OI in pediatrics and distinguish between chronic and acute OI. These common forms of OI include initial orthostatic hypotension (which is a frequently Disclaimer: The guidelines/recommendations in this article are not American Acaemy of Pediatrics seen benign condition in youngsters), true orthostatic hypotension policy, and publication herein does not imply (both neurogenic and nonneurogenic), vasovagal syncope, and postural endorsement. tachycardia syndrome. We also describe the influences of chronic bed rest and rapid weight loss as aggravating factors and causes of OI. Presenting aNew York Medical College, Valhalla, New York; bChildren’s signs and symptoms are discussed as well as patient evaluation and Hospital of Philadelphia, Philadelphia, Pennsylvania; c testing modalities. Putative causes of OI, such as gravitational and exercise Medical College of Wisconsin, Milwaukee, Wisconsin; dMayo Clinic, Rochester, Michigan; eAnn and Robert H. Lurie deconditioning, immune-mediated disease, mast cell activation, and Children’s Hospital of Chicago, Chicago, Illinois; fUniversity central hypovolemia, are described as well as frequent comorbidities, such of Toledo Medical Center, Toledo, Ohio; gNationwide Children’s Hospital, Columbus, Ohio; hTexas Children’s as joint hypermobility, anxiety, and gastrointestinal issues. The medical Hospital, Houston, Texas; iUniversity of Texas Houston, management of OI is considered, which includes both nonpharmacologic and Houston, Texas; and jChildren’s Hospital of Colorado, Aurora, Colorado pharmacologic approaches. Finally, we discuss the prognosis and long-term implications of OI and indicate future directions for research and patient Dr Stewart introduced the idea of the article, outlined sections, edited drafts and the final management. manuscript, contributed directly to the first draft of the manuscript, and extensively redacted the draft; Dr T. Chelimsky introduced the idea of the Consensus guidelines define to build a better understanding of article, outlined sections, edited drafts and the final manuscript, contributed directly to the first draft of orthostatic disorders in adults on– pathophysiology and treatment. the manuscript, and consolidated and secondarily the basis of expert opinion and 1 3 The Challenge of Orthostasis edited the draft; Drs Boris, G. Chelimsky, Fischer, randomized controlled studies. (Standing Upright) Fortunato, Grubb, Heyer, Jarjour, Numan, Pianosi, These conclusions incompletely extend Singer, and Tarbell contributed directly to the first to children, for whom large trials draft of the manuscript; Dr Medow contributed directly to the first draft of the manuscript, and even small controlled studies Humans are bipedal. While upright, extensively redacted the draft, and did the bulk of are sparse. Pediatric orthostatic our brain is above our heart, whereas the revision and response to comments; and all intolerance (OI) has drawn increasing 70% of our blood volume is below authors commented on the draft, approved the final manuscript as submitted, and agree to be attention in recent– publications the heart. If not for autonomic accountable for all aspects of the work. from different4 groups7 with different and cardiovascular compensatory perspectives. The high and possibly mechanisms, hypotension and loss DOI: https://doi.org/10.1542/peds.2017-1673 increasing prevalence of orthostatic of consciousness would ensue after Accepted for publication Sep 6, 2017 disorders in teenagers prompted orthostasisOrthostatic. Intolerance the American Autonomic Society to To cite: Stewart JM, Boris JR, Chelimsky G, et al. convene member experts to draft Pediatric Disorders of Orthostatic Intolerance. an evidence-based State of the Art OI can be defined as having difficulty Pediatrics. 2018;141(1):e20171673 document. This document is intended tolerating the upright posture to provide common ground on which because of symptoms that abate Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 141, number 1, January 2018:e20171673 State-of-the-Art Review Article when returned to supine. Typical prognosis, and future directions for symptoms include a sense of research and therapy. impending loss of consciousness, Individual Entities cognitive deficits (memory loss and decreased reasoning and Initial Orthostatic Hypotension concentration), visual difficulties, lightheadedness, headache, fatigue, weakness, nausea, abdominal On standing, there is symptomatic discomfort, tremulousness, exercise hypotension because of the caudal intolerance, and reported signs such transference of blood because as pallor, diaphoresis, tachycardia, of gravity and a time delay8 in bradycardia, or hypotension. sympathetic activation. Blood pressure (BP) can decrease by >30%, This definition encompasses all reaching a nadir at 10 to 15 seconds FIGURE 1 forms of orthostatic disorders, such after standing. Lightheadedness A standing test of IOH is shown. The upper panel shows HR in beats per minute, and the as postural faint and orthostatic and reflex tachycardia occur. BP lower panel shows BP in mm Hg. The vertical hypotension (OH), but not others, is restored within –30 seconds, but line indicates standing. BP decreases, and HR increases briefly. Hypotension resolves within such as a broken leg or overt muscle cerebral blood flow9 11 and heart rate disease. The definition is sufficiently (HR) take longer. Clinically 30 seconds. HR stabilizes gradually to its upright, steady-state value. broad to encompass postural vertigo, significant initial orthostatic balance issues, and positional hypotension (IOH) is defined as a headache. decrease in systolic BP of >40 mmHg
or a decrease in diastolic BP of >20 Chronic OI is defined as OI that 10 mmHg. The fall in BP is enhanced is present for at least 3 months, by the duration of the previous although symptoms may wax and supine position. A history of transient wane. An example is postural lightheadedness dissipating in <1 tachycardia syndrome (POTS). minute7,10, should12 be considered as Acute and subacute OI are defined as IOH. Syncope is uncommonly OI that has been present for <1 week reported with IOH. Countermeasures and <3 months, respectively, or is to obviate symptoms include active restricted to recurrent episodes, such contraction of lower-body9,10 muscles as with postural vasovagal syncope or recumbence. IOH is 9,the12, 13 (VVS). most common form of OI. A FIGURE 2 representative standing test in which A tilt table test shows true OH. The upper panel Some OI represents an extension of IOH is experienced is shown in Fig 1. shows HR in beats per minute, and the lower normal physiology, such as transient panel shows BP in mm Hg. The vertical line OH is defined by the steady decrease indicates tilt. There is a monotonic decrease lightheadedness immediately on in BP exceeding 20 mmHg systolic in BP and a compensatory increase in HR, standing. Some consider infrequent which can often exceed 40 beats per minute in or 10 mmHg diastolic within 3 VVS to be a normal response to 1,7, 14 youngsters. central hypovolemia because its minutes of standing from supine. lifetime incidence approaches The associated compromise 40%, and it can be universally in brain blood flow may cause syncope. OH may be nonneurogenic occurs in familial dysautonomia induced with sufficient orthostatic 18,19 2 from severe central hypovolemia provocation. However, OI that 15 and autoimmune disorders. or pharmaceutical vasodilation. importantly diminishes quality of life There may be little postural deserves treatment. There is supine tachycardia, which increases markedly when HR increase in adults because of frequent, associated cardiac In what follows, we more specifically upright. OH may be neurogenic 1,18 define individual entities comprising (nOH) because of an inadequate denervation. In contrast, children OI and discuss how best to test for release of norepinephrine1 from typically mount a compensatory and diagnose OI. We review the sympathetic neurons. nOH results tachycardia, suggesting intact cardiac epidemiology, predisposing factors, from primary autonomic failure– or 6 parasympathetic efferents. A putative causes, and frequent secondary autonomic failure,14,16 as18 in comorbidities of OI and focus on diabetes and amyloidosis. representative tilt table test in which POTS. We discuss management, nOH is uncommon in pediatrics but OH is experienced is shown in Fig 2. Downloaded from www.aappublications.org/news by guest on September 26, 2021 2 Stewart et al Postural Vasovagal Syncope
Syncope is defined by a transient loss of consciousness and postural tone because of global cerebral hypoperfusion characterized by rapid onset, short duration (<2 minutes),20 and spontaneous recovery. Postural VVS is syncope occurring after several (>3) minutes upright. Characteristic history features environmental precipitating factors, a prodrome of lightheadedness, diaphoresis, warmth, nausea, hyperventilation,– FIGURE 3 FIGURE 4 A tilt test shows VVS. The upper panel shows HR A tilt test shows POTS. The upper panel shows pallor, and a postdrome2,21 23 of fatigue and headache. Cardiac in beats per minute, and the lower panel shows HR in beats per minute, and the lower panel BP in mm Hg. Vertical lines indicate the start shows BP in mm Hg. Vertical lines indicate the causes for7, syncope24 must be and end of tilt. On tilt, BP is initially stable then start and end of tilt. On tilt, BP is initially stable, ruled out. Hypotension slowly falls because HR rises often by >40 beats with a small downward drift during tilt. There is and bradycardia typically occur per minute. BP then falls rapidly, followed by HR excessive tachycardia but no hypotension. together. Postural VVS is aborted by (hypotension bradycardia). lying down; consciousness returns within seconds. VVS is also– provoked by noxious stimuli, such as venipuncture identified (eg, Addison disease), 2,21 23 excessive upright tachycardia in the or emotional stress. The some discard the POTS label in favor absence of postural hypotension. The most common age of onset is of the disease name, whereas others origins of POTS are heterogeneous. 15 years. VVS occurs twice as often 7,28, 29 prefer to call it secondary POTS. Most cases are in girls (>80%). in female adolescents, with sex ratios Regardless, POTS is a syndrome, 25 Symptoms are initiated by an upright equalizing later in life. Athletic and evaluations for underlying posture and abate when supine (ie, youngsters have an increased 30 causes, such as dehydration, anemia, they must be postural to be POTS). prevalence of VVS. Postexercise VVS hyperthyroidism, and autonomic Excessive upright tachycardia is can occur in patients with postural neuropathies, are necessary in all defined in adults as an average VVS. Low-serum iron and/or ferritin cases. A representative tilt table test sustained increase in HR of >30 can contribute to the occurrence in a patient with POTS is shown in 26,27 beats per minute or to an HR of >120 of VVS. VVS can be induced in Fig 4. beats per minute within 10 minutes healthy volunteers in the laboratory of standing or upright tilt. Excessive Prolonged bed rest (>23 hours) but is only clinically important in upright tachycardia is defined in induces gravitational deconditioning daily life. Reflex syncope occurs in adolescents 18 years or younger by with concomitant physiologic OH and situational variants, such as an increase in HR of >40 beats per findings and is distinct from exercise deglutition, defecation, micturition, 29 minute. By definition, sustained deconditioning; these include a and cough syncope, but rarely from 6,7 hypotension must be absent. POTS markedly reduced blood volume, IOH. Asystolic or convulsive does not cause a transient loss of blood volume redistribution, trophic syncope may occur in VVS without consciousness, per se, although VVS cardiac atrophy, baroreflex changes, prodrome and with tonic posturing 7 may also occur in some patients. reduced vasoconstriction to pressor after loss of consciousness. Physical A secondary form of POTS can drugs, skeletal muscle atrophy with injury is common in these patients occur with any central hypovolemic loss of the skeletal muscle pump, and because of falls and other related state, such as dehydration or osteoporosis. The earliest changes trauma. In adults, pacing has been hemorrhage, and can progress are detectable within 24 hours. In a used to prevent these injuries. In 28 to OH. Excessive tachycardia bed-rested patient, OI may take the patients with presumptive VVS, also occurs in young VVS patients form of POTS, OH, or– VVS, and bed competing diagnoses include preceding syncope, but sustained rest worsens these7,31 states35 if they are epilepsy and pseudosyncope. A hypotension precludes POTS. Halreadyypocaloric present. Weight Loss representative tilt table test in which POTS can be evoked by excessive VVS is experienced is shown in Fig 3. upright sympathetic activation POTS is defined by daily symptoms of or excessive parasympathetic A study of healthy volunteers chronic OI combined with sustained, withdrawal. When a cause is showed a deterioration of orthostatic Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 141, number 1, January 2018 3 TABLE 1 Predominant Presenting Symptoms of OI Affected System Symptoms Present While Upright tolerance with weight loss of 1% to 4%, which is likely because General Fatigue, heat intolerance, weakness, temperature regulation difficulties Cardiovascular Lightheadedness, tachycardia, chest pain, palpitations, exercise of a reduced blood volume, the intolerance, syncope, acrocyanosis, diaphoresis, pallor, flushing modulation of autonomic function, Gastrointestinal Nausea, abdominal pain, dysmotility altered baroreflex function, and Respiratory Dyspnea, hyperpnea altered vascular smooth muscle Neurologic Headaches, paresthesias, balance problems 36 Neuropsychological Memory and attention issues (brain fog) tone and responsiveness. 36 This is potentiated by bed rest. OI resembling POTS or OH occurs in anorectic states and during Standing is arguably the most Onset may be gradual or acute and starvation and may precede the37 well- known terminal bradycardia. physiologic orthostatic test, although often occurs after– an infection, it is difficult to standardize. There immunization,46 surgery,49 sepsis, or Testing for OI is little consensus regarding how head trauma. Infectious50, 51diseases long a patient should stand, whether exacerbate preexisting OI. movement should be allowed or Demographic Characteristics Symptoms of OI must be present restricted, and how long a patient should be supine before standing. to merit testing. Autonomic and 51 vasoactive drugs should be stopped Validation of a standing test for Girls represent >80% of patients. POTS exists for adults but not yet for for at least 5 half-lives before testing. BMI is reduced in patients52 with children, for43 whom the tilt table is POTS and hypovolemia. Onset is Upright tilt table testing is the de standard. Standing is validated in often near puberty, but younger facto standard for orthostatic stress pediatric1,10 patients to diagnose OH and patients have been identified less ° ° 48,53 tests. The use of the tilt table at IOH. frequently. Literature on racial angles between 60 and 70 dates to Monitoring During Orthostatic differences is limited: orthostatic Testing tolerance characterizes African 1930, but its 38,use39 to diagnose VVS is – more recent. Tilt testing limits Americans, and most reported53 55 the effects of the skeletal muscle patients with POTS are white. pump. Diagnostic criteria for POTS The minimum requirementCurrent Procedural is an Family members of patients were also developed by using tilt Terminologyintermittent measurement of HR and with POTS 56often describe similar table testing. The standardization BP. Current US symptoms. Many young patients of tilt table testing for the diagnosis codes require the with POTS5, were53 formerly high of VVS has been problematic. The measurement of beat-to-beat9,12, 13 achievers. Yet, with the onset of so-called Italian protocol (20 minutes electrocardiogram and BP. symptoms, children experienced upright followed by sublingual Automated autonomic testing is not reduced participation in school, nitroglycerin as pharmacological validated and 44is not recommended social life, sports, and recreational ° ° potentiation) is now commonly for diagnoses. Other monitoring activities. Psychiatric comorbidities 40,41 ° used. Tilt angles of 60 to 70 are uses nasal capnography, EEG, in these patients are also common. ° advocated because angles of 80 to cerebral blood flow, or cerebral Predisposing and Contributing oximetry. Research measurements Factors and Putative Causes of 90 increase the incidence42 of false- positive test results. include regional blood flow and POTS blood volume, pneumotachography, Although a 10-minute tilt is standard microneurography, and combined for POTS, a 5-minute tilt may modalities. Up to 50% of case patients suffice. There is little consensus on Prevalence and Phenotype of have antecedent symptoms the duration of the supine period Pediatric POTS that suggest a viral infection preceding the tilt, although it affects with a prolonged course (eg,57 results. Extending the tilt past 10 infectious mononucleosis). minutes reduces the accuracy of The prevalence of45 POTS is not Others have previous stressors, the POTS diagnosis, although it may well established. Its incidence in such as pregnancy, injury, or provide additional information about pediatrics is not known because surgery; the remainder of patients58 the nature of43 OI and the diagnosis screening for OI is not routine. develop symptoms insidiously. of syncope. OH can be reliably OI affects a broad range of organ Inflammatory or autoimmune diagnosed1 by tilt or standing for 3 systems. Examples of common signs mechanisms may also be responsible. minutes. and symptoms are shown in Table 1. Patients with prolonged illness may Downloaded from www.aappublications.org/news by guest on September 26, 2021 4 Stewart et al β α confine themselves53 to bed, making autonomic denervation, suggestive N-methylhistamine, leukotriene79 E4, matters worse. of a limited autonomic neuropathy or 11- -prostaglandin F2 . Initial in some patients with POTS with a treatment targets the chemical Central hypovolemia reduces β female predominance and preceding being excessively released (aspirin cardiac venous return, resulting α viral syndrome with subacute or ibuprofen for 11- -prostaglandin in a compensatory tachycardia. – symptom onset, supports an F2 , montelukast for leukotriene Hypovolemia may be absolute underlying immune system related E4, and antihistamines for or distributive and accompanies 56,72, 73 79,80 cause. This is further supported histamine). Many patients exercise deconditioning and chronic 59,60 by the detection of nicotinic require a combination of H1 and H2 fatigue. Exercise deconditioning ganglionic acetylcholine receptor antihistamines, antileukotrienes, is a result rather than the cause β autoantibodies in a small percentage anti-inflammatory agents, and a mast of POTS, and some patients with 47 of patients with OI. Recent reports cell stabilizer (Cromolyn). -blockers, POTS have normal to supranormal postulate that autoantibodies cross- often used for POTS, may worsen cardiovascular responses to exercise, α β react with a wide range of cardiac MCAD symptoms. with a normal stroke volume in 30% 61,62 proteins and - and -adrenergic of patients. However, exercise Comorbidities in Pediatric OI receptors in many adult patients deconditioning can worsen POTS by with OI, although these findings have further reducing blood or plasma 74,75 thus far not been reproduced. volume, heart size, and stroke Several conditions are associated 61 A study in which evaluate the volume. with pediatric OI, including sera of patients with POTS found joint hypermobility, functional Gravitational deconditioning organ-specific autoantibodies, gastrointestinal disorders (functional occurs during microgravity and particularly thyroid-specific, to abdominal pain, nausea, and cyclic chronic bed rest and emulates the ∼ 63 be more76 common in patients with vomiting syndrome), chronic fatigue pathophysiology of POTS. Plasma POTS. The preliminary nature syndrome, headache, sleep disorders, volume decreases by 15% within of these findings prohibits any cognitive dysfunction (brain fog), several days, red cell mass declines, generalizable recommendations anxiety, and depression. Comorbidity and blood flow and blood volume 81 for immunomodulatory or does not signify direct causation. redistribute abnormally from skin immunosuppressive treatments at Most researchers evaluate and splanchnic reservoirs, reducing – this time. comorbidities in POTS; few address cardiac filling, particularly when Mast Cell Activation Disorders 28,51, 64 68 OH and VVS. upright and during exercise. Muscle atrophy increases leg venous Joint hypermobility is associated with pooling, contributing to acrocyanosis,– POTS was found in patients with mast POTS, syncope, presyncope,– fatigue, impaired vasoconstriction, and loss heat intolerance, and abnormal82 85 31,58, 68 70 cell activation77 disorders (MCADs) of the skeletal muscle pump. autonomic testing scores. 1 decade ago. MCADs and POTS78 The cardiovascular effects of are increasingly found together. Chronic pain and joint hypermobility prolonged bed rest contribute to MCADs are symptomatically similar are equally present in patients81 with the pivotal pathophysiology of POTS to attenuated mastocytosis, but they POTS versus those without. (central hypovolemia) and potentiate 71 are unassociated with increased Functional gastrointestinal– disorders OI and POTS. Measures that mast cell numbers. Instead, there is are associated86 with88 autonomic preserve peak oxygen uptake during an excessive release of biologically dysfunction. POTS is associated exercise do not necessarily reduce OI, active materials from otherwise79,80 with upper-gastrointestinal supporting the suggestion that POTS normally growing mast cells. In symptoms and antroduodenal and deconditioning each represent MCADs, mast cells release histamine, dysmotility,89 which exacerbate with separate downstream63 effects of an prostaglandins, and leukotrienes, standing and may improve when inciting cause. POTS symptoms are 90 often without a recognizable allergen. OI is treated– . Both delayed and often improved by physical activity, Symptoms may be episodic and rapid gastric89 92 emptying have been but not all patients with POTS are associated with facial flushing or reported. exerciseImmune deconditionedMechanisms . chronic with fatigue, dizziness, OI has been identified in both and abdominal discomfort, often younger and older case patients with posturally induced. Symptomatic 93 – cyclic vomiting syndrome, with The idea of a limited autonomic flares of MCADs may result in 93 95 POTS present in 35% of adults. neuropathy underlying POTS elevated serum tryptase levels. was suggested30 in its original Patients with chronic MCADs may Symptoms and patterns of description. Evidence of partial exhibit excessive amounts of urinary orthostatic HR and BP changes occur Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 141, number 1, January 2018 5 131,132 in adolescents– with chronic fatigue needed to elucidate the moderating drinks are preferred. A goal is syndrome96 99 and overlap with those of effects of sleep, cognitive, psychiatric, to achieve urine osmolality of <300 POTS. and social-interactional factors on mmol/L or urine sodium >200 mmol pediatric OI symptoms. per 24 hours. Intravenous hydration Headache, including migraine, is Management may be used acutely (eg, for commonly reported in POTS and 100,101 gastrointestinal so-called influenza) VVS. The association between but is strongly discouraged on a headaches and OI has been primarily Although pharmacologic and Exercisechronic basisTraining. documented in adults. A few studies – nonpharmacologic interventions that include children have shown 102 104 have not been compared, it is similar associations. In a study the opinion of the authors that Four trials in young adults using HR of adolescent headache patients nonpharmacologic interventions as the target for exercise training in a tertiary-care setting, 53% had 105 are more important to long-term showed efficacy in POTS. Exercise POTS. Although headache can be outcomes, and they are therefore can expand blood volume by 20% a symptom of OI, the relationship 133,134 ’ presentedNonpharmacologic first. Management to 25%. One approach aims is unclear. The treatment of POTS for 60% to 70% of a subject s has been found to be only partially Fluids and Exercise 106 HR achieved during maximal effective in relieving headache. exercise testing beginning with Sleep disorders, such as problematic Cell dehydration causes adverse semirecumbent exercise; there are sleep onset, maintenance, duration, responses, including exaggerated 5 minutes of warm-up to achieve quality, and daytime sleepiness,5,53, 57, 107, 108 cortisol response to exercise, target, 15 minutes at target, then 5 are consistently reported. minutes of cool down. As exercise decreased sympathetic nervous– However, sleep studies in adults tolerance improves, add 5 minutes activity, and impaired cognitive120 123 have shown little– differences in sleep and physical performance. per session at target until one can characteristics109 among112 POTS patients Adequate daily water intake is complete 30 minutes at the target HR. and controls. defined by the National Academy of Alternative nutritional, psychological, Cognitive symptoms or brain Medicine (formerly the Institute of and multidisciplinary therapies fog, which is described as Medicine) as 3.7 L for men and 3.0 L have been employed without having difficulty with attention, for women; however,124 euhydration is an evidence base. These have concentration, and memory, are difficult to assess. included biofeedback; acupressure commonly reported in POTS. Triggers Bed rest emulates POTS with and acupuncture; craniosacral include prolonged concentration108 decreased stroke volume and therapy; increased fiber intake; and sleep disorders. Cognitive increased HR to orthostasis, gluten avoidance; a diet of avoiding performance during tilt testing is fermentable oligosaccharides, which occur in125 response to central impaired because of an entrainment hypovolemia. Vigorous salt and disaccharides, monosaccharides and of cerebral blood flow by BP that polyols; and probiotics. water loading126 eliminates OH after reduces neurovascular coupling, the bed rest. Symptom severity Cognitive behavioral therapy link between an increase in neural negatively correlates127 with urinary and intensive multidisciplinary activity in response to a neural sodium excretion. Intravenous rehabilitative programs for activation task, and the resulting 113,114 saline and salt 108improve symptoms individuals with OI, particularly increase in cerebral blood flow. in adolescents. Large amounts POTS, report improvement in Increased depression and 135 of dietary128 salt improve symptoms functional outcomes. Further heightened anxiety in patients with in adults. Some patients with research is needed to evaluate the POTS negatively impact attention and 115 POTS have deficits in plasma and benefitsPharmacologic and durability Management of treatment. short-term memory. blood volume without increased Depression, anxiety, and pain plasma renin or aldosterone129,130 but with catastrophizing are common in increased angiotensin-II. Studies of pharmacologic pediatric POTS and– VVS, in which Target salt and water intakes of 2.5 interventions in OI are mostly they can mirror5,53, 116 parental119 psychiatric to 3 L daily in adolescent girls and retrospective or single-dose trials. symptoms. These types 3.0 to 3.5 L daily in adolescent boys Even documented therapies vary of studies are often associative and are recommended, which should with provider, involve off-label use, are complicated by an overlap of be accompanied by >8 g sodium and can produce variable clinical psychiatric symptoms with those chloride daily. Glucose polymers (eg, responses because of individual of OI. Therefore, further research is maltodextrins) in commercial sports differences in drug sensitivity, Downloaded from www.aappublications.org/news by guest on September 26, 2021 6 Stewart et al TABLE 2 Medications Medication Dose Side Effects Comments Circulatory support Fludrocortisone 0.1–0.2 mg qAM Peripheral edema, acne, headache, Monitor basic metabolic panel and hypokalemia, hypomagnesemia magnesium at higher doses90,136 Midodrine 2.5–10 mg TID q4h Tingling, goosebumps, headache, Check supine BP 30–60 min after a hypertension dose137–140 Desmopressin 0.1–0.4 mg BID Hyponatremia, headache141 — Octreotide 25–100 μg subcutaneously BID Injection site discomfort, diarrhea, thyroid Decreased gastrointestinal transit time may derangement be beneficial for some patients138,142, 143 Erythropoietin 10 000–20 000 IU subcutaneously Hypertension, arthralgias Ensure hematocrit <50%, ensure adequate weekly iron intake144,145 Acute normal saline infusion 1–2 L intravenous every 5–7 d Repeated phlebotomy can lead to scarring Intermittent rescue use may be beneficial in of veins acute management146
Ivabradine 2.5–10 mg BID Bradycardia without hypotension Inhibits If sinoatrial node, FDA approved for adult CHF. Small trials showed benefit in POTS147,148 Autonomic modulation Metoprolol succinate 12.5–100 mg daily Lightheadedness, decreased exercise Nighttime dosing may decrease Metoprolol tartrate 12.5–50 mg BID tolerance, fatigue, worsening asthma, lightheadedness139,149 depression Atenolol 12.5–50 mg BID Same as metoprolol succinate — Nebivolol 2.5–10 mg daily Same as metoprolol succinate Fewer overall side effects because of decreased blood–brain barrier penetration Propranolol — Same as metoprolol succinate — Citalopram 10–40 mg daily Nausea, headache, fatigue, increased Causes central sympathetic modulation, appetite, suicidal ideation requiring reduces abnormal autonomic response150 early and frequent monitoring Escitalopram 5–20 mg daily Same as citalopram — Sertraline 25–200 mg daily Same as citalopram — Clonidine 0.1–0.3 mg transdermal every Contact dermatitis with adhesive, fatigue, Centrally acting α-agonist, may also be used 7 d dry mouth, headache for insomnia151,152 Pyridostigmine 30–120 mg BID to TID Abdominal pain, muscle twitch, decreased May also be helpful for early satiety and intestinal transit time constipation153–155
BID, twice daily; CHF, congestive heart failure; FDA, Food and Drug Administration; If, sinus node inward “funny” pacemaker channel; q4h, every 4 hours; qAM, every morning; TID, thrice daily; —, not applicable.
Prognosis metabolism, or tolerance to adverse or resolution159 at 5.4 years after effects. diagnosis. Another center showed Patients with VVS improve in their – improvements among young adult Key therapies provide circulatory 20s, but symptoms often recur in 25 patients with POTS (aged 20 33 and autonomic support (Table 2), middle age. Recurrent syncope ± years) over a mean follow-up period including efforts to increase blood among children and adolescents 160 of 92 41 months. volume. However, we strongly can negatively affect health-related 156,157 Future Directions and Research discourage the chronic use of quality of life. central lines or ports because of the Little is known about the long- risk of infection, endocarditis, and term prognoses for pediatric Despite an evolving consensus of thrombosis. An enteral intake of fluids patients with POTS. Heterogeneous clinical phenotypes and medical and sodium is always preferred. pathophysiology leads to a common management of OI, underlying
Another common approach targets the phenotype, but prognosis depends30,72, 129, 158 mechanisms remain poorly treatment of specific symptoms. Often, on the underlying etiology. understood. To establish evidence- drugs are employed that successfully Comorbidities and treatments based diagnostic and treatment improve similar symptoms in other can influence short- and long-term strategies, diverse research findings diseases. These can include fatigue, outcomes. A survey from a single must be integrated to generate cognitive dysfunction, insomnia, tertiary center conducted by using a hypotheses, develop prognostic and chronic pain, gastrointestinal mailed questionnaire suggests a good natural history studies, and improve symptoms, and headaches. Further overall prognosis among adolescent patient care. Uniform, multicenter discussion of specific therapies is patients with POTS, with 86% databases and clinical registries will be beyond the scope of this review. reporting symptom improvement important in reaching this goal. This Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 141, number 1, January 2018 7 Abbreviations concept has been put into161 practice in to determine the impact of adult patients with POTS. treatment strategies ranging from pharmacological regimens, salt and BP: blood pressure Among the challenges in water requirements, and exercise. HR: heart rate characterizing pediatric patients with A better understanding of the effects IOH: initial orthostatic OI is defining a consistent method of of treatments on neurocognitive, hypotension performing orthostatic stress testing, autonomic, and cardiovascular signs including a proposed validation of MCAD: mast cell activation and symptoms underscores the practical standing tests. Also, recent disorder need to incorporate well-trained work shows the utility of measuring nOH: neurogenic orthostatic neuroscientists, psychologists, serum and urinary biomarkers hypotension immunologists, and physiologists in because they relate to different OI OH: orthostatic hypotension research and therapy. Studies relating phenotypes or because they predict OI: orthostatic intolerance 161,162 diagnostic tools such as functional treatment response. POTS: postural tachycardia brain imaging to objectively document syndrome Large prospective randomized neurocognitive assessments may be VVS: vasovagal syncope controlled studies are needed critical in this regard.
Address correspondence to Julian M. Stewart, MD, PhD, New York Medical College, Center for Hypotension, 19 Bradhurst Ave, Suite 1600S, Hawthorne, NY 10532. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2018 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Supported by the National Heart, Lung, and Blood Institute (R01HL112736); the National Institute of Neurological Disorders and Stroke (R21NS094644, R01 NS092625, K23 NS075141, and FD004789 [Food and Drug Administration]); the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK083538); Advancing a Healthier Wisconsin (grant 5520298); the Huseby family; the Hohmann Foundation; the US Department of Health and Human Services (HHSA290201500013I); Medtronic; and H. Lundbeck A/S. Funded by the National Institutes of Health (NIH). POTENTIAL CONFLICT OF INTEREST: Dr Boris has served as a paid expert witness on the subject of postural orthostatic tachycardia syndrome. H. Lundbeck A/S (which underwrote a meeting of the Pediatric Subgroup of the American Autonomic Society) produces Northera (droxidopa) to treat orthostatic intolerance as well as citalopram and escitalopram; the other authors have indicated they have no potential conflicts of interest to disclose.
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Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 141, number 1, January 2018 13 Pediatric Disorders of Orthostatic Intolerance Julian M. Stewart, Jeffrey R. Boris, Gisela Chelimsky, Phillip R. Fischer, John E. Fortunato, Blair P. Grubb, Geoffrey L. Heyer, Imad T. Jarjour, Marvin S. Medow, Mohammed T. Numan, Paolo T. Pianosi, Wolfgang Singer, Sally Tarbell, Thomas C. Chelimsky and The Pediatric Writing Group of the American Autonomic Society Pediatrics 2018;141; DOI: 10.1542/peds.2017-1673 originally published online December 8, 2017;
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Downloaded from www.aappublications.org/news by guest on September 26, 2021 Pediatric Disorders of Orthostatic Intolerance Julian M. Stewart, Jeffrey R. Boris, Gisela Chelimsky, Phillip R. Fischer, John E. Fortunato, Blair P. Grubb, Geoffrey L. Heyer, Imad T. Jarjour, Marvin S. Medow, Mohammed T. Numan, Paolo T. Pianosi, Wolfgang Singer, Sally Tarbell, Thomas C. Chelimsky and The Pediatric Writing Group of the American Autonomic Society Pediatrics 2018;141; DOI: 10.1542/peds.2017-1673 originally published online December 8, 2017;
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