Orthostatic intolerance is found in nearly 500,000 Americans (1). It is 4 to 5 times more prevalent among females than males (2,3). Most patients with orthostatic intolerance who are 15 to 45 years old display abnormal sympathetic nervous system functioning, resulting in amplification of the neurotransmitter norepinephrine to the heart (1). Common clinical findings associated with orthostatic intolerance include excessive tachycardia and cerebral hypoperfusion on standing (3,4). The onset of symptoms often follows an infectious disease (4). Chronic symptoms common among adolescents include headache, abdominal pain, backache, and morning fatigue (5). It has been reported that among adolescent girls, 20% to 30% experience headache, abdominal pain, and morning fatigue on a weekly basis (5).
A common type of orthostatic intolerance, postural orthostatic tachycardia syndrome (POTS), is defined by a heart rate increase of 30 or more beats per minute (bpm) on a head-up tilt table test (HUT) (6). POTS may result from sympathetic denervation (7) and often causes substantial disability (8). POTS is probably composed of a heterogeneous group of disorders, including various disorders that manifest the same clinical symptoms (4,8). Nonorthostatic symptoms include fatigue, headache, and gastrointestinal (GI) tract symptoms (3). Clinicians increasingly recognize a variety of patients with fatigue, dizziness, inappropriate tachycardia, and nonspecific GI symptoms (nausea and abdominal pain) who do not meet the strict definition for POTS by HUT but who likely fall into a broad spectrum of clinical dysautonomia (9). Some investigators suggest an overlap between clinical symptoms and the pathophysiology of chronic orthostatic intolerance (including POTS), chronic fatigue syndrome, and inappropriate sinus tachycardia (9).
Gastrointestinal symptoms are common among patients with orthostatic intolerance (10–14). In a study of adolescents with abnormal HUT results, 71% of patients presented with abdominal pain, 56% with nausea, and 50% with vomiting (14). Patients with a diagnosis of POTS often report the same GI symptoms (14,15). In a few reported cases, treatment for POTS (eg, β-adrenergic receptor blockers, low-dose fludrocortisone) has also resolved concomitant GI symptoms (11,12,16). The apparent correlation between autonomic and GI dysfunction may be due to reduced sympathetic input to the GI tract (11). A recent study has reported persistent splanchnic hyperemia in patients with POTS, possibly resulting from locally mediated vasodilation and deficient splanchnic vasoconstriction (17). Thus, sympathetic dysfunction, like that seen in POTS, may directly cause a disturbance in GI function. Alternatively, GI symptoms may arise indirectly as a delayed consequence of orthostatic intolerance via hyperfusion or hypoperfusion of the gut (12). Other investigators, taking the biopsychosocial approach, have suggested that each patient's subjective sense of malaise, suffering, and disability may heavily influence the interaction between the central, autonomic, and enteric nervous systems (18).
Patients with GI symptoms such as functional dyspepsia, abdominal pain, and nausea often experience delayed gastric emptying (19). It was hypothesized that patients with both GI symptoms and symptoms of orthostatic intolerance are more likely to have abnormal tilt table results and delayed gastric emptying. We further hypothesized that there would be a correlation between POTS and delayed gastric emptying.
PATIENTS AND METHODS
We reviewed the medical records of patients, ages 12 to 17 years, referred to either the Pediatric Diagnostic and Referral Service or the Pediatric Gastroenterology Service at Mayo Clinic Rochester with symptoms of nausea and/or dyspepsia. We recorded patient demographics, symptoms, history, medications, results of physical examination, diagnostic results, and final clinician diagnosis. We identified patients who had undergone both autonomic reflex screening (ARS) and gastric emptying testing (GET). This provided empirical grounds on which to relate the severity of orthostatic intolerance to gastric motility. The patients were seen after January 2002.
Patients fasted after 8 PM the night before undergoing the GET. They stopped medications, such as narcotics and prokinetic agents, 48 hours before undergoing their tests. A series of nuclear medicine examinations was performed initially and then 1, 2, and 4 hours later. Normal adult gastric emptying values for the 1-, 2-, and 4- hour intervals (11%–39%, 40%–76%, and 84%–98%, respectively) were used as the comparative normal standard in the assessment of adolescent gastric emptying of a technetium-99 radiolabeled meal.
The ARS included a quantitative sudomotor axon reflex test (QSART) and HUT (20). Either a reduced sweat response or absence of sweat response during QSART is indicative of postganglionic sympathetic sudomotor failure (9). Testing was done as previously described in the literature (20,21).
Patients with a heart rate change of 30 bpm or more on HUT were assigned to the POTS group, meeting the traditional HUT definition for POTS. Those with a heart rate change of fewer than 30 bpm on HUT were assigned to the non-POTS group. Heart rate change on HUT and gastric emptying results were compared and presenting symptoms were described between the 2 groups.
The ARS and the GET were conducted on 31 patients as part of their clinical evaluation. The average age of these patients was 14.6 years (SD 2.0), and 68% were female. The patients were from 13 different US states and had been symptomatic for an average of 13 months (SD 11).
Of the 31 patients who underwent both the GET and ARS, 21 were assigned to the POTS group (≥30 bpm heart rate change), and 10 were assigned to the non-POTS group (<30 bpm heart rate change). Overall, 6 (19%) of 31 patients had delayed gastric emptying, and 7 (23%) had accelerated gastric emptying.
There was no significant difference in presenting symptoms between those with and without heart rate change of fewer than 30 bpm (P > 0.05). Among the 21 patients in the POTS group, 71% presented with nausea, 67% presented with abdominal pain, 52% presented with dizziness, and 47% reported emesis. Of the 10 patients in the non-POTS group, 60% presented with nausea, 60% presented with abdominal pain, 30% presented with dizziness, and 40% reported emesis (Fig. 1). Other symptoms included diarrhea, altered temperature, weight loss, chest pain, sleep disorder, constipation, and palpitation (Fig. 1).
The mean gastric emptying values for both groups at all 3 time increments were, however, within the normal adult ranges. Pearson correlation tests indicated no significant association between heart rate change on HUT and gastric emptying values (r = −0.05, −0.15, and −0.19). (Table 1, Fig. 2)
Two of the patients in the POTS group also had a drop in systolic blood pressure of 25 mmHg or more during HUT consistent with neurally mediated hypotension. In the POTS group, 5 (24%) of the patients had reduced QSART, and in the non-POTS group, 2 (20%) of the patients had reduced QSART.
Although gastric dysmotility was commonly observed in this sample, the extent of heart rate change on HUT was not a significant predictor of the direction or extent of abnormal gastric emptying. The diagnosis of POTS in our patient sample, as defined by a HUT heart rate change of 30 bpm or more, was not a statistically significant predictor of abnormal gastric motility.
Most important, significant similarities between the POTS group and the non-POTS group give us a unique clinical opportunity to pragmatically reconsider how we approach and evaluate adolescent patients with symptoms and signs of orthostatic intolerance and autonomic dysfunction. Our data indicate that adolescents with a HUT heart rate change of fewer than 30 bpm have similar symptoms as those with a HUT heart rate change of 30 bpm or more. Although a heart rate change of 30 bpm or more has been described in the literature as a defining factor of POTS, in light of our review, a broader clinical approach that is less arbitrarily defined by heart rate change in the laboratory should be investigated. The traditionally accepted HUT change of 30 bpm or more does not seem to be sensitive or specific for confirming a clinical diagnosis of adolescent autonomic dysfunction, which we believe is different in presentation and course than adult POTS as classically reviewed in the medical literature. Furthermore, physicians should reconsider the use of tilt table testing and gastric emptying scans. These procedures are costly, time consuming, and in light of the current research have a low predictability for orthostatic intolerance.
Follow-up research is recommended to report the natural course of this spectrum of illness and to develop effective prospective clinical treatment trials for adolescents with symptoms and signs in the spectrum of orthostatic intolerance and autonomic dysfunction.
One limitation of this study is the lack of HUT and GET results for normal adolescents. Another limitation is the small number of subjects who underwent both HUT and GET, thus qualifying for our review. Although this group did not provide a representative sample of this population, the study is beneficial as preliminary data to direct further prospective studies that will examine the relationship between autonomic dysfunction and GI symptoms.
In summary, both GI symptoms and abnormal motility findings on GET are not predicted by the extent of postural tachycardia. Furthermore, none of the common symptoms of orthostatic intolerance or GI symptoms were predictive of tachycardia on HUT. Case-control prospective studies need to further examine the usefulness of other diagnostic tests in determining the underlying pathophysiology related to these disorders. Further tests should also examine the effectiveness of various treatment options. Specifically, it is recommended that further studies attempt to better define pediatric and adolescent POTS and to continue to investigate the relationships between GI function and orthostatic intolerance.
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Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
Orthostatic intolerance; Autonomic dysfunction; Postural orthostatic tachycardia syndrome; Nausea; Gastric emptying