Orthostatic intolerance (OI) is a term used to describe symptoms associated with a maladaptive circulatory response to upright posture (1,2). Two of the more common forms of OI are postural tachycardia syndrome (POTS) and neurally mediated hypotension (NMH). POTS is characterized by the development of an abnormally elevated heart rate within 10 minutes of standing or during upright tilt testing, which is associated with symptoms of impaired cerebral perfusion (3,4). NMH (5), also known as vasovagal or neurocardiogenic syncope, is characterized hemodynamically by a decrease in blood pressure after a variable period of quiet upright posture without an increase in heart rate. Associated symptoms include lightheadedness, visual disturbances, impaired cognition, fatigue and either presyncope or syncope. POTS and NMH are not mutually exclusive and often coexist in patients with OI (6,7).
It is estimated that over 500,000 Americans have some form of OI (8). Females are more commonly affected than males. The prevalence in children is unknown, as there have been no pediatric population-based studies. However, of children with otherwise unexplained syncope, 40% to 80% have an abnormal response to tilt testing, with a female to male ratio of 2:1 (9-12). The pathophysiologic mechanisms underlying POTS and NMH are not completely understood and are probably heterogeneous. In both conditions, upright posture is associated with pooling of blood in the dependent extremities and splanchnic circulation with resultant thoracic and cerebral hypoperfusion. At presentation, these patients often complain of lightheadedness, fatigue, nausea, difficulty thinking, chest discomfort, palpitations, headaches and syncope. Symptoms are made worse by quiet standing, and improve but do not always resolve on lying down.
Gastrointestinal (GI) symptoms have been described in patients with OI (3,13,14). Review of the pediatric literature identified two case reports (15,16) and one case series of eight patients (17) with autonomic dysfunction masquerading as functional abdominal pain. Treatment directed at the underlying OI led to complete resolution of symptoms in the two case reports. In this article, we describe a cohort of 24 pediatric patients whose chief complaints were gastrointestinal in nature and who were ultimately diagnosed with OI. Additionally, treatment of the OI resulted in improvement or resolution of the GI symptoms in the majority of patients.
MATERIALS AND METHODS
We reviewed the medical records of pediatric patients who had been referred to a pediatric gastroenterologist at the Johns Hopkins Children's Center and who also had an abnormal tilt table test between June 1996 and December 2000. The majority of the patients were evaluated during the last 2 years of the catchment period. Records were excluded if the patient had underlying cardiac, neurologic or other pathology to explain orthostasis. Patients reviewed did not have any definitive diagnosis referable to the gastrointestinal tract. They were referred from the gastroenterology clinic for tilt table testing if they had a history of chronic symptoms associated with OI such as lightheadedness or dizziness (particularly with changes in posture), fainting, headaches or fatigue. In general, the patients did not offer the clinical history of orthostasis, but rather these symptoms were elicited upon questioning. The referrals were equally distributed among seven staff pediatric gastroenterologists.
Head upright tilt table testing (TTT) was performed in a quiet room after at least a 4-hour fast. An intravenous catheter was inserted for administration of isoproterenol if needed. After orthostatic vital signs were obtained, patients were positioned supine on a tilt table with a footboard for weight bearing. Patients were maintained supine for a minimum of 10-15 minutes while heart rate and blood pressure were allowed to reach a steady state.
All patients were instructed to remain still, without movement of their feet, during TTT. Heart rate was continuously monitored during the procedure. Each patient's blood pressure was recorded in the supine position after 1 minute of tilt and thereafter at 5-minute intervals. The intermittent blood pressure was measured with an automatic sphygmomanometer with the arm positioned at the patient's side. During the test, patients were asked every 5 minutes to report any new or changing symptoms. If symptoms of severe light-headedness developed, the blood pressure was then recorded at 1-minute intervals.
A three-stage 70° TTT protocol was used. After the patient had been supine for 10 minutes, the table was tilted to 70° for 45 minutes (Stage 1). If hypotension was not observed, isoproterenol at a dose of 1 to 2 μg/min (titrated to achieve a 20% increase in heart rate) was infused for 10 minutes with the patient supine. The upright tilt was then repeated for 15 minutes (Stage 2). If this stage was tolerated, the patient was returned to the supine position and the dose of isoproterenol was increased to 4 μg/min. After the patient had been supine for 10 minutes, the upright tilt was repeated for 10 minutes (Stage 3). A test would be discontinued if requested by the patient, or if the patient developed NMH.
NMH was defined as syncope or presyncope associated with a drop in systolic blood pressure of more than 25 mm Hg from the baseline supine measurement with no associated increase in heart rate. POTS was defined as a 30 bpm increase in heart rate within the first 10 minutes of TTT or a heart rate of 120 bpm or greater during the same time period associated with orthostatic symptoms. The occurrence of POTS was not an indication to stop the TTT. Syncope was defined as a transient loss of consciousness and postural tone associated with spontaneous recovery. Presyncope was defined as a state of light-headedness usually associated with one or more of the following symptoms: decreased vision, sensation of hearing voices distantly, slow response to verbal stimuli, nausea, vomiting and loss of postural tone.
During the study period, 24 pediatric patients were evaluated by a pediatric gastroenterologist at the Johns Hopkins Children's Center before obtaining an abnormal tilt table test. In addition to their gastrointestinal complaints, when specifically asked, these patients gave a history of lightheadedness, dizziness, fatigue, headache or other symptoms associated with OI. Fifteen patients were female and nine were male. The mean age was 14.3 ± 2.4 years (range, 9-17 years).
The most common presenting symptoms were abdominal pain (71%), nausea (56%) and vomiting (50%) (Fig. 1). Additional gastrointestinal symptoms included diarrhea, weight loss, anorexia and heartburn. Eighty-seven percent of the patients had experienced gastrointestinal symptoms for more than 1 year and 48% had had symptoms for more than 3 years. Documentation was not available for most patients on the duration of orthostatic symptoms, although it in many circumstances the duration appeared to be of long standing.
Patients had undergone a median of 3 (range, 1-7) endoscopic and radiographic studies before the tilt table test. Approximately 92% of patients had undergone either upper or lower endoscopy. The most common radiologic procedures performed were upper GI series (60%), abdominal ultrasound (48%), and computed tomography of the abdomen (28%). Treatment with typical gastrointestinal medications such as gastric acid secretory blockers, antispasmodics and prokinetics had not led to symptom resolution. Fifty percent of patients had previously been referred to a psychiatrist or psychologist for evaluation and treatment of their gastrointestinal complaints before establishing the diagnosis of OI.
Based on TTT, four patients had isolated POTS, eight had both POTS and NMH, and 12 patients had NMH alone. Twenty-one of the 24 patients developed symptoms of hemodynamic instability before stage 3, with 17 of 24 symptomatic before stage 2 (Table 1). TTT reproduced the presenting gastrointestinal symptoms in 10 of 24 (42%) patients and in nine it occurred during stage 1 of the TTT. Of these 10 patients, six had NMH and three had both NMH and POTS.
After the diagnosis of NMH or POTS was made, consultation was obtained from a physician in our institution experienced in the treatment of OI. Clinical follow-up (mean, 33.2 ± 10.7 months) was available for 18 patients. Four patients experienced resolution of their symptoms with increased fluid and dietary salt intake alone. An additional nine improved when a medication was added. Of the patients who improved on medication, four received fludrocortisone and four received fludrocortisone plus sertraline and one midodrine. The doses used were typical of those used for patients with OI. Fourteen of the 18 patients (78%) experienced complete resolution of their GI symptoms when OI was treated.
Since Apley's first description of recurrent abdominal pain in children, our understanding of the origins of this chronic condition remains incomplete (18). Recent reports have demonstrated an association between functional abdominal pain syndromes and autonomic dysfunction (15-17). Our study is the first to describe in detail an association between a group of patients with chronic upper GI symptoms-particularly abdominal pain, nausea and vomiting-and OI.
The association between GI symptoms and OI is not unexpected in light of the concept that acquired autonomic dysregulation or dysautonomia is the cause of OI (19). Additional support for this concept comes from a study by Chelimsky et al., who described eight patients with recurrent abdominal pain who underwent extensive autonomic testing including a TTT. Of their eight patients, six were diagnosed with OI after TTT. Interestingly, seven of the eight were found to have generalized autonomic dysfunction restricted to the sympathetic branch (17). The authors hypothesized that unbalanced parasympathetic input to the gut might have caused intestinal dysmotility and pain in their patients. The connection between OI and intestinal dysmotility is strengthened by the observations of Darbari et al., who found abnormalities on antroduodenal manometry in 13 of 14 consecutive patients with TTT-confirmed OI (20). Effects on motility may be important throughout the GI tract, as an abnormal TTT was reported in three of five patients with OI and chronic constipation (21). Kelly et al. have also reported six patients whose refractory heartburn symptoms could be reproduced by upright tilt and who responded to treatment directed at NMH, suggesting that abnormal circulatory and neural responses might affect the esophagus as well (22).
Most of our patients had had GI symptoms for more than 1 year and almost half had had symptoms for more than 3 years before obtaining a diagnosis of OI. Before TTT, these patients had been seen by one or more gastroenterologists and had undergone multiple endoscopic and radiologic procedures that had not led to an organic diagnosis. The prolonged evaluations caused both patient morbidity and financial burden. Although we do not know when the OI symptoms developed in our patients relative to their GI symptoms, it is possible that the diagnosis of OI may have been delayed. Health care providers may not have questioned the patients specifically about symptoms of hemodynamic instability or, if they had obtained such a medical history, may not have regarded symptoms of fatigue or dizziness as particularly pertinent. Alternatively, patients may not have provided information about symptoms of hemodynamic instability because they may not have thought them to be important to the GI complaints or they may have felt that these more systemic symptoms were the result of their being chronically ill.
Children with chronic abdominal pain can experience impairment of daily functioning that is out of proportion to the observable pathology (23). Functional impairment is also found in patients with OI. In a group of young, primarily female patients with POTS, Benrud-Larson et al. (24) found that 25% were unable to work because of symptoms. Most reported pain, impairment in physical and social functioning and impaired general health. It is possible such functional manifestations coupled with chronic GI symptoms may have been the reason that half of our patient population had been evaluated or treated by a mental health specialist before diagnosis.
The treatment of OI includes both non-pharmacologic and pharmacologic therapy. Referral or consultation with an individual experienced in the management of OI is recommended. Mild to moderately affected patients may respond to simple avoidance of circumstances that bring on the symptoms and the use of pressure garments. Increasing salt and fluid intake is an essential component of successful therapy. More severely affected patients may require one or more medications such as fludrocortisone, beta-adrenergic antagonists, vasoconstrictor medications (stimulants or midodrine) or selective serotonin reuptake inhibitors. Of the 14 patients in this study who improved, 10 did so with increased fluid and salt intake and with fludrocortisone-therapies to expand the intravascular volume. Four patients improved with the addition of a selective serotonin reuptake inhibitor whose mechanism of action in this setting is not well defined.
We suggest that asking pediatric patients, particularly adolescents with chronic gastrointestinal complaints, about symptoms associated with OI may identify individuals that would benefit from TTT. Although this study does not prove causation, it does support an association between upper GI symptoms and orthostatic intolerance. Awareness of this association may facilitate an earlier diagnosis of OI, which may serve to minimize the cost and risk associated with the exhaustive evaluations performed in our patients. The validity of this study's results may be limited from the loss of specificity noted during stage 2 and, in particular, stage 3 of the TTT. There is evidence to suggest that sensitivity is increased at the expense of specificity when high-dose isoproterenol protocols are used in TTT (25). However, only three of 24 (12.5%) patients in this study required stage 3 to diagnose OI. Further work will be needed to define the prevalence of and predictive factors for positive tilt tests in patients with otherwise unexplained GI symptoms. A prospective study of patients with chronic upper GI symptoms and OI, incorporating more extensive autonomic testing, manometry and duplex Doppler of the mesenteric vasculature, could help determine whether autonomic dysfunction in this patient population is responsible for the GI symptoms.
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