Orthostasis, the Autonomic Nervous System, and Abdominal Pain in Children: Is There a Relation Between Postural Orthostatic Tachycardia and Recurrent Abdominal Pain?

The types of patients different subspecialists jointly manage often provide insights regarding shared pathophysiology and common treatment strategies. During the past decade, as cardiologists have increasingly recognized the subset of adolescents with multiple somatic symptoms and marked orthostatic tachycardia, our gastroenterology colleagues have started recognizing similar symptom complexes in teens with functional gastrointestinal disorders. PATHOPHYSIOLOGY OF POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME (POTS) The orthostatic shift, from supine to upright, represents an elegant homeostatic system. With standing there is prompt venous pooling of several units of blood. A feedforward circuit senses this using baroreceptors and via the nucleus tractus solitaris modulates both parasympathetic withdrawal and sympathetic activation. Together these changes result in peripheral vasoconstriction, increased cardiac inotropy, and a modest increase in heart rate that rapidly damps to near-baseline levels. Experimental data from a variety of sources have demonstrated that the homeostatic system is best viewed as a complex engineering system that has multiple sensors, amplifiers, and interactions. Each of these has a gain (slope of response) and a time constant (delay in response). Like any such engineering system the response oscillates, typically within a stable operating range. Syncope, or fainting, represents a failure of this operating system (1,2). A reasonable analogy is a stereo with the volume higher than the system can handle. After a period of distortion, the circuit breakers turn off to protect the overall system. With syncope there are 2 classically recognized patterns, the cardioinhibitory pattern most apparent in the pauses seen in needle phobia and a vasodepressor pattern characterized by acute loss of peripheral resistance. Not surprising, most common faints are a combination of these 2 normal, although exaggerated, physiological responses. These episodes of neurally mediated syncope are common. At least 20% of adults report having fainted. The incidence appears to peak in the teen years, with a marked female predominance. There is a typical prodrome, which correlates with exaggerated swings in heart rate and blood pressure. During this period, which can last minutes, patients report lightheadness, warmth, weakness, and more than half report nausea. They become pale and collapse; while they regain consciousness quickly, they have residual symptoms of fatigue, headache, and often other symptoms for minutes. There are often obvious triggers of prolonged standing, acute illness, and stress. This syndrome is well recognized by clinicians. POTS is a variant of neurally mediated syncope recognized by a marked (30–40 bpm) increase in heart rate either during a formal head-up tilt test (HUTT) or during 3- to 10-min stand tests in the office. Originally described in young adult women by Low and colleagues at the Mayo Clinic, the clinical syndrome is characterized by multiple somatic symptoms, similar to the prodrome and residual symptoms of a common faint. Like syncope patients, nearly 50% of patients have significant gastrointestinal symptoms (3,4). A majority of these patients do not faint, probably because of a combination of their compensatory tachycardia and because they have learned sufficient additional adaptive techniques. Although the precise pathophysiology of POTS remains obscure, there are a number of insights that inform our current understanding. Julian Stewart, a cardiologist at New York Medical College, has done the most systematic evaluation of adolescents with POTS. The critical observations have been excessive venous pooling not just in the legs but also in the pelvic and splanchnic venous compartments, with marked decrease in the thoracic blood pool (5). Despite the brisk heart rate increase, which succeeds in maintaining mean arterial blood pressure, there are at least transient declines in cerebral blood flow velocity, in part mediated by hypocapnea and relative hyperventilation. The majority of the data suggest that despite this shift in cerebral blood flow velocity and cerebral oxygenation, cerebral autoregulation remains intact. Similarly, despite the exaggerated sympathetic activation, most measures of baroreflex integrity are normal. There are variable neuroendocrine correlates. Many have decreased blood volume, although paradoxically they have normal plasma renin and low serum aldosterone (6). In addition, there is at least a subset of patients with increased angiotensin II and decreased cutaneous nitric oxide suggesting endothelial dysfunction (7,8). This pattern is different either from the acute but self-correcting heart rate increase seen in many adolescents and adults immediately upon standing, and from the steady loss of blood pressure seen in acute volume depletion or in adults with neurally mediated hypotension. ETIOLOGY AND DIFFERENTIAL DIAGNOSIS POTS, by definition, implies that the orthostatic tachycardia is an idiopathic disorder neither associated with a systemic autonomic neuropathy nor with a global medical condition. There are a number of systemic disorders that include significant orthostasis (Table 1). Malnutrition and anorexia nervosa probably represent the most relevant part of this differential diagnosis in teenagers. Rapid weight loss, even while maintaining a reasonable body weight, can exacerbate symptoms. In contrast to many of the primary autonomic disorders, baseline baroreflex function is normal in patients with POTS. Although a brief screen for systemic disease is warranted, a general physical examination, hemogram, and serum chemistries and probably thyroid screen give a relatively comprehensive initial screen. Despite some incidence of low-grade palpitations (typically hard and not rapid heart beats), there is remarkably little overlap with true cardiovascular disease or arrhythmias.TABLE 1: Diseases with high frequency of autonomic symptomsRECOGNIZING AND DIAGNOSING POTS The diagnosis of POTS is relatively straightforward and does not preclude other diagnoses. At its most basic, POTS is the observation that there is an exaggerated orthostatic heart rate increase, typically 30 bpm during orthostatic vital signs, and 30 to 40 bpm or heart rate >120 bpm 6 min into a 60° to 70° HUTT. For an adolescent, changes of <30 bpm during either of these evaluations are likely physiological. In addition, there should be some presence of typical orthostatic symptoms, although teens may have a difficult time articulating precise symptoms. Screening patients with a brief review of symptoms and formal orthostatic vital signs (supine heart rate and blood pressure that is repeated at 3 minutes; heart rate and blood pressure 1 and 3 minutes after standing) can be done relatively quickly in a busy office environment (Table 2).TABLE 2: Rapid clinical screen for orthostatic disordersFurther diagnostic testing (Table 3) is probably not required to consider the diagnosis and initiate therapy. In the author's practice, testing is largely reserved for patients (or physicians) refractory to initial therapy. HUTT deserves specific attention. Conceptually simple, patients are outfitted with monitoring that includes at least continuous heart rate and intermittent blood pressure. Additional monitoring used in specialized laboratories can include impedence cardiography, cerebral artery Doppler, venous capacitance, end tidal CO2 and more continuous arterial pressure monitoring. Once instrumented, patients are tilted up to 60° to 70° and observed for 6 to 30 minutes. Patients often find the test intolerable. Prolonged (longer than 16 minutes) and steep (>70°) tilts may have up to a 40% incidence of physiologically positive faints in adolescents (9,10). It can be particularly challenging to identify nonoverlapping patterns with even more complicated autonomic testing in adolescents, in part because they have a developmentally maximal amount of sinus arrhythmia and high levels of physiological orthostasis. Using an extensive battery of provocative HUTT testing and subsequent analysis, the author and colleagues evaluated patients with complex regional pain syndrome, who have a high frequency of autonomic symptoms and signs, and the only reliable difference between controls and between pre- and posttherapy visits was the presence of orthostatic tachycardia (11).TABLE 3: Diagnostic testing for postural tachycardia and autonomic function in the patient with POTSMost tests have been tried in systematic evaluations in which, despite limitations, they can provide useful physiological insights. In this setting shallow tilt angles can distinguish patients with chronic fatigue from age-matched controls (12). More comprehensive autonomic testing batteries can identify abnormalities missed in rapid clinical screens (13,14). Referral and ascertainment bias further complicate interpretation of data regarding links between orthostasis and other complaints. Although adolescents with sufficient disability to be labeled as having chronic fatigue syndrome do have a high incidence of orthostatic findings (both by tilt and examination), comparison of cohorts of adults with chronic fatigue to controls has not suggested a high incidence of orthostatic findings. Chronic pain, decreased activity, malnutrition, medications, and psychological concerns may increase either the symptoms profile or exacerbate some of the physiology. THERAPY OPTIONS FOR POTS Because the primary findings, heart rate and blood pressure, are readily measurable, the cardiovascular autonomic responses can be targeted for therapy. The natural history of POTS includes a relatively high frequency of spontaneous recovery for 2 to 3 years, which complicates judging any therapy. The foundation of therapy (Table 4) starts with nonpharmacological approaches that overlap with therapies for many chronic pain syndromes. This approach includes doing regular weight-bearing exercise, getting adequate sleep and hydration, considering the wearing of compression stockings to decrease peripheral venous pooling, and coaching patients on active antigravity maneuvers to augment blood pressure during postural change. Subsequent drug therapy is imperfect. The mineralocorticoid fludrocortisone, intended to increase blood volume, is the historical choice. Although a generally accepted therapy, there are no double-blind placebo-controlled trials supporting its use. Direct pressor agents, primarily midodrine hydrochloride, can rapidly increase afterload and decrease symptoms in well-designed studies. They require frequent dosing and an engaged patient. Well-designed but small studies have effectively used the peripheral muscarinic blocker pyridostigmine to enhance parasympathetic effects. Serotonin reuptake inhibitors have anecdotal data supporting their use, even in the absence of concomitant depression (15,16). Beta-blockers, although popular, have failed most controlled trials. Anecdotal data for other agents have not been systemically studied or embraced. Although not evaluated specifically for POTS, cognitive behavioral therapy is an accepted part of managing refractory syncope and patients disabled by chronic fatigue. Low doses of tricyclic antidepressants such as amitriptyline used for chronic pain do not seem to have significant cardiac side effects in most people.TABLE 4: Therapy choices for syncope and postural tachycardiaCONCLUSIONS POTS is a relatively chronic, idiopathic disorder of adolescents and young adults that may include abdominal symptoms. A rapid office screen of orthostatic vital signs and focused review of symptoms is likely to accurately identify at least a subgroup of recurrent abdominal pain patients who also have POTS features. Accurately characterizing what role POTS plays in these patients will likely require a series of systematic investigations, both with simple and more complicated physiological probes, and with controlled therapeutic approaches. There are not yet sufficient data to understand how much overlap there is between the cohorts of patients with recurrent abdominal pain and those with POTS (17).