Orthostatic Intolerance

When a syndrome has many different names, you can be sure of two things: first, it is common, and second, it is poorly understood. Such is the case with orthostatic intolerance, which, according to Dr. David Robertson, ¹ who has made a career of studying it and related conditions, has been given at least 18 different titles, including neurocirculatory asthenia, mitral valve prolapse syndrome, postural orthostatic tachycardia syndrome, and hyperadrenergic orthostatic tachycardia. It is now officially recognized as orthostatic intolerance (OI) by the American Autonomic Society. It may overlap with chronic fatigue syndrome. It is characterized by an exaggerated increase in heart rate (of more than 30 beats/minute) on standing with only a small decrease of blood pressure. This distinguishes it from orthostatic hypotension, which is defined by a fall of blood pressure of 20/10 mm Hg or more. Robertson has described it as an epidemic, ¹ not because its prevalence is increasing, but because it is common (in perhaps 500,000 Americans), although it is still not recognized by many practitioners. For reasons that are quite obscure, the syndrome is five times as common in women as in men, and typically presents between the ages of 15 and 45. It is actually not uncommon in children, and much of the research has been done by pediatricians.

As with other syndromes where the etiology is obscure, the symptoms are many and vague. They include lightheadedness, dizziness, anxiety, fatigue, and palpitations. A key feature is that all are made worse by the upright posture, and are relieved by lying down. This is an important point to remember when we are taking histories from our patients, because unless we specifically ask if such symptoms are related to posture, we may miss the diagnosis.

Da Costa ² first described the phenomenon of orthostatic tachycardia in soldiers of the Union Army during the US Civil War who were complaining of fatigue, dizziness, headache, and chest pain, noting that “the immediate effect of the exchange of position was most striking.” While it is easy to attribute these symptoms to stress and anxiety, several of the soldiers first developed their symptoms after a long march or an attack of diarrhea, suggesting that dehydration might have been a contributory factor. This condition was subsequently referred to as the Irritable Heart syndrome. During World War I, Sir Thomas Lewis ³ described the same set of symptoms as Soldier's Heart or the Effort Syndrome. He too noted the marked orthostatic tachycardia.

The principal signs and symptoms of OI are consistent with a failure to adjust the circulation to the upright posture, as if there were an inadequate blood volume. When we stand up, there is a sudden pooling of about 700 mL of blood in the abdomen and legs. ⁴ Our baroreceptor reflexes normally compensate for this very rapidly, and there is an increased heart rate, cardiac output, and vasoconstriction. If the autonomic nervous system is deficient, as in patients with idiopathic orthostatic hypotension, there is a gradual decrease of blood pressure until the brain is no longer adequately perfused and there is a gradual loss of consciousness. Patients with OI show an intermediate form of this phenomenon. The symptoms and physiologic manifestations of OI closely resemble those of the deconditioning which occurs after prolonged bedrest or spaceflight. ⁵ Some people with OI become so disabled by the condition that they drastically reduce their level of physical activity, such that the deconditioning may actually exacerbate their symptoms, and set up a vicious cycle.

Not only do patients with OI show an exaggerated tachycardia on standing, but also an exaggerated increase of plasma norepinephrine, and one of the diagnostic criteria is that norepinephrine while standing exceeds 600 pg/mL. The increase of heart rate on standing is normally mediated largely by vagal withdrawal, but tests of vagal function are usually normal in patients with OI, so the evidence points to an overactivity of the sympathetic nervous system. The big question here is whether it is the primary disturbance, or as seems more likely, it is an attempt to compensate for some defect of blood volume regulation. Thus in patients with mitral valve prolapse, a condition that has been associated with OI, ⁶ hemodynamic measurements are normal in the supine position, but when upright the stroke volume is lower than normal, suggesting some defect of venous return. Some patients compensate for this with an exaggerated increase of heart rate, while others show increased vasoconstriction.

The traditional explanation for OI is a defect in the regulation of the veins of the legs, such that there is excessive venous pooling during orthostasis. This was first demonstrated by Streeten, ⁴ who also showed that inflating antishock pants to prevent the venous pooling reduced the tachycardia. The idea that there might be a selective impairment of the autonomic innervation of the leg circulation to explain these findings has gained considerable supportive evidence. In patients who have true orthostatic hypotension and diffuse autonomic failure the sympathetic efferent nerves are damaged, and there is denervation hypersensitivity (an exaggerated response to circulating catecholamines). And in patients with OI it has been reported that the contractile response of the hand veins is normal, whereas the foot veins show hypersensitivity, which might be expected if they were denervated. ⁴

However, a recent study by Stewart ⁷ casts doubt on the idea that the venous circulation is to blame for OI. He took a group of adolescents with OI and measured arterial and venous hemodynamics in the arm and leg while supine and during tilting with strain gauge plethysmography. During head‐up tilt, the OI patients showed no changes in blood pressure measured in the arm, although they did show the usual excessive increase of heart rate. Where they differed from normal controls was what happened to the blood pressure in the calf: in the control subjects this increased by 31 mm Hg, the amount that would be expected by the increased hydrostatic pressure in the legs when upright, but in the OI patients this increase was only 21 mm Hg. This difference was attributed to a failure to increase the peripheral resistance of the leg circulation during tilting. In contrast, the pressure‐volume curves of both the arm and leg (a measure of venous capacitance) were the same in the OI patients and control subjects both while supine and during tilting. His conclusion was that the key abnormality is a blunted arterial vasoconstriction, and that the veins were behaving normally. As an aside, one of the refreshing features of this paper was that it was written in the first person—it is unfortunately rare these days to read in an original scientific paper statements like “I studied 15 patients…” and “I think…” Given the heterogeneous nature of OI, it may be that there are different mechanisms in different patients.

The renin‐angiotensin system has also been implicated. It has been observed that patients with OI have inappropriately low plasma renin activity; renin release is normally stimulated by the upright posture, mediated by the effect of sympathetic nerves going to the kidneys, suggesting that there may be partial renal denervation in OI. A wide variety of other abnormalities have been reported which could contribute to OI, and include a reduced plasma volume, reduced red cell mass, and circulating vasodilators (bradykinin and dopamine). These have recently been reviewed by Jacob & Biaggioni. ⁸ There may be genetic abnormalities underlying OI: one patient has been described who had an excessive increase of norepinephrine on standing that could be attributed to an abnormality in the norepinephrine‐transporter gene that resulted in impaired clearance of norepinephrine from the circulation. ⁹

There is even an animal model of OI, which was produced by partial chemical sympathectomy using 6‐hydroxydopamine. ¹⁰ This was done in rats, which admittedly in the normal course of events do not stand on their hind legs. Nevertheless, there was an initial fall of blood pressure, which then rose to be slightly lower than the control level for the duration of the study. There was also an increase of heart rate, which also persisted, and could be blocked by propranolol. The authors argued that this model is consistent with the human situation of postural tachycardia being the result of a partial impairment of sympathetic outflow.

Treatment of OI represents a real challenge. Two general strategies are to try to increase blood volume and to promote vasoconstriction. An interesting new discovery is the effect of drinking water. In patients with autonomic failure who have orthostatic hypotension a drink of water helps to prevent the fall of blood pressure that occurs on standing up, while in healthy subjects it has no effect. ¹¹ It also helps in patients with OI. Unfortunately, there are no randomized trials to guide us in our choice of treatments. Volume expansion can be promoted by increasing salt intake and fludrocortisone. However in reality it has been found that fludrocortisone does not increase the blood volume for more than a few days, and may act by potentiating the effects of adrenergic stimulation. Erythropoietin injections given to increase red cell mass have been found to be effective in patients with orthostatic hypotension and autonomic failure, but are costly and inconvenient, and whether they are effective in patients with OI is unclear. ⁸

The use of drugs that affect the sympathetic nervous system is also an issue that is confusing. ⁸ Some experts have advocated the use of drugs that inhibit central sympathetic outflow, on the grounds that increased central sympathetic outflow will tend to reduce blood volume over the long term (as happens in patients with a pheochromocytoma, for example). Clonidine and methyldopa have both been advocated, but without convincing evidence that they actually work. Another, and contradictory, approach has been to use sympathomimetic drugs such as midodrine and phenylpropanolamine. Midodrine is a short‐acting adrenergic stimulant that is quite effective in maintaining blood pressure in patients with orthostatic hypotension. Beta blockers have also been advocated for use in patients with OI, but as with all the other drugs, evidence for their effectiveness is lacking.

The confusion surrounding the nomenclature, symptoms, and treatment of OI suggest that it is most probably not a discrete entity with a single cause awaiting discovery. Perhaps essential hypertension is a good analogy here: so far as we know, there is also no single cause, and no sharp dividing line between those who have it and those who don't. In addition, psychologic factors have a major influence in the diagnosis of hypertension, as in patients with white coat hypertension. OI is probably also the result of multiple factors, both physiologic and psychologic. Although it is difficult to treat, it certainly deserves wider appreciation, and patients who suffer from it should not just be written off as being anxious or neurotic.