Treatment
In patients with OH with no apparent reversible cause, there is now established evidence to support the use of several different management strategies. In addition to the use of nonpharmacological management strategies, such as the use of lower-limb compression hosiery and physical counter-maneuvers, evidence to support the use of pharmacological antihypotensive agents is also available. The importance of lifestyle advice and patient education cannot be overlooked in this patient group. While extensive discussion of these areas is beyond the scope of this article, it should be borne in mind that sufficient fluid intake and avoidance of ethanol intake, particularly with large meals should be highlighted to patients in order to prevent any postprandial hypotension that may contribute to syncopal symptoms.
Caution should be exercised when interpreting results of individual studies examining pharmacolocgial treatment options for OH, as much of the evidence for individual drugs exists in the form of open uncontrolled trials and small case series, although double-blind placebo-controlled trial evidence is increasingly becoming available.[11] In addition to this, several different end points have been measured as being representative of a positive response to treatment, making evaluation of efficacy across different trials, for any given treatment, difficult. Concern over which BP cut off should be used, and over the inconsistent relationship between symptoms and observed BP changes, has led to the increasing use of symptom scores and validated clinical scales.[12] These are now being recorded, in combination with BP changes, as end points in clinical trials, rather than measuring BP changes alone.
In the clinical setting, treatment of OH should be preceded by an assessment of volume status and examination of medications for each individual patient. The propensity of medications such as α-blockers, calcium channel blockers used in combination with diuretics and older shorter-acting ACE-inhibitors to cause OH have been well described. Management of OH, however, often remains difficult because of the heterogeneity of the underlying pathophysiology, and because of the frequent coexistence of hypertension, particularly in older individuals.[13] Another limiting factor is lack of head-to-head trials of individual antihypotensive drugs, or between pharmacological and nonpharmacological treatments. Withdrawal, where possible, of medications with a particular tendency to exacerbate symptoms of OH by causing a relative volume contracted state, in the case of diuretics or through α-adrenoceptor antagonism, as seen with antihypertensive agents, such as doxazocin or prazocin, is a key component in initial patient assessment. Bearing in mind the potential underlying pathophysiological processes contributing to OH, pharmacological agents can also be used to improve symptom control in affected patients, principally after hypotension-predisposing drugs have been withdrawn and symptoms have persisted. Individual drugs used in the treatment of OH are now discussed, subcategorized by the principal mode of action involved in attenuating orthostatic symptoms.
Agents Acting on Blood Volume
Several different 'volume-expanding' agents have been used to treat OH or to improve orthostatic tolerance. Mtinangi and Hainsworth have reported the use of oral salt to improve orthostatic tolerance in patients with syncope.[14] A total of 12 young adults with syncopal histories and proven abnormal responses to head-up tilting had plasma volume changes, orthostatic tolerance changes and baroreceptor sensitivity changes documented before and after 'salt-loading'. Patients with low 24-h urinary sodium excretion, (<170 mmol in 24 h), showed increased plasma volume, normalized baroreceptor sensitivity and improved orthostatic tolerance to head-up tilting after receiving 120 mmol NaCl for 7 days. To date, no comparable study in older adults has been reported. Although there may be some significant pathophysiological differences between older and younger adult patients with syncope, it appears reasonable to speculate that older adults may also benefit from treatment with oral salt. However, physicians should keep in mind the need for close monitoring during its administration in order to ensure fluid overload and electrolyte abnormalities do not occur.
Fludrocortisone has been studied in many small, uncontrolled trials and has been shown to prevent tilt-induced syncope.[15] The introduction of fludrocortisone preceded evidence-based medicine and rigorous interrogation in clinical trials. Therefore, much of the emergence of use of the drug is based on clinical experience. Laterally, its effect on plasma volume and systemic vascular resistance has been studied by van Lieshout, and found to be beneficial on both parameters.[16] Fludrocortisone has also been shown to increase blood vessel sensitivity to circulating catecholamines.[17] Treatment is initiated with a 0.1-mg tablet and can be increased to 0.3–0.5 mg daily,[18] although many clinicians would not favor exceeding the 0.3-mg dose. It may be more prudent to ensure an increased salt intake with lower doses of fludrocortisone, rather than increasing the fludrocortisone to the maximum dose. Unfortunately, treatment may be limited by supine hypertension due to an increase in peripheral vascular resistance.[19] Other side effects include hypokalemia, often requiring potassium supplementation, headache and, rarely, congestive cardiac failure.
Vasopressin analogues may be used to supplement volume expansion. In some cases of autonomic failure there is interruption of the normal arginine–vasopressin circadian rhythm resulting in an increase in nocturnal urinary excretion.[20] Desmopressin (DDAVP), a synthetic vasopressin analogue acts on renal tubular vasopressin-2 receptors, diminishing nocturnal polyuria, weight loss and reduces the morning postural fall in blood pressure. DDAVP may be delivered as a nasal spray (5–40 µg) or orally (100–800 µg) at night.[21] Side effects include water intoxication and hyponatremia, but lower doses of the intranasal preparation may be adequate to attenuate the nocturnal diuresis without causing unacceptable adverse events.[22] In practice, however, DDAVP tends to be used less frequently than either midodrine of fludrocortisone. This may relate to concerns regarding development of serum sodium abnormalities. Unfortunately, the lack of direct clinical trial evidence in this area makes it difficult for clinicians to make informed decisions regarding appropriate medication use.
Pressor Agents
Drugs that produce their principal antihypotensive action by increasing SVR can be classified into those that act at efferent presynaptic adrenergic neurons, those that act at efferent postsynaptic adrenergic receptors and those that act by impeding peripheral vasodilatation.[23]
Agents that act directly at postsynaptic adrenergic receptors include clonidine and midodrine. Although animal model experimental evidence suggests that potentially beneficial hemodynamic effects may be associated with administration of clonidine, it is rarely used in clinical practice.[24] Midodrine is the most widely used and well-studied pharmacological antihypotensive agent, with 41 clinical trials indexed in the PubMed database. Its principal metabolite, desglymidodrine, acts in arterioles and veins at α1 receptors to produce vasoconstriction.[25] It does not cross the blood–brain barrier and, therefore, tends not to cause CNS adverse effects. A larger multicenter, placebo-controlled trial reporting on its efficacy was published in 1997.[26] A total of 171 patients were randomized to receive either 10 mg of midodrine three times a day, or placebo, for 6 weeks. The patients studied formed a relatively heterogeneous group (40 had multiple system atrophy, 37 had primary autonomic failure, 37 had autonomic neuropathy secondary to diabetes mellitus, 19 had OH related to idiopathic Parkinson's disease, 29 had 'miscellaneous causes'). The midodrine group had a significant increase in systolic BP compared with the placebo group, with a mean increase of 21 mmHg. Symptom scores were significantly better in the midodrine group by week 2 of treatment. Concomitant use of compression stockings or fludrocortisone did not affect BP changes or symptomatic outcomes in the midodrine group.
Midodrine should not be used in patients with a history of stroke or transient ischemic attack. In our view, midodrine is only suitable for patients who have had careful characterization of their BP (24-h ambulatory monitoring) and are known to be normotensive when seated or standing. It is available in the UK on a named-patient basis and is licensed for the treatment of OH. It is more widely used in North America and continental Europe. Treatment is titrated from 2.5 mg three-times daily to a maximum dose of 10 mg three-times daily depending on patient response. Most notably, midodrine can cause supine hypertension and, therefore, careful timing of administration is paramount. Midodrine has a half-life of 3.5 h, with the peak effect of this agent occurring 1 h post-administration.[27] Therefore, it should be avoided in patients close to time of recumbency, especially in individuals with nocturnal hypertension evident on 24-h ambulatory blood pressure monitoring. Correlation of dose timing with particular periods of symptom exacerbation is essential, for example, on getting out of bed in the morning or following main meals.
Another notable side effect of midodrine, particularly in an older adult men, is its propensity to precipitate acute urinary retention. On balance, it is probably best avoided in patients with a significant history of obstructive prostatic symptoms.
Drugs that Impede Peripheral Vasodilatation
Octreotide is a long-acting analogue of somatostatin that produces vasoconstriction in splanchnic blood vessels.[28] Subcutaneous administration of octreotide has been investigated in animal models of orthostatic hypotension. It failed to modify hemodynamic responses to head-up tilt.[29] Two small studies, however, have shown some benefit in patients with OH secondary to insulin-dependent diabetes mellitus,[30] and in multiple-system atrophy.[31] Its use in clinical practice is often limited by the need for subcutaneous injection and gastrointestinal side effects, particularly abdominal cramping. Although it has shown benefit in insulin-dependent diabetics, this group of patients seem particularly susceptible to the gastrointestinal side effects of octreotide.
The combination of a pressor agent and an agent that impedes peripheral vasodilatation has been studied in a randomized, double-blind, controlled trial.[32] Hoeldtke et al. compared treatment of OH with midodrine, octreotide or both. Standing time (i.e., the number of minutes subjects could stand before hypotensive symptoms or OH) was recorded as the primary end point of the trial. The combination of midodrine and octreotide was found to be more potent than either drug used on its own. Octreotide is administered subcutaneously commencing at 25–50 µg.
Droxidopa (L-DOPS) is a prodrug of norepinephrine, metabolized by aromatic L-amino acid decarboxylase to norepinephrine. In patients with depleted levels of norepinephrine, L-DOPS serves to increase peripheral norepinephrine levels, thus enabling the body to maintain blood pressure during standing. L-DOPS is currently being studied in Phase III trials in the USA, Canada, Australia and throughout Europe.[33]
Other Agents
Finally, a number of other pharmacological agents have been identified in studies, but in the absence of further clinical trial data, inadequate evidence exists to warrant their incorporation into treatment guidelines. They include ephedrine, which acts on α- and β-adrenergic receptors and may have use in central lesions such as medial septal area. Yohimibine, an α2-adrenoceptor antagonist with central and peripheral effects, has been used in refractory OH.[34] Dihydroergotamine (DHE), a direct α-adrenoceptor agonist stimulating constriction of venous capacity vessels, has shown limited benefit but may be used in severe OH.[35] Erythropoietin is recommended in anemic patients. It corrects the normochromic normocytic anemia that frequently accompanies automic failure and improves standing blood pressure and, thus, orthostatic tolerance in patients with OH (Table 1).[36]
