Version August 2025
COMMENT —
Orthostatic hypotension due to autonomic neuropathy is defined as a sustained fall in systolic blood pressure (decrease of ≥20 mmHg) or diastolic blood pressure (decrease of ≥10 mmHg) within three minutes of standing up [1]. The fall in blood pressure reflects failure of vasoconstriction in the splanchnic and peripheral vascular beds. The severity of symptoms varies from patient to patient. The symptoms may be exacerbated by prolonged standing or exposure to heat, insulin therapy, or meals. In severe cases, progression may be evaluated by assessing the patient's ability to stand, to get from bed to bathroom, or to walk from room to room. Many of these patients become bound to bed or wheelchair and may require care in a chronic care facility. Thus, a systematic approach to therapy is necessary.
It is essential to determine whether the signs and symptoms of orthostatic hypotension are caused or exacerbated by volume depletion or a medication before prescribing pharmacologic agents to treat this problem. Volume depletion may be due to suboptimal glycemic management, a diuretic agent, or another cause. Offending medications include antihypertensive agents, tricyclic agents, some selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, dopamine agonists, and alpha-receptor blockers such as those that are used for the treatment of bladder outlet obstruction. If one or more of these factors is causal or contributory, then the likelihood that any pharmacologic intervention will be successful is reduced, and the situation will be confounded.
Once volume depletion and the contribution of one or more medications have been addressed, the next step in treatment is expansion of the extracellular fluid volume. Fludrocortisone 0.05 to 0.2 mg a day and a high salt diet are appropriate, although the data in support of this approach are limited and of poor quality [2]. This approach is only sometimes effective. This may reflect the fact that autonomic orthostatic hypotension is due not only to pooling of volume in the lower extremities but also to splanchnic vasodilatation, which is not addressed by expansion of the extracellular fluid volume. Side effects include hypokalemia, peripheral edema, and supine hypertension. This consultant limits doses to 0.2 mg a day. While higher doses are sometimes recommended, there is no evidence that they are effective, and they may be associated with a higher incidence of side effects. (See "Treatment of orthostatic and postprandial hypotension", section on 'Fludrocortisone'.)
When, as is often the case, the above interventions are not effective, midodrine (an alpha-1 selective adrenergic agonist) may be helpful in increasing upright systolic blood pressure readings and in alleviating symptoms [3-6]. The usual dose is 10 mg by mouth three times a day. Midodrine, a prodrug, and its active metabolite desglymidodrine are excreted in the urine. In the presence of kidney disease, it is prudent to start with a dose of 2.5 mg three times a day. The duration of action is four hours [4], so patients should be cautioned about loss of effect between doses, especially at night, and doses should be coordinated with the patient's daily routine. (See "Treatment of orthostatic and postprandial hypotension", section on 'Midodrine'.)
Supine hypertension may exist in association with autonomic orthostatic hypotension, related to impaired baroreflexes and loss of postural regulation of blood pressure [1]. It is also a potentially serious adverse effect of midodrine. Elevation of the head of the bed relieves this problem in many patients. Other side effects of midodrine include urinary retention, paresthesias, piloerection, and pruritus. Midodrine is contraindicated in patients with severe heart disease, uncontrolled supine hypertension, acute kidney disease, urinary retention, and hyperadrenergic states such as thyrotoxicosis and pheochromocytoma.
Other agents are sometimes effective in this setting. Beta-adrenergic antagonists may be helpful. Their efficacy may reflect inhibition of beta-adrenergic vasodilatation and persistence of alpha-adrenergic vasoconstriction. They do not cause supine hypertension. Octreotide may also be effective. Unlike other agents, it causes vasoconstriction in the splanchnic bed. A plethora of other agents are sometimes recommended or utilized for symptomatic autonomic orthostatic hypotension based on evidence of low quality. The large number of agents in this category bespeaks the lack of consistent benefit from any one of them.
The goal of therapy is the elimination of symptoms. Complete correction of the orthostatic fall in blood pressure is not usually possible or necessary. For each patient, there appears to be an upright systolic blood pressure above which symptoms do not occur.
In the patient under consideration, symptoms of orthostatic hypotension were resolved by cessation of an alpha-1 adrenergic antagonist and a diuretic. The upright systolic blood pressure rose to a level where the patient no longer had symptoms. The persistence of an orthostatic fall in blood pressure probably reflects an underlying diabetic autonomic neuropathy, the effects of which were exacerbated by the use of these medications.
