Approach

The goal of treatment is to improve symptoms and quality of life by increasing standing blood pressure to a level that does not cause symptoms of cerebral hypoperfusion, and to prevent falls and morbidities associated with orthostatic hypotension (OH). It is important to treat symptoms rather than blood pressure levels.[29][38]​​​ OH can be effectively treated with a combination of pharmacological and non-pharmacological interventions.[39][40]​ However, anti-hypotensive drugs frequently worsen supine hypertension, and most are recommended based upon expert opinion with limited evidence supporting their use.[41]

Elimination of aggravating factors

Medications that induce or aggravate OH (e.g., alpha-blockers, central sympatholytics such as tizanidine or methyldopa, tricyclic antidepressants, phosphodiesterase-5 inhibitors, beta-blockers) should be carefully reviewed and eliminated, if appropriate.[15][18][38]​​​​ As ‘bladder-selective’ alpha-blockers, such as tamsulosin, can aggravate OH in older men, this in turn may increase the risk of hip fracture.[42][43]

Orthostatic hypotension in hypertensive patients

Hypertension is a risk factor for OH, and both conditions commonly co-exist in older patients. Although certain antihypertensive agents can trigger or worsen OH, complete withdrawal of antihypertensives is not appropriate as this will lead to pressure diuresis and worsening of OH. One meta-analysis found that effective antihypertensive treatment is possible without worsening of OH.[44]

Three particular patterns of hypertension are most closely associated with OH: white coat effect, nocturnal hypertension, or non-dipping (absence of normal drop in blood pressure while asleep), and morning hypotension (thought to be caused by the transient effect of pressure diuresis driven by supine hypertension overnight).[15]

For hypertensive patients with co-existing OH, it is important to individualise the approach, and first characterise the patterns, triggers and cause, as this will vary markedly between patients. Non-pharmacological approaches are always first-line, as is optimisation of non-antihypertensive drugs.[15]

Judicious use of antihypertensives (e.g., ACE inhibitors, angiotensin-II receptor antagonists) and avoiding agents likely to cause OH (e.g., alpha-blockers, central sympatholytics, beta-blockers) is recommended.[15][18]​​

Pharmacological treatment of OH for hypertensive patients is challenging because we are, by turns, trying to both lower and raise their blood pressure according to the relevant circumstance.

Lifestyle changes

Patients should first sit when going from a supine to a standing position. Straining during bowel movements or performing Valsalva-like manoeuvres during isometric exercise may significantly reduce venous return to the heart and worsen OH, leading to syncope. Constipation should therefore be treated aggressively. Eating frequent, small meals is often effective in lessening postprandial blood pressure falls. Patients should be aware that hot environments lead to cutaneous vasodilation to dissipate heat and may worsen OH.

Patients should liberalise their dietary salt intake or use sodium chloride tablets with each meal and drink at least 2 litres of water a day.[29] ​Tilting the head of the bed up during the night, by inserting blocks 15-22 cm (6-9 inches) high under the headposts, reduces overnight sodium and water excretion by the kidney and lessens OH in the morning. Another effective strategy is to rapidly drink 500 mL (16 oz) of tap water, as a fluid bolus, in 3-4 minutes. This can be used as a rescue measure for patients who are symptomatic on standing, and takes effect within 5-10 minutes, peaking at 30 minutes. This is thought to be a sympathetic reflex induced by the hypotonicity of the water rather than a volume effect.[15]

Physical measures

The use of physical counter-manoeuvres when upright, such as leg-crossing, standing on tiptoes, and muscle tensing, increases venous return to the heart and enhances orthostatic tolerance. Custom-made full-length elastic stockings can be useful in preventing pooling in the lower extremities but can be difficult to use. An abdominal binder may be as effective as a vasopressor, and can be tried first.[45][46]

More research is needed to define the efficacy of non-pharmacological interventions in the management of OH.[47]

Short-acting pressor agents

Only two medications are approved for the treatment of OH: midodrine and droxidopa. Evidence for the use of fludrocortisone is weak, as it increases supine more than standing blood pressure, and it is contraindicated in the presence of heart failure - a common comorbidity in patients with OH.[15]​ Droxidopa and fludrocortisone are discussed separately below.

When non-pharmacological measures are not sufficient to alleviate symptoms, short-acting pressor agents are used. These agents are certainly first-line for patients with hypertension or heart failure, and are now generally used first-line in all patients.[38][48]

Vasoconstrictor agents such as the selective alpha-1-adrenoreceptor agonist midodrine increase blood pressure and improve symptoms of OH.[38] Adverse effects of midodrine include pilomotor reactions, pruritus, supine hypertension, and urinary retention.[49]

Pyridostigmine, an acetylcholinesterase inhibitor, is used in the treatment of OH.[50] It has modest pressor effects, and is often used in combination with midodrine. It is arguably, the safest drug to use for OH in hypertensive patients as it is engaged only during the sympathetic activation that occurs while upright to selectively increase upright blood pressure without worsening supine hypertension. However, overall evidence is limited, and it may not be effective in severely affected patients.[15]

The noradrenaline-reuptake inhibitor atomoxetine can acutely improve upright blood pressure and ameliorate symptoms in some patients, but long-term efficacy has not been demonstrated.[51][52]

Pressor agents are best given on an as-required basis, within the prescribed daily frequencies, taken 30-45 minutes before upright activity or meals (according to the precipitating factor for an individual patient), and their effect lasts for 2-3 hours.[38]​ They should be avoided before bed.

Droxidopa

Droxidopa is a prodrug that is converted to noradrenaline (norepinephrine) in the body (by the same enzyme that converts levodopa to dopamine).[53] It is an alternative option to short-acting pressor agents. Droxidropa increases blood pressure, with a peak effect about 3 hours after administration, and improves symptoms associated with OH. Droxidopa has been approved by the US Food and Drug Administration (FDA) for the treatment of neurogenic OH, based upon randomised controlled trials (RCTs) demonstrating symptom improvement after 1 week of treatment.[54][55]​​ A post-marketing study to determine persistence of effects is ongoing.[56]​ It may not be available in countries outside the US.

Mineralocorticoid therapy

In non-hypertensive patients in whom non-pharmacological measures do not achieve the desired result, consideration can be given to treatment with fludrocortisone (a synthetic mineralocorticoid).[38]​ When combined with a high salt intake, fludrocortisone raises blood pressure.[57]​ Evidence for fludrocortisone is, however, limited to small RCTs (of people with diabetes or Parkinson’s disease) and observational studies.[58]​ Potassium supplementation may be needed, because fludrocortisone increases renal potassium excretion. Fludrocortisone should be used with extreme caution as it results in hypertension when supine, promotes cardiac fibrosis, and may accelerate progression of renal deterioration.[59]​ It is generally contraindicated in patients with heart failure.

Treatment of co-existing conditions

Other agents that have been tested in specific conditions that co-exist with OH are erythropoietin in anaemia, desmopressin in nocturnal polyuria, and octreotide in postprandial OH, but evidence supportive of clinical benefit is weak.[48]

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