The levels of evidence (Class I-IV) supporting the recommendations and ratings of recommendations (A-C, Good Practice Point [GPP]) are defined at the end of the "Major Recommendations" field.
- Orthostatic testing should take place in a quiet room, at a temperature between 20º C and 24º C. The patient should rest while supine for ideally 5 minutes before head-up tilt testing (HUT) is started. Emptying the bladder before testing is recommended.
- Passive HUT to an angle between 60º and 80º for 3 minutes is recommended for the diagnosis of orthostatic hypotension (OH).
- HUT is considered positive if systolic blood pressure (BP) falls below 20 mm Hg and diastolic BP below 10 mm Hg of baseline. If symptoms occur, the patient should be tilted back to the supine position immediately.
- Measurement of plasma noradrenaline levels while supine and upright may be of value.
- In contrast with cardiologic guidelines, pharmacological provocation with sublingual nitroglycerine or intravenous isoproterenol is not recommended to diagnose OH as it reduces sensitivity and will result in false positive outcomes.
- Combination of HUT and physiological measures, such as lower body negative pressure application, as used in neurally mediated syncope, is not recommended for diagnosis of OH.
HUT is a safe procedure for the diagnosis of OH. However, as syncope and arrhythmias have been described, the investigating staff should be adequately trained to recognize such problems. Resuscitation equipment and a team experienced in cardiac life support should be available at short notice (GPP).
Level C Recommendations
- Structured history taking
- Detailed physical examination
- 12-lead electrocardiogram (ECG) recording
- Routine laboratory testing
- BP measurements while supine and upright
- Cardiologic referral, if heart disease or abnormal ECG is present or suspected
- Active standing or HUT, ideally with continuous assessment of BP and heart rate (HR) for 3 min
- Further autonomic nervous system (ANS) screening tests, with other appropriate investigations, depending on the possible aetiology of the underlying disorder (Mathias, 2003)
The following recommendations are mainly a result of panel consensus and qualified as GPP.
Elevated environmental temperatures, a hot bath or shower, and sauna should be avoided as they cause venous pooling. Prolonged recumbence during daytime and sudden head up postural change, particularly in the morning, when BP may be lowered by nocturnal polyuria, should be avoided. Post-prandial hypotension may increase OH (vasodilatation in splanchnic vessels). Large meals, especially carbohydrate-rich, and alcohol should be avoided. A carefully controlled and individualized exercise training (swimming, aerobics, and, if possible, cycling and walking) often improves OH.
Supine hypertension may be a problem, resulting from medication and/or being part of the disease. Therefore, 24 hour measurement of BP is best before and if needed after starting a new therapy. Patients may self-monitor BP daily at about the same time, and when they experience symptoms. Pressor medications should be avoided after 6 pm and the bed head elevated (20–30 cm). On occasion, short acting antihypertensive drugs may be considered (e.g., nitroglycerine sublingual).
Avoidance of factors that may induce OH is recommended first line, particularly in mild forms. Educating the patients and carers on the mechanisms of OH is important. The next step includes a range of non-pharmacological strategies.
Patients should be advised to move to head-up position slowly, sit on the edge of the bed for some minutes after recumbence, and activate calf muscles while supine. Physical counter manoeuvres can be applied immediately at the onset of pre-syncopal symptoms. They need to be explained and trained individually. In case of motor disabilities and compromised balance, as in the cerebellar forms of multiple system atrophy (MSA), programmes with appropriate aids have to be developed. Leg crossing with tension of the thigh, buttock and calf muscles (party position), bending over forward to reduce the orthostatic difference between the heart and brain and compress the splanchnic vessels by increasing abdominal pressure, squatting to reduce blood pooling are effective in temporarily reducing OH. Not all patients can perform these manoeuvres and sitting or lying down, and using a cane that can be folded into a tripod chair, are useful. Elastic stockings and abdominal compression bands reduce venous pooling and have been shown effective in small studies. Sleeping with elevation of the head-end of the bed (20 to 30 cm), particularly in combination with low dose fludrocortisone, improves OH.
To compensate for renal salt loss a liberal intake of salt, at least 8 g (150 mmol) of sodium chloride daily, if needed as salt tablets (starting dose 500 mg three times a day [t.i.d.]), are recommended. Water repletion (2 to 2.5 l/day) is important, while 500 mL of water is effective in rising BP immediately.
Cardiac pacing is not recommended in neurogenic OH.
Level C Recommendations
- Fludrocortisone as first line drug monotherapy of OH (0.1 to 0.2 mg per day)
- Full benefit requires a high dietary salt and adequate fluid intake
- Combination of a high salt diet, head-up tilt sleeping (20 to 30 cm) and a low dose of fludrocortisone (0.1 to 0.2 mg) is an effective means of improving OH (van Lieshout, ten Harkel, & Wieling, 2000)
Mild dependent oedema can be expected and fludrocortisone should be used with caution in patients with a low serum albumin. Higher doses of fludrocortisone can result in fluid overload and congestive heart failure, severe supine hypertension and hypokalaemia (Schatz, Miller, & Frame, 1976). To prevent hypokalaemia, food rich in potassium such as fruits, vegetables, poultry, fish and meat is advisable. Headache may occur, especially while supine.
Level A Recommendations
- Midodrine is recommended for mono- or combined therapy (e.g., with fludrocortisone).
- Initial dosage is 2.5 mg orally two to three times daily increasing gradually up to 10 mg t.i.d.
- Supine hypertension is a common (25%) adverse effect and may be severe. The last dose should be administered at least 4 hours before going to sleep and BP should be monitored.
- Adverse effects are piloerection (goose bumps, 13%), scalp or general pruritus (10% and 2%), scalp or general paraesthesia (9% each), urinary retention (6%), and chills (5%).
Some patients worsen on midodrine, maybe due to adrenoceptor desensitization (Kaufmann et al., 1988). It should be administered with caution in patients with hepatic dysfunction and is contraindicated in severe heart disease, acute renal failure, urinary retention, phaeochromocytoma, and thyrotoxicosis (McClellan, Wiseman, & Wilde, 1998).
Level A Recommendations
In a dosage between 200 and 400 mg per day L-DOPS reduces OH. It is the only effective treatment of dopamine beta-hydroxylase deficiency. In all studies reviewed, no major side effects were reported. Future studies will have to investigate which patient groups benefit most from this drug.
Level C Recommendations
Subcutaneous doses of 25 to 150 µg 30 minutes before a meal may be used to reduce postprandial OH. It does not increase supine hypertension. Nausea and abdominal cramps may occur.
Other Treatment Options
For the drugs listed below there is no clear evidence for use in OH. Many are recommended as GPP and warrant future studies.
Ephedrine that acts on alpha- and beta-adrenergic receptors is recommended by the authors, as it reduces OH in many patients, particularly with central lesions like MSA (15 mg t.i.d.). Yohimbine, an alpha-2-adrenoceptor antagonist with central and peripheral effects, has been used in refractory OH (6 mg daily) (Class III).
Dihydroergotamine (DHE), a direct alpha-adrenoceptor agonist stimulating constriction of venous capacity vessels, has shown some benefit and may be used in severe OH (3 to 5 mg t.i.d. oral) (Level C, Class III, Class IV).
Desmopressin, a vasopressin analogue, acts on renal tubular vasopressin-2 receptors, diminishing nocturnal polyuria, and may be applied as nasal spray (10 to 40 µg) or orally (100 to 400 µg) at night (Class IV).
Erythropoietin is recommended in anaemic patients, particularly in familial amyloidosis. Indomethacin, a prostaglandin synthetase inhibitor, has been used in severe OH (75 to 150 mg/day) (Class IV, Class III).
Pyridostigmine may be effective in the treatment of OH through potentiation of sympathetic cholinergic ganglionic transmission, leading to increased vascular tone in the upright position. In a double-blind, randomized, four-way crossover study the acute effects of 60 mg pyridostigmine bromide on supine and upright BP were tested against midodrine and placebo. Pyridostigmine significantly improved standing BP without worsening supine hypertension. However, further studies on the long-term efficacy and on possible adverse effects have to be performed before this treatment can be evaluated.
- OH is defined as fall in BP within 3 minutes of active standing or HUT.
- The key to managing OH is individually tailored therapy. The goal of treatment is to improve the patient's functional capacity and quality of life, preventing injury, rather than to achieve a target BP.
- Management of patients with OH consists of education, advice and training on various factors that influence blood pressure, and special aspects that have to be avoided (foods, habits, positions and drugs).
- Physical measures include leg crossing, squatting, elastic abdominal binders and stockings, and careful exercise (GPP).
- Increased water (2 to 2.5 l/day) and salt ingestion (>8 g or 150 mmol/day) effectively improve OH.
- Fludrocortisone is a valuable starter drug (0.1 to 0.2 mg day, Level C). Second-line drugs include sympathomimetics, such as midodrine (start with 2.5 mg twice daily (b.i.d.) and increase to 10 mg t.i.d., Level A) or ephedrine (15 mg t.i.d., GPP). DOPS (200 to 400 mg daily, Level A) reduces OH with only minor side effects. It is an effective treatment in dopamine beta-hydroxylase deficiency.
- Supine hypertension has to be considered.
- Individual testing with a series of drugs, based on the risk of side effects, pharmacological interactions and probability of response in the individual patient, may be considered when the measures shown here should not be satisfactory.
Evidence Classification Scheme for a Diagnostic Measure
Class I: A prospective study in a broad spectrum of persons with the suspected condition, using a 'gold standard' for case definition, where the test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy
Class II: A prospective study of a narrow spectrum of persons with the suspected condition, or a well-designed retrospective study of a broad spectrum of persons with an established condition (by 'gold standard') compared to a broad spectrum of controls, where test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy
Class III: Evidence provided by a retrospective study where either persons with the established condition or controls are of a narrow spectrum, and where test is applied in a blinded evaluation
Class IV: Any design where test is not applied in blinded evaluation OR evidence provided by expert opinion alone or in descriptive case series (without controls)
Evidence Classification Scheme for a Therapeutic Intervention
Class I: An adequately powered prospective, randomized, controlled clinical trial with masked outcome assessment in a representative population or an adequately powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations. The following are required:
- Randomization concealment
- Primary outcome(s) is/are clearly defined
- Exclusion/inclusion criteria are clearly defined
- Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias
- Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences
Class II: Prospective matched-group cohort study in a representative population with masked outcome assessment that meets a–e above or a randomized, controlled trial in a representative population that lacks one criteria a–e
Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment
Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion
Rating of Recommendations for a Diagnostic Measure
Level A rating (established as useful/predictive or not useful/predictive) requires at least one convincing class I study or at least two consistent, convincing class II studies.
Level B rating (established as probably useful/predictive or not useful/predictive) requires at least one convincing class II study or overwhelming class III evidence.
Level C rating (established as possibly useful/predictive or not useful/predictive) requires at least two convincing class III studies.
Rating of Recommendations for a Therapeutic Intervention
Level A rating (established as effective, ineffective, or harmful) requires at least one convincing class I study or at least two consistent, convincing class II studies.
Level B rating (probably effective, ineffective, or harmful) requires at least one convincing class II study or overwhelming class III evidence.
Level C rating (possibly effective, ineffective, or harmful) requires at least two convincing class III studies.
Good Practice Point Where there was a lack of evidence but consensus was clear, the task force has stated their opinion as Good Practice Points.