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ORTHO­STATIC HYPO­TENSION

Orthostatic hypotension (OH) is characterized by a drop in blood pressure upon standing, with accompanying symptoms including dizziness and lightheadedness. Usually, the autonomic nervous system regulates blood pressure (BP) and increases blood vessel constriction upon standing to keep BP constant. In MSA, disturbances in the autonomic nervous system leads to neurogenic orthostatic hypotension (nOH), defined as a drop in systolic BP ≥ 14 mmHg or in diastolic BP ≥ 6 mmHg. Lying-to-sitting drops in blood pressure can also be used to diagnose OH in patients if standing is not feasible, with drops in sitting systolic BP ≥ 14 mmHg or diastolic BP ≥ 6 mmHg indicating the presence of nOH. (Sun 2016) These drops in blood pressure can lead to dizziness, problems maintaining balance, walking and an increased risk of falls. nOH occurs in anywhere from 54%-81% of patients with MSA.

1. Non-pharmaceutical treatments for OH include correcting aggravating factors and implementing other measures to decrease symptoms and risk of fall. OH has been found to be worse in the morning, in hot weather, after eating large meals (especially carbohydrate-heavy meals) and from lifting heavy objects. Avoiding exposure to these factors can decrease the frequency and severity of OH instances. Other non-pharmaceutical interventions include:

  • Expanding blood volume with salt and water supplementation may help minimize symptoms of OH, though the evidence for this is fairly weak. Patients may be encouraged to consume an additional 1-2 teaspoons of salt per day and increase their water consumption by their doctors.
  • Exercise, when done in a safe environment, can improve symptoms of OH. Exercise can even be performed in a sitting or recumbent position, either on a recumbent stationary bike or rowing machine, for example. Exercise in a pool is also a safe option for those who have this option available.
  • Compression stockings have been shown be an effective treatment for OH by increasing venous return. Waist-high stockings have been found to be most effective in preventing OH4.
  • The Valsalva maneuver that occurs during bowel movements can be a precipitating factor for OH, so the straining that occurs during constipation must be avoided. This can be avoided through dietary changes such as increasing fiber in diet and increasing water intake. Fermented milk products with probiotics, such as kefir, have been shown to prevent constipation in patients with Parkinson’s disease and may be of use in MSA5. When dietary changes are not enough to avoid constipation, laxatives are sometimes needed.
  • Supplementation with coenzyme Q10 has also shown promise to treat the symptoms of OH.
  • Raising the head of the bed about 10 cm can also help decrease the symptoms of OH, especially those that occur in the morning.
  • Postural maneuvers can also be used to combat the drop in blood pressure that defines OH. These include muscle tensing and swaying while standing, bending forward, leg crossing and squatting and have been found to have significant effects on blood pressure.

2. Pharmaceutical treatments for nOH try to either increase plasma volume or to increase peripheral resistance through various mechanisms of action. Drugs used to treat MSA are described in Table 1.

Table 1: Medications to Treat Orthostatic Hypotension in MSA

DrugHow it WorksHow It is UsedSide Effects
FludrocortisoneSynthetic adrenal corticosteroid hormone that
increases sodium and water absorption, increases blood volume, sensitivity to adrenaline, and causes contraction of blood vessels and increases in BP.
Commonly used in conjunction with a drug that increases blood vessel constriction, such as midodrine, droxidopa or other agents.Can lead to hypertension and end organ damage, leading to heart and renal failure and has been found to increase risk of hospitalization.
Side effects include ankle swelling, hypokalemia or low potassium levels, and headache.
MidodrineVasoconstrictive agent that leads to increased BP in laying down, sitting and standing positions.It has been shown to be effective in the treatment of nOH among MSA patients, with an increase in standing systolic BP of nearly 22mg Hg.Found to cause an increase in supine hypertension, or dangerous increases in BP while lying down, and should not be taken close to bedtime.
DroxidopaConverted to norepinephrine, a hormone that increases BP and has shown significant reductions in BP in several small clinical trials, while results from larger clinical trials have been mixed.Patients with a lower level of norepinephrine while lying down tend to have better success with droxidopa and may be used to predict success.Can have central nervous system side effects including behavioral changes, including memory difficulties, confusion, mania, and irritability. Other side effects include headache, dizziness and nausea.
PyridostigmineStops the breakdown of acetylcholine, the main neurotransmitter of the autonomic nervous system, increases the release of adrenalin.Has been shown to cause an increase of an average of 4mm HG in systolic BP.Side effects can include stomach pain, nausea, vomiting, diarrhea, blurred vision, muscle cramps and twitching.
Epoetin alfaRecombinant erythropoietin that increases the sensitivity of the blood vessels to the hormone angiotensin, which increases vasoconstriction and consequently BP.The use of this to treat nOH is not widely recommend as the evidence to support it is weak. 
Non-steroidal anti-inflammatory drugsBlocks prostaglandin-mediated vasodilation and has been hypothesized as using this mechanism to prevent OH.Results haven’t been validated in large trials.Possible gastrointestinal irritation.
YohimbineLeads to increases in the activity of the autonomic nervous system through increases in norepinephrine.Clinical evidence of effective control of OH is scarce.Side effects can include anxiety, palpitation, tremor and confusion.
Desmopressin (DDAVP)Helps to contract blood vessels and may combat OH by mimicking the action of the hormone vasopressin.Helps to prevent nocturnal urination thereby improving BP control in the morning. Limited data on this agent make recommendations for the use of this agent weak.Alternations in blood chemistry, specifically low sodium levels.
AtomoxetineShort acting norepinephrine transport inhibitor, increases BP in nOH.Especially effective with patients with high levels of norepinephrine.Side effects can include gastrointestinal and urinary symptoms.
 

References

  1. Sun Z, Jia D, Shi Y, et al. Prediction of orthostatic hypotension in multiple system atrophy and Parkinson disease. Sci Rep. 2016;6:21649.
  2. Eschlböck, S., Wenning, G. & Fanciulli, A. Evidence-based treatment of neurogenic orthostatic hypotension and related symptoms. J Neural Transm124, 1567–1605 (2017).
  3. Palma JA, Norcliffe-Kaufmann L, Kaufmann H. An orthostatic hypotension mimic: The inebriation-like syndrome in Parkinson disease. Mov Disord. 2016;31(4):598–600.
  4. Tanaka K, et al. Compression stocking length effects on arterial blood pressure and heart rate following head-up tilt in healthy volunteers. Nursing Research. 2014;63(6):435–438.
  5. Barichella M, Pacchetti C, Bolliri C, et al. Probiotics and prebiotic fiber for constipation associated with Parkinson disease: An RCT. Neurology. 2016; 87(12):1274–1280.
  6. Rembold CM. Coenzyme Q10 Supplementation in Orthostatic Hypotension and Multiple-System Atrophy: A Report on 7 Cases. Am J Med. 2018;131(4):444-446.
  7. Figueroa JJ, Basford JR, Low PA. Preventing and treating orthostatic hypotension: As easy as A, B, C. Cleve Clin J Med. 2010;77(5):298–306.
  8. Wieling, W., van, Dijk, N., Thijs, R.D., de, Lange, F.J., Krediet, C.T.P. and Halliwill, J.R. (2015), Physical countermeasures to increase orthostatic tolerance. J Intern Med, 277: 69-82.
  9. Grijalva CG, Biaggioni I, Griffin MR, Shibao CA. Fludrocortisone Is Associated With a Higher Risk of All-Cause Hospitalizations Compared With Midodrine in Patients With Orthostatic Hypotension. J Am Heart Assoc. 2017; 6(10).
  10. Parsaik AK, Singh B, Altayar O, et al. Midodrine for orthostatic hypotension: a systematic review and meta-analysis of clinical trials. J Gen Intern Med. 2013;28(11):1496–1503.
  11. Pérez-Lloret S, et al. Droxidopa for the treatment of neurogenic orthostatic hypotension in neurodegenerative diseases, Expert Opinion on Pharmacotherapy. 2019;(20)6:635-645.
  12. Palma JA, Norcliffe-Kaufmann L, Martinez J, Kaufmann H. Supine plasma NE predicts the pressor response to droxidopa in neurogenic orthostatic hypotension. Neurology. 2018;91(16):e1539–e1544.
  13. Singer W, Sandroni P, Opfer-Gehrking TL, et al. Pyridostigmine treatment trial in neurogenic orthostatic hypotension. Archives of neurology. 2006; 63(4):513–518.
  14. Shibao C, Martinez J, Palma JA, Kaufmann H, Biaggioni I. Norepinephrine levels predicts the improvement in orthostatic symptoms after atomoxetine in patients with neurogenic orthostatic hypotension (P5.320). Neurology. 2017; 88(16 Supplement).