Skip to main content
SpringerLink
Log in

Management of Supine Hypertension Complicating Neurogenic Orthostatic Hypotension

  • Therapy in Practice
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Neurogenic orthostatic hypotension (NOH) can be present in a number of disorders, including synucleinopathies, autoimmune disorders, and various genetic disorders. All are characterized by defective norepinephrine release from sympathetic terminals upon standing, resulting in impaired vasoconstriction. NOH is defined as a drop in systolic blood pressure ≥20 mmHg or diastolic blood pressure ≥10 mmHg, or both, within 3 minutes of standing or head up-tilt at a minimum of 60°. However, approximately 50% of patients have associated supine hypertension, which greatly complicates treatment. Supine hypertension not only is a common side effect of many anti-hypotensive agents but is also present in untreated patients, suggesting it is, in part, innate to the pathophysiology of autonomic dysfunction. Pathological mechanisms differ depending on the underlying autonomic disorder. In central neurodegenerative disorders, residual post-ganglionic sympathetic activity is likely the primary mechanism, whereas plasma angiotensin, aldosterone, and inappropriate mineralocorticoid receptor activity may contribute in peripheral autonomic lesions. Baroreflex failure/loss of baroreflex buffering is common to both. More work is required. Clinically, there is much dispute regarding the treatment of supine hypertension when there is a risk of exacerbating orthostatic hypotension. However, given the similar levels of end-organ damage (i.e., heart attack and stroke) seen with transient hypertension, it seems clear that treatment is important. Current therapies for both NOH and supine hypertension include a combination of pharmacological and conservative measures. However, in addition to the current standard of care, protocols may consider 24-h blood pressure monitoring and potential future examination of the peripheral post-ganglionic sympathetic nerves in order to apply individualized adjunct therapies. Finally, no anti-hypertensive agents are currently approved for use in this patient population, and development of novel therapies should focus on short-acting agents, selective to the supine position, that act primarily at night when hypertension is most severe/prolonged.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Tilvis RS, Hakala S, Valvanne J, Erkinjuntti T. Postural hypotension and dizziness in a general aged population: a four-year follow-up of the Helsinki aging study. J Am Geriatr Soc. 1996;44:809–14.

    Article  CAS  PubMed  Google Scholar 

  2. Rutan G, Hermanson B, Bild D, Kittner S, LaBaw F, Tell G. Orthostatic hypotension in older adults: the cardiovascular health study. Hypertension. 1992;19:508–19.

    Article  CAS  PubMed  Google Scholar 

  3. Goldstein DS, Sharabi Y. Neurogenic orthostatic hypotension: a pathophysiological approach. Circulation. 2009;119:139–46.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Low P, Sandroni P, Benarroch E. Clinical autonomic disorders: classification and clinical evaluation. In: Low P, Benarroch E, editors. Clinical autonomic disorders. 3rd ed. Baltimore: Lippincott Williams & Wilkins; 2008.

    Google Scholar 

  5. Gibbons CH, Freeman R, Kaufmann H. The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension. J Neurol. 2017. doi:10.1007/s00415-016-8375-x.

  6. Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res. 2011;21:69–72.

    Article  PubMed  Google Scholar 

  7. Low P, Singer W. Management of neurogenic orthostatic hypotension: an update. Lancet Neurol. 2008;7:451–8.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Bendini C, Angelini A, Salsi F, Finelli M, Martini E, Neviani F, et al. Relation of neurocardiovascular instability to cognitive, emotional and functional domains. Arch Gerontol Geriatr. 2007;1:69–74.

    Article  Google Scholar 

  9. Cordeiro RC, Jardim JR, Perracini MR, Ramos LR. Factors associated with functional balance and mobility among elderly diabetic outpatients. Arq Bras Endocrinol Metabol. 2009;53:834–43.

    Article  PubMed  Google Scholar 

  10. Rose KM, Eigenbrodt ML, Biga RL, Couper DJ, Light KC, Sharrett R, et al. Orthostatic hypotension predicts mortality in middle-aged adults: the Atherosclerosis Risk In Communities (ARIC) Study. Circulation. 2006;114:630–6.

    Article  PubMed  Google Scholar 

  11. Velseboer DC, De Haan RJ, Wieling W, Goldstein DS, De Bie RMA. Prevalence of orthostatic hypotension in Parkinson’s disease: a systematic review and meta-analysis. Parkinsonism Relat Disord. 2011;17:724–9.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Shannon J, Jordan J, Costa F, Robertson R, Biaggioni I. The hypertension of autonomic failure and its treatment. Hypertension. 1997;30(5):1062–7.

    Article  CAS  PubMed  Google Scholar 

  13. Shannon JR, Jordan J, Diedrich A, Pohar B, Black BK, Robertson D, et al. Sympathetically mediated hypertension in autonomic failure. Circulation. 2000;101:2710–5.

    Article  CAS  PubMed  Google Scholar 

  14. Goldstein DS, Pechnik S, Holmes C, Eldadah B, Sharabi Y. Association between supine hypertension and orthostatic hypotension in autonomic failure. Hypertension. 2003;42:136–42.

    Article  CAS  PubMed  Google Scholar 

  15. Biaggioni I, Robertson RM, Robertson D. Manipulation of norepinephrine metabolism with yohimbine in the treatment of autonomic failure. J Clin Pharmacol. 1994;34:418–23.

    Article  CAS  PubMed  Google Scholar 

  16. Onrot J, Goldberg MR, Biaggioni I, Wiley RG, Hollister AS, Robertson D. Oral yohimbine in human autonomic failure. Neurology. 1987;37:215–20.

    Article  CAS  PubMed  Google Scholar 

  17. Senard J, Rascol O, Durrieu G, Tran M, Berlan M, Rascol A, et al. Effects of yohimbine on plasma catecholamine levels in orthostatic hypotension related to Parkinson disease or multiple system atrophy. Clin Neuropharmacol. 1993;16:70–6.

    Article  CAS  PubMed  Google Scholar 

  18. Sharabi Y, Eldadah B, Li S-T, Dendi R, Pechnik S, Holmes C, et al. Neuropharmacologic distinction of neurogenic orthostatic hypotension syndromes. Clin Neuropharmacol. 2006;29:97–105.

    Article  PubMed  Google Scholar 

  19. Garland EM, Gamboa A, Okamoto L, Raj SR, Black BK, Davis TL, et al. Renal impairment of pure autonomic failure. Hypertension. 2009;54:1057–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Biaggioni I, Garcia F, Inagami T, Haile V. Hyporeninemic normoaldosteronism in severe autonomic failure. J Clin Endocrinol Metab. 1993;79:580–6.

    Google Scholar 

  21. Gustafsson F, Azizi M, Bauersachs J, Jaisser F, Rossignol P. Targeting the aldosterone pathway in cardiovascular disease. Fundam Clin Pharmacol. 2012;26:135–45.

    Article  CAS  PubMed  Google Scholar 

  22. Arnold AC, Okamoto LE, Gamboa A, Shibao C, Raj SR, Robertson D, et al. CHBPR: angiotensin II, independent of plasma renin activity, contributes to the hypertension of autonomic failure. Hypertension. 2013;61:701–6.

    Article  CAS  PubMed  Google Scholar 

  23. Arnold AC, Okamoto LE, Gamboa A, Black BK, Raj SR, Elijovich F, et al. Mineralocorticoid receptor activation contributes to the supine hypertension of autonomic failure. Hypertension. 2016;67:424–9.

    Article  CAS  PubMed  Google Scholar 

  24. Robertson D, Hollister AS, Carey EL, Tung C, Goldberg MR, Marie Robertson R, et al. Increased vascular beta2-adrenoceptor responsiveness in autonomic dysfunction. J Am Coll Cardiol. 1984;3:850–6.

    Article  CAS  PubMed  Google Scholar 

  25. Jordan J, Shannon JR, Black BK, Lance RH, Squillante MD, Costa F, et al. N(N)-nicotinic blockade as an acute human model of autonomic failure. Hypertension. 1998;31:1178–84.

    Article  CAS  PubMed  Google Scholar 

  26. Shannon JR, Jordan J, Black BK, Costa F, Robertson D. Uncoupling of the baroreflex by N(N)-cholinergic blockade in dissecting the components of cardiovascular regulation. Hypertension. 1998;32:101–7.

    Article  CAS  PubMed  Google Scholar 

  27. Sharabi Y, Goldstein DS. Relationship of supine hypertension to baroreflex-cardiovagal and baroreflex-sympathoneural dysfunction in chronic autonomic failure. J Am Soc Hypertens. 2015;9:e96.

    Article  Google Scholar 

  28. Furlan R, Piazza S, Bevilacqua M, Turiel M, Norbiato G, Lombardi F, et al. Autonomic nervous system pure autonomic failure: complex abnormalities in the neural mechanisms regulating the cardiovascular system. J Auton Nerv Syst. 1995;51:223–35.

    Article  CAS  PubMed  Google Scholar 

  29. Sharabi Y, Goldstein DS. Mechanisms of orthostatic hypotension and supine hypertension in Parkinson disease. J Neurol Sci. 2011;310:123–8.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Grossman E, Rea RF. Hoffman a, Goldstein DS. Yohimbine increases sympathetic nerve activity and norepinephrine spillover in normal volunteers. Am J Physiol. 1991;260:R142–7.

    CAS  PubMed  Google Scholar 

  31. Goldberg MR, Hollister AS, Robertson D. Influence of yohimbine on blood pressure, autonomic reflexes, and plasma catecholamines in humans. Hypertension. 1983;5:772–8.

    Article  CAS  PubMed  Google Scholar 

  32. Shibao C, Okamoto LE, Gamboa A, Yu C, Diedrich A, Raj SR, et al. Comparative efficacy of yohimbine against pyridostigmine for the treatment of orthostatic hypotension in autonomic failure. Hypertension. 2010;56:847–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sharabi Y, Imrich R, Holmes C, Pechnik S, Goldstein DS. Generalized and neurotransmitter-selective noradrenergic denervation in Parkinson’s disease with orthostatic hypotension. Mov Disord. 2008;23:1725–32.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Goldstein DS, Zimlichman R, Stull R, Keiser HR. Plasma catecholamine and hemodynamic responses during isoproterenol infusions in humans. Clin Pharmacol Ther. 1986;40:233–8.

    Article  CAS  PubMed  Google Scholar 

  35. Imrich R, Eldadah B, Bentho O, Pechnik S, Sharabi Y, Holmes C, et al. Functional effects of cardiac sympathetic denervation in neurogenic orthostatic hypotension. Parkinsonism Relat Disord. 2009;15:122–7.

    Article  PubMed  Google Scholar 

  36. Robertson D, Goldberg MR, Tung C-S, Hollister AS, Robertson RM. Use of Alpha2 adrenoreceptor agonists and antagonists in the functional assessment of the sympathetic nervous system. J Clin Invest. 1986;78:576–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Goldstein DS, Eisenhofer G, Kopin IJ. Sources and significance of plasma levels of catechols and their metabolites in humans. J Pharmacol Exp Ther. 2003;305:800–11.

    Article  CAS  PubMed  Google Scholar 

  38. Goldstein DS, Holmes C, Sharabi Y, Brentzel S, Eisenhofer G. Plasma levels of catechols and metanephrines in neurogenic orthostatic hypotension. Neurology. 2003;60:1327–32.

    Article  CAS  PubMed  Google Scholar 

  39. Goldstein DS, Holmes C, Stuhlmuller JE, Lenders JW, Kopin IJ. 6-[18F]fluorodopamine positron emission tomographic scanning in the assessment of cardiac sympathoneural function: studies in normal humans. Clin Auton Res. 1997;7(1):17–29.

    Article  CAS  PubMed  Google Scholar 

  40. Satoh A, Serita T, Tsujihata M. Total defect of metaiodobenzylguanidine (MIBG) imaging on heart in Parkinson’s disease: assessment of cardiac sympathetic denervation. Nihon Rinsho. 1997;55:202–6.

    CAS  PubMed  Google Scholar 

  41. Goldstein DS, Holmes C, Li S-T, Bruce S, Metman LV, Cannon RO. Cardiac sympathetic denervation in Parkinson disease. Ann Intern Med. 2000;133:338.

    Article  CAS  PubMed  Google Scholar 

  42. Tipre DN, Goldstein DS. Cardiac and extracardiac sympathetic denervation in Parkinson’s disease with orthostatic hypotension and in pure autonomic failure. J Nucl Med. 2005;46:1775–81.

    CAS  PubMed  Google Scholar 

  43. Cook GA, Sullivan P, Holmes C, Goldstein DS. Cardiac sympathetic denervation without Lewy bodies in a case of multiple system atrophy. Parkinsonism Relat Disord. 2014;20:926–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Goldstein DS. Dysautonomia in Parkinson’s disease: neurocardiological abnormalities. Compr Physiol. 2014;4:805–26.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Low P, Opfer-Gehrking TL. The autonomic laboratory. Am J Electroneurodiagnostic Technol. 1999;39:65–76.

    CAS  PubMed  Google Scholar 

  46. Coon EA, Fealey RD, Sletten DM, Mandrekar JN, Benarroch EE, Sandroni P, et al. Anhidrosis in multiple system atrophy involves pre- and postganglionic sudomotor dysfunction. Mov Disord. 2016;32:397–404.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Palma J-A, Gomez-Esteban JC, Kaufmann L, Martinez J, Tijero B, Berganzo K, et al. Orthostatic hypotension in Parkinson disease: how much you fall or how low you go? Mov Disord. 2015;30:639–45.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Low PA, Gilden JL, Freeman R, Sheng KN, McElligott MA. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine Study Group. JAMA. 1997;277:1046–51.

    Article  CAS  PubMed  Google Scholar 

  49. Wright RA, Kaufmann HC, Perera R. A double-blind, dose-response study of rnidodrine in neurogenic orthostatic hypotension. Neurology. 1998;51:120–4.

    Article  CAS  PubMed  Google Scholar 

  50. Kaufmann H, Saadia D, Voustianiouk A, Goldstein DS, Holmes C, Yahr MD, et al. Norepinephrine precursor therapy in neurogenic orthostatic hypotension. Circulation. 2003;108:724–8.

    Article  CAS  PubMed  Google Scholar 

  51. Goldstein DS, Holmes C, Kaufmann H, Freeman R. Clinical pharmacokinetics of the norepinephrine precursor L-threo-DOPS in primary chronic autonomic failure. Clin Auton Res. 2004;14:363–8.

    Article  PubMed  Google Scholar 

  52. Elgebaly A, Abdelazeim B, Mattar O, Gadelkarim M, Salah R, Negida A. Meta-analysis of the safety and efficacy of droxidopa for neurogenic orthostatic hypotension. Clin Auton Res. 2016;26:171–80.

    Article  PubMed  Google Scholar 

  53. Chobanian AV, Volicer L, Tifft CP, Gavras H, Liang CS, Faxon D. Mineralocorticoid-induced hypertension in patients with orthostatic hypotension. N Engl J Med. 1979;301:68–73.

    Article  CAS  PubMed  Google Scholar 

  54. van Lieshout JJ, ten Harkel AD, Wieling W. Fludrocortisone and sleeping in the head-up position limit the postural decrease in cardiac output in autonomic failure. Clin Auton Res. 2000;10:35–42.

    Article  PubMed  Google Scholar 

  55. Singer W, Opfer-Gehrking TL, Nickander KK, Hines SM, Low PA. Acetylcholinesterase inhibition in patients with orthostatic intolerance. J Clin Neurophysiol. 2006;23:476–81.

    Article  PubMed  Google Scholar 

  56. Singer W, Sandroni P, Opfer-Gehrking TL, Suarez G, Klein CM, Hines S, et al. Pyridostigmine treatment trial in neurogenic orthostatic hypotension. Arch Neurol. 2006;63:513–8.

    Article  PubMed  Google Scholar 

  57. Mazza A, Ravenni R, Antonini A, Casiglia E, Rubello D, Pauletto P. Arterial hypertension, a tricky side of Parkinson’s disease: physiopathology and therapeutic features. Neurol Sci. 2013;34:621–7.

    Article  PubMed  Google Scholar 

  58. Berganzo K, Begoñ D-A, Tijero B, Somme J, Lezcano E, Llorens V, et al. Nocturnal hypertension and dysautonomia in patients with Parkinson’s disease: are they related? J Neurol. 2013;260:1752–6.

    Article  CAS  PubMed  Google Scholar 

  59. Vagaonescu TD, Saadia D, Tuhrim S, Phillips R, Kaufmann H. Hypertensive cardiovascular damage in patients with primary autonomic failure. Lancet. 2000;355:725–6.

    Article  CAS  PubMed  Google Scholar 

  60. Bannister R, Iodice V, Vichayanrat E, Mathias CJ. Clinical features and evaluation of the primary chronic autonomic failure syndromes. In: Mathias CJ, Bannister R, editors. Autonomic failure: a textbook of clinical disorders of the autonomic nervous system. Oxford: Oxford University Press; 1992. p. 531–47.

    Google Scholar 

  61. Sandroni P, Benarroch EE, Wijdicks EFM, Rochester MC. Caudate hemorrhage as a possible complication of midodrine-induced supine hypertension. Mayo Clin Proc. 2001;7676:1275–9.

    Article  Google Scholar 

  62. Davidson C, Smith D, Morgan DB. Diurnal pattern of water and electrolyte excretion and body weight in idiopathic orthostatic hypotension. The effect of three treatments. Am J Med. 1976;61:709–15.

    Article  CAS  PubMed  Google Scholar 

  63. Jordan J, Shannon JR, Pohar B, Paranjape SY, Robertson D, Robertson RM, et al. Contrasting effects of vasodilators on blood pressure and sodium balance in the hypertension of autonomic failure. J Am Soc Nephrol. 1999;10:35–42.

    CAS  PubMed  Google Scholar 

  64. Shibao C, Gamboa A, Abraham R, Raj SR, Diedrich A, Black B, et al. Clonidine for the treatment of supine hypertension and pressure natriuresis in autonomic failure. Hypertension. 2006;47:522–6.

    Article  CAS  PubMed  Google Scholar 

  65. Robertson D, Goldberg MR, Hollister AS, Wade D, Robertson RM. Clonidine raises blood pressure in severe idiopathic orthostatic hypotension. Am J Med. 1983;74:193–200.

    Article  CAS  PubMed  Google Scholar 

  66. Kooner JS, Raimbach S, Bannister R, Peart S, Mathias CJ. Angiotensin converting enzyme inhibition lowers blood pressure in patients with primary autonomic failure independently of plasma renin levels and sympathetic nervous activity. J Hypertens Suppl. 1989;7(6):S42–3.

    Article  CAS  PubMed  Google Scholar 

  67. Norcliffe-Kaufmann L, Kaufmann H. Is ambulatory blood pressure monitoring useful in patients with chronic autonomic failure? Clin Auton Res. 2014;24:189–92.

    Article  PubMed  Google Scholar 

  68. Voichanski S, Grossman C, Leibowitz A, Peleg E, Koren-Morag N, Sharabi Y, et al. Orthostatic hypotension is associated with nocturnal change in systolic blood pressure. Am J Hypertens. 2012;25:159–64.

    Article  PubMed  Google Scholar 

  69. Cuspidi C, Meani S, Salerno M, Valerio C, Fusi V, Severgnini B, et al. Cardiovascular target organ damage in essential hypertensives with or without reproducible nocturnal fall in blood pressure. J Hypertens. 2004;22:273–80.

    Article  CAS  PubMed  Google Scholar 

  70. Verdecchia P, Schillaci G, Zampi I, Gatteschi C, Battistelli M, Bartoccini C. Blunted nocturnal fall in blood pressure in hypertensive women with future cardiovascular morbid events. Circulation. 1993;88:986–92.

    Article  CAS  PubMed  Google Scholar 

  71. Gamboa A, Shibao C, Diedrich A, Paranjape SY, Farley G, Christman B, et al. Excessive nitric oxide function and blood pressure regulation in patients with autonomic failure. Hypertension. 2008;51:1531–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Goldstein DS, Eisenhofer G, Dunn BB, et al. Positron emission tomographic imaging of cardiac sympathetic Innervation using 6-[18F]Fluorodopamine: Initial findings in humans. J Am Coll Cardiol. 1993;22(7):1961–71.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Kinesiology, Western University, London, ON, Canada

    Jacquie Baker & Kurt Kimpinski

  2. Department of Clinical Neurological Sciences, Rm. C7-131, University Hospital, London Health Sciences Centre, 339 Windermere Road, London, ON, N6A 5A5, Canada

    Jacquie Baker & Kurt Kimpinski

  3. Schulich School of Medicine and Dentistry, Western University, London, ON, Canada

    Kurt Kimpinski

Authors
  1. Jacquie Baker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kurt Kimpinski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kurt Kimpinski.

Ethics declarations

Funding

No sources of funding were used to prepare this manuscript.

Conflict of interest

Jacquie Baker and Kurt Kimpinski have no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Baker, J., Kimpinski, K. Management of Supine Hypertension Complicating Neurogenic Orthostatic Hypotension. CNS Drugs 31, 653–663 (2017). https://doi.org/10.1007/s40263-017-0453-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-017-0453-9

Search

Navigation