Individuals with spinal cord injury (SCI) above T6 experience impaired descending cortical control of the autonomic nervous system, which predisposes them to hypotension. However, treatment of hypotension is uncommon in the SCI population because there are few safe and effective pharmacological options available. The primary aim of this investigation was to test the efficacy of a single dose of midodrine (10 mg), compared with placebo, to increase and normalize systolic blood pressure (SBP) between 110 and 120 mmHg during cognitive testing in hypotensive individuals with SCI. Secondary aims were to determine the effects of midodrine on cerebral blood flow velocity (CBFv) and global cognitive function.
United States clinical research laboratory.
Forty-one healthy hypotensive individuals with chronic (≥1-year post injury) SCI participated in this 2-day study. Seated SBP, CBFv, and cognitive performance were monitored before and after administration of identical encapsulated tablets, containing either midodrine or placebo.
Compared with placebo, midodrine increased SBP (4 ± 13 vs. 18 ± 24 mmHg, respectively; p < 0.05); however, responses varied widely with midodrine (−15.7 to +68.6 mmHg). Further, the proportion of SBP recordings within the normotensive range did not improve during cognitive testing with midodrine compared with placebo. Although higher SBP was associated with higher CBFv (p = 0.02), global cognitive function was not improved with midodrine.
The findings indicate that midodrine increases SBP and may be beneficial in some hypotensive patients with SCI; however, large heterogeneity of responses to midodrine suggests careful monitoring of patients following administration.
Clinical trials registration
Subscribe to Journal
Get full journal access for 1 year
only $24.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
The data sets generated and analyzed in the current study are available from the corresponding authors upon request.
Miller ER 3rd, Appel LJ. High prevalence but uncertain clinical significance of orthostatic hypotension without symptoms. Circulation. 2014;130:1772–4.
Hildrum B, Mykletun A, Stordal E, Bjelland I, Dahl AA, Holmen J. Association of low blood pressure with anxiety and depression: the Nord-Trondelag Health Study. J Epidemiol Community Health. 2007;61:53–8.
Lindholm L, Lanke J, Bengtsson B, Ejlertsson G, Thulin T, Scherstén B. Both high and low blood pressures risk indicators of death in middle-aged males: isotonic regression of blood pressure on age applied to data from a 13-year prospective study. Acta Med Scand. 1985;218:473–80.
Angelousi A, Girerd N, Benetos A, Frimat L, Gautier S, Weryha G, et al. Association between orthostatic hypotension and cardiovascular risk, cerebrovascular risk, cognitive decline and falls as well as overall mortality: a systematic review and meta-analysis. J Hypertens. 2014;32:1562–71.
Czajkowska J, Ozhog S, Smith E, Perlmuter LC. Cognition and hopelessness in association with subsyndromal orthostatic hypotension. J Gerontol A Biol Sci Med Sci. 2010;65:873–9.
Moretti R, Torre P, Antonello RM, Manganaro D, Vilotti C, Pizzolato G. Risk factors for vascular dementia: hypotension as a key point. Vasc Health Risk Manag. 2008;4:395–402.
Min M, Shi T, Sun C, Liang M, Zhang Y, Wu Y, et al. The association between orthostatic hypotension and dementia: a meta-analysis of prospective cohort studies. Int J Geriatr Psychiatry. 2018;33:1541–7.
Jegede AB, Rosado-Rivera D, Bauman WA, Cardozo CP, Sano M, Moyer JM, et al. Cognitive performance in hypotensive persons with spinal cord injury. Clin Auton Res. 2010;20:3–9.
Carlozzi NE, Fyffe D, Morin KG, Byrne R, Tulsky DS, Victorson D, et al. Impact of blood pressure dysregulation on health-related quality of life in persons with spinal cord injury: development of a conceptual model. Arch Phys Med Rehabil. 2013;94:1721–30.
Katzelnick CG, Weir JP, Chiaravalloti ND, Wylie GR, Dyson-Hudson TA, Bauman WA, et al. Impact of blood pressure, lesion level, and physical activity on aortic augmentation index in persons with spinal cord injury. J Neurotrauma. 2017;34:3407–15.
Wu JC, Chen YC, Liu L, Chen TJ, Huang WC, Cheng H, et al. Increased risk of stroke after spinal cord injury: a nationwide 4-year follow-up cohort study. Neurology. 2012;78:1051–7.
Phillips AA, Warburton DE, Ainslie PN, Krassioukov AV. Regional neurovascular coupling and cognitive performance in those with low blood pressure secondary to high-level spinal cord injury: improved by alpha-1 agonist midodrine hydrochloride. J Cereb Blood Flow Metab. 2014;34:794–801.
Wecht JM, Zhu C, Weir JP, Yen C, Renzi C, Galea M. A prospective report on the prevalence of heart rate and blood pressure abnormalities in veterans with spinal cord injuries. J Spinal Cord Med. 2013;36:454–62.
Zhu C, Galea M, Livote E, Signor D, Wecht JM. A retrospective chart review of heart rate and blood pressure abnormalities in veterans with spinal cord injury. J Spinal Cord Med. 2013;36:463–75.
Hopman MT, Dueck C, Monroe M, Philips WT, Skinner JS. Limits to maximal performance in individuals with spinal cord injury. Int J Sports Med. 1998;19:98–103.
Chao CY, Cheing GL. The effects of lower-extremity functional electric stimulation on the orthostatic responses of people with tetraplegia. Arch Phys Med Rehabil. 2005;86:1427–33.
Vallbona C, Spencer WA, Cardus D, Dale JW. Control of orthostatic hypotension of quadriplegic patients with a pressure suite. Arch Phys Med Rehabil. 1963;44:7–18.
Frisbie JH. Postural hypotension, hyponatremia, and salt and water intake: case reports. J Spinal Cord Med. 2004;27:133–7.
Krassioukov A, Eng JJ, Warburton DE, Teasell R, Spinal Cord Injury Rehabilitation Evidence Research T. A systematic review of the management of orthostatic hypotension after spinal cord injury. Arch Phys Med Rehabil. 2009;90:876–85.
Nieshoff EC, Birk TJ, Birk CA, Hinderer SR, Yavuzer G. Double-blinded, placebo-controlled trial of midodrine for exercise performance enhancement in tetraplegia: a pilot study. J Spinal Cord Med. 2004;27:219–25.
Wecht JM, Rosado-Rivera D, Weir JP, Ivan A, Yen C, Bauman WA. Hemodynamic effects of L-threo-3,4-dihydroxyphenylserine (Droxidopa) in hypotensive individuals with spinal cord injury. Arch Phys Med Rehabil. 2013;94:2006–12.
Groomes TE, Huang CT. Orthostatic hypotension after spinal cord injury: treatment with fludrocortisone and ergotamine. Arch Phys Med Rehabil. 1991;72:56–8.
Frisbie JH, Steele DJ. Postural hypotension and abnormalities of salt and water metabolism in myelopathy patients. Spinal Cord. 1997;35:303–7.
Arterial hypertension: report of a WHO expert committee. World Health Organization Technical Report Series no. 62; 1978. p. 7–56.
Wecht JM, Rosado-Rivera D, Handrakis JP, Radulovic M, Bauman WA. Effects of midodrine hydrochloride on blood pressure and cerebral blood flow during orthostasis in persons with chronic tetraplegia. Arch Phys Med Rehabil. 2010;91:1429–35.
Blackstone K, Moore DJ, Franklin DR, Clifford DB, Collier AC, Marra CM, et al. Defining neurocognitive impairment in HIV: deficit scores versus clinical ratings. Clin Neuropsychol. 2012;26:894–908.
Carey CL, Woods SP, Gonzalez R, Conover E, Marcotte TD, Grant I, et al. Predictive validity of global deficit scores in detecting neuropsychological impairment in HIV infection. J Clin Exp Neuropsychol. 2004;26:307–19.
Hinkin CH, Hardy DJ, Mason KI, Castellon SA, Durvasula RS, Lam MN, et al. Medication adherence in HIV-infected adults: effect of patient age, cognitive status, and substance abuse. AIDS. 2004;18:S19–25.
Huck SaM RA. Using a repeated measures ANOVA to analyze the data from a pretest-posttest design: a potentially confusing task. Psychol Bull. 1975;82:511–8.
Lakens D. Calculating and reporting effect sizes to facilitate cumulative science: a practical primer for t-tests and ANOVAs. Front Psychol. 2013;4:863.
Wagenmakers EJ, Love J, Marsman M, Jamil T, Ly A, Verhagen J, et al. Bayesian inference for psychology. Part II: example applications with JASP. Psychon Bull Rev. 2018;25:58–76.
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.
Klohr S, Roth R, Hofmann T, Rossaint R, Heesen M. Definitions of hypotension after spinal anaesthesia for caesarean section: literature search and application to parturients. Acta Anaesthesiol Scand. 2010;54:909–21.
Dahlgren G, Irestedt L. The definition of hypotension affects its incidence. Acta Anaesthesiol Scand. 2010;54:907–8.
Kim BS, Bae JN, Cho MJ. Depressive symptoms in elderly adults with hypotension: different associations with positive and negative affect. J Affect Disord. 2010;127:359–64.
Pilgrim JA, Stansfeld S, Marmot M. Low blood pressure, low mood? Bmj. 1992;304:75–8.
Krassioukov A, Biering-Sorensen F, Donovan W, Kennelly M, Kirshblum S, Krogh K, et al. International standards to document remaining autonomic function after spinal cord injury. J Spinal Cord Med. 2012;35:201–10.
Robbins JM, Korda H, Shapiro MF. Treatment for a nondisease: the case of low blood pressure. Soc Sci Med. 1982;16:27–33.
Briggs R, Kenny RA, Kennelly SP. Does baseline hypotension predict incident depression in a cohort of community-dwelling older people? Data from The Irish Longitudinal Study on Ageing (TILDA). Age Ageing. 2017;46:648–53.
Whelton PK, Carey RM, Aronow WS, Casey DE Jr., Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. J Am Coll Cardiol. 2018;71:e127–e248.
Hubli M, Gee CM, Krassioukov AV. Refined assessment of blood pressure instability after spinal cord injury. Am J Hypertens. 2015;28:173–81.
Katzelnick CG, Weir JP, Jones A, Galea M, Dyson-Hudson TA, Kirshblum SC, et al. Blood pressure instability in persons with SCI: evidence from a 30-day home monitoring observation. Am J Hypertens. 2019;32:938–944.
Jones PP, Christou DD, Jordan J, Seals DR. Baroreflex buffering is reduced with age in healthy men. Circulation. 2003;107:1770–4.
Courtois FJ, Charvier KF, Leriche A, Vezina JG, Cote M, Belanger M. Blood pressure changes during sexual stimulation, ejaculation and midodrine treatment in men with spinal cord injury. BJU Int. 2008;101:331–7.
We would like to thank all the study participants for their involvement in this study and want to acknowledge Beatrice Ugiliweneza, Samineh Mesbah and Susan Harkema for their programming and statistical skills in creating the area-under-the-curve analyses.
This project was funded by the Craig H Neilsen Foundation (Grant #284196) and the Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service Center for the Medical Consequences of Spinal Cord Injury (Grants #D1382-P and #B2020-C).
Conflict of interest
The authors declare that they have no conflict of interest.
The authors certify that all applicable institutional and governmental regulations concerning the ethical use of human volunteers were followed during the course of this research.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Wecht, J.M., Weir, J.P., Katzelnick, C.G. et al. Double-blinded, placebo-controlled crossover trial to determine the effects of midodrine on blood pressure during cognitive testing in persons with SCI. Spinal Cord 58, 959–969 (2020). https://doi.org/10.1038/s41393-020-0448-0