Double-blinded, placebo-controlled crossover trial to determine the effects of midodrine on blood pressure during cognitive testing in persons with SCI

Abstract

Study design

Clinical trial.

Objectives

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.

Setting

United States clinical research laboratory.

Methods

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.

Results

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.

Conclusions

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

NCT02307565.

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Fig. 1: Resting systemic and cerebral hemodynamic responses to placebo and midodrine.
Fig. 2: Relationship between change in SBP and change in MFV.
Fig. 3: Systolic blood pressure following placebo and midodrine.
Fig. 4: Stability of systolic blood pressure during cognitive testing before and after midodrine.

Data availability

The data sets generated and analyzed in the current study are available from the corresponding authors upon request.

References

  1. 1.

    Miller ER 3rd, Appel LJ. High prevalence but uncertain clinical significance of orthostatic hypotension without symptoms. Circulation. 2014;130:1772–4.

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    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.

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    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.

    CAS  PubMed  Google Scholar 

  4. 4.

    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.

    CAS  PubMed  Google Scholar 

  5. 5.

    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.

    PubMed  Google Scholar 

  6. 6.

    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.

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    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.

    PubMed  Google Scholar 

  8. 8.

    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.

    PubMed  Google Scholar 

  9. 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.

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    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.

    PubMed  Google Scholar 

  11. 11.

    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.

    PubMed  Google Scholar 

  12. 12.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    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.

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    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.

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    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.

    CAS  PubMed  Google Scholar 

  16. 16.

    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.

    PubMed  Google Scholar 

  17. 17.

    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.

    CAS  PubMed  Google Scholar 

  18. 18.

    Frisbie JH. Postural hypotension, hyponatremia, and salt and water intake: case reports. J Spinal Cord Med. 2004;27:133–7.

    PubMed  Google Scholar 

  19. 19.

    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.

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    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.

    PubMed  Google Scholar 

  21. 21.

    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.

    PubMed  Google Scholar 

  22. 22.

    Groomes TE, Huang CT. Orthostatic hypotension after spinal cord injury: treatment with fludrocortisone and ergotamine. Arch Phys Med Rehabil. 1991;72:56–8.

    CAS  PubMed  Google Scholar 

  23. 23.

    Frisbie JH, Steele DJ. Postural hypotension and abnormalities of salt and water metabolism in myelopathy patients. Spinal Cord. 1997;35:303–7.

    CAS  PubMed  Google Scholar 

  24. 24.

    Arterial hypertension: report of a WHO expert committee. World Health Organization Technical Report Series no. 62; 1978. p. 7–56.

  25. 25.

    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.

    PubMed  Google Scholar 

  26. 26.

    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.

    CAS  PubMed  Google Scholar 

  27. 27.

    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.

    PubMed  Google Scholar 

  28. 28.

    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.

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    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.

    Google Scholar 

  30. 30.

    Lakens D. Calculating and reporting effect sizes to facilitate cumulative science: a practical primer for t-tests and ANOVAs. Front Psychol. 2013;4:863.

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    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.

    PubMed  Google Scholar 

  32. 32.

    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.

    CAS  PubMed  Google Scholar 

  33. 33.

    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.

    CAS  PubMed  Google Scholar 

  34. 34.

    Dahlgren G, Irestedt L. The definition of hypotension affects its incidence. Acta Anaesthesiol Scand. 2010;54:907–8.

    CAS  PubMed  Google Scholar 

  35. 35.

    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.

    PubMed  Google Scholar 

  36. 36.

    Pilgrim JA, Stansfeld S, Marmot M. Low blood pressure, low mood? Bmj. 1992;304:75–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    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.

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Robbins JM, Korda H, Shapiro MF. Treatment for a nondisease: the case of low blood pressure. Soc Sci Med. 1982;16:27–33.

    CAS  PubMed  Google Scholar 

  39. 39.

    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.

    PubMed  Google Scholar 

  40. 40.

    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.

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Hubli M, Gee CM, Krassioukov AV. Refined assessment of blood pressure instability after spinal cord injury. Am J Hypertens. 2015;28:173–81.

    PubMed  Google Scholar 

  42. 42.

    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.

    PubMed  Google Scholar 

  43. 43.

    Jones PP, Christou DD, Jordan J, Seals DR. Baroreflex buffering is reduced with age in healthy men. Circulation. 2003;107:1770–4.

    PubMed  Google Scholar 

  44. 44.

    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.

    PubMed  Google Scholar 

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Acknowledgements

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.

Funding

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).

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Contributions

JMW oversaw and was primarily responsible for designing the study, participant enrollment, data collection procedures, database management, data analysis, result dissemination, and regulation compliance; JPW was primarily responsible for designing the study, data analysis, and result dissemination; CGK was primarily responsible for participant enrollment, data collection procedures, database management, and regulation compliance; NDC oversaw study design pertaining to the cognitive outcomes and was primarily responsible for the cognitive data analyses; SCK was responsible for monitoring patient safety at the Kessler Foundation; TAD was responsible for participant enrollment and monitoring patient safety at the Kessler Foundation; EW was responsible for analysis of the cognitive outcomes; WAB monitored patient safety at the VA and oversaw data analysis and result dissemination.

Corresponding author

Correspondence to Jill M. Wecht.

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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

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