Clinical trial of home blood pressure monitoring following midodrine administration in hypotensive individuals with spinal cord injury.

BACKGROUND: Individuals with spinal cord injury (SCI) above thoracic level-6 (T6) experience impaired descending cortical control of the autonomic nervous system which predisposes them to blood pressure (BP) instability, including includes hypotension, orthostatic hypotension (OH), and autonomic dysreflexia (AD). However, many individuals do not report symptoms of these BP disorders, and because there are few treatment options that have been proven safe and effective for use in the SCI population, most individuals remain untreated. OBJECTIVE: The primary aim of this investigation was to determine the effects of midodrine (10 mg) prescribed TID or BID in the home environment, compared to placebo, on 30-day BP, study withdrawals, and symptom reporting associated with OH and AD in hypotensive individuals with SCI. DESIGN/METHODS: Participants were randomly assigned to received midodrine/placebo or placebo/midodrine, with a 2-weeks washout period in between, and both the participants and investigators were blinded to randomization order. Study medication was taken 2 or 3 times/day, depending on their sleep/wake schedule, BP, and any related symptoms were recorded before and 1 h after each dosage and periodically throughout the day. RESULTS: Nineteen individuals with SCI were recruited; however, 9 withdrew prior to completion of the full protocol. A total of 1892 BP recordings (75 ± 48 recordings/participant/30-day period) were collected in the 19 participants over the two 30-day monitoring periods. Average 30-day systolic BP was significantly increased with midodrine compared to placebo (114 ± 14 vs. 96 ± 11 mmHg, respectively; P = 0.004), and midodrine significantly reduced the number of hypotensive BP recordings compared to placebo (38.7 ± 41.9 vs. 73.3 ± 40.6, respectively; P = 0.01). However, compared to placebo, midodrine increased fluctuations in BP, did not improve symptoms of OH, but did significantly worsen the intensity of symptoms associated with AD (P = 0.03). CONCLUSION: Midodrine (10 mg) administered in the home environment effectively increases BP and reduces the incidence of hypotension; however these beneficial effects come at the expense of worsened BP instability and AD symptom intensity.

Increased pulse wave velocity in persons with spinal cord injury: the effect of the renin-angiotensin-aldosterone system.

Increased pulse wave velocity (PWV), a marker of cardiovascular disease (CVD), has been reported in otherwise healthy individuals with spinal cord injury (SCI) compared with age-matched uninjured controls. Due to decentralized descending sympathetic vascular control, individuals with injuries above T6 are prone to orthostatic hypotension and, as a result, depend on the renin-angiotensin-aldosterone system (RAAS) to maintain orthostatic blood pressure (BP). The purpose of this study was to determine resting PWV, a noninvasive surrogate of central arterial stiffness, in individuals with cervical (C4-T1; n = 11) and thoracic (T6-T12; n = 11) SCI, compared with age-matched controls (controls; n = 11). Next, our aim was to describe group differences in BP, plasma norepinephrine (NE), and renin response to head-up tilt (HUT). Finally, we sought to determine the relationship between PWV and the orthostatic change in BP, NE, and the plasma renin during HUT among the groups. PWV was significantly increased in both cervical (8.81 ± 1.91 m/s) and thoracic (7.36 ± 1.58 m/s) SCI compared with the controls (5.53 ± 0.95 m/s; P < 0.05). The change from supine to 60° HUT in BP and NE was significantly reduced and change in plasma renin was significantly increased in the cervical group compared with the thoracic and control groups. Group affiliation and change in plasma renin were significant predictors of PWV (R2 = 0.63, P = 0.001). These data suggest that dependency on the RAAS for orthostatic BP maintenance may be associated with increased PWV and risk of CVD in the SCI population.NEW & NOTEWORTHY Our novel findings suggest that increased arterial stiffness in individuals with SCI may be due to greater dependency on the RAAS to maintain hemodynamic stability during an orthostatic challenge. Asymptomatic orthostatic hypotension can occur in persons with SCI during transition from the supine to the seated position and during other upright activities of daily living; however, it is seldom addressed by clinicians.

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

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.

Blood Pressure Instability in Persons With SCI: Evidence From a 30-Day Home Monitoring Observation.

BACKGROUND: To determine the degree of blood pressure instability over a 30-day home observation in participants with spinal cord injury grouped by level of injury pertaining to cardiovascular autonomic regulation. METHODS: This is an observational study completed at the Kessler Foundation and James J. Peters Veterans Medical Center. Seventy-two participants with tetraplegia (C1-T1), 13 with high thoracic (T2-T4), and 28 with low thoracic (T5-T12) injury participated in this study. Participants were asked to record their blood pressure using an ambulatory blood pressure monitor three times a day for 30 days. RESULTS: The number of blood pressure fluctuations was significantly increased in the tetraplegia group compared with the paraplegia groups. Age and duration of injury contributed to an increase in the observation of 30-day blood pressure instability; however, completeness of injury did not. CONCLUSION: The data indicate significant blood pressure instability that may not be exclusive to persons with tetraplegia; in fact, individuals with low thoracic injuries demonstrated severe blood pressure fluctuations. The use of a monitor at home for an extended period may help document dangerous and extreme fluctuations in blood pressure and should be considered an important adjunctive clinical practice for tracking of the secondary consequences in the spinal cord injury population.

Systemic and Cerebral Hemodynamic Contribution to Cognitive Performance in Spinal Cord Injury.

Cognitive deficits are prevalent in the spinal cord injury (SCI) population, and consensus suggests that concomitant traumatic brain injury or comorbid conditions are primarily responsible for these deficits. However, mounting evidence supports the possibility that systemic and cerebral hemodynamic dysfunction may contribute to the cognitive deficits reported in persons with SCI. We sought to determine the contribution of changes in blood pressure (BP) and changes in cerebral blood flow velocity (CBFv) to test performance on the Symbol Digit Modalities Test (SDMT) in persons with SCI compared with matched non-SCI controls. Participants included 36 non-SCI controls and 67 persons with SCI: 33 with paraplegia (T2-T12) and 34 with tetraplegia (C3-T1). Continuous beat-to-beat BP and simultaneous CBFv was monitored for 5 min during seated rest and during the SDMT, which assesses information processing speed, sustained attention, and visual working memory. The results indicate significantly lower SDMT scores in the group with tetraplegia (44 ± 10) compared to the non-SCI controls (53 ± 14; p < 0.01); however, SDMT scores did not differ significantly between the non-SCI controls and the group with paraplegia (49 ± 13). Whereas group affiliation was the most significant predictor of test performance (F = 4.84; p = 0.010, η2 = 0.088), change in systolic BP (SBP) (r2 = 0.047, p = 0.028) and change in diastolic CBFv (DFV) (r2 = 0.047, p = 0.028) contributed significantly to SDMT scores. Further, change in SBP accounted for a significant amount of variance in change in DFV in the total study sample (r2 = 0.090; p = 0.002). These results support previous findings of cognitive deficits in persons with SCI and indicate that inadequate systemic and cerebral hemodynamic responses to testing contribute to test performance. Therefore, clinical treatment of cognitive dysfunction in the SCI population should consider focusing on increasing systemic BP to improve CBFv, particularly in individuals with lesions above T1.

Impact of Blood Pressure, Lesion Level, and Physical Activity on Aortic Augmentation Index in Persons with Spinal Cord Injury.

Individuals with chronic spinal cord injury (SCI) are at a heightened risk of cardiovascular disease (CVD) resulting from autonomic nervous system dysfunction, physical inactivity, and increased inflammatory processes. Arterial stiffness (AS) is recognized as an independent risk factor for CVD and, specifically, pulse wave analysis (PWA) has proven to be a useful tool to predict and track structural arterial changes that reflect arteriosclerosis. The augmentation index (AI) can be used to estimate AS and is derived from the amplitude and timing of the blood pressure (BP) wave reflection in a peripheral artery. Recently, AS has been shown to be increased in persons with SCI compared with the uninjured population; however, possible contributors to increased AS in the SCI population have not been fully explored. In this study, increased radial artery AI is demonstrated in persons with high cord lesions (above T6) compared with individuals with low cord lesions (T7 and below) and uninjured controls. The association between age and AI was not significant in the SCI population; however, there was a direct association between AI and level of injury. Further, AI was inversely associated with seated systolic blood pressure (SBP) and was increased in individuals who reported orthostatic hypotension (OH) and in those who were physically inactive. In conclusion, individuals with higher cord lesions have more severe cardiovascular autonomic disruption, leading to orthostatic BP dysregulation and physical inactivity, which appear to contribute independently to increased AS in these individuals.