Blood Pressure, Cerebral Blood Flow and Cognition in SCI
Phase: PHASE3
Conditions: Spinal Cord Injury
Sponsor: James J. Peters Veterans Affairs Medical Center



Background and Significance
 
Individuals with tetraplegia and paraplegia above T5 struggle with persistent hypotension,4-11 episodic 
orthostatic hypotension (OH) 12-16 and post-prandial hypotension.17 Although we routinely observe and have 
reported a systolic BP (SBP) below 100 mmHg, 63, 64 most of these individuals remain overtly asymptomatic. 
There is a growing body of evidence supporting associations between asymptomatic hypotension and 
cognitive deficits.  In otherwise healthy non-SCI individuals, asymptomatic hypotension is associated with 
slowed cognitive speed, 19 fewer word recall, 20 decreased accuracy of response,21 limited attention,20 
prolonged reaction times,19, 21, 22 and reduced memory and concentration capacity. 21, 22  We recently reported 
preliminary evidence of significant deficits in memory and marginal deficits in attention and processing speed in 
hypotensive individuals with spinal cord injury (SCI) compared to a normotensive SCI cohort.33 Therefore, 
although many hypotensive individuals with SCI remain asymptomatic and do not raise clinical suspicion 
warranting intervention, chronic hypotension may have significant adverse cognitive consequences.   
 
 Furthermore, the superimposition of hypotension and cognitive impairment on the physical, social and 
emotional limitations already experienced by many individuals with SCI can severely impact autonomy, social 
independence and quality of life (QOL).36, 37  In the 1990’s the British Journal of Medicine published a series of 
papers on the association between low BP and mood disorders.24, 31, 32, 65  The findings suggest that, compared 
to normotensive individuals, those with chronic hypotension report significantly increased incidence of 
depression,23-30 anxiety,25, 26 unexplained tiredness,24, 31 and poor perception of well being.32  Because these 
associations were made in large epidemiological studies the clinical implication has met with some 
skepticism.66  With that appreciated, a more recent report, which aimed to determine the influence of high BP 
on depression and anxiety found an inverse relationship, suggesting that low BP may confer greater risk.67  
Significantly increased reporting of depression and anxiety have been repeatedly reported in the SCI 
population,68-70 and we found significantly increased Becks Depression Index score in hypotensive individuals 
with SCI compared to the normotensive SCI cohort.33  Despite these data, chronic asymptomatic hypotension 
has not attracted clinical attention; in a retrospective chart review we found that nearly 40% of veterans with 
SCI had clinical BP values entered into the medical record indicative of hypotension;71 however less than 1% 
carried the diagnosed or were prescribed anti-hypotensive therapy.52   
 
Although as early as 1927 individuals with low BP were described as those who lacked stamina, tired 
easily, complained of cold extremities and showed an inability to do prolonged mental or physical work; 1 the 
notion that hypotension may be a clinical concern has yet to gain substantial traction. In fact, several more 
recent papers have challenged the notion that low BP is a health concern, suggesting that hypotension is the 
ideal “normal” BP and a benefit to longevity and cardiovascular health.3, 72  In addition, there is a general lack 
of consensus regarding the definition of hypotension, as well as whether chronic hypotension exists,73 or is a 
problem. 2, 74  In 1978, the World Health Organization (WHO) defined hypotension as a SBP ≤ 110 mmHg for 
males and ≤ 100 mmHg for females, without regard to diastolic BP (DBP).  However, much of the literature on 
hypotension is equivocal regarding its definition.  Large epidemiological studies discuss hypotension as BP in 
the lowest 5-30% of the population,25, 26, 28 while smaller studies report cut-offs to define systolic hypotension of 
between 100 and 120 mmHg.24, 27, 31, 32, 65  In addition, there is discussion about whether or not “constitutional 
hypotension” exists, 73 and while several Eastern European countries diagnose and treat individuals with 
hypotension, many English speaking countries are not convinced that low BP is a clinical syndrome, and 
actually believe that hypotension conveys significant cardiovascular benefit.3  Yet, compared to normotensive 
males, 13-year mortality risk for all causes and cardiovascular disease was 2.4 to 3.4 times greater, 
respectively, in men ages 40-49 with systolic hypotension; by comparison, systolic hypertension conveyed a 
1.7 fold increase in all cause mortality. 62   
 
We understand that the diagnosis and treatment of disease is usually based on causal associations 
between symptoms and physiological pathology;2 and the “non-disease state” was described as the diagnosis 
of a particular disease when confirmatory ‘symptomology’ is not readily apparent, 75 as in the case of low blood 
pressure.2 Therefore, the clinical diagnosis of hypotension is most often made based on the presence of 
significant symptomology, which includes dizziness, light-headedness, pre-syncope and syncope, as well as 
non-specific symptoms of generalized weakness, fatigue, nausea, cognitive slowing, blurry vision, leg buckling 
or headache.  Because most hypotensive individuals with SCI remain asymptomatic, the vast majority is not 
diagnosed, let alone treated, which is in sharp contrast to persons diagnosed with asymptomatic hypertension, 

and aggressive treatment if often recommended.   Moreover, OH was defined in 1996 by the American 
Autonomic Society and the American Academy of Neurology as a fall in SBP of greater than or equal to 20/10 
mmHg within 3 minutes of standing, regardless of symptoms, 76-79  and in fact, a dissociation between OH and 
orthostatic dizziness has been reported.58, 60, 80  Regardless of symptoms, however, several large epidemiologic 
studies report associations between OH and increased hospitalizations,81 incidence of ischemic stroke54 and 
coronary heart disease risk59 and higher mortality in the elderly subjects after controlling for confounding 
factors.57, 60, 61  While the predominance of information on OH and mortality has been reported in elderly 
cohorts, several investigators have demonstrated significantly poorer prognosis among younger individuals 
(early to mid 40s) who were OH positive compared to OH negative individuals.55, 58, 59 Of note, these individuals 
were otherwise healthy and remained asymptomatic during episodes of OH, and therefore, did not raise clinical 
concern.55, 58  
 
There is a clear discrepancy between the empirical evidence, which indicates adverse consequences in 
association with chronic asymptomatic hypotension and the clinical diagnosis, treatment and appreciation of 
this condition.  Because our unpublished data suggest that the incidence of hypotension is 2.5 fold increased in 
veterans with SCI compared to veterans without SCI, gaining a better understanding of the possible causal 
association between asymptomatic hypotension and clinically relevant outcomes should be a priority in this 
population.   
 
Laboratory evidence in the general medical literature suggests that elevation in BP improves cognitive 
performance in healthy subjects and in post-acute stroke patients.38, 39, 82  Compared to placebo, administration 
of an alpha-adrenergic agonist (midodrine hydrochloride) induced significant elevations in BP which were 
associated with increased resting cerebral blood flow (CBF) and a more pronounced rise in CBF with the 
execution of a cued reaction time task.38  Moreover, subjects who received midodrine experienced greater 
improvement in attentional performance than those who received placebo, and the degree of performance 
enhancement was positively correlated to the increase in resting CBF.38, 39  In addition, cognitive function was 
significantly improved, in association with reduced hypoperfused tissue on neuro-imaging scans of the brain, 
following induced BP elevation in a randomized-comparative group trial in 15 post-stroke patients.82  Although 
the effects of induced BP elevation on cognitive performance have not been described in persons with SCI, we 
have demonstrated that 10 mg midodrine increases orthostatic BP during a head-up tilt maneuver and 
attenuates the orthostatic fall in CBF.43, 44   Further, our preliminary evidence suggests diminished CBF 
responses to cognitive testing in persons with SCI compared to controls, which may contribute to poor test 
performance.35   
 
Midodrine hydrochloride [d,1-alpha-(2’5’-dimethoxyphenyl)-β-(glycinamidoethanol); C12H19N2O4Cl] is a pro-
drug that undergoes enzymatic hydrolysis in the systemic circulation to form the active metabolite 
desglymidodrine; midodrine is nearly completely absorbed after oral administration,83 even in models of NOH 
in which gastroparesis is common.84  It has been shown that midodrine does not cross the blood brain barrier; 
therefore, it is not associated with central nervous system effects.85 A few relatively small multi-center, 
randomized placebo-controlled clinical trials have been conducted to determine the efficacy of midodrine to 
treat symptomatic OH in various models of autonomic failure (Bradbury-Eggleston [pure autonomic failure], 
Shy-Dragers syndromes [multiple system atrophy], Parkinson’s disease and diabetic neuropathy).46, 84, 86, 87 
Compared to placebo, 10 mg midodrine TID increased standing BP and improved symptoms of dizziness or 
light-headedness during standing.46, 84, 86, 87  Of note, two reports suggest that midodrine improves subjective 
reporting of energy level and depression.46, 47  
 
Although our data indicate that between 39% and 70% of the SCI population is hypotensive, less than 1% 
of veterans with SCI is diagnosed or prescribed treatment for this condition.52, 71  Disparity between the 
prevalence of hypotension and the diagnosis in the SCI population is disturbing because of the possible 
deleterious effects on cognitive function, mood and QOL; adverse effects which may be magnified in 
individuals with a long-term physical disability.36, 37  Further, although these individuals do not complain of 
symptoms, a recent report found significantly increased incidence of ischemic stroke in the Taiwan’s SCI 
population compared to age-, sex- and propensity-matched controls, which may relate to persistent cerebral 
hypoperfusion, secondary to systemic hypotension.88 
 
 

Preliminary Studies  
 
Dr. Jill Wecht has been funded since 2000 by the VA RR&D Service to investigate the consequences of 
decentralized cardiovascular autonomic control on BP in persons with SCI.  She has received four investigator-
initiated Merit Reviews (#B3203R, #F6980R, #B6999R and #B7537R), two Career Development Awards (RCD 
#B3346V and CDA II #A6161W), and she is the Principal Investigator of the Cardiovascular Autonomic 
Program in the Center of Excellence for the Medical Consequences of SCI (CoE: B4162C).  Dr. Wecht’s VA 
funded research has involved the study of the mechanisms of BP control as well as testing the efficacy and 
safety of therapeutic treatment options for hypotension and OH in persons with SCI.  Although Dr. Wecht has 
been successful in securing funding for these investigator-initiated projects, her studies have been limited by 
relatively small in sample sizes.  It must be appreciated that before long term treatment of chronic 
asymptomatic hypotension should be recommended in the SCI population, a large
-scale randomized 
placebo -controlled clinical trial must be conducted.  It is our primary 
objective that the data generated 
by this investigation will provide the preliminary evidence to power such a large
-scale study to 
determine the effects of sustained elevation in BP, to normotensive levels (SBP 111
-139 mmHg), on 
CBF, cognitive function, mo
od and QOL in persons with SCI
.  Until that time, the following text describes 
advances made on several research initiatives conducted by Dr. Wecht and her associates to identify the 
prevalence and adverse consequences of hypotension in persons with SCI.    
 
Prevalence of hypotension in veterans with SCI
 
 
In 2008, Dr. Wecht and colleagues had a Pilot 
Merit Review application funded by the RR&D Service 
(#B6999R) entitled “Prevalence of Blood Pressure 
Abnormalities among Veterans with SCI”.  The 
investigation determined the rates of BP abnormalities 
diagnosed and treated in a veteran SCI population based 
on the medical record charting over a 5-year span of time 
and rates observed in a subset of veterans with SCI.   The 
data, which have been accepted for publication (Appendix 
3), suggest an increased prevalence of hypotension 
among veterans with SCI (28.79%) compared to a 
matched non-SCI veteran cohort (11.89%) (χ2=10.4; 
p<0.01).  Further delineation by age indicates that the 
prevalence of hypotension is increased from the 3rd 
decade of life in those with SCI, but an increased 
observation of hypotension does not become obvious until the 7th decade of life in the matched non-SCI 
veteran cohort (Figure 1).   
 
Although the prevalence of hypotension was increased in veterans with tetraplegia (T [C3-C8]: 35.07%) 
and high paraplegia (HP [T1-T6]: 26.59%) compared to those with low paraplegia (LP [T7 and below]: 4.42%), 
the use of anti-hypotensive agents was comparable, and essentially negligible, among the 3 groups (0.1, 0.5 
and 0.3%, respectively).   Furthermore, prescription of anti-hypertension agents was substantially increased 
compared to anti-hypotensive agents and was comparable among individuals with T (54%), HP (55%) and LP 
(54%); although the diagnosis of hypertension was significantly reduced in those with T (39.1%) and HP 
(44.2%) compared to veterans with LP (59.6%; p<0.05).  Thus, the prevalence of hypotension is increased in 
veterans with SCI; the incongruously low prescription of anti-hypotensive agents may reflect general lack of 
clinical appreciation of the adverse affects of hypotension on QOL and/or a paucity of data supporting the safe 
and efficacious use of these agents in the SCI population. 
 
Hypotension and Cognitive Performance in Persons with SCI
 
In 2008 the VA RR&D Service funded an Associate Investigator Award to Adejoke Jegede , PhD  (# 
B4968R) entitled “Relationship between Blood Pressure, Cerebral Blood Flow, and Learning in Persons with 
Spinal Cord Injury”;  Dr. Wecht was her Primary Mentor.   The findings, which have been published in two 
reports, 33, 35  suggest that hypotensive individuals with SCI, regardless of level of lesion, years of education or 
premorbid IQ, perform significantly more poorly on neuropsychological tasks of memory and attention & 
processing speed compared to normotensive individuals with SCI; it should be noted that the self-reported 
Hypotensive observations (%)
20-29
30-39
40-49
50-59
60-69
70-79
80+
0
5
10
15
20
25
30
35
40
non-SCI
SCI
Figure 1
Observation of a SBP at or below the W.H.O. threshold by age 
category in veterans with and without SCI. 

incidence of traumatic brain injury was comparable between the hypo- and normotensive cohorts. 33  Findings 
from a second manuscript suggest an inappropriate reduction in CBF during cognitive testing in individuals with 
SCI compared to a statistically significant increased in CBF during testing in the non-SCI controls.  Although 
we were unable to establish a relationship between BP, CBF and cognitive performance, subjects with SCI, 
regardless of lesion level, had significantly reduced SBP [A], CBF during testing [B] and poorer test 
performance on the Stroop color task [C] compared to the non-SCI controls (Figure 2).  In fact, 62% of the SCI 
group met criteria the WHO for hypotension (100±20 mmHg), compared to 38% of the non-SCI controls 
(117±19 mmHg) and, 46% of the SCI cohort had cognitive t-scores 1.5 standard deviations below the 
normative mean (mild cognitive impairment) compared to 19% of the controls.   These observations strongly 
support an increased prevalence of hypotension in the SCI population and suggest that relatively reduced CBF 
in concert with systemic hypotension may be associated with diminished cognitive performance. 
 
Effects of Midodrine on BP, CBF and Cognitive Performance in P
ersons with SCI  
In 2006 The VA RR&D Service renewed Dr. William A. Bauman’s CoE (#B4162C), and a component of 
the Cardiovascular Autonomic Program within the CoE was entitled “Determination of the Efficacy of an α-
Agonist on BP and CBF in Patients with Tetraplegia”.  The results of this initiative have been published in two 
manuscripts. 43, 44  We documented an increase in BP and an attenuated fall in CBF during head-up tilt in 
persons with SCI following midodrine 10 mg administration.44  In addition, a portion of Dr.Wecht’s CDA II award 
(#A6161W) was determined the effect of midodrine (10 mg) on 4-hour seated BP, CBF and performance on a 
serial subtraction task in hypotensive individuals with SCI.  
Data collection is ongoing but testing is complete in 14 
individuals with lesions from C3-T4.  There was a significant 
increase in seated BP from the baseline (BL: 90±12/58±11 
mmHg) to the 4-hour post drug (midodrine) average 
(119±18/76±14 mmHg; p<0.0001) and a statistically significant 
increase in CBF (39±9 to 44±11 cm/sec, respectively; p<0.01).  
Further the relationship between the change in SBP and the 
change in MFV following administration of midodrine was 
statistically significant (Figure 3).  To address the impact of 
significant increases in SBP and CBF on cognitive 
performance subjects performed a serial subtraction task, to 
assess intellectual efficiency, before and after midodrine 
administration.  Following midodrine administration the 
number of attempts was increased from BL (50.7±29.6 vs. 
43.2±28.2, respectively; p<0.05), and the number of correct 
response was also significantly increased (44.6±30 vs. 
40.0±28.7, respectively; p<0.05) in subjects with SCI.  
Although these data suggest that improved cognitive 
performance may be associated with elevation in BP and CBF 
following midodrine administration, this work was performed in a relatively small number of subjects, and the 
multiple regression model between physiological increases (i.e., change in BP and CBF) and cognitive 
improvements (i.e., # correct responses after drug) was not statistically significant (r2=0.264; p=0.19). 
SBP (mmHg)
SBP (mmHg)
60
80
100
120
140
160
non-SCI
SCI
**
** p<0.01 vs. non-SCI
CBF during Testing (cm/sec)
non-SCI
SCI
20
30
40
50
60
70
80
non-SCI
SCI
*
* p<0.05 vs. non-SCI
Stroop color (t-score)
non-SCI
SCI
20
30
40
50
60
non-SCI
SCI
*
* p<0.05 vs. non-SCI
Figure 2
A
B
C
 
Systolic BP [A], and CBF [B] during cognitive testing and cognitive t-score on the Stroop color task [C] in the non-SCI (open bars) and SCI 
(closed bars) groups. 
SBP change (mmHg)
CBF change (cm/sec)
-20
0
20
40
60
80
-5
0
5
10
15
Figure 3
r2=0.276; p<0.05
The relationship between the change in systolic BP and 
the change in mean flow velocity (MFV) from seated 
baseline to the average of the 4-hour seated observation 
after administration of midodrine. 

 
BP Dysregulation and Quality of Life in Persons with SCI
 
 
In 2010, Dr. Wecht was awarded a Merit Review by the VA RR&D Service (#B7537R) entitled 
“Development of the Blood Pressure Symptom Subdomain for the SCI-QOL”.  This project will use qualitative 
research techniques and validated psychometric analysis (i.e., Item Response Theory) to develop a bank of 
questions which will help identify the impact of BP dysregulation (BPD) on QOL, and will assist in efforts to 
determine the efficacy of treatments for BPD on Patient Reported Outcomes (PROs) in persons with SCI.  The 
results of the first phase of investigation, focus group testing, has been accepted for publication (Appendix 3); 
the findings suggest that individuals with SCI and SCI clinical experts, with at least 5 years experience, were 
readily able to identify areas of everyday life that may be adversely impacted by the inability to appropriately 
regulate BP (Figure 4).  While there was relatively good coherence in symptoms reporting between the patients 
and clinicians, reporting of fatigue, in association with BPD, was greater in the patients (18%) than providers 
(3%).  The total BPD item bank (BPQOL), which contains 196 unique and validated items, is currently being 
field tested in a sample of 600 persons with SCI.   
 
Research Design and Methods
 
 
We propose to determine the effects of midodrine, administered in a randomized, double blind, placebo-
controlled, outpatient trial to normalize BP over a 30-day period, on CBF, cognitive function, mood and QOL 
Our primary objective is to generate pilot data describing the effect size of change in CBF, cognit
ive 
test score, mood and QOL following sustained elevation in BP, to normal levels, in hypotensive 
individuals with SCI. .   
 
Approximately 50 subjects with SCI will be screened for study eligibility.  We anticipate that approximately 
40 of the subjects screened will be eligible and will undergo a 4-hour laboratory dose-effect trial.  Once dose 
has been determined subjects will be randomized by IVAN (Interactive Touch Tone Randomization System) to 
receive either midodrine or placebo for the 30-day out-patient drug treatment intervention.  Randomization will 
occur in a double-blinded manner, and individuals that use an abdominal binder regularly will be stratified 
equally as will those with a positive history of traumatic brain injury (TBI).  Our recruitment target is 20 subjects 
per randomization category.  We estimate approximately 10% attrition during the 30-day out-patient treatment 
protocol; as such, complete data will be available in ~36 subjects.  Study medication and placebo will be 
distributed by the James J Peters VAMC Pharmacy Service. The study is proposed to be completed in two 
years. Total enrollment will be accomplished within 18 months of obtaining full IRB approval, which should be 
complete within 6 months of funding, and subject participation is estimated to last about 6-8 weeks.  
 
Eligibility Criteria 
– Inclusion Criteria: (1) males and non pregnant females; (2) 18 – 65 years of age; (3) 
chronic SCI (≥ 1 year post injury); (4) ability to provide informed consent; (5) laboratory or clinical evidence of 
hypotension (WHO criteria - SBP ≤ 110 mmHg in males and ≤ 100 mmHg in females).  Exclusion Criteria: (1) 
SBP > 110 mmHg for males and > 100 mmHg for females (2) documented history of: (a) coronary artery 
disease, (b) stroke, (c) diabetes mellitus, (d) current pregnancy or lactation, (e) cardiac arrhythmias; (f) 
significant systemic, hepatic, cardiac or renal illness, (g) suspected malignancy, (h) neurological disease other 
Percent Reporting (%)
Fatigue
Vision problems
Head-ache
Faint
non-well
Adverse mood
Dizziness
Body ache
0
5
10
15
20
25
SCI patients
SCI clinicians
Figure 4
 

than SCI; (i) history of frequent and/or severe autonomic dysreflexia (AD)*; (j) known drug allergy to midodrine; 
(k) acute current illness or infection (l) psychiatric disorders and (m) substance abuse.   
 
*The incidence of AD is reported to be between 48-90% during rehabilitation in individuals with tetraplegia and 
high paraplegia (above T6), 89-91 and may increase with time post-injury.90  However, in our review of the 
medical record, the diagnosis of AD was about 6% of veterans with tetraplegia and high paraplegia (T1-T6), 
the diagnosis of AD was less than 1% in those with lower thoracic lesions (T7 and below).52   Because 
administration of midodrine may worsen BP elevations during episodes of AD, and we cannot rely on the 
medical record for an accurate report of this condition, we will administer an AD questionnaire (Appendix 4) to 
all participants, any potential subject with frequent (3+ episodes/week) or severe (BP elevation ≥ 150/95 
mmHg and/or self-reported adverse symptomology) episodes of AD will be excluded.  To evaluate the impact 
of midodrine on BP elevations during AD, eligible subjects will be sent home with the same survey, modified to 
include: subject number, the date and the BP readings.  
 
Screening Visit – Individuals with SCI will be approached by investigators and asked to provide informed 
consent to participate in the Screening Phase to determine eligibility. Any subject taking a vasoconstrictor 
agent will be asked to stop these medications 2 days or 5 half lives (whichever is longer) prior to the screening 
visit.  The screening assessments will include: medical intake information (Appendix 5), medical history 
(Appendix 6), physical examination, American Spinal Cord Injury Impairment Scale (AIS) classification, clinical 
symptoms survey for OH and BP monitoring.  The BP monitoring will include brachial manual assessments for 
10 minutes in the seated and 10 minutes in the supine position and will be recorded each minute.  Individuals 
will be eligible to participate if the average seated or supine recordings meets the WHO criteria and there is no 
evidence of sustained elevation in BP >135/85 mmHg.  This visit will take about 2 hours. 
 
Dose Determination Visit 
– The dose determination visit will be scheduled to begin no less than 2 days 
and no more than 14 days after completion of the screening visit. Our preliminary data suggest that midodrine 
10 mg normalized seated SBP during a 4-hour laboratory observation in 55% of the patients with SCI tested.  
Therefore, it is anticipated that the 10 mg dose of midodrine will be adequate to normalize seated BP in about 
half of our sample.  However, we appreciate that some subjects with SCI will not respond adequately to 10 mg 
dose (our preliminary data suggest that 28% may require a higher dose), and others may have a hypertensive 
response (>139 mmHg: 17%, based on preliminary evidence).  Eligible participants will be administered 
midodrine 10 mg, open-label, and BP will be monitored for 4-hours; individuals with an average 4-hour seated 
SBP between 111-135 mmHg will be randomized to receive 10 mg midodrine (or placebo) during the 
Treatment Phase.  However in those with inadequate responses to 10 mg, a second open-label trial will be 
carried out to determine 4-hour seated SBP responses at a higher dose (15 mg) for individuals with an average 
SBP ≤ 110 mmHg, and at a lower dose (5 mg) for those with an average SBP > 135 mmHg.  Individuals that 
respond to midodrine, at any of the doses tested, with two or more consecutive BP observations of >135/85 
mmHg, will be excluded from the treatment phase of the investigation.  Brachial BP will be recorded at 15 
minute intervals and these visits will take about 5 hours.  
 
Pre- and Post -Treatment Visits – Within 1 week of determining the appropriate dose of midodrine for 
each subject, eligible participants will return to the laboratory for pre-randomization testing including: (1) 
laboratory BP and heart rate (HR) assessments, (2) CBF measurement at rest and during cognitive testing, (3) 
cognitive testing, (4) mood and QOL surveys, (5) 24-hour ambulatory BP monitoring and (6) 24-urine volume.  
Subjects will arrive at the laboratory between 10AM and 1PM after a 4 hour fast, and having avoided alcohol, 
caffeine, and nicotine for 12-hours.  Subjects will remain in their wheelchair for instrumentation, which will 
include: 1) electrocardiogram (ECG): three surface electrodes will be applied to the chest for continuous 3-lead 
recording of heart rate (HR); 2) brachial BP: will be monitored using a manual sphygnomometer and finger 
arteriolar beat-to-beat BP will be recorded using a photoplethysmograph placed around the middle and index 
fingers of the left hand; 3) CBF: will be monitored and recorded from the right and left middle cerebral artery 
(MCA) using transcranial Doppler ultrasound technology.  Subjects will remain in the seated position for 30 
minutes of baseline (BL) data collection; HR, BP, CBF will be monitored continuously for 5-minutes at 0, 10 
and 20 minutes, brachial BP will be monitored and recorded at 30-second intervals during each of the 5-minute 
data collections periods.  After the BL assessments subjects will be asked to participate in a complete 
neuropsychological battery (Appendix 7) which will include assessments of: pre-morbid intellectual abilities, 
attention & concentration, information processing, memory, and executive control.  The NP battery will take 

about 60 minutes to complete and HR, BP, and CBF will be monitored and recorded during this testing.  After 
the NP battery is complete, subjects will be asked to answer questions related to how BPD impacts their mood 
and QOL (Appendix 8); these short form questionnaires were developed for use in the SCI population and will 
take about 15-minutes to complete.  In addition, to scales developed for use in the SCI population, because 
fatigue was ranked highest in terms of the adverse impact of hypotension on QOL by subjects with SCI from 
our focus group sessions (Figure 4), we will assess fatigue specifically using the PROMIS short form and the 
fatigue severity scale (Appendix 8). Finally, subjects will be equipped with a 24-hour BP monitor, and will be 
sent home with a log to record their activities of daily living (ADL) in association with the BP recordings 
(Appendix 9).  In addition, subjects will be sent home with a 24-hour urine collection contained and will be 
asked to empty their leg bag, or to urinate into this contained at each voiding for a 24-hour period to assess 
hydration status.  Post-randomization testing will be scheduled for approximately 30±3 days after 
randomization and, prior to returning to the laboratory, subjects will be asked to take their morning dose of the 
study medication.  These visits will take about 4 hours. 
 
Treatment Phase –After pre-randomization testing, subjects will be randomized to either midodrine (at the 
individually effective dose) or matching placebo and will be sent home with a one-month (30±3 day) supply. 
Subjects will be asked to take the study medication three times per day, at approximately 8 am, 12 noon and 4 
pm; however, each patient will establish his/her daily regimen with Dr. Galea based on their individual 
sleep/wake schedules and ADLs. Subjects will be asked to keep a log of the time of day each dose was taken 
along with their BP and any adverse events (Appendix 10).  Three BP values will be recorded and uploaded 
directly to www.HealthVault.com at the time of dosing and 1 hour after taking each daily dose (total of 18 BP 
entries daily).  Only study investigators will have access to; this website, which will be password protected and 
the data will be stored behind the VA firewall. Study investigators will review daily BP entries and will contact 
the subject if data are missing or if there is evidence of a hypertensive episode.  Subjects will be asked to 
report, immediately (within 1 hour), any significant AE, and study investigators will contact each subject weekly 
to discuss study specific information and general health and wellbeing.  If an individual develops a fever or any 
other symptom of an acute illness or infection they will be taken off study medication and discontinued from 
participation and will be encouraged to visit their primary care physician for an evaluation.  If after treatment of 
the illness or infection the subject is cleared for participation by the treating physician he/she may resume 
participation beginning with pre-randomization testing.  
 
Interim Visit : Subjects will be asked to return to the laboratory approximately 10 days after randomization, in 
the late morning or early afternoon, after taking their scheduled daily dose for assessment of BP, HR and CBF 
and AE reporting.  This visit will take about 2 hours. 
 
Follow -up Visit – A follow-up visit will be scheduled 7 to 10 days after completion of the Treatment Phase to 
collect information on any AE(s) experienced after discontinuation of study medication and for a final laboratory 
assessment of HR, BP and CBF.  This visit will take about 2 hours. 
 
Data and Statistical Analysis
 – The objectives of this proposed investigation are to determine the effects of 
normalizing BP for 30-days on with midodrine hydrochloride compared to matching placebo, in hypotensive 
individuals with SCI, on: 1) CBF at rest and during cognitive testing, 2) cognitive function, 3) mood and QOL, 
and (4) the number and severity of AE reporting.  A similar proposal was submitted to the VA Cooperative 
Studies Program, but was not funded due to the lack of convincing preliminary data demonstrating that 
increases in systemic BP, secondary to extended use of midodrine in hypotensive individuals with SCI, raises 
CBF at rest and during cognitive testing and improves test performance (Appendix 11).  Therefore, this 
project will test the following hypotheses in an effort to provide sufficient and convinci
ng data to 
support a large -scale clinical trial to determine the long term benefits of normalizing BP in individuals 
with SCI across multiple VA sites through the VA Cooperative Studies Program. 
 
 
Study  Objective s:  
Based on our pilot data we believe that the proportion of individuals classified as normotensive will be 
increased after 30-days of treatment with midodrine compared to those treated with placebo. We plan to 
classify individuals as normotensive if SBP is within the target range of 111-139 mmHg for ≥ 50% of the 24-
hour observation (i.e., about 60 BP recordings) during the post-treatment period and the post-treatment relative 
risk of hypotension in the midodrine group versus placebo group will be assessed. Relative risk will be 

determined by casting raw data into simple counts in a 2x2 contingency table, from which the proportion of 
cases that are classified as hypotensive in the midodrine group will be divided by the proportion of hypotensive 
cases in the placebo group. The 95% confidence interval for the relative risk value will be constructed, as 
described by Newcombe and Altman.92  In addition, clinical relevance will be quantified by calculating the 
number needed to treat (NNT) from the relative risk calculation as follows: NNT = 1 / (hypotension rate in 
midodrine group – hypotension rate in placebo group).  
 
We hypothesize that, during a typical 24-hour day, the proportion of SBP observations within the target range 
of 111-139 mmHg will be increased after treatment with midodrine compared to placebo, after controlling for 
the baseline proportion. We anticipate that about >50% of the subjects randomized to midodrine will have 
normal 24-hour SBP after 30-days of treatment.  In contrast we expect < 25% of individuals randomized to 
receive placebo to have normal 24-hour SBP after the 30-day intervention.  If our postulated values are 
accurate, the relative risk for hypotension for the subjects on midodrine would be ~0.67, which represents 
about a 33% reduction in the rate of hypotension in subjects treated with midodrine compared to those 
randomized to placebo.  The resulting NNT is ~ 4, which suggests that about 4 subjects with SCI would need 
to be treated with midodrine to normalize BP in one subject.  
 
We will then determine the effect of increasing SBP to normal levels on the following outcome parameters: 
Cerebral Blood Flow:  
 
Analysis of covariance (ANCOVA) will be used to determine the change in CBF  at rest and during 
cognitive testing following randomization to midodrine versus placebo.  Pre-randomization CBF will be 
used as the covariate. Our hypothesis is that there will be a significant increase in CBF, both at rest 
and during cognitive testing, after 30-days treatment with midodrine compared to placebo.     
Memory and Attention Processing
: 
 
ANCOVA will be used to determine the change in cognitive function
 from baseline to post-treatment 
following randomization to midodrine versus placebo, using the pre-randomization t-score as the 
covariate. Our hypo thesis is that there will be a significant improvement in cognitive function in 
individuals treated with midodrine as assessed by standardized cognitive tests of memory and attention 
& processing speed compared to those randomized to placebo.  
Depression, Anxiety and Fatigue : 
 
ANCOVA will be used to determine the change in mood and QOL score
 from baseline to post-
treatment following randomization to midodrine versus placebo, using the pre-randomization QOL score 
as the covariate.  Our hypothesis  is that there will be a significant improvement in QOL in individuals 
treated with midodrine as assessed by the BPQOL compared to those randomized to placebo.  
Adverse Events Reporting
: 
 
To determine the differences in AEs reported
 at the end of 30-days treatment following randomization 
to midodrine versus placebo.  Our hypothesis  is that there will be an increase in mild and moderate 
drug-related AEs in individuals treated with midodrine compared to those on placebo.  A few AE's may 
be expected to include supine hypert
ension (may not have been present prior to drug 
administration), exacerbation of AD (elevated BPs recorded during known trigger’s for AD, such 
as bowel care, bladder distension, transfers), 
pruritis, urinary retention and more severe or more 
frequent heada ches.   
Secondary Analyses : 
 
Our conceptual model is that prescription medication class, use of support stockings, abdominal 
binders and history of TBI may function as mediator variables between SCI and the dependent 
variables. To explore this mediation, at a first level of analysis we will examine the bivariate 
relationships between the mediator and dependent variables. Second, we will build hierarchical multiple 
regression models in which a potential mediator variable and SCI status (dummy coded) are both 
forced into the model. In addition, examination of the partial correlation between SCI and dependent 
variables (after partialing out the effect of the mediators relative to the zero order correlation will provide 
insight into the effect size.