Nieshoff et al. 2004; USA
PEDro=6
RCT
N=4

Population: Chronic motor complete tetraplegia
Treatment: Midodrine 5mg, 10 mg, or placebo (unmarked capsule). Double-blind, placebo-controlled cross-over design.
Outcome Measures: Measure of cardiovascular parameters during wheelchair ergometer test.

1. Midodrine, 10 mg elevated systolic blood pressure during exercise in 3 participants. Peak systolic BPs ranged from 90 to 126 mmHg under baseline and placebo conditions, 114-148 after 5 mg of midodrine, and 104 to 200 mmHg after 10 mg.
2. Two participants showed ↓perceived exertion and ↑VO2.
3. No adverse effects of midodrine.

Wecht et. al. 2009
USA
Downs & Black=15
Prospective Controlled Trial
N = 12

Population: 5 subjects with chronic tetraplegia (1 AIS A and 4 AIS B); 7 age-, height-, and weight matched able-bodied controls. All subjects were between 19 and 53 years old
Treatment: SCI subjects underwent treatment of 1.0 mg/kg of nitro-L-arginine methyl ester (L-NAME), as well as placebo control; the control group received only placebo.
Outcome Measures: Heart rate (continuously monitored by ECG), blood pressure; active plasma renin and serum aldosterone concentrations, mean arterial pressure (MAP)

1. Supine systolic, diastolic, and mean arterial blood pressure were significantly higher after L-NAME infusion compared to placebo
2. Orthostatic (450) MAP was significantly reduced after placebo infusion in SCI compared with controls (66+13 vs. 88+10 mmHg); MAP after placebo was also significantly lower compared with L-NAME infusion (83+13 mmHg)
3. Orthostatic aldoesterone levels were increased after placebo compared to L-NAME infusion (216.9+105.6 vs. 83.8+28.6 pg/mL)

Senard et al. 1991; France
Downs & Black=11
Pre-post
N=7

Population: 45-year-old subject with chronic complete traumatic paraplegia; 6 non-SCI male controls
Treatment: Clonidine (150 µg, 2X/day) and midodrine (specific alpha 1-agonist) (10 mg, 2X daily) Heart rate assessed by blinded tester.
Outcome Measures: Blood pressure, heart parameters, plasma catecholamine, alpha-adrenoceptor sensitivity.

1. The increase in systolic blood pressure induced by midodrine (10 mg) was significantly higher in the patient (change of 56 mmHg) than in controls (change of 15 mmHg).
2. Midodrine and clonidine alone or two drugs in combination led to an increase in resting BP and decrease severity of OH.

Barber et al. 2000; USA
Downs & Black=9
Case Series
N=2

Population: 2 cases of acute motor complete tetraplegia.
Treatment: Fludrocortisone acetate 0.1 mg 4X/day or midodrine 10 mg 3X/day.
Outcome Measures: Blood pressure, heart rate, and symptoms of OH.

1. Fludrocortisone in both patients resulted in pitting edema of hands and lower limbs.  No effect of fludrocortisone on OH.
2. Initiation of the midodrine hydrochloride resolved orthostatic symptoms in both individuals without any complications.

Frisbie & Steele 1997; USA
Downs & Black=13
Observational
N=231

Population: SCI; ephedrine (medically treated for OH) group: mean age=57±15 years, duration of paralysis 26±15 years; No ephedrine group: mean age=51±15.2 years, 22±13.5 years post-injury
Treatment: Retrospective chart review of use of ephedrine (n=30), salt supplementation (n=6), fludrocortisone (n=3) or physical therapy.
Outcome Measures:OH symptoms, serum sodium and urine osmolality.

1. Single dose of ephedrine usually sufficient to prevent symptoms but observed that some patients failed to recognize need for repeat doses later in day.
2. Symptoms of OH were reduced consciousness (100% of subjects), strength (75%), vision (56%) and breath (53%). Precipitating factors were hot weather (77%), bowel care (33%) and meals (30%).
3. Low blood sodium found in 54% of the OH patients and 16% of those without, P < 0.001.

Frisbie 2004; USA
Downs & Black=8
Observational
N=4

Population: Chronic cervical complete tetraplegia; AIS A
Treatment: Evaluation of urinary salt and water output in relation to prescribed dosage of ephedrine (doses range from 0 to 100 mg daily)
Outcome Measures: Severity of OH, urinary output.

1. With decreasing ephedrine dose (and OH severity), there was a ↑mean daily output of urine sodium (from 50 to 181 mEq), ↑water (from 1.5 to 5.3 L),↑ rate of creatinine secretion, ↑rates of water excretion, ↓urine osmolality, and ↑sodium concentrations.

Mukand et al. 2001; USA
Downs & Black=11
Case Report
N=1

Population: 21-year old male with traumatic C6 tetraplegia; AIS C, with symptomatic orthostatic hypotension.
Treatment: Midodrine (2.5 to 15 mg 3X/day).
Outcome Measures: Blood pressure, symptoms of OH.

1. Gradual increase of dose of midodrine from 2.5mg to 10 mg (at 0800, 1200 and 1600 hrs) resulted in resolution of symptoms and orthostasis. Patient able to participate fully in the rehab program.

Muneta et al. 1992; Japan
Downs & Black=11
Case Report
N=1

Population: 72-year old woman with non-traumatic SCI and paroxysmal hypotension.
Treatment: Several weeks of salt supplement (7 then 15 g/day) was followed by L-threo-3,4-dihydroxyphenylserine (100 mg up to 600 mg/day)
Outcome Measures: Blood pressure, catecholamines (epinephrine & norepinephrine), plasma renin activity.

1. After salt supplement, a marked ↑BP, ↑norepinephrine and ↓ basal plasma renin activity was observed in response to sitting.
2. Addition of L-threo-3,4-dihydroxyphenylserine for 2 weeks, showed elevation in catecholamines about 5 and 10 times without an apparent increase in resting BP level.
3. Significant improvement in the symptoms of the paroxysmal hypotension and patient able to participate in rehabilitation program.

Groomes & Huang 1991; USA
Downs & Black=9
Case Report
N=1

Population: 28-year-old with chronic C5 tetraplegia.
Treatment: Ergotamine (2 mg), daily combined with fludrocortisone (0.1- .05 mg)
Outcome Measures: Blood pressure.

1. Following 10 days with fludrocortisone patient able to tolerate sitting. Following additional ergotamine, the patient able to tolerate an upright position without symptoms.