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Pharmacological Management of OH in SCI

The majority of our knowledge in managing OH has been obtained from patients with neurological causes other than SCI (e.g. diabetic neuropathy, heart disease, multiple system atrophy, pure autonomic failure, Parkinson’s disease, dysautonomia). Numerous medications, including midodrine hydrochloride, fludrocortisone, and ephedrine, have been successful in managing OH in these chronic conditions. However, as the mechanisms underlying the development of OH in the SCI population differ from those in these non-SCI populations, it is important to assess the effectiveness of these medications specifically in people with SCI.

Table 4: Pharmacological Management of OH in SCI


Author Year; Country
Score
Research Design
Total Sample Size
MethodsOutcome
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 reduced perceived exertion and increased VO2 following midodrine 10 mg.

3.   No adverse effects of midodrine were noted.

Phillips et al. 2014a

Canada

Prospective controlled trial

N=16

Population: 8 persons with SCI (1 female) and 8 age-and-sex matched able bodied controls

Participants with SCI:

Mean (SD) age: 30 (11) years

DOI: 7 subjects <1 year post injury, 1 subject >1 year post injury

All motor complete cervical spinal cord injuries

AIS grade A: 6; AIS grade B: 2

 

Treatment: Subjects tested supine and during upright tilt. SCI group had 2 treatment sessions, one with midodrine and one without. AB group had one session without midodrine.

 

Outcome Measures: Beat-by-beat BP and HR, common carotid artery (CCA) diameter. Calculated arterial distensibility and arterial stiffness (β-stiffness index)

1.     Systolic BP was lower in SCI while supine vs. AB; BP, CCA diameter and diameter difference were reduced in SCI while upright vs. AB; β-stiffness index was elevated in SCI when upright (+12%) and relative decrease in baroreflex sensitivity (BRS) was greater in SCI vs. AB

2.     Negative relationship between BRS and β-stiffness in SCI; no relationship in AB

3.     Midodrine led to increased BP and decreased HR in both supine and upright positions; no change in BRS or CCA parameters

4.     Reduced BRS is closely related to increased arterial stiffness in the SCI population

Phillips et al. 2014b

Canada

Prospective controlled trial

N=20

Population: 10 persons with SCI (3 females) and 10 age-and-sex matched able bodied controls

Participants with SCI:

Mean (SD) age: 29 (10) years

DOI: 8 subjects <1 year post injury, 2 subject >1 year post injury

8 cervical injuries, 2 thoracic injuries

AIS grade A: 8; AIS grade B: 2

 

Treatment: Subjects tested supine and during progressive upright tilt. SCI group had 2 treatment sessions, one with midodrine and one without. AB group had one session without midodrine.

 

Outcome Measures:  beat-by-beat BP, middle and posterior cerebral artery blood velocity (MCAv, PCAv, respectively)

1.     Coherence increased in SCI between BP-MCAv and BP-PCAv by 35% and 22% respectively compared to AB.

2.     SCI BP-PCAv gain was reduced 30% compared to AB.

3.     The acute (0–30 s after tilt) MCAv and PCAv responses were similar between groups.

4.     In SCI, midodrine led to improved PCAv responses 30 – 60 s following tilt (10+/- 3% vs. 4+/- 2% decline)

5.     In SCI, midodrine led to a 59% improvement in orthostatic tolerance

 

Phillips et al. 2014c

Canada

Prospective controlled trial

N=20

Population: 10 persons with SCI (3 females) and 10 age-and-sex matched able bodied controls

Participants with SCI:

Mean (SD) age: 29 (10) years

DOI: 8 subjects <1 year post injury, 2 subject >1 year post injury

8 cervical injuries, 2 thoracic injuries

AIS grade A: 8; AIS grade B: 2

 

Treatment: Visual and verbal fluency task to assess neurovascular coupling (NVC).  SCI group had 2 sessions, one with midodrine and one without. AB group had one session without midodrine.

 

Outcome Measures: beat-by-beat BP, middle and posterior cerebral artery blood velocity (MCAv, PCAv, respectively)

1.     At rest: mean BP was lower in SCI (70±10 versus 92±14 mm Hg); PCAv conductance was higher in SCI (0.56±0.13 versus 0.39±0.15 cm/second/mm Hg)

2.     AB had a 20% increase in PCAv during cognition while this response was absent in SCI

3.     With midodrine, NVC was improved by 70% in SCI, and cognitive function improved by 13%

4.     Improvements in BP were related to improvements in cognitive function in those with SCI

 

La Fountaine et al. 2013;

USA

Prospective controlled trial

N=27

Population: Study 1: 7 tetraplegic subjects (38±10 years; 2 complete AIS A injury), 6 age-matched neurologically intact controls (32±8 years).

Study 2: 7 tetraplegic subjects (41±9 years; 1 complete AIS A injury), 7 age-matched neurologically intact controls (33±9).

Treatment: Study 1: open-label trial with intravenous administration of L-NAME at specific doses (0, 1, 2, or 4 mg×kg-1) in the supine position. Study 2: orthostatic challenge (head-up tilt) with or without L-NAME (0, 1, or 2 mg×kg-1), controls completed a single visit (0 mg×kg-1).

Outcomes Measures: Study 1: Digital ECGs obtained at baseline, immediately after infusion (60 min) and 1 hour post-infusion (120 min).   Study 2: Digital ECGs obtained at baseline, 60 min, and at 2 10 min post-infusion time points after head-up tilt.

1.  Escalating dose of L-NAME (0.0, 1.0, 2.0, 4.0 mg/kg) did not significantly change heart rate, PQ, QT or QTC (heart-corrected QT) intervals at rest or during head-up tilt in subjects with tetraplegia or controls.

2.  Escalating dose of L-NAME (0.0, 1.0, 2.0, 4.0 mg/kg) did not significantly change resting heart rate, PQ, QT or QTC intervals in those with tetraplegia or controls.

3.  L-NAME administration does not appear to affect cardiac rate or conduction.

Wecht et al. 2013;

USA

Prospective controlled trial

N=10

Population: 10 hypotensive subjects with SCI (8M; 2F); 8 tetraplegic, 1 high thoracic (T4) and 1 low thoracic (T10); age: 44±10 years; duration of injury 15±13 years.
Treatment: Escalating dose of L-Threo-3, 4-dihydroxyphenylserine (droxidopa) (100mg, 200mg, 400mg) given over four lab visits with placebo on first visit. Each visit involved 30 min seated baseline, 30- to 60 min supine, and a 4 hour seated post-drug observation.
Outcome measures: Blood pressure and heart rate changes from baseline to the post-drug period; orthostatic heart rate and blood pressure responses; reporting of subjective adverse effects.
1.  Seated blood pressure was significantly elevated with 400mg droxidopa compared with placebo and 100mg droxidopa for 3 hours, and was elevated for 2 hours compared with 200mg droxidopa.

2.  Increase in supine blood pressure was not worsened following droxidopa.

3.  Expected fall in blood pressure when transferred from the supine to the seated position was prevented with droxidopa 200mg and 400mg.

4.  Peak seated blood pressure reached the hypertensive range in 3 study subjects following the 400-mg dose of droxidopa (156/100, 150/94, 149/93 mmHg). These episodes occurred 100 minutes after administration of droxidopa and were resolved within 30 minutes.

Wecht et al. 2011;

USA

Prospective controlled trial

N=7

Population: 5 male and 2 female healthy subjects (26-54 years old, level of injury C4-C7, duration of injury 8-37 years).

Treatment:  Subjects were studied during 3 laboratory visits: no drug, midodrine (10mg; administered orally 30 min before HUT), and L-NAME (1.0 mg/kg; infused over a 60-min period).

Outcome measures: Heart rate, blood pressure (systolic and diastolic), mean arterial pressure (MAP), cerebral blood flow (CBF), and markers of the renin-angiotensin- aldosterone system (RAAS, plasma renin and serum aldosterone) were measured in the supine position at baseline (BL) and during a 45° HUT manoeuver.

1.   L-NAME and midodrine reduced OH symptoms compared to the no-drug trial.

2.   L-NAME significantly increased orthostatic MAP compared with the no drug and midodrine trials.

3.   There was a trend for midodrine to increase MAP during HUT.

4.   Modest suppression of renin and aldosterone responses to HUT with L-NAME and midodrine.

5.  There was a significant relationship between change in MAP and change in CBF with HUT among the subjects tested (r2=0.592).

Wecht et al. 2010;

USA

Prospective controlled trial

N=10

Population: 8 males, 2 females; 43±9 years; duration of injury 22±11 years; SCI C4-C7; AIS A or B

Treatment: Midodrine (no drug, 5 mg or 10 mg) over 3 testing days.

Outcome Measures: Blood pressure (BP), heart rate (HR), mean arterial pressure (MAP) and middle cerebral artery mean blood flow velocity (MCA MFV) during supine and head-up tilt (HUT) of 45 min at 45°.

1.   10 mg midodrine increased supine diastolic BP and MAP, and increased systolic BP and MAP after tilt test compared to control.

2.   The significant increase in systolic BP during HUT was due to an augmented response in 2 subjects with little to no change in the 8 other individuals.

 

Wecht et al. 2009;

USA

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 L-NAME, as well as placebo control at supine rest and during head-up tilt (HUT); the control group received only placebo.

Outcome Measures: Heart rate    (continuously monitored by ECG), mean arterial blood pressure (MAP); active plasma renin and serum aldosterone concentrations.

1.   Supine systolic, diastolic, and mean arterial blood pressure were significantly higher in subjects with SCI after L-NAME infusion compared to placebo

2.   Orthostatic (45° HUT) MAP was significantly reduced after placebo infusion in SCI compared to controls (66±13 vs. 88±10 mmHg);

3.   MAP during HUT was comparable to controls (88±10 mmHg) following L-NAME infusion in subjects with SCI (83±3 mmHg).

4.   Serum aldosterone levels were reduced during HUT after L-NAME infusion (120±45 pg/mL) compared to placebo (259±69 pg/mL; p<0.05) in subjects with SCI.

Wecht et al. 2008;

USA

Prospective controlled

trial

N=14

Population: 7 subjects with tetraplegia; age 38±10 years; duration of injury 18±11 years and 7 neurologically intact controls 34±9 years.

Treatment: Escalating dose of L-NAME (0.0, 1.0, 2.0, 4.0 mg/kg).

Outcome Measures: Supine heart rate (HR), mean arterial blood pressure (MAP) and plasma norepinephrine (NE) concentrations.

1.  There was a heightened MAP response to escalating dose of L-NAME in subjects with tetraplegia compared to the controls.

2.  HR was reduced in a dose dependent manner, and this response did not differ comparing subjects with tetraplegia to the controls.

3.  Plasma NE was significantly at baseline in subjects with tetraplegia compared to the controls.

4.  Following L-NAME infusion, plasma NE was reduced in a dose dependent manner in the controls, whereas plasma NE levels were un-changed following L-NAME infusion in subjects with tetraplegia.

Wecht et al. 2007;

USA

Prospective controlled

trial

N=14

Population: 7 subjects with tetraplegia; age 38±10 years; duration of injury 18±11 years and 7 neurologically intact controls 34±9 years.

Treatment: Placebo versus L-NAME (1.0 mg/kg).

Outcome Measures: Supine heart rate (HR), and mean arterial blood pressure (MAP).

1.  Supine MAP was significantly reduced in subjects with tetraplegia compared to controls at baseline.

2.  Supine HR did not differ between the groups at baseline.

3.  MAP was significantly reduced in subjects with tetraplegia compared to the controls following placebo infusion.

4.  Differences in MAP between subjects with tetraplegia and controls were no longer evident following L-NAME infusion.

Frisbie 2004;

USA

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 an increase in 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, sodium concentrations, and reduced urine osmolality.
Mukand et al. 2001;

USA

Case report

N=1

Population: 21-year old male with traumatic C6 tetraplegia; AIS C, with symptomatic OH.

Treatment: Midodrine (2.5 to 15 mg 3X/day).

Outcome Measures: Blood pressure, symptoms of OH.

1.   Gradual increase in dose of midodrine from 2.5mg to 10 mg (at 0800, 1200 and 1600 hours) resulted in resolution of symptoms of OH. Patient was able to participate fully in the rehabilitation program.
Barber et al. 2000;

USA

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.   No effect of fludrocortisone on OH.

2.   Fludrocortisone in both patients resulted in pitting edema of hands and lower limbs.

3.   Initiation of midodrine hydrochloride resolved orthostatic symptoms in both individuals without any complications.

Frisbie & Steele 1997; USA

Observational

N=231

Population: SCI; ephedrine (medically treated for OH) group age, 57±15 years; duration of injury 26±15 years.  SCI no ephedrine group: 51±15 years, duration of injury 22±14 years.

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.

Muneta et al. 1992; Japan

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 and 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.

3.   Significant improvement in the symptoms of OH and patient was able to participate in rehabilitation program.

Senard et al. 1991; France

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 tetraplegic patient (change of 56 mmHg) compared to controls (change of 15 mmHg).

2.   Midodrine and clonidine alone or the two drugs in combination led to an increase in resting BP and decrease severity of OH.

Groomes & Huang 1991; USA

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 was able to tolerate an upright position without symptoms.

Discussion

Midodrine (ProAmatine)

Midodrine, a selective alpha1 adrenergic agonist, exerts its actions by activating the alpha-adrenergic receptors of the arteriolar and venous vasculature, thus producing an increase in vascular tone and blood pressure. Midodrine has a half-life of approximately 25 minutes. Specifically, plasma levels of Midodrine peak approximately half an hour after oral ingestion, with this amount halved every 25 minutes. However, the primary metabolite reaches peak blood concentrations about 1 to 2 hours after a dose of Midodrine and has a half-life of about 3 to 4 hours. Usual starting dose is 2.5mg two or three times daily. Doses are increased quickly until a response occurs or a maximum recommended dose of 10 mg dose, 2-3 times per day (total 30 mg/day) is attained (Wright et al. 1998). Midodrine does not cross the blood-brain barrier and is not associated with CNS effects. Benefits of Midodrine in the management of OH in individuals with SCI were reported in a level 2 RCT (Nieshoff et al. 2004), in four level 2 prospective controlled trials (Phillips et al. 2014a; Phillips et al. 2014b; Phillips et al. 2014c; Wecht et al. 2010) and three level 4 studies (Mukand et al. 2001; Barber et al. 2000; Senard et al. 1991) and one level 5 study (Mukand et al. 1992). Of note, a recent case report on 2 male subjects demonstrated urinary bladder dysreflexia with the use of midodrine (Vaidyanathan et al. 2007) which suggests Midodrine should be employed cautiously.

Although the only controlled trial consisted of 4 subjects (Nieshoff et al. 2004), this study used a rigorous double-blind placebo-controlled, randomized, within-subjects cross-over trial. Not only was systolic blood pressure increased during peak exercise in 3 of the 4 subjects tested, but exercise performance was also enhanced. Thus, there is level 2 evidence (Nieshoff et al. 2004) that Midodrine may increase blood pressure and enhance exercise performance in some (75%) individuals with SCI, similar to other clinical populations with cardiovascular autonomic dysfunction. Furthermore, there are four additional prospective controlled trials (n=10-20), which support the positive effect of midodrine on orthostatic tolerance (Phillips et al. 2014a; Phillips et al. 2014b; Phillips et al. 2014c; Wecht et al. 2010). Nevertheless, it would be important to confirm this evidence with a larger trial.

Fludrocortisone (Florinef)

Fludrocortisone is a mineralocorticoid that induces more sodium to be released into the bloodstream. Because water follows the movement of sodium, fludrocortisone increases blood volume. Furthermore, fludrocortisone may enhance the sensitivity of blood vessels to circulating catecholamines (Van Lieshout et al. 2000; Schatz 1984). The starting dose is generally 0.1 mg daily. Blood pressure rises gradually over several days with maximum effect at 1-2 weeks. Doses should be adjusted at weekly or biweekly intervals. Adverse effects include hypokalemia (low potassium), which occurs in 50% of individuals, and hypomagnesemia, which occurs in 5%. Both may need to be corrected with supplements. Fludrocortisone should not be used in persons with congestive heart failure due to its effect on sodium retention. Headache is a common side effect. The benefit of Fludrocortisone has not been sufficiently proven in individuals with SCI. One level 4 case series (Barber et al. 2000), one level 5 case report (n=1) (Groomes & Huang 1991), and one level 5 observational (Frisbie & Steele 1997) study have described the use of Fludrocortisone for the management of OH in a SCI population.

Barber et al. (2000) studied two patients and did not observe an effect of fludrocortisone. Frisbie and Steele (1997) combined fludrocortisone with other pharmacological and physical agents in three patients; unfortunately, since outcomes specific to this group were not described, the specific effects of fludrocortisone could not be discerned. Therefore, there is level 4 evidence (Barber et al. 2000) from one case series of two patients that fludrocortisone is not effective for OH in SCI.

Dihydroergotamine

Dihydroergotamine, or Ergotamine, is an ergot alkaloid that interacts with alpha adrenergicreceptors and has selective vasoconstrictive effects on peripheral and cranial blood vessels. Plasma levels peak around 2 hours after ingestion. One case report combined Ergotamine with fludrocortisone to successfully prevent symptomatic OH in one individual with SCI (Groomes & Huang 1991). Hence, there is level 5 (Groomes & Huang 1991) evidence that Ergotamine, taken daily combined with fludrocortisone, successfully prevents OH in one individual with SCI.

Ephedrine

Ephedrine, a non-selective, alpha and beta receptor agonist, acts centrally and peripherally. Its peripheral actions are attributed partly to norepinephrine release and partly to direct effects on receptors. Ephedrine is usually given at a dosage of 12.5-25 mg, administered orally, three times a day. Side effects may include tachycardia, tremor and supine hypertension. Ephedrine raises blood pressure both by increasing cardiac output and inducing peripheral vasoconstriction. Its plasma half-life ranges from 3 to 6 hours (Kobayashi et al. 2003). Systematic review of the literature found level 5 evidence based on one retrospective chart review (Frisbie & Steele 1997) and a cross-sectional observation study (Frisbie 2004). Frisbie (2004) reported that daily urinary output of sodium and fluid was inversely related to the prescribed dose of Ephedrine in 4 patients with OH. While results suggest that Ephedrine resulted in an improvement in hyponatremia, renal conservation of water still exceeded that of sodium in 3 of the 4 cases. Frisbie and Steele (1997) report in their retrospective review of 30 patients taking Ephedrine that one dose in the morning is usually sufficient to reduce symptoms of OH; however, some patients failed to recognize the need for a repeated dose later in the day. Hence, there is level 5 evidence (Frisbie & Steele 1997) that Ephedrine may reduce symptoms of OH.

L-threo-3,4-dihydroxyphenylserine (L-DOPS)

L-DOPS is an exogenous, neutral amino acid that is also a precursor of noradrenalin. Two published studies (Wecht et al. 2013; Muneta et al. 1992) evaluate the effects of L-DOPS on OH. Wecht et al. (2013) in a pre-post study found that the use of increased doses of L-threo-3,4-dihydroxyphenylserine (droxidopa 100 mg, 200 mg, 400 mg) in hypotensive subjects did not cause excessive increases in supine blood pressure. Additionally, the 400-mg dose of droxidopa was found to be effective for increasing seated blood pressure for up to 3 hours in study subjects. The expected fall in blood pressure when transferred to the seated position from supine was prevented with droxidopa 200 and 400mg. There is level 4 evidence based on one pre-post study (Wecht et al. 2013) that L-threo-3,4-dihydroxyphenylserine at the doses tested is safe and moderately effective for the treatment of hypotension and OH.

Muneta et al. (1992) conducted a level 5 study involving one person with nontraumatic SCI. They showed that treatment with sodium supplementation in combination with L-threo-3,4-dihydroxyphenylserine, markedly improved the syncope and drowsiness associated with hypotension and increased the patient’s daily activity. There is level 5 evidence based on one case study (Muneta et al. 1992) that L-DOPS, in conjunction with sodium supplementation may be effective for reducing OH.

Nitro-L-arginine methyl ester (L-NAME)

L-NAME decreases the production of the vasodilator nitric oxide by inhibiting the expression of its enzyme, nitric oxide synthase. Increased nitric oxide release has been associated with orthostatic intolerance after cardiovascular deconditioning and has been proposed to play a role in OH after SCI (Wecht et al. 2007). Three studies (La Fountaine et al. 2013; Wecht et al. 2009; Wecht 2011) examined the use of L-NAME in the treatment of OH following SCI. These studies found that after infusion of 1.0 or 2.0 mg/kg of L-NAME, individuals with tetraplegia had a higher mean arterial pressure in response to orthostatic challenge (a head tilt procedure) compared with those individuals who received a placebo. It should be noted that the increase in mean arterial pressure in the treatment group was not maintained over the entire head tilt procedure for all 3 studies. In La Fountaine et al. (2013), the effect was maintained for 1 additional hour post-infusion. In summary, there is level 2 evidence that L-NAME increases the blood pressure of SCI subjects following a head up tilt procedure.

General Discussion

In summary, the studies addressing the pharmacological management of OH following SCI are limited by a small number of trials with low numbers of subjects and numerous case reports. Furthermore, it is often difficult to determine the effects of individual medications when used as combination therapies. There is sufficient evidence to suggest that Midodrine hydrochloride should be included in the management protocol of OH. Further research needs to quantify the effects of the many pharmacological interventions which have been shown to be effective in conditions other than spinal cord injury.

Conclusion

There is level 2 evidence (from 1 RCT and 4 prospective controlled trials) (Nieshoff et al. 2004; Wecht 2010; Phillips et al. 2014a; Phillips et al. 2014b; Phillips et al. 2014c) that Midodrine may be effective in reducing OH in individuals with SCI.

There is level 2 evidence (from 4 prospective controlled trials) (Wecht et al. 2011, 2009, 2008, 2007) that L-NAME may be effective for reducing OH.

There is level 4 evidence (from 1 case series) (Barber et al. 2000) that fludrocortisone is not effective for OH in SCI.

There is level 5 evidence (from 1 case report) (Groomes & Huang 1991) that Ergotamine, combined daily with fludrocortisone, may successfully prevent symptomatic OH.

There is level 5 evidence (from 1 observational study) (Frisbie & Steele 1997) that Ephedrine may prevent some symptoms of OH.

There is level 4 evidence (from 1 pre-pos study) (Wecht et al. 2013) that droxidopa may be effective for reducing OH.

There is level 5 evidence (from 1 case report) (Muneta et al. 1992) that L-DOPS, in conjunction with salt supplementation may be effective for reducing OH.

Midodrine hydrochloride should be included in the management protocol
of OH in individuals with spinal cord injury.There is limited evidence that the following agents are effective for the management of OH in SCI – ergotamine, fludrocortisone, ephedrine, L-DOPS, L-NAME.