Pharmacological Management of OH in SCI

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.