Pharmacological Management of OH
The majority of our knowledge in managing OH has been obtained from people with neurological causes other than SCI, such as diabetic neuropathy, heart disease, multiple system atrophy, pure autonomic failure, Parkinson’s disease, and 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.
Discussion
Midodrine (ProAmatine)
Midodrine, a selective alpha1 adrenergic agonist, works by activating the alpha-adrenergic receptors of the arteriolar and venous vasculature, consequently increasing vascular tone and blood pressure. Midodrine has a half-life of approximately 25 minutes, meaning plasma levels of Midodrine peak at 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. The usual starting dose of Midodrine 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 for the management of OH in individuals with SCI were reported in three level 2 RCTs (Wecht et al. 2020; Wecht et al. 2023; Nieshoff et al. 2004), four level 2 prospective controlled trials (Phillips et al. 2014a; Phillips et al. 2014b; Phillips et al. 2014c; Wecht et al. 2010), three level 4 studies (Mukand et al. 2001; Barber et al. 2000; Senard et al. 1991) and one level 5 study (Mukand et al. 2001). Of note, a case report on 2 male individuals demonstrated urinary bladder dysreflexia with the use of midodrine (Vaidyanathan et al. 2007) which suggests that Midodrine should be employed cautiously.
Three randomized control trials examined the effects of midodrine on blood pressure in individuals with SCI (Wecht et al. 2020; Wecht et al. 2023; Nieshoff et al. 2004). 10mg of Midodrine was found to increase sBP 18±24 mmHg (p<0.05) in 41 individuals with SCI and hypotension, while the placebo increased sBP 4±13 mmHg (p<0.05) (Wecht et al. 2020). Additionally, Midodrine significantly increased average 30-day sBP by a mean of 12.6 mmHg (p<0.0001) and dBP by a mean of 7.7 mmHg (p<0.0001) compared to a placebo (Wecht et al. 2023). Further, the counts of sBP and dBP that remained below a predetermined target range were significantly reduced with Midodrine (∼1.7 times lower, p=0.001 and ∼1.5 times lower, p< 0.001, respectively) compared to placebo (Wecht et al. 2023). Similarly, the counts of sBP and dBP recordings within the predetermined target range were significantly increased with Midodrine (∼2-times higher, p<0.001 and ∼1.5-times higher, p<0.001, respectively) compared to placebo (Wecht et al. 2023). In the RCT by Nieshoff et al. (2004), sBP increased during peak exercise in 3 of the 4 participants and exercise performance was also enhanced with Midodrine. Moreover, 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 is important to confirm this evidence with larger trials.
Fludrocortisone (Florinef)
Fludrocortisone is a mineralocorticoid that induces more sodium to be released into the bloodstream. Since water follows the movement of sodium, fludrocortisone subsequently 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, and blood pressure will rise gradually over several days with the 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, hypomagnesemia, which occurs in 5% of individuals, and headaches. Hypokalemia and hypomagnesemia may need to be corrected with supplements. Moreover, fludrocortisone should not be used in people with congestive heart failure because of its effect on sodium retention. Overall, the benefit of Fludrocortisone has not been sufficiently proven in individuals with SCI. One level 4 case series (Barber et al. 2000), and one level 3 retrospective chart review (Frisbie & Steele 1997) have described the use of fludrocortisone for the management of OH in a SCI population.
Barber et al. (2000) studied two individuals and did not observe an effect of fludrocortisone. Frisbie and Steele (1997)combined fludrocortisone with other pharmacological and physical agents in three participants; however, 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.
Ephedrine
Ephedrine, a non-selective, alpha and beta receptor agonist, acts both centrally and peripherally. Its peripheral actions are attributed to both norepinephrine release and to direct effects on receptors. Ephedrine raises blood pressure by increasing cardiac output as well as inducing peripheral vasoconstriction. It is typically administered orally at a dosage of 12.5-25 mg, three times a day. Side effects may include tachycardia, tremor, and supine hypertension. Further, its plasma half-life ranges from 3 to 6 hours (Kobayashi et al. 2003). Systematic reviews of the literature found level 3 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 participants 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 individuals that taking one dose of Ephedrine in the morning is usually sufficient to reduce symptoms of OH; however, some participants failed to recognize the need for a repeated dose later in the day.
L-threo-3,4-dihydroxyphenylserine (L-DOPS, Droxidopa)
L-DOPS is an exogenous, neutral amino acid that is also a precursor of noradrenalin. The pre-post study by Wecht et al. (2013) found that the use of increased doses of L-threo-3,4-dihydroxyphenylserine (droxidopa 100 mg, 200 mg, 400 mg) in hypotensive individuals 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. The expected fall in blood pressure when transferred to the seated position from supine was prevented with droxidopa 200 and 400mg, suggesting that L-threo-3,4-dihydroxyphenylserine is relatively safe and moderately effective for treating OH in people with SCI (Wecht et al. 2013).
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 to those 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.
The studies addressing the pharmacological management of OH following SCI are limited by a small number of trials with few participants and numerous case reports. Furthermore, it is often difficult to determine the effects of individual medications when used in combination therapies. However, there is sufficient evidence to support the inclusion of Midodrine hydrochloride in the management protocol of OH. Further research is needed to quantify the effects of other pharmacological interventions that have been shown to be effective in conditions other than spinal cord injury.
Conclusions
There is level 1/2 evidence from 2 RCTs (Wecht et al. 2020; Wecht et al. 2023) that Midodrine may be effective in increasing BP in individuals with SCI who have OH.
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, Wecht et al. 2009; Wecht et al. 2008; Wecht et al. 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 3/5 evidence (from 1 retrospective chart review and survey) (Frisbie & Steele 1997) that Ephedrine may prevent some symptoms of OH.
There is level 4 evidence (from 1 pre-post study) (Wecht et al. 2013) that droxidopa may be effective for reducing OH.
