The Consensus Committee of the American Autonomic Society and the American Academy of Neurology (CCAAS&AAN 1996) defined orthostatic hypotension (OH) as a decrease in systolic blood pressure of at least 20mmHg, or a reduction in diastolic blood pressure of at least 10mmHg, upon the change in body position from a supine position to an upright posture, regardless of the presence of symptoms. Several studies have documented the presence of OH following SCI (Chelvarajah, 2009, Cariga et al. 2002, Faghri et al. 2001; Mathias 1995). This condition occurs during the acute period of injury and persists in a significant number of individuals for many years (Claydon et al. 2006; Frisbie & Steele 1997). Standard mobilization treatment during physiotherapy (e.g. sitting or standing) is reported to trigger blood pressure decreases that are diagnostic of OH in 74% of SCI patients, and cause symptoms of OH (such as lightheadedness or dizziness) in 59% of SCI individuals (Illman et al. 2000). Thus, this may discourage individuals with SCI from participating in rehabilitation. Management of OH consists of pharmacological and non-pharmacological interventions.
The low level of efferent sympathetic nervous activity and the loss of the reflex vasoconstriction following SCI are the two major causes of OH (Table 1). Decreases in blood pressure (BP) following the change to an upright position in individuals with SCI may be related to excessive pooling of blood in the abdominal viscera and lower extremities (Krassioukov & Claydon, 2006; Claydon et al. 2006; Mathias 1995). This decrease in BP is compounded by the loss of lower extremity muscle function post-SCI that is known to be important in counteracting venous pooling in the upright position. Excessive venous pooling in the lower extremities coupled with reduced blood volume in the intrathoracic veins lead to a decrease in ventricular end-diastolic filling pressure and end-diastolic volume thereby decreasing left ventricular stroke volume (Ten Harkel et al. 1994). Reduced ventricular filling and emptying ultimately lead to a reduction in cardiac output, and thus, arterial pressure (provided the reductions in cardiac output are marked). Unloading of the arterial baroreceptors induces a reflexive reduction in cardiac parasympathetic (vagal) activity. As a result, tachycardia may occur, although this is usually insufficient to compensate for decreased stroke volume. A reduction in cardiac output results and in turn, arterial blood pressure is reduced. Subsequently, pooling of blood in the lower extremities and decreased blood pressure results in reduced cerebral flow, which may present with a number of signs and symptoms (Table 2).
In addition to central causes of OH following SCI, there is also some evidence suggesting peripheral contributions. For example, upregulation of the potent vasodilator nitric oxide (NO) could potentially contribute to the orthostatic intolerance in this population (Vaziri 2003). In animal studies, it has been shown that NO synthase expression is dysregulated following SCI (Zhao et al. 2007). Moreover, Wecht and co-investigators found that intravenous infusion of a relatively low dose of the NO synthase inhibitor L-arginine-N-methyl-ester (L-NAME) normalized blood pressure in individuals with SCI (Wecht et al. 2007).
Several other factors may predispose individuals with SCI to OH, including low plasma volume, hyponatremia, and cardiovascular deconditioning due to prolonged bed-rest (Claydon et al. 2006; Illman et al. 2000; Mathias 1995). The prevalence of OH is greater in patients with higher spinal cord lesions, and thus it is more common in tetraplegia (Claydon et al. 2006; Mathias 2006; Frisbie & Steele 1997). Furthermore, individuals with cervical SCI also experience greater posture-related decreases in blood pressure than those with paraplegia (Claydon et al. 2006; Mathias 1995). There is also an increased risk of OH in individuals who sustain a traumatic SCI versus a nontraumatic injury such as spinal stenosis (McKinley et al. 1999).
Table 1: Factors Predisposing to OH following SCI
| Multifactorial | Claydon et al. 2006 |
| Loss of tonic sympathetic control | Houtman et al. 2000; Wallin & Stjernberg 1984 |
| Altered baroreceptor sensitivity | Wecht et al. 2003; Munakata et al. 1997; |
| Lack of skeletal muscle pumps | Faghri & Yount 2002; Raymond et al. 2002 Ten Harkel et al. 1994 |
| Cardiovascular deconditioning | Hopman et al. 2002; Vaziri 2003 |
| Altered salt and water balance | Frisbie 2004 |
Table 2: Signs and Symptoms of OH
|
As the body of knowledge is growing in the field of OH management for SCI, it is becoming increasingly important to review the literature and ensure that the information used both in research and clinical practice is current and evidence based. The aim of this section of the OH chapter is to provide an overview of the current systematic reviews available for in areas related to OH management in SCI population.
Table 3: Orthostatic Hypotension Systematic Review
Discussion
We found only one systematic review on OH management for individuals with SCI by Krassioukov et al (2009). Although the authors found that the overall quality of the literature was poor and that higher quality research assessing the treatments for OH in the SCI population is needed, there is level 2 evidence that pressure from elastic stockings and abdominal binders may improve cardiovascular physiologic responses during submaximal upper-extremity exercises. In addition, FES is an important adjunct treatment to minimize cardiovascular changes during postural orthostatic stress and that simultaneous upper-extremity exercises may increase orthostatic tolerance during a progressive tilt exercise in subjects with paraplegia.
The majority of our knowledge in managing OH is obtained from patients presenting OH consequent to non-SCI causes (e.g. heart disease, Parkinson’s disease, dyautonomia). 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 are different in individuals with SCI, it is important to assess the effectiveness of these medications specifically in people with SCI.
Table 4: Pharmacological Management of OH in SCI
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. In the body, Midodrine has a half-life of approximately 25 minutes. Specifically, plasma levels of Midodrine peak at about half an hour, 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 doses are 2.5mg two or three times daily. Doses are increased quickly until a response occurs or a dose of 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 OH management in individuals with SCI were reported in a level 2 RCT (Nieshoff et al. 2004), as well as in a level 2 pre-post trial and three level 4 studies (Wecht et al. 2010; 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) and 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 (3/4 subjects), but exercise performance was also enhanced. Thus, there is level 2 evidence (Nieshoff et al. 2004) that Midodrine enhances exercise performance in some individuals with SCI, similar to other clinical populations with cardiovascular autonomic dysfunction. Nevertheless, it would be useful to confirm this evidence with a larger trial.
Fludrocortisone (Florinef)
Fludrocortisone is a mineralocorticoid that induces more salt to be released into the bloodstream. As water follows the movement of salt, fludrocortisone increases blood volume. Furthermore, fludrocortisone may enhance the sensitivity of blood vessels to circulating catecholamine (Van Lieshout et al. 2000; Schatz 1984). The starting dose is 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 described the use of Fludrocortisone for management of OH in the SCI population.
In Barber et al.’s (2000) study involving two patients, no effect of fludrocortisone was observed. However, Groomes & Huang (1991) found an improvement in one patient within 10 days of treatment. The other study conducted by 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, at this point, there remains only 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 from one retrospective chart review (Frisbie & Steele 1997) and a cross-sectional observation study (Frisbie 2004). Frisbie (2004) reported that daily urinary output of salt and water 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 but that 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. Only one published study (Muneta et al. 1992)evaluates the effects of L-DOPS on OH. This level 5 study involving one person with nontraumatic SCI, showed that treatment with salt 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 (Muneta et al. 1992) based on one case study that L-DOPS, in conjunction with salt 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 is proposed to play a role in OH after SCI (Wecht et al. 2007). Two studies (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 mg/kg of L-NAME, people with tetraplegia had a higher mean arterial pressure in response to a head tilt procedure compared with people who received a placebo and this pressure was not significantly different than non-SCI controls. It should be noted that the increase in mean arterial pressure in the treatment group was not maintained over the entire head tilt procedure. In summary, there is level 2 evidence that L-NAME increases the blood pressure of SCI subjects following a head up tilt procedure.
In summary, the studies addressing the pharmacological management of OH following SCI involve a small number of trials with low number of subjects and numerous case reports. Furthermore, it is often difficult to determine the effects of individual medications when used as combination therapies. 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.
Of the non-pharmacological studies, three involved the regulation of fluid and salt intake while 14 investigated physical modalities such as abdominal binders, physical activities, and electrical muscle stimulation.
OH is common among patients with higher levels of paralysis, presents variable symptoms, and often coexists with abnormal salt and water metabolism. Increases in fluid intake and a diet high in salt can expand extracellular fluid volume and augment orthostatic responses. This simple intervention appears to be effective in patients with idiopathic OH without SCI (Claydon & Hainsworth 2004; Davidson et al. 1976).
Table 5: Fluid and Salt Intake for Management of OH in SCI
Three out of 4 subjects taking salt supplementation with meals in Frisbie and Steele’s (1997) study became independent of their use of Ephedrine. In 4 patients with OH, Frisbie (2004) demonstrated that the estimated daily intake of salt and water was inversely related to their Ephedrine requirements and suggested that greater salt and water intake may lead to a more balanced renal action. Thus, level 5 evidence from two observation studies (Frisbie & Steele 1997; Muneta et al. 1992) suggest that salt and fluid regulation in conjunction with other pharmacological interventions may reduce symptoms of OH. However, as no evidence exists on the effect of salt or fluid regulation alone for OH management in SCI, these conclusions should be interpreted with caution. As of now, there are no guidelines suggesting appropriate water and salt intake specific to individuals with SCI.
The application of external counterpressure by devices such as abdominal binders or pressure stockings is thought to decrease capacitance of the vasculature beds in the legs and abdominal cavity, both major areas of blood pooling during standing.
Table 6: Pressure Interventions for Management of OH in SCI
The studies examining pressure interventions generally test different pressure conditions with the same group of individuals (e.g. with and without stockings) either in a randomized order (RCT) (Hopman et al. 1998a,b) or assigned order (non-RCT) (Krassioukov & Harkema 2006).
The application of these interventions must be interpreted with caution, as none of these studies assessed more than the acute effect of pressure application. Thus, whether these effects would persist with chronic use or cause any detrimental effects upon removal after extended use is unknown. Rimaud et al. (2009), after observing a decrease in venous capacitance, suggest that graduated compression stockings worn by individuals with paraplegia may prevent blood pooling in the legs. However, these effects were observed when the subjects were at rest and in the absence of orthostatic stress however. Kerk et al. (1995) reported that application of an abdominal binder did not significantly improve cardiovascular or kinematic variables at submaximal or maximal levels of exercise. In his review, Bhambhani (2002) concluded that the use of abdominal binders does not influence cardiovascular responses. Conversely, Hopman et al. (1998b) demonstrated in a small group of SCI subjects (n=9) that stockings and an abdominal binder do have effect on cardiovascular responses during submaximal exercises, but not during maximal exercises (Hopman et al. 1998a). Krassioukov & Harkema (2006) found that the use of a harness (which applies abdominal pressure) during locomotor training increased diastolic BP in those with SCI, but not in able-bodied individuals. Therefore, there is level 2 evidence (from 1 RCT) that pressure from elastic stocking and abdominal binders may improve cardiovascular physiological responses during submaximal, but not maximal, arm exercise.
The application of FES triggers intermittent muscle contractions that activate the physiologic muscle pump. The physiologic muscle pump facilitates venous return via compression of the superficial and deep veins of the legs.
FESmay be an important treatment adjunct to minimize cardiovascular changes during postural orthostatic stress in individuals with SCI. Several studies have suggested that FES-induced contractions of the leg muscles increases cardiac output and stroke volume, which increases venous return (Raymond et al. 2002). Subsequently, this increases ventricular filling and left ventricular end-diastolic volume (i.e., enhanced cardiac preload). According to the Frank-Starling effect, an increase in ventricular preload will lead to a greater stretch of the myocytes and a concomitant increase in left ventricular stroke volume. The increased stroke volume may produce greater cardiac output and in turn, greater arterial blood pressure. In this manner, FES-induced contraction of the leg muscles may attenuate the drop in systolic BP in response to an orthostatic challenge.
FES-induced contraction of the leg muscles may also artificially restore the body’s ability to redistribute blood from below the level of the lesion back to the heart.In fact, it is through this means that Davis et al. (1990) attributes FES’s effectiveness during an orthostatic challenge. In their study, Davis et al. found FES of leg muscles resulted in increase of cardiac output and stroke volume in 6 males with paraplegia performing maximal arm-crank exercise. These results suggest that FES of leg muscles could alleviate the lower limb pooling effect during the orthostatic challenge. Chi et al. (2009) suggest that the alleviation of the pooling effect could be further enhanced when FES of leg muscles is combined with passive mobilization. The clinical utility of this combination must be examined further in subjects with SCI because subjects in Chi et al. (2009) were able-bodied.
FES results in a dose-dependent increase in BP independent of stimulation site that may be useful in treating OH (Sampson et al. 2000) and may be an important treatment adjunct to minimize cardiovascular changes during postural orthostatic stress in individuals with acute SCI. Three level 2 RCTs (Faghri & Yount 2002; Elokda et al. 2000; Sampson et al. 2000) and five non-randomized controlled trials (Chao & Cheing 2005; Raymond et al. 2002; Faghri et al. 2001; Faghri et al. 1992; Davis et al. 1990) with small sample sizes provide support for use of FES in individuals with SCI.FES of the lower extremity could be used by persons with SCI as an adjunct during standing to prevent OH and circulatory hypokinesis. An FES-induced leg muscle contraction is an effective adjunct treatment to delay OH caused by tilting; it allows people with tetraplegia to stand up more frequently and for longer durations (Elokda et al. 2000; Sampson et al. 2000). This effect may be more beneficial to those with tetraplegia who have a greater degree of decentralized cardiovascular autonomic control and may not be able to adjust their hemodynamics to the change in position (Faghri et al. 2001).
Current protocols predominantly evaluate BP after a single application of FES with a single change in position. The feasibility and practicality of implementing FES to influence orthostatic BP throughout the whole day needs to be further explored.
Following exercise, individuals with SCI may experience improvements in the autonomic regulation of their cardiovascular system (Lopes et al. 1984). Exercise, or even passive movement of the legs, could potentially attenuate reduced central blood volume in individuals with SCI during an orthostatic challenge. For example, Dela et al. 2003, found a pronounced increase in BP in individuals with tetraplegia when their legs were passively moved on a cycle ergometer. There is also some evidence that exercise training could enhance sympathetic outflow in individuals with SCI, as shown by an increase in catecholamine response to maximal arm ergometry exercise (Bloomfield et al. 1994).
Table 8: Exercise on OH in SCI
Only three exercise studies have attempted to assess the effect of exercise on orthostatic tolerance in subjects with SCI and these reports are very diverse in protocol. Lopes et al. (1984) found no effects on orthostatic tolerance with the addition of upper extremity exercises during a progressive HUT protocol. Such findings are not surprising given the small muscle mass involved in the upper limbs and the fact that venous pooling occurs primarily in the lower limbs. Ditor et al. (2005) demonstrated that individuals with incomplete tetraplegia retain the ability to make positive changes in cardiovascular autonomic regulation with BWSTT. However, six months of BWSTT did not adversely affect the orthostatic tolerance in subjects with SCI. The authors found this encouraging as it suggests that orthostatic tolerance is retained after exercise training, even though this intervention probably reduced peripheral vascular resistance. Otsuka et al. (2008) found that individuals with complete tetraplegia who were involved in regular physical activity training (2 hrs/day, 2 days/wk, ≥2 yrs) demonstrated greater orthostatic tolerance to orthostatic stress than inactive individuals with SCI (<30 mins/wk).
Active stand training that emphasizes active weight bearing is thought to stimulate the neuromuscular system below the level of injury in individuals with SCI and may affect the response to orthostatic stress by increasing venous return (Harkema et al. 2008).
Table 9: Standing on OH in SCI
Only one study examines the effect of active stand training using the body weight support treadmill system on cardiovascular function among individuals with complete SCI. Harkema et al., (2008) found that after 80 sessions (60 mins 5x/wk) of active stand training, individuals with complete cervical SCI demonstrated increased resting blood pressure and improvements in the cardiovascular responses to standing.
The major part of our present understanding of pathophysiology and management of incapacitating symptoms of OH is derived from the management of this condition in individuals with both central autonomic neurodegenerative disorders, such as multiple system atrophy and Parkinson’s disease, and peripheral autonomic disorders, such as the autonomic peripheral neuropathies and pure autonomic failure (Freeman 2003; Mathias 1995). From previous studies in non SCI individuals it is well established that combining patient education with the use of pharmacological and non-pharmacological modalities could lead to successful management of OH. The therapeutic goal for management of OH is not to normalize the BP values but rather to ameliorate symptoms while avoiding side effects. (Kaufmann et al. 2006) The general approach to management of OH is that the therapeutic interventions should be implemented in stages dependent upon the severity of symptoms (Kaufmann et al. 2006). It is also well known from previous studies in non-SCI population that nonpharmacologic measures alone are often insufficient to prevent symptoms of OH. Pharmacological interventions are needed, particularly in SCI patients with moderate to severe OH symptoms.
Although a wide array of physical and pharmacological measures are recommended for the general management of OH (Kaufman et al. 2006), very few have been evaluated for use in SCI. Of the pharmacological interventions, only midodrine has some evidence supporting its use and FES is one of the only non-pharmacological interventions having limited evidence to support efficacy. Furthermore, the number of studies addressing the pharmacological management of OH following SCI are few and most are case reports comprised of a small sample size. It is often difficult to determine the effects of individual medications when they are used in combination therapies. Nonetheless, Midodrine hydrochloride should be included in the management protocol of OH in individuals with SCI while further research is needed to quantify the effects of the many pharmacological interventions which have been shown to be effective in other conditions of neurogenic OH.