Orthostatic hypotension (OH) is defined as a reduction in systolic blood pressure (BP) of at least 20 mm Hg or a reduction in diastolic (BP) of at least 10 mm Hg while sitting upright or head-up tilt to 60 degrees for at least three minutes.1 A smaller drop in blood pressure may be equally important when associated with relevant symptoms that indicate impaired perfusion. Some have defined OH simply as a symptomatic fall in blood pressure in the upright posture.2 OH following spinal cord injury (SCI) is common and well-documented, most often seen with complete lesions above neurological level T6 and most severe during the acute phase.2,3
SCI may cause dysregulation in the autonomic nervous system and associated reflexes. The prevalence of OH as well as the degree of the fall in blood pressure is higher with cervical than with thoracic SCI. Low plasma volume, hyponatremia, and cardiovascular deconditioning may be additional contributing factors in some instances.3
Epidemiology including risk factors and primary prevention
OH has been reported to be more common after traumatic than nontraumatic SCI. Prevalence in acute SCI has been reported to be as high as 74%, though it depends on the population being studied.3 Symptoms are less likely to occur in SCI below the origin of the major splanchnic outflow at T6 and with incomplete injuries.
The major underlying abnormality in SCI-related OH is due to sympathetic interruption. The lack of sympathetically mediated reflex vasoconstriction, especially in large vascular beds, such as those supplying the splanchnic region and skeletal muscle result in an inability to compensate for changes in posture.3,4 The gravitational effect of venous pooling in the lower extremities is accompanied by a lack of compensatory changes in other vascular beds, leading to a fall in blood pressure. Venous pooling results in reduced filling pressure at the heart, and a decrease in the end-diastolic filling volume and stroke volume. Tachycardia may occur because of reflex vagal inhibition, but is not sufficient to compensate for the reduced sympathetic response.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
OH following SCI often, but not always, improves over time.2-4 Compensatory changes in other vascular beds may contribute to blood pressure homeostasis. Reduced blood flow to the kidneys may activate afferent glomerular dilatation and result in the stimulation of the renin-angiotensin aldosterone system. Other potential mechanisms for improvement over time include vascular wall receptor hypersensitivity, some recovery of postural reflexes at the spinal level, and increased skeletal muscle tone. Tolerance to symptoms of OH often develops over time even with continued evidence of postural reduction in blood pressure in the upright position. It has been suggested that autoregulation of cerebral blood flow, rather than systemic blood pressure, may play a dominant role in the adaptation to OH.5 In the acute stage, OH is a result of losing vasomotor tone coupled with venous pooling in the peripheral and splanchnic vasculature. In the chronic stage, OH is due to the reduction/loss of sympathetic activity below the level of the injury. Muscle atrophy below the level of the lesion also contributes to venous pooling in the lower extremity.6,7
Specific secondary or associated conditions and complications
Postural hypotension may be influenced by several factors, many of which are reversible.2,3 These include rapid changes in position and prolonged recumbency. Hypotension may be worse in the morning on rising. Heavy meals may exacerbate a fall in blood pressure in response to shunting of blood to the splanchnic circulation after a meal. Physical exertion, alcohol intake, or a hot environment can precipitate hypotension by promoting vasodilatation. Sepsis and dehydration can worsen symptoms. Several medications can induce or worsen OH, which include the following common medications: tricyclic antidepressants, antihypertensives, diuretics, and narcotic analgesics. Deconditioning after prolonged bedrest exacerbates OH. The late development or worsening of OH months or years after injury may be a sign of posttraumatic syringomyelia.
2. ESSENTIALS OF ASSESSMENT
Many of the symptoms of OH occur as a result of cerebral hypoperfusion.8 These include dizziness, light-headedness, loss of consciousness, impaired concentration, and visual disturbances such as blurred vision, scotoma, tunnel vision, or color defects. Pallor or auditory deficits may also occur. Sometimes symptoms may only be nonspecific, for example generalized weakness, lethargy, or nausea. A suboccipital/paracervical headache (aka “coat hanger headache) may be a manifestation of hypoperfusion of continuously active paracervical muscles. Excess sweating may occur above the level of injury. The presence of secondary or associated factors mentioned above that could be precipitating or worsening to OH should be assessed during history taking.
Blood pressure should be measured when the patient is in the supine position and at least 3 minutes after assuming the upright position.1
OH may hinder functional assessment and participation in rehabilitation therapies because of the occurrence of symptoms with sitting up or standing. This can result in missed therapy sessions and also play a role in patient safety and falls.
Laboratory studies may be indicated to assess for associated conditions, such as sepsis or dehydration with electrolyte imbalance, and to rule out conditions, such as hypoglycemia or severe anemia, that could present with similar symptoms.
Late occurrence or worsening of OH should prompt suspicion of posttraumatic syringomyelia, and appropriate diagnostic imaging such as spinal magnetic resonance imaging is indicated.
Supplemental assessment tools
Autonomic testing may be done in specialized centers,8 but its role in SCI-related neurogenic OH is not established. Examples include testing heart rate variability with deep breathing and during Valsalva maneuver, and a head-up tilt table test as a tool for evaluation of orthostatic stress.
Early predictions of outcomes
Frequency and severity of symptoms, time upright before onset of symptoms, influence on activities of daily living, and blood pressure can provide an indication of the severity of OH or response to treatment.9 Those with incomplete or thoracic injuries are more likely to resolve rapidly, though symptoms improve in most cases irrespective of level and completeness of injury.
Social role and social support system
Severe, protracted OH can limit time in a wheelchair and curtail community participation with a negative impact on quality of life.
Reassurance about the typical time course of SCI-related OH with improvement in symptoms after the acute phase is helpful to patients and caregivers who are struggling with OH.
3. REHABILITATION MANAGEMENT AND TREATMENTS
At different disease stages
No single treatment for OH in SCI is consistently effective. Success may be increased by combining and individualizing management.3,8,9
A number of practical nonpharmacologic measures can be taken to minimize the hypotensive effects, although evidence of effectiveness in SCI is limited for some.3,8 Small, frequent meals may minimize postprandial symptoms, as well as limiting alcohol intake with meals. Patients may have greater functional capacity before a meal than in the hour following it and may be able to adjust their activities accordingly. If blood pressure is higher later in the day, physical exertion, such as exercise programs or physical therapy, may be better tolerated in the afternoon rather than the early morning. The nocturnal diuresis that sometimes occurs in SCI may lead to inadequate blood volume. Elevating the head of the bed by 5-10 (reverse Trendelenberg position) may reduce nocturnal diuresis, morning postural hypotension, hypovolemia, and supine hypertension, although patients may not be able to tolerate more than a few degrees of head-up tilt during the night. Rapid changes in position should be avoided, as should excessive exertion in hot environments. A review of patient medications is essential and modification may be indicated to minimize hypotensive side effects. Administering vasoactive medications with meals may be particularly disabling. Liberalizing salt and water intake may improve blood volume, although the benefit of salt loading has not been sufficiently proven in people with SCI. Abdominal binders and compressive stockings may be used in an attempt to reduce venous pooling through decreased capacitance of leg and abdominal vascular beds. However, donning these may present practical problems for people with SCI and there is conflicting evidence of effectiveness. Repeated and gradual increase in postural challenges, such as with the use of a tilt-table, may be useful in the acute stages. A tilt-in-space or reclining wheelchair is beneficial for accommodating a progressive increase in the sitting angle and also allows reclining in response to symptoms. Evidence for use of body weight-supported treadmill training to improve orthostatic tolerance is currently insufficient. There is some evidence to support a role for functional electrical stimulation (FES) in the treatment of OH in SCI.3 FES-induced contraction of leg muscles may increase venous return and increase cardiac output and stroke volume that can increase blood pressure and decrease hypotension-related symptoms. The response appears to be dose dependent and independent of the site of stimulation. Further research in this area is warranted. Biofeedback has also been tried for the management of OH in SCI.
Several drugs have been used to treat OH, though effectiveness varies.7,8 The drugs for which there has been the most experience in use for SCI-related OH include fludrocortisone and midodrine (Table 1).3,10 Of these, only Midodrine is currently approved by the Food and Drug Administration (FDA) for the treatment of neurogenic OH.7,9,10
Table 1. Pharmacological Agents used in the Treatment of OH in SCI13
Commonly used in SCI
|Midodrinea||Increases arteriolar and venous tone via vasoconstriction, increasing standing, sitting, and supine systolic/diastolic blood pressure||10 mg PO TID during daylight hours||Use with caution in patients with renal impairment. Recommend starting dose is 2.5 mg|
|Fludrocortisone||Expanding intravascular volume through increasing sodium reabsorption from the distal tubules, enhances the sensitivity of α-adrenoreceptors||0.1 mg PO daily. Can be uptitrated per week as needed to 0.3 mg daily||N/A|
Potentially useful, though experience in SCI is limited
|Droxidopa||Synthetic amino acid analog metabolized directly to norepinephrine by dopadecarboxylase inducing peripheral arterial and venous vasoconstriction||100 mg PO TID. Can be uptitrated every 24-48 hours as needed to max dose of 1800 mg daily||N/A|
|Atomoxetine||Selectively inhibits the reuptake of norephinephrine with little to no activity at the other neuronal reuptake pumps or receptor||18 mg PO daily||Moderate hepatic impairment (Child-Pugh class B): doses should be reduced to 50%. Severe hepatic impairment (Child-Pugh class C): doses should be reduced to 25%|
|Pyridostigmine||Prevents the metabolism of acetylcholine and increase tone via action on the nicotinic receptor||60 mg PO TID||Lower initial doses may be required in patients with renal impairment|
|Octreotide||Mimics natural somatostatin by inhibiting serotonin release and the secretion of gastin, VIP, insulin, glucagon, secretin, motilin, and pancreatic polypeptide||12.5-25 micrograms PO daily||N/A|
a Only midodrine is FDA-approved for the indication of orthostatic hypotension.10
Coordination of care
Activities requiring exertion in the upright position should not be scheduled first thing in the morning when orthostatic tolerance is lowest or right after meals; therefore, a therapy schedule may need to be adjusted accordingly.
Patient & family education
Counseling about avoidance of exacerbating factors and measures that patients and caregivers can take is helpful. For example, patients should be advised to move from a supine to upright position gradually, especially in the morning and to avoid exertion in hot weather.
The goal of treatment is to alleviate the disability caused by symptoms, rather than to achieve an optimal target blood pressure reading. Ensuring patient safety should continue to be a priority while optimizing the patient so that they can carry out the prescribed therapy.
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
Patients with coexisting OH and supine hypertension are especially challenging to manage, and require careful titration and trial of medications.7,9 Short-acting antihypertensive agents at night, for example a nitroglycerin patch, may help control nocturnal hypertension without exacerbating daytime OH. Raising the head end of the bed may also mitigate nocturnal supine hypertension.
CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
Cutting edge concepts and practice
Droxidopa, a synthetic amino acid precursor of epinephrine, is being studied for use in SCI-related OH.12 A recent 2017 study in Spain found that droxidopa at the 300 mg BID dose increased BP levels and improved patient symptoms and may be appropriate option to consider in cases refractory to physical and pharmacologic interventions.13 A study was also published with data from a VA Hospital showing that 400 mg dose of droxidopa did not cause excessive increases in supine BP and was effective at increasing seated BP for up to 3 hours in SCI patients.14 The variance in dosage suggests that more studies must be done to arrive at a consensus. The norepinephrine reuptake inhibitor, atomoxetine, is also being studied but neither droxidopa nor atomoxetine are currently FDA-approved for the treatment of OH.10
GAPS IN THE EVIDENCE-BASED KNOWLEDGE
Gaps in the evidence-based knowledge
Given the lack of consistently effective treatment, current emerging therapies need to be further examined and newer therapies need to be developed. Well-designed controlled studies for current treatments are very limited.3 Lack of post-marketing efficacy studies led to threats of withdrawal of FDA approval of midodrine for neurogenic OH in 2010, but an extension was granted contingent on additional studies by the manufacturer.15 Newer medications which show promising initial results such as droxidopa and atomoxetine also require extensive studies over the long term.
- Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, et al. Consensus statement on the definition of orthostatic hypotension, neutrally mediated syncope and the postural tachycardia syndrome. Clin Auton Res 2011:21(2):69-72.
- Nobunaga AI. Orthostatic hypotension in spinal cord injury. Top Spinal Cord Inj Rehabil. 1997;4:73-80.
- Krassioukov A, Warburton DER, Teasell RW, Eng JJ. Orthostatic hypotension following spinal cord injury. In: Eng JJ, Teasell RW, Miller WC, Wolfe DL, Townson AG, Aubut J, Abramson C, Hsieh JTC, Connolly, S, eds. Spinal Cord Injury Rehabilitation Evidence. Vancouver, Canada: SCIRE Project; 2006:16.1-16.7.
- Teasell RW, Arnold MO, Krassioukov A, et al. Cardiovascular consequences of loss of supraspinal control of the sympathetic nervous system after spinal cord injury. Arch Phys Med Rehabil. 2000;81:506-516.
- Gonzalez F, Chang JY, Banovac K, et al. Autoregulation of cerebral blood flow in patients with orthostatic hypotension after spinal cord injury. Paraplegia. 1991;29:1-7.
- Philips AA, Krassioukov AV. Contemporary Cardiovascular Concerns after Spinal Cord Injury: Mechanisms, Maladaptations, and Management. J Neurotrauma. 2015 Dec 15;32(24):1927-42
- Krassioukov A, Eng JJ, Warburton DE, Teasell R. A system review of the management of orthostatic hypotension after spinal cord injury. Arch Phy Med Rehabil. 2009 May:90(5):876-85.
- Freeman R. Clinical practice. Neurogenic orthostatic hypotension. N Engl J Med. 2008;358:615-24.
- Low PA, Singer W. Management of neurogenic orthostatic hypotension: an update. Lancet Neurol. 2008;7:451-458.
- Hale GM, Valdes J, Brenner M. A review of the Treatment of primary Orthostatic Hypotension. The Annals of Pharmacotherapy. 2017 May;51(5):417-428.
- Groomes TE, Huang CT. Orthostatic hypotension after spinal cord injury: treatment with fludrocortisone and ergotamine. Arch Phys Med Rehabil. 1991;72:56-58.
- Kaufmann H. L-dihydroxyphenylserine (Droxidopa): a new therapy for neurogenic orthostatic hypotension: the US experience. Clin Auton Res. 2008;18 Suppl 1:19-24.
- Canosa-Hermida E, Mondelo-Garcia C, et al. Refractory orthostatic hypotension in a patient with spinal cord injury: Treatment with droxidopa. J Spinal Cord Med. 2017 Jan 24:1-4
- Wecht JM, Rosado-Rivera D, Weir JP, Ivan A, Yen C, Bauman WA. Hemodynamic effects of L-threo-3,4-dihydroxyphenylserine (Droxidopa) in hypotensive individuals with spinal cord injury. Arch Phys Med Rehabil. 2013 Oct:94(10):2006-12.
- Mitka M. Trials to address efficacy of midodrine 18 years after it gains FDA approval. JAMA. 2012;307:1124-1127.
Sabharwal S. Orthostatic Hypotension. In: Sabharwal S, ed. Essentials of Spinal Cord Medicine. New York, NY: Demos Publishing; 2014:257-262.
Vincent Huang, MD
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Raman Sharma, MD
Nothing to Disclose
Sunil Sabharwal, MD
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