Pharmacological Management of Hemodynamic Complications Following Spinal Cord Injury

The damage from primary and secondary insults of spinal cord injury can result in various hemodynamic alterations. It is important to understand the presentation and time course of these changes, in addition to the management of each, to avoid further clinical deterioration and complications.

Traumatic spinal cord injury has an incidence of 10,000 cases per year with a prevalence of approximately 200,000 people in the United States.1 These numbers do not account for deaths in the field, which are estimated to occur in 16% to 30% of these cases. The patient demographics mirror that of the general trauma population with the average age around 30 years and a male predominance. Although motor vehicle collisions account for roughly half of all spinal cord injury cases, other events including assaults, falls, work-place injuries, and sporting accidents account for a large portion of the rest.2

Two phases are responsible for the damage that occurs in spinal cord injuries. The primary stage is caused by tissue destruction to the spinal pathways during the initial trauma. Whether it is from spinal cord contusion, direct compression, penetration, or maceration, the damage disrupts the afferent and efferent pathways, preventing the normal sensory function and motor responses distal to the level of injury. On a cellular level, the injury results in apoptosis and death of certain cell types, such as neurons, oligodendrocytes, astrocytes, and various precursor cells. This disrupts the ascending and descending tracts within the white matter of the spinal cord. Damage occurring within the dorsal columns or corticospinal or spinothalamic tracts are immediately detectable on physical examination through an associated loss of motor and sensory function.2-4

Secondary injury describes the damage occurring during the hours to days subsequent to the primary insult. Localized ischemia results in expansile destruction of both white and gray matter. Systemic hypotension, tissue edema, thrombosis, and vasospasm all contribute to perpetuate the injury. At a microscopic level, impaired autoregulation, endothelial damage releasing inflammatory mediators, and microvascular collapse act to potentiate the damage. The secondary damage eventually increases glial scarring and causes irreversible loss of function.2,4,5

Hemodynamic Consequences and Management

The damage from primary and secondary insults of spinal cord injury can result in various hemodynamic alterations. It is important to understand the presentation and time course of these changes, in addition to the management of each, to avoid further clinical deterioration and complications.

Neurogenic Shock

Neurogenic shock is a complication of spinal cord injury at or above the level of T6 and is manifest by a reduction in blood pressure and systemic vascular resistance caused by sympathetic denervation. Interruption in sympathetic output via the intermediolateral cell columns of the spinal cord (T1-L2, 3) results in arteriolar dilation, decreased venous return to the heart, and subsequent systemic hypotension. Neurogenic shock can occur any time after injury, from initial presentation to several weeks after the event. Without prompt treatment, the hypotension, particularly early after injury, causes hypoperfusion of the injured spinal cord leading to secondary injury.4,6

To mitigate the harmful effects of shock in patients with spinal cord injury, fluid resuscitation is used first-line to maintain perfusion. When intravenous fluids fail to reverse shock or signs of volume overload are present, vasopressors must be used.6

Although an exact target pressure has not been identified through large clinical trials, the most recent spinal cord injury guidelines suggest that blood pressure should be maintained at a mean arterial pressure of 85 to 90 mm Hg to ensure adequate spinal cord perfusion and prevent neurogenic shock.5 Two small studies are often cited to support this recommendation.7,8

Levi et al7 aimed for a goal mean arterial pressure of >90 mm Hg in their study of 50 patients with cervical spinal cord injury. Their study was not designed to evaluate this intervention’s effect on clinical outcomes but rather to show that invasive monitoring techniques should be used in the acute management of spinal cord injury.7 Vale et al8 targeted a mean arterial pressure >85 mm Hg in 64 nonpenetrating cervical or thoracic spinal cord injury patients showing improvements from baseline in American Spinal Injury Association impairment scores, ambulatory ability, and bladder function. Of note, the patients initially presenting in neurogenic shock did not experience an improvement in clinical outcomes despite their aggressive management strategy. The study lacked a control group, restricting reporting to observational findings.8 Readers are also referred to a recent review of vasopressor therapy and treatment of neurogenic shock.9

Symptomatic Bradycardia

Sympathetic denervation following spinal cord injury may be accompanied by bradycardia secondary to unopposed vagal stimulation and is typically exacerbated by endotracheal suctioning, turning, or hypoxia. Although it may resolve within 6 to 8 weeks after injury, it is an important consideration in the initial management of spinal cord injury, as it can progress to complete heart block and cardiac arrest.

Atropine, an anticholinergic agent, can be used for the acute management of symptomatic bradycardia. This option is typically used first-line in cases of bradycardia following spinal cord injury. The dose ranged from 0.4 to 0.6 mg, administered intravenously every 4 hours for short-term therapy.10-17 Atropine should be kept readily available at the bedside at all times with this patient population, as periods of bradycardia and hypotension may occur suddenly causing spinal cord ischemia, particularly early after spinal cord injury. Continuous infusions of dopamine at a rate of 2 to 10 mcg/kg/min or epinephrine at a rate of 0.01 to 0.1 mcg/kg/min may also be helpful in the acute setting.10,12,17 For those patients requiring long-term management or for those who do not respond to atropine or other chronotropic infusions, the methylxanthines or propantheline have been used either to avoid or as a bridge to pacemaker implantation. Cardiac pacing is typically required for those failing medical therapy.

The methylxanthine agents, including aminophylline and theophylline, have been used effectively for the management of refractory symptomatic bradycardia when other agents have failed.11,13-16 An intravenous or oral loading dose between 200 and 300 mg of either drug was administered in most cases with maintenance doses staring around 100 mg 3 times daily and continued for up to 12 weeks. Drug serum levels were variable and differed widely among patients. No therapeutic index for symptomatic bradycardia has been established, so the methylxanthine dose was titrated according to clinical response. No adverse effects were noted in any of the reports, but some potential methylxanthine-induced effects are nausea, vomiting, tremor, headache, seizures, or irritability. Their use has been associated with diaphragmatic strengthening in animal models, another possible beneficial effect to consider in spinal cord injury patients who potentially may be able to be weaned off mechanical ventilation.16

Two case reports describe successful treatment with propantheline 7.5 to 30 mg every 4 to 6 hours in patients requiring long-term vagolytic therapy.10,17 The propantheline was successfully tapered over the course of a few months without recurrent bradycardia.10 The main side effect reported from chronic propantheline therapy was a reduction in gastrointestinal motility due to its anticholinergic effects. Spinal cord injury patients are prone to constipation, so specific attention should be paid to this potential adverse effect to prevent an ileus or impaction.

Autonomic Dysreflexia

In addition to neurogenic shock, patients with spinal cord injury at or above the sixth thoracic vertebrae may experience autonomic dysreflexia. Autonomic dysreflexia is caused by the destruction of descending vasomotor pathways and can commence within days to weeks of injury.4 This phenomenon presents with hemodynamic instability, namely a reduction in baseline blood pressure with dangerous, intermittent elevations in pressure. Associated symptoms experienced above the level of the spinal cord lesion include vasodilation-associated problems such as headache, bradycardia, flushing, diaphoresis, nasal or conjunctival congestion, blurred vision, and nausea, while excessive cutaneous vasoconstriction, piloerection, and bladder spasm may present below the level of the lesion.

Vigilant prevention and prompt management of autonomic dysreflexia is imperative to prevent serious neurologic and cardiovascular complications that can arise such as encephalopathy, ischemic or hemorrhage strokes, seizures, arrhythmias, myocardial infarction, congestive heart failure, and potentially death. Bladder and abdominal distension often cause acute elevations in blood pressure; therefore, prevention of these triggers is of the utmost importance. Proper bladder catheterization, aggressive bladder and bowel regimens, prevention of pressure ulcers, and pain management can help alleviate patients’ discomfort and limit autonomic dysreflexia.

Anticholinergic agents, like oxybutynin and tolterodine, can be used to reduce spontaneous reflex contractions of the bladder’s detrusor muscle mediated through the parasympathetic nervous system. Oxybutynin 5 mg is administered 1 to 4 times daily, while tolterodine 2 mg is given twice daily. Both agents reduced the mean number of daily voids, urge incontinence episodes, and number of incontinence pads per 24-hour period in a randomized-controlled trial.18 Extended-release products are available for both agents, minimizing dosing to once daily for patients who can swallow. Adverse effects of the anticholinergic medications include xerostoma, urinary retention, blurred vision, and constipation. Tolterodine may be associated with less anticholinergic effects than oxybutynin.18

For those patients who do not respond to anticholinergics alone, several other pharmacologic options exist. The α-1 adrenoreceptor antagonists have been used in combination with anticholinergic agents to reduce detrusor pressure. In patients with neurogenic bladder dysfunction due to spinal cord injury, daily doses of tamsulosin 4 or 8 mg led to a reduction of maximum urethral pressure over a 1-year period (P<.001).19 Schurch et al20 investigated the use of intramuscular injections of botulinum toxin A in either 200- or 300-unit doses into the detrusor muscle in addition to a stable anticholinergic regimen and in between intermittent self-catherization, which alleviated urinary incontinence in both groups compared with placebo (P<0.05). Patients who received a 500-unit dose of botulinum toxin A for urinary leakage required less tolterodine than the placebo group (P=.003) per Ehren et al.21 Few pharmacological agents have been studied for neurogenic bowel management in spinal cord injury, but suppositories, enemas, and laxatives have been used to prevent the abdominal pain and distension that may trigger a hypertensive episode.4 Judicious consumption of high fiber foods (which may lead to abdominal bloating) or use of low residual enteral products may also be helpful in preventing autonomic dysreflexia episodes.

Orthostatic Hypotension

Similar to autonomic dysreflexia and symptomatic bradycardia, orthostatic hypotension can present during the acute or chronic stages of spinal cord injury. It is defined as a reduction in systolic blood pressure by >20 mm Hg or diastolic blood pressure by >10 mm Hg when moving from a supine to an upright position. The blood pressure decline occurs within 3 minutes of the postural change and is accompanied by symptoms of dizziness, fatigue, blurred vision, restlessness, or syncope. Orthostatic hypotension is caused by excessive venous pooling secondary to a reduction in the efferent sympathetic nervous system activity, reduced lower extremity muscle tone, and decreased venous return to the heart.

Normally, a decrease in venous return and subsequent decrease in stroke volume causes a decrease in blood pressure sensed by baroreceptors, mainly located in the aortic arch and carotid sinus. Consequentially, unloading the baroreceptors promotes sympathetic output by the hypothalamus, yielding increased sympathetic tone via the intermediolateral cell columns of the spinal cord. This in turn results in increased systemic vascular resistance, increased venous return, and a corresponding increase in systemic blood pressure. In spinal cord injury, the parasympathetic baroreceptor reflex is usually intact, but the intermediolateral cell columns that carry the sympathetic response are damaged, thus limiting the body’s ability to decrease venous pooling and maintain systemic blood pressure.4,22

Treatment for orthostatic hypotension aims to improve venous return to the heart, either through the prevention of excessive venous pooling or plasma volume expansion. Maintaining a supine position and elevating the lower extremities can help alleviate the symptoms of orthostatic hypotension. Midodrine, other oral vasopressor agents, and fludrocortisone are all treatment options for orthostatic hypotension and can be an alternative when positioning is not enough to overcome symptoms.22 Selection of agents used for orthostatic hypotension should be based on the patient’s symptoms and comorbid disease states to maximize effect while avoiding any predictable, untoward adverse effects.

Midodrine is a sympathomimetic α-1 agonist that causes vasoconstriction with a subsequent increase in peripheral vascular resistance, improving venous return to the heart.23 It has been used for orthostatic hypotension in doses of 2.5 to 10 mg, 3 times daily, administered every 3 or 4 hours while the patient is in an upright position.23,24 Midodrine is well-absorbed, does not cross the blood brain barrier, and has a short duration of action, minimizing supine hypertension. Common adverse effects include piloerection, paresthesias, and pruritus.23

Similarly to midodrine, other oral vasopressors, including ephedrine, pseudoephedrine, and phenylpropanolamine, increase venous return to the heart through direct action on α-adrenoreceptors. Ephedrine also acts as a non-selective β-agonist and has more central sympathomimetic effects than pseudoephedrine or phenylpropanolamine as a result.25 In studies of patients with orthostatic hypotension, ephedrine 25 to 50 mg, pseudoephedrine 30 to 60 mg, and phenylpropanolamine 12.5 to 25 mg, administered 3 times per day have been used.24,26,27 Adverse reactions associated with direct sympathomimetics include headache, diaphoresis, tremor, and insomnia. Phenylpropanolamine has been largely replaced by pseudoephedrine in the United States market due to the possible risk of hemorrhagic stroke.26,27

In contrast to midodrine and oral vasopressors, fludrocortisone expands plasma volume secondary to enhanced renal sodium reabsorption and water retention. Initial oral doses of 0.1 to 0.2 mg daily titrated to effect have been used for orthostatic hypotension. As a result of its mineralocorticoid activity, fludrocortisone is associated with supine hypertension, pitting ankle edema, hypokalemia, and potential worsening of congestive heart failure.28,29

By Deanna McMahon, PharmD, BCPS; Matthew Tutt, MD; Aaron M. Cook, PharmD
ORTHOPEDICS 2009; 32:331

The Bottom Line

  • Spinal cord injury is often associated with neurogenic hemodynamic alterations, which should be anticipated and promptly reated to prevent further damage to the spinal cord and other systemic complications.
  • Resuscitation with fluid and intravenous vasopressors is used in initial neurogenic shock to maintain an appropriate mean arterial pressure target to prevent further spinal cord ischemia.
  • The methylxanthines (aminophylline and theophylline) and propantheline are treatment options for recurrent symptomatic bradycardia when atropine is ineffective or when chronic therapy is required.
  • First-line management of autonomic dysreflexia includes identification and removal of triggers.
  • Midodrine, oral vasopressors, or fludrocortisone may improve symptoms of orthostatic hypotension.


1. Dawodu S. Spinal cord injury: definition, epidemiology, pathophysiology. eMedicine from WebMD. Updated March 30, 2009. Accessed February 5, 2009.
2. Stevens RD, Bhardwaj A, Kirsch JR, Mirski MA. Critical care and perioperative management in traumatic spinal cord injury. J Neurosurg Anesthesiol. 2003; 15(3):215-229.
3. Thuret S, Moon LD, Gage FH. Therapeutic interventions after spinal cord injury. Nat Rev Neurosci. 2006; 7(8):628-643.
4. Krassioukov A, Claydon VE. The clinical problems in cardiovascular control following spinal cord injury: an overview. Prog Brain Res. 2006; (152):223-229.
5. Blood pressure management after acute spinal cord injury. Neurosurgery. 2002; 50(3 Suppl):S58-S62.
6. Consortium for Spinal Cord Medicine. Early acute management in adults with spinal cord injury: a clinical practice guideline for health-care professionals. J Spinal Cord Med. 2008; 31(4):403-479.
7. Levi L, Wolf A, Belzberg H. Hemodynamic parameters in patients with acute cervical cord trauma: description, intervention, and prediction of outcome. Neurosurgery. 1993;33(6):1007-1016; discussion 1016-1007.
8. Vale FL, Burns J, Jackson AB, Hadley MN. Combined medical and surgical treatment after acute spinal cord injury: results of a prospective pilot study to assess the merits of aggressive medical resuscitation and blood pressure management. J Neurosurg. 1997; 87(2):239-246.
9. Stratman RC, Wiesner AM, Smith KM, Cook AM. Hemodynamic management after spinal cord injury. Orthopedics. 2008;31(3):252-256.
10. Abd AG, Braun NM. Management of life-threatening bradycardia in spinal cord injury. Chest. 1989; 95(3):701-702.
11. Pasnoori VR, Leesar MA. Use of aminophylline in the treatment of severe symptomatic bradycardia resistant to atropine. Cardiol Rev. 2004; 12(2):65-68.
12. Piepmeier JM, Lehmann KB, Lane JG. Cardiovascular instability following acute cervical spinal cord trauma. Cent Nerv Syst Trauma. 1985; 2(3):153-160.
13. Sakamoto T, Sadanaga T, Okazaki T. Sequential use of aminophylline and theophylline for the treatment of atropine-resistant bradycardia after spinal cord injury: a case report. J Cardiol. 2007; 49(2):91-96.
14. Schulz-Stubner S. The use of small-dose theophylline for the treatment of bradycardia in patients with spinal cord injury. Anesth Analg. 2005; 101(6):1809-1811.
15. Weant KA, Kilpatrick M, Jaikumar S. Aminophylline for the treatment of symptomatic bradycardia and asystole secondary to cervical spine injury. Neurocrit Care. 2007; 7(3):250-252.
16. Whitman CB, Schroeder WS, Ploch PJ, Raghavendran K. Efficacy of aminophylline for treatment of recurrent symptomatic bradycardia after spinal cord injury. Pharmacotherapy. 2008; 28(1):131-135.
17. Winslow EB, Lesch M, Talano JV, Meyer PR Jr. Spinal cord injuries associated with cardiopulmonary complications. Spine. 1986; 11(8):809-812.
18. Malone-Lee J, Shaffu B, Anand C, Powell C. Tolterodine: superior tolerability than and comparable efficacy to oxybutynin in individuals 50 years old or older with overactive bladder: a randomized controlled trial. J Urol. 2001; 165(5):1452-1456.
19. Abrams P, Amarenco G, Bakke A, et al. Tamsulosin: efficacy and safety in patients with neurogenic lower urinary tract dysfunction due to suprasacral spinal cord injury. J Urol. 2003; 170(4 Pt 1):1242-1251.
20. Schurch B, de Seze M, Denys P, et al. Botulinum toxin type a is a safe and effective treatment for neurogenic urinary incontinence: results of a single treatment, randomized, placebo controlled 6-month study. J Urol. 2005; 174(1):196-200.
21. Ehren I, Volz D, Farrelly E, et al. Efficacy and impact of botulinum toxin A on quality of life in patients with neurogenic detrusor overactivity: a randomised, placebo-controlled, double-blind study. Scand J Urol Nephrol. 2007; 41(4):335-340.
22. Sclater A, Alagiakrishnan K. Orthostatic hypotension. A primary care primer for assessment and treatment. Geriatrics. 2004; 59(8):22-27.
23. Wright RA, Kaufmann HC, Perera R, et al. A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension. Neurology. 1998; 51(1):120-124.
24. Fouad-Tarazi FM, Okabe M, Goren H. Alpha sympathomimetic treatment of autonomic insufficiency with orthostatic hypotension. Am J Med. 1995; 99(6):604-610.
25. Freeman R. Treatment of orthostatic hypotension. Semin Neurol. 2003; 23(4):435-442.
26. Jordan J, Shannon JR, Diedrich A, Black B, Robertson D, Biaggioni I. Water potentiates the pressor effect of ephedra alkaloids. Circulation. 2004; 109(15):1823-1825.
27. Jordan J, Shannon JR, Biaggioni I, Norman R, Black BK, Robertson D. Contrasting actions of pressor agents in severe autonomic failure. Am J Med. 1998; 105(2):116-124.
28. Chobanian AV, Volicer L, Tifft CP, Gavras H, Liang CS, Faxon D. Mineralocorticoid-induced hypertension in patients with orthostatic hypotension. N Engl J Med. 1979; 301(2):68-73.
29. van Lieshout JJ, ten Harkel AD, Wieling W. Fludrocortisone and sleeping in the head-up position limit the postural decrease in cardiac output in autonomic failure. Clin Auton Res. 2000; 10(1):35-42.


Drs McMahon, Tutt, and Cook are from University of Kentucky HealthCare, Lexington, Kentucky.

Drs McMahon, Tutt, and Cook have no relevant financial relationships to disclose.

Correspondence should be addressed to: Aaron M. Cook, PharmD, 800 Rose St, H-110, Lexington, KY 40536-0293.

Copyright ® 2009 SLACK Incorporated. All rights reserved.
Exit mobile version