Pharmacologic Treatment of Spinal Cord Injury

h1 class=”calibre8″>26 Pharmacologic Treatment of Spinal Cord Injury

Swetha J. Sundar and Michael P. Steinmetz

Abstract

Spinal cord injury (SCI) causes irreversible damage to neuronal pathways and structures, both through the initial insult itself (termed primary injury) and through a complex set of biochemical processes that act to worsen the damage (termed secondary injury). The various mechanisms through which this secondary injury occurs, including ischemic damage, lipid peroxidation, endogenous opioid release, inflammation, and free radical changes, all present potential targets for medical therapy for the body to attempt neurorestoration. In this chapter, we will discuss the use of pharmacologic agents such as corticosteroids, riluzole, lithium, glyburide, gangliosides, naloxone, signaling proteins, and tetracycline that work to mitigate secondary injury after SCI. We will also discuss the roles of blood pressure control and therapeutic hypothermia in minimizing injury following SCI.

Keywords: spinal cord injury, secondary injury, corticosteroids, neurorestoration

26.1 Introduction

Traumatic spinal cord injury (SCI) causes irreversible damage to neuronal pathways through numerous pathophysiologic mechanisms, prompting a multifaceted management schema. In the United States, it is estimated that about 250,000 individuals suffer acute SCI annually, with a 6.3% 1-year mortality rate, significant morbidity and disability to affected individuals, and nearly 10 million dollars in annual costs to the health care system. ¹^,²^,³ Irreversible changes to neuronal components can occur as soon as within 1 hour of initial injury and continue for several days. Presenting factors such as neurologic deficits, age, respiratory status, and level of consciousness can be predictors of survival and better outcomes. Death of SCI patients is usually due to complications secondary to extent of neurologic damage and length of hospital stays, including respiratory failure, cardiac arrest, septicemia, pulmonary embolism, or suicide. ⁴^,⁵^,⁶ About half of these complications manifest within 1 week of presentation and 75% within 2 weeks, highlighting the importance of optimizing early management protocols of SCI patients.

26.2 Pathophysiology

Both physical and biochemical processes in the spinal cord following acute trauma contribute to the loss of neurologic function. Primary injury is caused directly by mechanical forces at initial impact. ⁷ Compression of the spinal cord can be transient, such as in hyperextension injuries in patients with advanced cervical degenerative disease (which momentarily reduce the AP diameter of the canal), or persistent, in instances of burst fractures with bony retropulsion or fracture-dislocations. Patients with constant compression are most likely to benefit from urgent surgical intervention to decompress neural elements. ⁸^,⁹ Primary injury can also occur through direct laceration or transection of the cord when there are severe distraction injuries, penetrating traumas, or sharp bony fragments in the canal. The transmission of energy to the cord associated with penetrating trauma can cause ischemia by interrupting vascular supply. ¹⁰^,¹¹ Mechanical forces preferentially damage the gray matter, which sustains irreversible damage within 1 hour of acute injury. ⁷ Surgery can halt the primary injurious process by decompressing the spinal cord, but otherwise, minimizing effects of the traumatic insult can only come by avoiding the injury itself.

Minutes to hours after the primary injury occurs, a complicated, diverse cascade of biochemical pathways become activated, which entail the secondary injury. ¹²^,¹³ This process will expand the initial impact through a variety of mechanisms including ischemia, free radical damage, lipid peroxidation, neuronal apoptosis, electrolyte imbalances, inflammatory processes, and neurogenic shock. Secondary injury is a time-sensitive process that worsens the extent of injury and limits the body’s attempts at neurorestoration. Damage to microvasculature results in ischemia and hemorrhage, leading to regions of infarcts, increases in lactic acid, and edema. Release of endogenous opioids in response to the initial trauma leads to hypotension and worsening cord ischemia. The autoregulation of the microcirculation becomes disrupted and can cause reperfusion damage to areas of initial infarct. ¹⁴^,¹⁵ Neurologic function can be compromised due to increases in intracellular K⁺, causing membrane depolarization and decreased adenosine triphosphate (ATP) production. Ischemic damage generates oxidized free radicals in nonphysiologic quantities, causing a self-propagating cascade of oxidative damage to cell membranes via lipid peroxidation. Intracellular Ca²⁺ rises and calcium-dependent enzymes become activated as well. Mitochondria are damaged due to oxidative stress, and ultimately, the combined result of these biochemical processes is cellular necrosis and apoptosis. ¹⁶ Knowledge of these pathways allows for medical therapies that specifically target mechanisms to limit neuronal damage and loss of function after initial injury.

26.3 Medical Management in ICU Setting

Minimizing the secondary injury is an important focus of treating SCI. These patients are best served in an intensive care unit (ICU), which allows for strict blood pressure control and close monitoring of respiratory function.

26.4 Maintaining Perfusion

SCI patients can often be hypotensive, not only from acute volume loss due to trauma, but also because of loss of sympathetic tone, microvascular damage, inflammation, and impaired autoregulatory processes. Patients who initially present with hypotension are noted to have poor long-term outcomes compared to those presenting in a normotensive state. ¹⁰^,¹⁷^,¹⁸^,¹⁹^,²⁰ Optimizing oxygenation and perfusion to the cord is the immediate goal of resuscitating SCI patients. Research demonstrates improved outcomes when mean arterial pressure (MAP) is kept greater than 85 mm Hg. ¹⁷^,²¹^,²²^,²³^,²⁴ If fluid resuscitation with crystalloids and/or colloids is not successful in maintaining MAPs, patients should have blood pressure augmentation with pressors. The Guidelines for the Management of Acute Cervical Spine and Spinal Cord Injuries recommend keeping MAPs greater than 85 mm Hg for 1 week, when the cord is most susceptible to autoregulation dysfunction. ²⁵ The desire to increase perfusion must be balanced with the risk of hemorrhage and worsening edema. Additionally, patients with high cervical injury can be hypoxic from impaired respiratory function, secondary to diaphragmatic paralysis, loss of accessory muscle function, or direct neck/tracheal trauma; in these cases, early intubation may be considered. ²⁶

26.5 Hypothermia

Therapeutic hypothermia has demonstrated neuroprotective properties for pathologies where edema and oxidative stress mediate neuronal damage, such as cardiac arrest, stroke, and traumatic brain injury. ²⁷^,²⁸^,²⁹^,³⁰^,³¹ In traumatic SCI, animal evidence supports that hypothermia is efficacious in improving outcomes in mild to moderate cases. ³² Cooling (32–34°C) can decrease oxidative stress, limit apoptosis, minimize neuronal swelling, and inhibit the inflammatory process in instances of SCI. However, all the patient’s injuries and management goals need to be considered because systemic hypothermia can increase infectious complications and/or impair respiratory status. ³³

26.6 Pharmacologic Agents

26.6.1 Methylprednisolone

The use of corticosteroids for patients with SCI has been repeatedly studied in animal and human models and remains a controversial topic. Methylprednisolone (MP) is a glucocorticoid that is thought to minimize secondary injury by protecting lipid membranes, increasing Na⁺/K⁺ ATPase activity, reducing inflammation, and scavenging free radicals to minimize lipid peroxidation. When excess Ca²⁺ influx is halted, it is believed that lysosomes and protease release is prevented. ³⁴^,³⁵^,³⁶^,³⁷^,³⁸

The debate regarding MP use for post-SCI stems in part from inconsistent conclusions between multiple animal and human studies. Many studies utilizing MP have demonstrated reductions in lipid peroxidation at various time points. However, animal studies have concluded no functional benefits. ³⁹^,⁴⁰^,⁴¹^,⁴²^,⁴³^,⁴⁴^,⁴⁵^,⁴⁶^,⁴⁷ The administration of MP is not risk-free, with side effects of hyperglycemia, gastrointestinal hemorrhage, increased infection risk, and myopathy; the extent of traumatic injury and patient comorbidities must be taken into account when considering its use. ⁴⁸

There have been three major clinical trials examining the use of MP for acute SCI, known as the National Acute Spinal Cord Injury Studies (NASCIS). The NASCIS I was a randomized control trial where MP was administered within 48 hours of injury and patients were randomized to receiving either 100 or 1,000 mg over 10 days total. ⁴⁹^,⁵⁰ Patient outcomes were analyzed at 6 weeks and 6 months, and there were no significant differences demonstrated between the two groups. The patients in the 1,000-mg group did have more wound infections.

The main criticism of the NASCIS I is that dosages of MP were inappropriately low to demonstrate efficacy. This was adjusted for the NASCIS II, a prospective randomized control trial where patients were given either MP, naloxone, or a placebo. The MP group received an initial bolus of 30 mg/kg followed by 5.4 mg/kg/hour infusion for 23 hours. Although overall analyses did not demonstrate significant benefits, subgroup analyses of patients receiving MP within 8 hours of nonpenetrating injuries showed significant improvements in motor and sensory functions when compared to the placebo group. The NASCIS II is largely responsible for the widespread practice of giving patients MP after acute SCI in the 1990s. ⁵¹^,⁵²

The NASCIS III was the subsequent trial where patients were randomized to receiving MP for 24 or 48 hours or tirilazad mesylate for 48 hours. The patients receiving 48 hours of MP post-SCI demonstrated improved motor recovery at 6 weeks and 6 months, especially when treatment was initiated within 8 hours of injury, as similarly demonstrated in the NASCIS II trial. However, there was also an increased incidence of infections in the 48-hour MP group compared to the 24-hour MP group. In the subset of patients with penetrating injury, there were no benefits shown with MP use. ⁵³

Both the NASCIS II and III have been extensively reevaluated since their initial publication, with significant criticisms—the NASCIS II for flawed study design and subgroup analysis, and NASCIS III due to clinically insignificant differences in motor outcomes. These trials have failed to demonstrate relevant benefits for the treatment groups and, moreover, have repeatedly shown increased risk of infectious complications. The use of MP for acute SCI patients remains a treatment option with careful consideration of traumatic injury type and comorbidities, but is not considered a standard of care. Current level I recommendations state that MP administration for acute SCI is not recommended and is not approved by the Food and Drug Administration (FDA). ⁵⁴^,

Only gold members can continue reading. Log In or Register to continue