Once the diagnosis of an SCI has been established, prevention of decubiti, maintenance of adequate oxygenation and hemodynamic parameters, the role of pharmacologic and cellular interventions, and timing of surgical decompression must be considered (Table 23-1).
Prevention of Decubitus Ulcer
In the insensate patient, it is important to limit the time on a spine board (ideally, less than 2 hours) to avoid the development of ischemia of soft tissue. In patients with SCI, 8 hours on a backboard has been associated with a 95% likelihood that a decubitus ulcer will form.38 Although the damage is done in the acute setting, the decubitus may not become evident for several days. Patients who cannot be mobilized immediately can be temorized in a rotating bed. These beds provide continuous mobilization (rotation of the bed along its longitudinal axis), improve drainage of lung secretions and ventilation, and reduce the risk of DVT and VTE.
Maintenance of Oxygenation and Hemodynamic Parameters
Maintenance of adequate arterial oxygenation and blood pressure is critical as ischemia, whether as a result of hypoxia or decreased perfusion, may potentiate secondary injury of the spinal cord. Patients should be placed in intensive care during the acute phase of care to ensure these parameters are optimized. Central venous and indwelling arterial catheters can be used to monitor hemodynamic parameters and responses to therapy, and a Swan–Ganz catheter may be necessary. Current treatment guidelines for patients with SCI recommend maintenance of systolic blood pressure >90 mm Hg and mean arterial blood pressure between 85 and 90 mm Hg for the first week after injury.39 Although there are limited data, volume resuscitation supplemented by inotropic or chronotropic support as needed to maintain these parameters has been shown to improve neurologic outcomes.
Pharmacologic and Cellular Interventions
Neuroprotective interventions aim to attenuate the effects of secondary injury. How much secondary injury mechanisms contribute to overall neurologic deficit in patients with acute SCI is unknown. Atomic absorption spectroscopy suggests that secondary injury mechanisms may only account for 10% of the total pathology after SCI; however, the relative benefit of this small amount of preserved neural tissue may be significant.
The administration of high-dose methylprednisolone (30 mg/kg bolus followed by a 5.4 mg/kg infusion), in accordance with the findings of the second and third National Acute Spinal Cord Injury Studies (NASCIS), had been the standard of care at most North American institutions for over a decade.40 Steroids effectively limit the cellular and molecular events of the inflammatory cascade and are hypothesized to decrease the extent of secondary injury. The improvement in motor scores in the NASCIS trials, however, was minimal and, many have argued, not clinically significant. Recent criticism of the methodology (i.e., post hoc analysis) and interpretation of data from these trials has resulted in changing practice patterns, and currently, the use of methylprednisolone therapy is controversial.41–44
This is because the routine use of methylprednisolone has significant adverse side effects. In the NASCIS III trial, severe pneumonia affected twice as many patients and severe sepsis four times as many patients in the 48-hour steroid group compared with the 24-hour group. Six times as many patients died from respiratory complications in the 48-hour steroid group.40
Overall, the literature only, but not the ATLS course, supports the use of methylprednisolone within an acute time frame after injury (≤8 hours) and in adult patients with nonpenetrating injuries. Whether or not to administer steroids, however, should be individualized for each patient. The risk of infection in patients with certain comorbidities (e.g., diabetes mellitus, HIV infection) probably outweighs any potential improvement in the SCI. Additionally, patients with thoracic injuries are unlikely to improve with steroids. The ideal patient for steroid administration is young and healthy and has an incomplete injury to the cervical spinal cord.
While technically not a “drug,” systemic hypothermia is relatively noninvasive, systemically applied proposed treatment for patients with SCI. Though its use in this application was studied in the early 1990s with little success, renewed interest has resulted from its well-publicized application in Kevin Everett, an NFL football player who sustained a cervical SCI in 2007.45 He had immediate immobilization, steroids, hypothermia, and urgent surgery, though it is impossible to say which one of these contributed to his neurologic improvement. Systemic hypothermia is hypothesized to reduce the effects of secondary injury mechanisms through attenuation of the inflammatory cascade, but animal studies have had mixed results. Human clinical trials have not shown a consistent benefit, and, therefore, systemic hypothermia cannot be considered the standard of care.
Other agents under investigation such as GM1 ganglioside, naloxone, thyrotropin-releasing hormone, nimodipine, and tirilazad mesylate have proven promising in animal studies, also, but have not demonstrated sufficient efficacy in clinical trails.
Minocycline, erythropoietin, neurotrophic growth factors, and cellular therapies are promising neuroprotective agents and are being investigated. Minocycline, a tetracycline derivative, exhibits its neuroprotective properties by inhibiting matrix metalloproteinases, microglial activation (both are present during neuroinflammation), and preventing cell apoptosis.46 The administration of minocycline shortly after an experimentally induced SCI increased axonal sparing, reduced the apoptotic demise of oligodendrocytes, diminished axonal death, and culminated in improved locomotor and behavioral outcomes in animals.47 Erythropoietin, a hormone produced primarily by the kidney in response to hypoxia, has proven to be especially capable of minimizing SCI in ischemic models based on aortic occlusion.48 It has prevented motor neuron apoptosis and promoted motor functional recovery in animal models of SCI. Interestingly, erythropoietin reduced lipid peroxidation at the site of injury to a greater extent than methylprednisolone at the doses recommended in the Second National Acute Spinal Cord Injury Study (NASCIS II).
Recently, there has been a renewed interest in applying neurotrophic factors, growth factors, cytokines, and various forms of cell therapies in the treatment of SCI. Neurite outgrowth at the site of injury can be inhibited by myelin, myelin-associated protein (MAG), and Nogo protein.49 The application of specific Nogo receptor blockers facilitates axonal sprouting and enhanced functional recovery in rats. Both brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factors (GDNF) increase the levels of cyclic adenosine monophosphate (cAMP) in neurons and promote axonal regeneration over the long distances relevant for functional recovery of the spinal cord.50 In addition, several types of bone morphogenetic proteins (BMPs) and interleukin-6 (IL-6) are being actively investigated to elucidate their roles in triggering reparative cascades in the injured spinal cord.51
Cellular therapies aim to deliver committed or uncommitted cells locally to the injury site in an effort to restore a functionally competent cellular environment to the injured cord. The primary cell types used in this approach include Schwann cells, olfactory ensheathing cells (OECs), and uncommitted stems cells. Schwann cells have been recognized as the key cellular constituent for peripheral nerve regeneration. Several animal studies have demonstrated that transected spinal cords can be bridged with Schwann cells delivered to the site of injury where they function as chaperones, guiding the sprouting axons.52 OECs are distinct glial cells that guide the growing axons and play a crucial role in the renewal of sensory neurons within the olfactory epithelium. Unlike Schwann cells, OECs have demonstrated the unique ability to extend across glial scar within the transected cord.53 In animal models, the transplantation of OECs into a completely transected spinal cord facilitated the long-distance regeneration of corticospinal, noradrenergic, and serotonergic fibers culminating in significant functional recovery.54 Prompted by these results, many SCI centers have initiated human trials that focus on the application of putative OECs.
Uncommitted mesenchymal and hematopoietic cells in the bone marrow are particularly promising for spinal cord repair due to their apparent ability to transdifferentiate into neurons and glia without cell fusion.55 These cells have great appeal because they can be easily procured, expanded in culture, and delivered intravenously. Preclinical studies have supported the feasibility of this approach and have confirmed the ability of intravenously administered mesenchymal stem cells to target regions of intraspinal cavitation.56 Significant concerns, however, exist for the potential of developing cancer from uncontrolled differentiation of these stem cell populations in vivo.
Experimental animal models of SCI have generated a number of promising experimental neuroprotective interventions, but have also exposed the overwhelming complexity of the neurobiological challenges. A greater understanding of this technology will be necessary for the further development of the optimal therapeutic approaches to the injured spinal cord.