R. John Hurlbert

Acute spinal cord injury, part I: pathophysiologic mechanisms.

Spinal cord injury (SCI) is a devastating and common neurologic disorder that has profound influences on modern society from physical, psychosocial, and socioeconomic perspectives. Accordingly, the present decade has been labeled the Decade of the Spine to emphasize the importance of SCI and other spinal disorders. Spinal cord injury may be divided into both primary and secondary mechanisms of injury. The primary injury, in large part, determines a given patients neurologic grade on admission and thereby is the strongest prognostic indicator. However, secondary mechanisms of injury can exacerbate damage and limit restorative processes, and hence, contribute to overall morbidity and mortality. A burgeoning body of evidence has facilitated our understanding of these secondary mechanisms of injury that are amenable to pharmacological interventions, unlike the primary injury itself. Secondary mechanisms of injury encompass an array of perturbances and include neurogenic shock, vascular insults such as hemorrhage and ischemia–reperfusion, excitotoxicity, calcium-mediated secondary injury and fluid–electrolyte disturbances, immunologic injury, apoptosis, disturbances in mitochondrion function, and other miscellaneous processes. Comprehension of secondary mechanisms of injury serves as a basis for the development and application of targeted pharmacological strategies to confer neuroprotection and restoration while mitigating ongoing neural injury. The first article in this series will comprehensively review the pathophysiology of SCI while emphasizing those mechanisms for which pharmacologic therapy has been developed, and the second article reviews the pharmacologic interventions for SCI.

The role of steroids in acute spinal cord injury: an evidence-based analysis.

STUDY DESIGN Literature review. OBJECTIVES The purpose of this article is to review the available literature and formulate evidence-based recommendations for the use of methylprednisone in the setting of acute spinal cord injury (SCI). SUMMARY OF BACKGROUND DATA Since the early 1990s, methylprednisolone has become widely prescribed for the treatment of acute SCI. Arguably, it has become a standard of care. METHODS Through an electronic database search strategy and by cross-reference with published literature, appropriate clinical studies were identified. They were reviewed in chronologic order with respect to study design, outcome measures, results, and conclusions. RESULTS Nine studies were identified that attempted to evaluate the role of steroids in nonpenetrating (blunt) spinal cord injury. Five of these were Class I clinical trials, and four were Class II studies. All of the studies failed to demonstrate improvement because of steroid administration in any of the a priori hypotheses testing. Although post hoc analyses were interesting, they failed to demonstrate consistent significant treatment effects. CONCLUSIONS From an evidence-based approach, methylprednisolone cannot be recommended for routine use in acute nonpenetrating SCI. Prolonged administration of high-dose steroids (48 hours) may be harmful to the patient. Until more evidence is forthcoming, methylprednisolone should be considered to have investigational (unproven) status only.Study Design. Literature review. Objectives. The purpose of this article is to review the available literature and formulate evidence-based recommendations for the use of methylprednisone in the setting of acute spinal cord injury (SCI). Summary of Background Data. Since the early 1990s, methylprednisolone has become widely prescribed for the treatment of acute SCI. Arguably, it has become a standard of care. Methods. Through an electronic database search strategy and by cross-reference with published literature, appropriate clinical studies were identified. They were reviewed in chronologic order with respect to study design, outcome measures, results, and conclusions. Results. Nine studies were identified that attempted to evaluate the role of steroids in nonpenetrating (blunt) spinal cord injury. Five of these were Class I clinical trials, and four were Class II studies. All of the studies failed to demonstrate improvement because of steroid administration in any of the a priori hypotheses testing. Although post hoc analyses were interesting, they failed to demonstrate consistent significant treatment effects. Conclusions. From an evidence-based approach, methylprednisolone cannot be recommended for routine use in acute nonpenetrating SCI. Prolonged administration of high-dose steroids (48 hours) may be harmful to the patient. Until more evidence is forthcoming, methylprednisolone should be considered to have investigational (unproven) status only.

Pharmacological Therapy for Acute Spinal Cord Injury

• Administration of methylprednisolone (MP) for the treatment of acute spinal cord injury (SCI) is not recommended. Clinicians considering MP therapy should bear in mind that the drug is not Food and Drug Administration (FDA) approved for this application. There is no Class I or Class II medical evidence supporting the clinical benefit of MP in the treatment of acute SCI. Scattered reports of Class III evidence claim inconsistent effects likely related to random chance or selection bias. However, Class I, II, and III evidence exists that high-dose steroids are associated with harmful side effects including death. • Administration of GM-1 ganglioside (Sygen) for the treatment of acute SCI is not recommended.

Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury

Preclinical studies have attributed neuroprotective properties to the antibiotic minocycline. Animal studies and early clinical trials support its use in several neurological diseases. In animal spinal cord injury models, minocycline improved neurological and histological outcomes, reduced neuronal and oligodendroglial apoptosis, decreased microglial activation and reduced inflammation. A single-centre, human, double-blind, randomized, placebo-controlled study of minocycline administration after spinal cord injury was undertaken for the purposes of dose optimization, safety assessment and to estimate outcome changes and variance. Neurological, functional, pharmacological and adverse event outcomes were compared between subjects administered 7 days of intravenous minocycline (n = 27) or placebo (n = 25) after acute traumatic spinal cord injury. The secondary outcome used to assess neurological differences between groups that may warrant further investigation was motor recovery over 1 year using the American Spinal Cord Injury Association examination. Recruitment and analyses were stratified by injury severity and injury location a priori given the expected influence of these on the sensitivity of the motor exam. Minocycline administered at higher than previously reported human doses produced steady-state concentrations of 12.7 µg/ml (95% confidence interval 11.6-13.8) in serum and 2.3 µg/ml (95% confidence interval 2.1-2.5) in cerebrospinal fluid, mimicking efficacious serum levels measured in animal studies. Transient elevation of serum liver enzymes in one patient was the only adverse event likely related to the study drug. Overall, patients treated with minocycline experienced six points greater motor recovery than those receiving placebo (95% confidence interval -3 to 14; P = 0.20, n = 44). No difference in recovery was observed for thoracic spinal cord injury (n = 16). A difference of 14 motor points that approached significance was observed in patients with cervical injury (95% confidence interval 0-28; P = 0.05, n = 25). Patients with cervical motor-incomplete injury may have experienced a larger difference (results not statistically significant, n = 9). Functional outcomes exhibited differences that lacked statistical significance but that may be suggestive of improvement in patients receiving the study drug. The minocycline regimen established in this study proved feasible, safe and was associated with a tendency towards improvement across several outcome measures. Although this study does not establish the efficacy of minocycline in spinal cord injury the findings are encouraging and warrant further investigation in a multi-centre phase III trial. ClinicalTrials.gov number NCT00559494.

Acute spinal cord injury, part II: contemporary pharmacotherapy.

Spinal cord injury (SCI) remains a common and devastating problem of modern society. Through an understanding of underlying pathophysiologic mechanisms involved in the evolution of SCI, treatments aimed at ameliorating neural damage may be developed. The possible pharmacologic treatments for acute spinal cord injury are herein reviewed. Myriad treatment modalities, including corticosteroids, 21-aminosteroids, opioid receptor antagonists, gangliosides, thyrotropin-releasing hormone (TRH) and TRH analogs, antioxidants and free radical scavengers, calcium channel blockers, magnesium replacement therapy, sodium channel blockers, N-methyl-D-aspartate receptor antagonists, &agr;-amino-3-hydroxy-5-methylisoxazole-4-propionic acid–kainate receptor antagonists, modulators of arachadonic acid metabolism, neurotrophic growth factors, serotonin antagonists, antibodies against inhibitors of axonal regeneration, potassium channel blockers (4-aminopyridine), paclitaxel, clenbuterol, progesterone, gabexate mesylate, activated protein C, caspase inhibitors, tacrolimus, antibodies against adhesion molecules, and other immunomodulatory therapy have been studied to date. Although most of these agents have shown promise, only one agent, methylprednisolone, has been shown to provide benefit in large clinical trials. Given these data, many individuals consider methylprednisolone to be the standard of care for the treatment of acute SCI. However, this has not been established definitively, and questions pertaining to methodology have emerged regarding the National Acute Spinal Cord Injury Study trials that provided these conclusions. Additionally, the clinical significance (in contrast to statistical significance) of recovery after methylprednisolone treatment is unclear and must be considered in light of the potential adverse effects of such treatment. This first decade of the new millennium, now touted as the Decade of the Spine, will hopefully witness the emergence of universal and efficacious pharmacologic therapy and ultimately a cure for SCI.

Guidelines for the management of acute cervical spine and spinal cord injuries: 2013 update.

In 2002, an author group selected and sponsored by the Joint Section on Spine and Peripheral Nerves of the American Association of Neurological Surgeons and Congress of Neurological Surgeons published the first evidence-based guidelines for the management of patients with acute cervical spinal cord injuries (SCIs). In the spirit of keeping up with changes in information available in the medical literature that might provide more contemporary and more robust medical evidence, another author group was recruited to revise and update the guidelines. The review process has been completed and is published and can be once again found as a supplement to Neurosurgery. The purpose of this article is to provide an overview of the changes in the recommendations as a result of new evidence or broadened scope.

Strategies of medical intervention in the management of acute spinal cord injury.

Study Design. Literature review. Objective. The purpose of this paper is to review clinical treatment strategies and future developments in the treatment of acute spinal cord injury. Summary of Background Data. The treatment of acute spinal cord injury continues to be supportive. The search for specialized pharmacologic agents to prevent secondary injury and promote repair or regeneration remains heated. Methods. Medline search from 1996 to present limited to clinical research and basic science review articles in the English Language. Results. Steroids continue to be administered in the clinical setting of acute spinal cord injury primarily out of peer pressure and fear of litigation. Basic science experiments suggest that modulation of post-traumatic inflammation may provide the best opportunity to arrest the secondary injury cascade. Protein kinase and metalloproteinase inhibition are promising treatment strategies. Regeneration techniques are concentrating on cell transplantation and manipulating glial receptors and protein production. Clinical investigations are limited to Phase III trials on a very select few of these drugs. Conclusions. While many advances in the basic science of spinal cord injury provide optimism for future treatments, clinical science lags. At present, there are no pharmacologic strategies of proven benefit. Although steroids continue to be given to patients with spinal cord injury in many institutions, evidence of deleterious effects continues to accumulate. Current standard of care management includes support of arterial oxygenation and spinal cord perfusion pressure.

Methylprednisolone for acute spinal cord injury: 5-year practice reversal.

OBJECTIVE To re-evaluate practice patterns for methylprednisolone (MP) administration in patients with acute spinal cord injury (SCI) within the spinal surgery community across Canada five years after the publication of practice recommendations. METHODS Canadian orthopedic and neurological spine surgeons were surveyed at their respective annual meetings about their practice of steroid administration for acute SCI by means of a questionnaire comprised of the same seven questions posed five years ago plus an additional question related to change of view. RESULTS Forty-two surgeons and twenty-one residents directly involved in the acute management of SCI completed the questionnaire. Seventy-six percent of spinal surgeons do not prescribe MP for SCI in sharp contrast to 76% who prescribed it five years ago. Of the 24% who use steroids, the NASCIS II dosing regimen is most commonly followed. One third of physicians continue to administer MP because of fear of litigation. CONCLUSIONS Over a five year period there has been a complete reversal in practice patterns of MP administration for SCI, along with an increased familiarity of the published literature. Attendance at meetings, participation in local group discussions, and peer-reviewed publications appear effective in altering practice preferences arising from peer pressure and even fear of litigation.

Surgical Decision Making for Unstable Thoracolumbar Spine Injuries: Results of a Consensus Panel Review by the Spine Trauma Study Group

Objectives: The optimal surgical approach and treatment of unstable thoracolumbar spine injuries are poorly defined owing to a lack of widely accepted level I clinical literature. This lack of evidence-based standards has led to varied practice patterns based on individual surgeon preferences. The purpose of this study was to survey the leaders in the field of spine trauma to define the major characteristics of thoracolumbar injuries that influence their surgical decision making. In the absence of good scientific data, expert consensus opinions may provide surgeons with a practical framework to guide therapy and to conduct future research. Methods: A panel of 22 leading spinal surgeons from 20 level I trauma centers in seven countries met to discuss the indications for surgical approach selection in unstable thoracolumbar injuries. Injuries were presented to the surgeons in a case scenario survey format. Preferred surgical approaches to the clinical scenarios were tabulated and comments weighed. Results: All members of the panel agreed that three independent characteristics of thoracolumbar injuries carry primary importance in surgical decision making: the injury morphology, the neurologic status of the patient, and the integrity of the posterior ligaments. Six clinical scenarios based on the neurologic status of the patient (intact, incomplete, or complete) and on the status of the posterior ligamentous complex (intact or disrupted) were created, and consensus treatment approaches were described. Additional circumstances capable of altering the treatments were acknowledged. Conclusions: Decision making for the surgical treatment of thoracolumbar injuries is largely dependent on three patient characteristics: injury morphology, neurologic status, and posterior ligament integrity. A logical and practical decision-making process based on these characteristics may guide treatment even for the most complicated fracture patterns.

The Acute Cardiopulmonary Management of Patients With Cervical Spinal Cord Injuries

M anagement of patients with an acute cervical spinal cord injury in an intensive care unit or similar monitored setting is recommended. • Use of cardiac, hemodynamic, and respiratory monitoring devices to detect cardiovascular dysfunction and respiratory insufficiency in patients following acute spinal cord injury is recommended. • Correction of hypotension in spinal cord injury (systolic blood pressure , 90 mm Hg) when possible and as soon as possible is recommended. • Maintenance of mean arterial blood pressure between 85 and 90 mm Hg for the first 7 days following an acute spinal cord injury is recommended.