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George M. Ghobrial, Christopher M. Maulucci, Mitchell Maltenfort, Richard T. Dalyai, Alexander R. Vaccaro, Michael G. Fehlings, John Street, Paul M. Arnold and James S. Harrop

Object

Thoracolumbar spine injuries are commonly encountered in patients with trauma, accounting for almost 90% of all spinal fractures. Thoracolumbar burst fractures comprise a high percentage of these traumatic fractures (45%), and approximately half of the patients with this injury pattern are neurologically intact. However, a debate over complication rates associated with operative versus nonoperative management of various thoracolumbar fracture morphologies is ongoing, particularly concerning those patients presenting without a neurological deficit.

Methods

A MEDLINE search for pertinent literature published between 1966 and December 2013 was conducted by 2 authors (G.G. and R.D.), who used 2 broad search terms to maximize the initial pool of manuscripts for screening. These terms were “operative lumbar spine adverse events” and “nonoperative lumbar spine adverse events.”

Results

In an advanced MEDLINE search of the term “operative lumbar spine adverse events” on January 8, 2014, 1459 results were obtained. In a search of “nonoperative lumbar spine adverse events,” 150 results were obtained. After a review of all abstracts for relevance to traumatic thoracolumbar spinal injuries, 62 abstracts were reviewed for the “operative” group and 21 abstracts were reviewed for the “nonoperative” group. A total of 14 manuscripts that met inclusion criteria for the operative group and 5 manuscripts that met criteria for the nonoperative group were included.

There were a total of 919 and 436 patients in the operative and nonoperative treatment groups, respectively. There were no statistically significant differences between the groups with respect to age, sex, and length of stay. The mean ages were 43.17 years in the operative and 34.68 years in the nonoperative groups. The majority of patients in both groups were Frankel Grade E (342 and 319 in operative and nonoperative groups, respectively). Among the studies that reported the data, the mean length of stay was 14 days in the operative group and 20.75 in the nonoperative group.

The incidence of all complications in the operative and nonoperative groups was 300 (32.6%) and 21 (4.8%), respectively (p = 0.1065). There was no significant difference between the 2 groups with respect to the incidence of pulmonary, thromboembolic, cardiac, and gastrointestinal complications. However, the incidence of infections (pneumonia, urinary tract infection, wound infection, and sepsis) was significantly higher in the operative group (p = 0.000875). The incidence of instrumentation failure and need for revision surgery was 4.35% (40 of 919), a significant morbidity, and an event unique to the operative category (p = 0.00396).

Conclusions

Due to the limited number of high-quality studies, conclusions related to complication rates of operative and nonoperative management of thoracolumbar traumatic injuries cannot be definitively made. Further prospective, randomized studies of operative versus nonoperative management of thoracolumbar and lumbar spine trauma, with standardized definitions of complications and matched patient cohorts, will aid in properly defining the risk-benefit ratio of surgery for thoracolumbar spine fractures.

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Robert G. Grossman, Ralph F. Frankowski, Keith D. Burau, Elizabeth G. Toups, John W. Crommett, Michele M. Johnson, Michael G. Fehlings, Charles H. Tator, Christopher I. Shaffrey, Susan J. Harkema, Jonathan E. Hodes, Bizhan Aarabi, Michael K. Rosner, James D. Guest and James S. Harrop

Object

The aim of this multicenter, prospective study was to determine the spectrum, incidence, and severity of complications during the initial hospitalization of patients with spinal cord injury.

Methods

The study was conducted at 9 university-affiliated hospitals that comprise the clinical centers of the North American Clinical Trials Network (NACTN) for Treatment of Spinal Cord Injury. The study population comprised 315 patients admitted to NACTN clinical centers between June 25, 2005, and November 2, 2010, who had American Spinal Injury Association (ASIA) Impairment Scale grades of A–D and were 18 years of age or older. Patients were managed according to a standardized protocol.

Results

The study population was 79% male with a median age of 44 years. The leading causes of injury were falls (37%) and motor vehicle accidents (28%). The distribution of initial ASIA grades were A (40%), B (16%), C (15%), and D (29%). Fifty-eight percent of patients sustained 1 or more severe, moderate, or mild complications. Complications were associated with more severe ASIA grade: 84% of patients with Grade A and 25% of patients with Grade D had at least 1 complication. Seventy-eight percent of complications occurred within 14 days of injury. The most frequent types of severe and moderate complications were respiratory failure, pneumonia, pleural effusion, anemia, cardiac dysrhythmia, and severe bradycardia. The mortality rate was 3.5% and was associated with increased age and preexisting morbidity.

Conclusions

Knowledge of the type, frequency, time of occurrence, and severity of specific complications that occur after spinal cord injury can aid in their early detection, treatment, and prevention. The data are of importance in evaluating and selecting therapy for clinical trials.

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Jeffrey D. Coe, Alexander R. Vaccaro, Andrew T. Dailey, Rick C. Sasso, Steven C. Ludwig, James S. Harrop, Joseph R. Dettori, Christopher I. Shaffrey, Sanford E. Emery and Michael G. Fehlings

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Diana S. L. Chow, Yang Teng, Elizabeth G. Toups, Bizhan Aarabi, James S. Harrop, Christopher I. Shaffrey, Michele M. Johnson, Maxwell Boakye, Ralph F. Frankowski, Michael G. Fehlings and Robert G. Grossman

Object

The aim of this paper was to characterize individual and population pharmacokinetics of enterally administered riluzole in a Phase 1 clinical trial of riluzole as a neuroprotective agent in adults 18–70 years old with acute spinal cord injury (SCI).

Methods

Thirty-five individuals with acute SCI, American Spinal Injury Association Impairment Scale Grades A–C, neurological levels from C-4 to T-12, who were enrolled in the Phase 1 clinical trial sponsored by the North American Clinical Trials Network for Treatment of Spinal Cord Injury, received 50 mg riluzole twice daily for 28 doses. The first dose was administered at a mean of 8.7 ± 2.2 hours postinjury. Trough plasma samples were collected within 1 hour predose, and peak plasma samples were collected 2 hours postdose on Days 3 and 14 of treatment. Riluzole concentrations were quantified by high-performance liquid chromatography assay. The data were analyzed for individual and population pharmacokinetics using basic structural and covariate models. The pharmacokinetic measures studied were the peak concentration (Cmax), trough concentration (Cmin), systemic exposure (AUC0–12), clearance (CL/F), and volume of distribution (V_F) normalized by the bioavailability (F).

Results

The Cmax and AUC0–12 achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher CL and larger V. The pharmacokinetics of riluzole (Cmax, Cmin, AUC0–12, CL, and V) changed during the acute and subacute phases of SCI during the 14 days of therapy. It was consistently observed in patients at all clinical sites that Cmax, Cmin, and AUC0–12 (128.9 ng/ml, 45.6 ng/ml, and 982.0 ng × hr/ml, respectively) were significantly higher on Day 3 than on Day 14 (76.5 ng/ml, 19.1 ng/ml, and 521.0 ng × hr/ml, respectively). These changes resulted from lower CL (49.5 vs 106.2 L/hour) and smaller V (557.1 vs 1297.9/L) on Day 3. No fluid imbalance or cytochrome P 1A2 induction due to concomitant medications was identified during the treatment course to account for such increases in V and CL, respectively. Possible mechanisms underlying these changes are discussed.

Conclusions

This is the first report of clinical pharmacokinetics of riluzole in patients with SCI. The Cmax and AUC0–12 achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher clearance and larger volume of distribution in SCI patients. The finding in SCI patients of an increase in the clearance and distribution of riluzole between the 3rd and 14th days after SCI, with a lower plasma concentration of riluzole on the 14th day, stresses the importance of monitoring changes in drug metabolism after SCI in interpreting the safety and efficacy of therapeutic drugs that are used in clinical trials in SCI. Clinical trial registration no.: NCT00876889.

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Michael G. Fehlings, Jefferson R. Wilson, Ralph F. Frankowski, Elizabeth G. Toups, Bizhan Aarabi, James S. Harrop, Christopher I. Shaffrey, Susan J. Harkema, James D. Guest, Charles H. Tator, Keith D. Burau, Michele W. Johnson and Robert G. Grossman

In the immediate period after traumatic spinal cord injury (SCI) a variety of secondary injury mechanisms combine to gradually expand the initial lesion size, potentially leading to diminished neurological outcomes at long-term follow-up. Riluzole, a benzothiazole drug, which has neuroprotective properties based on sodium channel blockade and mitigation of glutamatergic toxicity, is currently an approved drug that attenuates the extent of neuronal degeneration in patients with amyotrophic lateral sclerosis. Moreover, several preclinical SCI studies have associated riluzole administration with improved functional outcomes and increased neural tissue preservation. Based on these findings, riluzole has attracted considerable interest as a potential neuroprotective drug for the treatment of SCI. Currently, a Phase I trial evaluating the safety and pharmacokinetic profile of riluzole in human SCI patients is being conducted by the North American Clinical Trials Network (NACTN) for Treatment of Spinal Cord Injury. The current review summarizes the existing preclinical and clinical literature on riluzole, provides a detailed description of the Phase I trial, and suggests potential opportunities for future investigation. Clinical trial registration no.: NCT00876889.

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Bizhan Aarabi, James S. Harrop, Charles H. Tator, Melvin Alexander, Joseph R. Dettori, Robert G. Grossman, Michael G. Fehlings, Stuart E. Mirvis, Kathirkamanathan Shanmuganathan, Katie M. Zacherl, Keith D. Burau, Ralph F. Frankowski, Elizabeth Toups, Christopher I. Shaffrey, James D. Guest, Susan J. Harkema, Nader M. Habashi, Penny Andrews, Michele M. Johnson and Michael K. Rosner

Object

Pulmonary complications are the most common acute systemic adverse events following spinal cord injury (SCI), and contribute to morbidity, mortality, and increased length of hospital stay (LOS). Identification of factors associated with pulmonary complications would be of value in prevention and acute care management. Predictors of pulmonary complications after SCI and their effect on neurological recovery were prospectively studied between 2005 and 2009 at the 9 hospitals in the North American Clinical Trials Network (NACTN).

Methods

The authors sought to address 2 specific aims: 1) define and analyze the predictors of moderate and severe pulmonary complications following SCI; and 2) investigate whether pulmonary complications negatively affected the American Spinal Injury Association (ASIA) Impairment Scale conversion rate of patients with SCI. The NACTN registry of the demographic data, neurological findings, imaging studies, and acute hospitalization duration of patients with SCI was used to analyze the incidence and severity of pulmonary complications in 109 patients with early MR imaging and long-term follow-up (mean 9.5 months). Univariate and Bayesian logistic regression analyses were used to analyze the data.

Results

In this study, 86 patients were male, and the mean age was 43 years. The causes of injury were motor vehicle accidents and falls in 80 patients. The SCI segmental level was in the cervical, thoracic, and conus medullaris regions in 87, 14, and 8 patients, respectively. Sixty-four patients were neurologically motor complete at the time of admission. The authors encountered 87 complications in 51 patients: ventilator-dependent respiratory failure (26); pneumonia (25); pleural effusion (17); acute lung injury (6); lobar collapse (4); pneumothorax (4); pulmonary embolism (2); hemothorax (2), and mucus plug (1). Univariate analysis indicated associations between pulmonary complications and younger age, sports injuries, ASIA Impairment Scale grade, ascending neurological level, and lesion length on the MRI studies at admission. Bayesian logistic regression indicated a significant relationship between pulmonary complications and ASIA Impairment Scale Grades A (p = 0.0002) and B (p = 0.04) at admission. Pulmonary complications did not affect long-term conversion of ASIA Impairment Scale grades.

Conclusions

The ASIA Impairment Scale grade was the fundamental clinical entity predicting pulmonary complications. Although pulmonary complications significantly increased LOS, they did not increase mortality rates and did not adversely affect the rate of conversion to a better ASIA Impairment Scale grade in patients with SCI. Maximum canal compromise, maximum spinal cord compression, and Acute Physiology and Chronic Health Evaluation–II score had no relationship to pulmonary complications.

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James S. Harrop, Alexander R. Vaccaro, R. John Hurlbert, Jared T. Wilsey, Eli M. Baron, Christopher I. Shaffrey, Charles G. Fisher, Marcel F. Dvorak, F. C. Öner, Kirkham B. Wood, Neel Anand, D. Greg Anderson, Moe R. Lim, Joon Y. Lee, Christopher M. Bono, Paul M. Arnold, Y. Raja Rampersaud, Michael G. Fehlings and The Spine Trauma Study Group

Object

A new classification and treatment algorithm for thoracolumbar injuries was recently introduced by Vaccaro and colleagues in 2005. A thoracolumbar injury severity scale (TLISS) was proposed for grading and guiding treatment for these injuries. The scale is based on the following: 1) the mechanism of injury; 2) the integrity of the posterior ligamentous complex (PLC); and 3) the patient’s neurological status. The reliability and validity of assessing injury mechanism and the integrity of the PLC was assessed.

Methods

Forty-eight spine surgeons, consisting of neurosurgeons and orthopedic surgeons, reviewed 56 clinical thoracolumbar injury case histories. Each was classified and scored to determine treatment recommendations according to a novel classification system. After 3 months the case histories were reordered and the physicians repeated the exercise. Validity of this classification was good among reviewers; the vast majority (> 90%) agreed with the system’s treatment recommendations. Surgeons were unclear as to a cogent description of PLC disruption and fracture mechanism.

Conclusions

The TLISS demonstrated acceptable reliability in terms of intra- and interobserver agreement on the algorithm’s treatment recommendations. Replacing injury mechanism with a description of injury morphology and better definition of PLC injury will improve inter- and intraobserver reliability of this injury classification system.