Browsing by Author "Guest, James D"
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Item Open Access A clinical prediction model for long-term functional outcome after traumatic spinal cord injury based on acute clinical and imaging factors.(Journal of neurotrauma, 2012-09) Wilson, Jefferson R; Grossman, Robert G; Frankowski, Ralph F; Kiss, Alexander; Davis, Aileen M; Kulkarni, Abhaya V; Harrop, James S; Aarabi, Bizhan; Vaccaro, Alexander; Tator, Charles H; Dvorak, Marcel; Shaffrey, Christopher I; Harkema, Susan; Guest, James D; Fehlings, Michael GTo improve clinicians' ability to predict outcome after spinal cord injury (SCI) and to help classify patients within clinical trials, we have created a novel prediction model relating acute clinical and imaging information to functional outcome at 1 year. Data were obtained from two large prospective SCI datasets. Functional independence measure (FIM) motor score at 1 year follow-up was the primary outcome, and functional independence (score ≥ 6 for each FIM motor item) was the secondary outcome. A linear regression model was created with the primary outcome modeled relative to clinical and imaging predictors obtained within 3 days of injury. A logistic model was then created using the dichotomized secondary outcome and the same predictor variables. Model validation was performed using a bootstrap resampling procedure. Of 729 patients, 376 met the inclusion criteria. The mean FIM motor score at 1 year was 62.9 (±28.6). Better functional status was predicted by less severe initial American Spinal Injury Association (ASIA) Impairment Scale grade, and by an ASIA motor score >50 at admission. In contrast, older age and magnetic resonance imaging (MRI) signal characteristics consistent with spinal cord edema or hemorrhage predicted worse functional outcome. The linear model predicting FIM motor score demonstrated an R-square of 0.52 in the original dataset, and 0.52 (95% CI 0.52,0.53) across the 200 bootstraps. Functional independence was achieved by 148 patients (39.4%). For the logistic model, the area under the curve was 0.93 in the original dataset, and 0.92 (95% CI 0.92,0.93) across the bootstraps, indicating excellent predictive discrimination. These models will have important clinical impact to guide decision making and to counsel patients and families.Item Open Access A prospective, multicenter, phase I matched-comparison group trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord injury.(Journal of neurotrauma, 2014-02) Grossman, Robert G; Fehlings, Michael G; Frankowski, Ralph F; Burau, Keith D; Chow, Diana SL; Tator, Charles; Teng, Angela; Toups, Elizabeth G; Harrop, James S; Aarabi, Bizhan; Shaffrey, Christopher I; Johnson, Michele M; Harkema, Susan J; Boakye, Maxwell; Guest, James D; Wilson, Jefferson RA prospective, multicenter phase I trial was undertaken by the North American Clinical Trials Network (NACTN) to investigate the pharmacokinetics and safety of, as well as obtain pilot data on, the effects of riluzole on neurological outcome in acute spinal cord injury (SCI). Thirty-six patients, with ASIA impairment grades A-C (28 cervical and 8 thoracic) were enrolled at 6 NACTN sites between April 2010 and June 2011. Patients received 50 mg of riluzole PO/NG twice-daily, within 12 h of SCI, for 14 days. Peak and trough plasma concentrations were quantified on days 3 and 14. Peak plasma concentration (Cmax) and systemic exposure to riluzole varied significantly between patients. On the same dose basis, Cmax did not reach levels comparable to those in patients with amyotrophic lateral sclerosis. Riluzole plasma levels were significantly higher on day 3 than on day 14, resulting from a lower clearance and a smaller volume of distribution on day 3. Rates of medical complications, adverse events, and progression of neurological status were evaluated by comparison with matched patients in the NACTN SCI Registry. Medical complications in riluzole-treated patients occurred with incidences similar to those in patients in the comparison group. Mild-to-moderate increase in liver enzyme and bilirubin levels were found in 14-70% of patients for different enzymes. Three patients had borderline severe elevations of enzymes. No patient had elevated bilirubin on day 14 of administration of riluzole. There were no serious adverse events related to riluzole and no deaths. The mean motor score of 24 cervical injury riluzole-treated patients gained 31.2 points from admission to 90 days, compared to 15.7 points for 26 registry patients, a 15.5-point difference (p=0.021). Patients with cervical injuries treated with riluzole had more-robust conversions of impairment grades to higher grades than the comparison group.Item Open Access History and Accomplishments of the North American Clinical Trials Network (NACTN) for Spinal Cord Injury, 2004 to 2022.(Journal of neurotrauma, 2022-12) Tator, Charles H; Guest, James D; Neal, Chris J; Howley, Susan P; Toups, Elizabeth G; Harrop, James S; Aarabi, Bizhan; Shaffrey, Christopher I; Fehlings, Michael GThis is a historical account of the origin and accomplishments of the North American Clinical Trials Network (NACTN) for traumatic spinal cord injury (SCI), which was established in 2004 by Christopher Reeve and Dr. Robert Grossman. Christopher Reeve was an actor who became quadriplegic and started the Christopher and Dana Reeve Foundation, while Robert Grossman was a neurosurgeon experienced in neurotrauma and a university professor in Houston. NACTN has member investigators at university and military centers in North America and has contributed greatly to the improvement of care, primarily acute care, of patients sustaining traumatic SCI. Its accomplishments are a clinical registry database of more than 1000 acute SCI patients documenting the care pathways, including complications. NACTN determined the effectiveness of treatment, including pharmacotherapy and the role and timing of surgery, and barriers to early surgery with a focus on neurological recovery. NACTN has assessed the effectiveness of treatment, including pharmacotherapy and the role and timing of surgery, and has also identified barriers to early surgery. The principal focus has been on improving neurological recovery. It has trained many SCI practitioners and has collaborated with many other SCI networks and organizations internationally to promote the care of SCI patients.Item Open Access Incidence and severity of acute complications after spinal cord injury.(Journal of neurosurgery. Spine, 2012-09) Grossman, Robert G; Frankowski, Ralph F; Burau, Keith D; Toups, Elizabeth G; Crommett, John W; Johnson, Michele M; Fehlings, Michael G; Tator, Charles H; Shaffrey, Christopher I; Harkema, Susan J; Hodes, Jonathan E; Aarabi, Bizhan; Rosner, Michael K; Guest, James D; Harrop, James SObject
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.Item Open Access Interhospital Transfer delays care for spinal cord injury patients: A Report from the North American Clinical Trials Network for Spinal Cord Injury.(Journal of neurotrauma, 2023-04) Kelly-Hedrick, Margot; Ugiliweneza, Beatrice; Toups, Elizabeth G; Jimsheleishvili, George; Kurpad, Shekar N; Aarabi, Bizhan; Harrop, James S; Foster, Norah; Goodwin, Rory C; Shaffrey, Christopher I; Fehlings, Michael G; Tator, Charles H; Guest, James D; Neal, Chris J; Abd-El-Barr, Muhammad M; Williamson, TheresaThe North America Clinical Trials Network (NACTN) for Spinal Cord Injury (SCI) is a consortium of tertiary medical centers that has maintained a prospective SCI registry since 2004, and has espoused that early surgical intervention is associated with improved outcome. It has previously been shown that initial presentation to a lower acuity center and necessity of transfer to a higher acuity center reduce rates of early surgery. The NACTN database was evaluated to examine the association between interhospital transfer (IHT), early surgery, and outcome, taking into account distance traveled and site of origin for the patient. Data from a 15-year period of the NACTN SCI Registry were analyzed (years 2005-2019). Patients were stratified into transfers directly from the scene to a level I trauma center (NACTN site) versus IHT from a level II or III trauma facility. The main outcome was surgery within 24 hours of injury (yes/no) while secondary outcomes were length of stay, death, discharge disposition, and 6-month AIS grade conversion. For the IHT patients, distance traveled for transfer was calculated by measuring the shortest distance between origin and NACTN hospital. Analysis was performed with Brown-Mood test and chi-square tests. Of 724 patients with transfer data, 295 (40%) underwent IHT and 429 (60%) were admitted directly from the scene of accident. Patients who underwent IHT were more likely to have a less severe SCI (AIS D) (p=.002), have a central cord injury (p=.004), and have a fall as their mechanism of injury (p<.0001) than those directly admitted to a NACTN center. Of the 634 patients who had surgery, direct admission to a NACTN site was more likely to result in surgery within 24 hours compared to IHT patients (52% vs. 38%) (p< .0003). Median IHT distance was 28 miles (interquartile range=13-62 miles). There was no significant difference in death, length of stay, discharge to a rehab facility versus home, or 6-month AIS grade conversion rates between the two groups. Patients who underwent IHT to a NACTN site were less likely to have surgery within 24 hours of injury, compared to those directly admitted to the level I trauma facility. While there was no difference in mortality rates, length of stay, or 6-month AIS conversion between groups, patients with IHT were more likely be older with a less severe level of injury (AIS D). This work suggests there are barriers to timely recognition of SCI in the field, appropriate admission to a higher level of care after recognition, and challenges related to the management of individuals with less severe SCI.Item Open Access Longitudinal Impact of Acute Spinal Cord Injury on Clinical Pharmacokinetics of Riluzole, a Potential Neuroprotective Agent.(Journal of clinical pharmacology, 2021-09) Nguyen, Ashley; Chow, Diana S-L; Wu, Lei; Teng, Yang Angela; Sarkar, Mahua; Toups, Elizabeth G; Harrop, James S; Schmitt, Karl M; Johnson, Michele M; Guest, James D; Aarabi, Bizhan; Shaffrey, Christopher I; Boakye, Maxwell; Frankowski, Ralph F; Fehlings, Michael G; Grossman, Robert GRiluzole, a benzothiazole sodium channel blocker that received US Food and Drug Administration approval to attenuate neurodegeneration in amyotrophic lateral sclerosis in 1995, was found to be safe and potentially efficacious in a spinal cord injury (SCI) population, as evident in a phase I clinical trial. The acute and progressive nature of traumatic SCI and the complexity of secondary injury processes can alter the pharmacokinetics of therapeutics. A 1-compartment with first-order elimination population pharmacokinetic model for riluzole incorporating time-dependent clearance and volume of distribution was developed from combined data of the phase 1 and the ongoing phase 2/3 trials. This change in therapeutic exposure may lead to a biased estimate of the exposure-response relationship when evaluating therapeutic effects. With the developed model, a rational, optimal dosing scheme can be designed with time-dependent modification that preserves the required therapeutic exposure of riluzole.Item Open Access Natural History, Predictors of Outcome, and Effects of Treatment in Thoracic Spinal Cord Injury: A Multi-Center Cohort Study from the North American Clinical Trials Network.(Journal of neurotrauma, 2018-11) Wilson, Jefferson R; Jaja, Blessing NR; Kwon, Brian K; Guest, James D; Harrop, James S; Aarabi, Bizhan; Shaffrey, Christopher I; Badhiwala, Jetan H; Toups, Elizabeth G; Grossman, Robert G; Fehlings, Michael GThe course, treatment response, and recovery potential after acute traumatic spinal cord injury (SCI) have been shown to differ depending on the neurological level of injury. There are limited data focused on thoracic-level injuries, however. A cohort of 86 patients from the prospectively maintained North American Clinical Trials Network SCI registry were identified and studied to characterize the patterns of neurological recovery and to determine rates of acute hospital death and pulmonary complications. Regression analyses were used to examine the relationship between timing of surgery and administration of methylprednisolone on neurologic and clinical outcomes. Neurological conversion (≥1 American Spinal Injury Association Impairment Scale [AIS] grade improvement) was poorest for AIS grade A patients; 14.3% converted at last available follow-up (mean eight months). While rates of conversion were more optimistic for AIS-B patients (54.5%) and AIS C injuries (77.8%) at the same time point, none of the AIS grade D patients converted to AIS E. At last available follow-up (mean eight months), the magnitudes of lower motor extremity score (LEMS) change were highest for AIS C injuries (21.9 points), then AIS B (17.7 points), AIS D (16.4 points), and finally AIS A (2.5 points) (p < 0.05). Early surgical intervention (<24 h post-injury) was independently associated with an additional seven points in motor recovery and a 60% decreased incidence of pulmonary events (p < 0.05). Methylprednisolone administration was not an independent predictor of neurological outcome or pulmonary complications. Evaluation of this cohort obtained from a modern multi-center SCI registry provides an update on the natural history, acute death, and incidence of pulmonary complications after traumatic thoracic SCI. Although small sample size limited the extent of analyses possible, early surgical treatment was associated with significantly larger motor recovery and lower rates of pulmonary complications.Item Open Access Predictors of pulmonary complications in blunt traumatic spinal cord injury.(Journal of neurosurgery. Spine, 2012-09) Aarabi, Bizhan; Harrop, James S; Tator, Charles H; Alexander, Melvin; Dettori, Joseph R; Grossman, Robert G; Fehlings, Michael G; Mirvis, Stuart E; Shanmuganathan, Kathirkamanathan; Zacherl, Katie M; Burau, Keith D; Frankowski, Ralph F; Toups, Elizabeth; Shaffrey, Christopher I; Guest, James D; Harkema, Susan J; Habashi, Nader M; Andrews, Penny; Johnson, Michele M; Rosner, Michael KObject
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.Item Open Access Riluzole for the treatment of acute traumatic spinal cord injury: rationale for and design of the NACTN Phase I clinical trial.(Journal of neurosurgery. Spine, 2012-09) Fehlings, Michael G; Wilson, Jefferson R; Frankowski, Ralph F; Toups, Elizabeth G; Aarabi, Bizhan; Harrop, James S; Shaffrey, Christopher I; Harkema, Susan J; Guest, James D; Tator, Charles H; Burau, Keith D; Johnson, Michele W; Grossman, Robert GIn 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.Item Open Access The bulbocavernosus reflex (BCR) has no prognostic features during the acute evaluation of spinal cord injuries.(Journal of neurotrauma, 2023-03) Mansoor Ali, Daniyal; Sivaganesan, Ahilan; Neal, Chris J; Thalheimer, Sara; Ugiliweneza, Beatrice; Toups, Elizabeth G; Abd-El-Barr, Muhammad; Jimsheleishvili, George; Kurpad, Shekar N; Aarabi, Bizhan; Shaffrey, Christopher I; Fehlings, Michael G; Tator, Charles H; Grossman, Robert G; Guest, James D; Harrop, James SThe bulbocavernosus reflex (BCR) has been used during the initial evaluation of a spinal cord injury patient as a metric to determine prognosis and whether the patient is in "spinal shock". This reflex has been less utilized over the last decade and therefore, a review was performed to assess the value of BCR in patient prognosis. The North American Clinical Trials Network (NACTN) for Spinal Cord Injury is a consortium of tertiary medical centers that includes a prospective SCI registry. The NACTN registry data was analyzed to evaluate the prognostic implication of the BCR during the initial evaluation of a spinal cord injury patient. SCI patients were divided into those with an intact or absent BCR during their initial evaluation. Associations of participants' descriptors and neurological status on follow up were performed followed by associations with the presence of a BCR. 769 registry patients with recorded BCRs were included in the study. The median age was 49 years (32-61 years), majority were male (n=566, 77%), and white (n=519, 73%). Among included patients, high blood pressure was the most common comorbidity (n=230, 31%). Cervical spinal cord injury was the most common (n=470, 76%) with fall (n=320, 43%) being the most frequent mechanism of injury. BCR was present in 311 patients (40.4%), while 458 (59.6%) had a negative BCR within 7 days of injury or before surgery. At 6 months post-injury, 230 patients (29.9%) followed up, of which, 145 had a positive BCR while 85 had a negative BCR, respectively. The presence/absence of BCR was significantly different in patients with cervical (p=0.0015) or thoracic SCI (p=0.0089), or conus medullaris syndrome (p=0.0035), and in those who were AIS grade A (p=0.0313). No significant relationship was observed between BCR results and demographics, AIS grade conversion, motor score changes (p=0.1669), and changes in pin prick (p=0.3795) and light touch scores (p=0.8178). In addition, cohorts were not different in surgery decision (p=0.7762) and injury to surgery time (p=0.0681). In our review of the NACTN spinal cord registry, the BCR did not provide prognostic utility in the acute evaluation of spinal cord injury patients. Therefore, it should not be used as a reliable marker for predicting neurological outcomes post-injury.Item Open Access Trends in the Use of Corticosteroids in the Management of Acute Spinal Cord Injury in North American Clinical Trials Networks (NACTN) Sites.(Journal of neurotrauma, 2023-01) Hejrati, Nader; Aarabi, Bizhan; Neal, Chris J; Ugiliweneza, Beatrice; Kurpad, Shekar N; Shaffrey, Christopher I; Guest, James D; Toups, Elizabeth G; Harrop, James S; Fehlings, Michael GImmunomodulatory therapeutics represent a potential neuroprotective strategy for the management of acute spinal cord injury (SCI). One of the most intensely debated neuroprotective drugs has been methylprednisolone sodium succinate (MPSS). MPSS was initially investigated for its role in mitigating lipid peroxidation. More recently, the anti-inflammatory/immunomodulatory properties of MPSS have been increasingly appreciated. Over the past two decades, several systematic reviews and clinical practice guidelines related to MPSS use in SCI have been published. The goal of this study was to investigate the temporal changes in the use of steroids at North American Clinical Trials Network (NACTN) centers and to correlate these with the evolution in published literature and guidelines. Data on patients enrolled from 2008 - 2018 in the prospective, multicenter NACTN registry, and in whom information related to the use of steroids was available, were analyzed. Patients were stratified as to whether they received steroids or not. The primary outcome was the change in the rate of steroid use per year between 2008 and 2018. Secondary outcomes included cardiac, gastrointestinal & genitourinary (GIGU), pulmonary and dermatologic complications. We identified 608 patients, of whom 171 (28.1%) were given steroids. In 2008 and 2009, the prevailing paradigm across NACTN centers was in favor of steroid administration and as such 70% (n=56) of patients received steroids in 2008 and 71.9% (n=46) in 2009. An abrupt practice reversal was observed in 2010, whereby only 19.7% of patients (n=14) received steroids, a trend that continued over subsequent years. Increasing literature in the 2000s arguing against the use of steroids culminated in the 2013 CNS/AANS practice guidelines for the management of acute SCI. These guidelines recommended against the use of MPSS for the treatment of acute SCI. Over the following years (2013-2018), steroids continued to be an uncommonly used therapeutic option in NACTN centers (range 3.9-16.9%). Patients receiving steroids had significantly higher rates of pulmonary complications (87%, n=147) compared to those not receiving steroids (73%, n=265; p=0.0003). However, compared to patients receiving steroids, those who did not receive steroids had significantly higher rates of cardiac (40%, [n=146] versus 23%, [n=39]; p=0.0001) and gastrointestinal/genitourinary complications (55%, [n=189], versus 31%, [n=52]; p<0.0001). The 2013 AANS/CNS guidelines and preceding literature appeared to have an impact on dramatically lowering the rates of corticosteroid use for acute SCI in NACTN sites after 2009. Of note, this analysis may not reflect the impact of the 2017 AO Spine Clinical Practice guidelines, which suggested the use of methylprednisolone as a valid practice option for acute SCI, especially for cervical injuries. Enhanced patient involvement in the clinical decision-making process and opportunities to personalize SCI management exist in reference to the use of MPSS in acute SCI.