Abstract
Study Design
Review of the literature with critical appraisal and clinical recommendations.
Objective
To highlight contemporary concepts involving adjunctive medical and non-surgical therapies in the management of acute traumatic spinal cord injury (tSCI) that may be integrated into clinical practice.
Methods
Three recent articles relating to the management of acute tSCI were selected and critically appraised. Clinical practice recommendations were developed and evaluated using the GRADE criteria.
Results
Article 1: A Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury: Recommendations on Hemodynamic Management.
Conclusions
The management of tSCI extends beyond the operating room. The development of emerging medical and non-surgical treatments to augment timely and adequate decompression requires critical consideration as new data becomes available. While some topics do not have the scientific backing to be able to make a recommendation at this time, they point towards areas of future study.
Introduction
The treatment of Traumatic Spinal Cord Injury (tSCI) is in continuous evolution as new data and treatment strategies emerge. As information becomes available and previous practices are re-evaluated, novel treatment paradigms are constructed. Over the years, there have been many novel therapeutics that have been proposed and trialed in the management of tSCI. While the literature supporting early surgery has continued to grow, other nonsurgical therapeutic measures have been proposed with various degrees of data to support their use.1-5 In an effort to positively impact a clinical situation that can be dire for the patient with an acute tSCI, we need to continuously ensure that our treatments are safe and efficacious.
With the initial publication of guidelines in the management of tSCI in 2002 and updates in 2013 by the American Association of Neurological Surgeons and the Congress of Neurological Surgeons, a significant step forward in the organized management of tSCI was made.6,7 Since those guidelines were published, new studies continue to be published in the clinical treatment of acute tSCI. New data requires critical appraisal as the field continues to develop.
The purpose of this article is not to provide a comprehensive replacement of previously published guidelines, but to provide the practitioner a concise update of the literature regarding current adjuncts to surgery and evolving therapies for acute tSCI. We prioritized topics that have recent, substantive evidence updates, directly influence bedside decision-making, and represent different maturities of evidence—from guideline-level hemodynamics to emerging SCPP strategies and a large phase-III pharmacologic trial.8-10 The topic of medical and adjunct therapies in acute tSCI, article selection, and comprehensive review was made by the AO Spine Knowledge Forum SCI, representing an international group of clinicians, researchers, and those with lived experience in tSCI. The well-established Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) system was utilized for the review. 11
Article 1
B. K. Kwon, L. A. Tetreault, A. R. Martin et al. A Clinical Practice Guideline for the Management of Patients With Acute Spinal Cord Injury: Recommendations on Hemodynamic Management. Global Spine J 2024 Vol. 14 Issue 3_suppl Pages 187s-211s. DOI: 10.1177/21925682231202348.
Clinical Rationale
After a traumatic Spinal Cord Injury (SCI), there exist only limited options for improving neurological function aside from urgent surgical decompression and hemodynamic management.1,12-14 The optimization of hemodynamics after SCI is one of the only non-operative interventions available, with the aim to enhance vascular perfusion and oxygenation of the injured spinal cord to minimize ischemic damage and mitigate secondary injury development. The objective of this Clinical Practice Guideline (GPG) was to establish recommendations that acknowledged the significant body of clinical literature that had been published on the topic of hemodynamic management for acute traumatic SCI since the 2013 AANS/CNS recommendations. Here, we sought to establish recommendations on the target range of mean arterial pressure (MAP) to be maintained, the optimal duration of MAP augmentation, the choice of vasopressors, and on preferrable spinal cord perfusion pressure (SCPP) targets.7,8
Study Summary
The guideline development group (GDG) consisted of 20 members (11 spine surgeons, 3 (neuro)critical care physicians, 2 neurologists, 1 psychiatrist, and 2 individuals living with SCI).
As a first recommendation, this CPG suggested that MAP should be augmented between 75-80 mmHg as the “lower limit”, but not actively augmented beyond the “upper limit” of 90-95 mmHg to optimize spinal cord perfusion after acute traumatic SCI. The quality of evidence available was classified as very low, and the strength of recommendation as weak.
In the development of these recommendations, a systematic review of the literature identified 14 studies specifically examining the relationship between lower MAP limit and neurological outcome. However, none of these studies reported causation, but rather an association between poor recovery and a certain MAP threshold, and were of small sample sizes, included a restrictive patient population, or focused on a discrete period after injury. Three studies were identified discussing an upper limit of MAP target range beyond which no further neurological improvement was reported. Five studies were additionally identified that dealt with complications associated with MAP elevation and vasopressor or inotrope use. Given that those studies were mostly published after the 2013 AANS/CNS guidelines, the GDG acknowledged the importance of defining an “upper limit” beyond which there is no neurological benefit, but potential complications from vasopressor use predominate.
As a second recommendation, this CPG suggests a duration of 3-7 days of MAP augmentation within the identified threshold. The quality of evidence was classified as very low, and the strength of recommendation as weak. The recommendation acknowledged the fact that for many centers, keeping all acute traumatic SCI patients in an ICU environment where they could have MAP maintained for 7 days was practically very challenging.
Regarding the development of this recommendation, the systematic literature review identified 14 studies that discussed the duration of hemodynamic management after acute traumatic SCI that were notably of considerable variability regarding the duration of MAP management and respective monitoring. Five studies monitored and managed MAP over a 7-day period and reported variable impact on neurologic recovery. While some evidence in the systematic review suggested that augmenting MAP during the first few days post-injury was the most important, other studies concluded that hemodynamic management significantly affects neurologic outcomes when sustained over a 7-day period, which led to the weak recommendation to augment MAP for a duration of 3-7 days.
Given the lack of reliable evidence, no conclusions or recommendations were available regarding the choice of vasopressors, or preferrable SCPP targets.
Methodological Review
This CPG on hemodynamic management for acute SCI adheres to the GRADE approach. This robust framework is evident in the explicitly stated study design and the confirmed adherence to PRISMA standards for the systematic review, which was also registered in PROSPERO. A key strength of the GRADE methodology, the formation of a multidisciplinary guideline development group (GDG), including healthcare professionals from diverse specialties, patient advocates, and individuals living with SCI, ensured a comprehensive perspective in the guideline’s formulation.
A significant, and repeatedly acknowledged, limitation within the paper is the “very low” quality of evidence that underpins the core recommendations concerning both the MAP target range and the duration of MAP augmentation. This pervasive low quality primarily stems from the absence of high-quality comparative studies, such as randomized controlled trials, directly assessing various MAP targets or durations on patient outcomes. The evidence largely comprises observational studies reporting associations rather than causation, often with small sample sizes and heterogeneity in methodologies and outcome assessments. While the GRADE approach is designed to account for such limitations by downgrading evidence quality, the consistently “very low” rating for the quality of the evidence inherently impacts the overall strength of the recommendation that can be made, as a “strong recommendation” is inadvisable if the scientific evidence is known to be weak.
Despite these limitations, the overall methodological approach remains sound. The transparency regarding evidence quality, the systematic review process, the broad multidisciplinary input, and the clear articulation of the decision-making process—which balances benefits, harms, and other factors—collectively contribute to a methodologically strong guideline, especially given the inherent challenges of the available evidence in this complex clinical area.
Recommendation for Integrating into Your Clinical Practice
Based on the very low quality of evidence, which prevents strong recommendations, we conditionally recommend augmenting mean arterial blood pressure to at least 75-80 mmHg but not higher than 90-95 mmHg for a duration of 3-7 days to optimize spinal cord perfusion in acute traumatic SCI. This approach, while uncertain in its precise effect, acknowledges the limitations in the scientific literature, but warns against hypotension whilst balancing the potential for neurologic improvement with increased MAP against the potential risks from vasopressor use. The expanded range of treatment duration (3 to 7 days) and the choice of vasopressor or inotrope offers some element of clinical flexibility to the treating physician and institution.
Article 2
J. W. Squair, L. M. Bélanger, A. Tsang et al. Spinal cord perfusion pressure predicts neurologic recovery in acute spinal cord injury. Neurology 2017 Vol. 89 Issue 16 Pages 1660-1667. DOI: 10.1212/wnl.0000000000004519.
Clinical Rationale
The widely adopted 2013 AANS/CNS guidelines on the hemodynamic management of acute traumatic spinal cord injury (tSCI) were based on low quality evidence. 7 The resulting uncertainty has led to substantial heterogeneity in global clinical practice regarding blood pressure management following tSCI. 15 Interestingly, while neurosurgical guidelines support cerebral perfusion pressure (CPP)-guided therapy in severe traumatic brain injury with level IIB evidence, the analogous concept of SCPP-guided management in tSCI has not yet been widely investigated. 16 The aim of this study was to determine whether spinal cord perfusion pressure (SCPP), measured via a lumbar intrathecal catheter, is a more reliable predictor of neurologic outcome than the traditionally used mean arterial pressure (MAP). 9
Study Summary
This prospective, multicenter observational study investigated the prognostic value of SCPP in predicting neurological recovery following acute traumatic spinal cord injury (tSCI) in 92 patients with AIS grades A to C injuries. Participants received a lumbar intrathecal catheter within 48 hours of injury, which remained in place for up to 120 hours. MAP was continuously measured intra-arterially and maintained at a target range of 80-85 mmHg. Cerebrospinal fluid pressure (CSFP) was recorded but not manipulated during the observation period. Adjustments in MAP were made via fluid volume enhancement followed by the use of vasopressors. Patients underwent decompressive surgery on average within 20 hours of injury. Neurological function was assessed at admission and at 6 months post-injury using the AIS grading system.
The results demonstrated that both MAP and CSFP during the first 5 days post-injury were independently predictive of AIS conversion at 6 months. Specifically, higher MAP (OR 1.037, 95% CI 1.011-1.063, P = 0.004) and lower CSFP (OR 0.958, 95% CI 0.923-0.995, P = 0.027) were associated with increased odds of conversion. Importantly, lower SCPP was strongly predictive of the lack of subsequent neurological improvement. The study identified a critical SCPP threshold of 50 mmHg. Patients whose SCPP dropped below this value were significantly less likely to experience AIS conversion, and the number of such episodes correlated with worse outcomes (P = 0.023). In contrast, episodes of MAP falling below 70 mmHg were not significantly associated with neurologic outcome (all P > 0.32). Cox hazard ratio models confirmed that exposure to SCPP below 50 mmHg significantly predicted both lack of AIS conversion and limited improvement in total motor scores, while MAP-based thresholds did not yield significant associations.
In conclusion, SCPP was shown to be a more reliable and sensitive predictor of neurological recovery after tSCI than either MAP or CSFP alone. The findings support the use of SCPP-guided management, with an emphasis on maintaining SCPP above 50 mmHg as a potential therapeutic target to optimize neurological outcomes.
Methodological Review
The findings from this study are important, but some caveats must be kept in mind. This was a purely observational study of acute SCI patients with lumbar catheters inserted to monitor CSFP and SCPP, and as such, there was no “intervention” or “control” arm per se. The CSFP was measured at the lumbar cistern, which may not accurately reflect the pressure at the level of the injury. It remains uncertain whether intrathecal pressures at these 2 sites are equivalent. Although not an objective of the study, no attempts were made to drain CSF, which might have facilitated further increases in SCPP by lowering CSFP. Consequently, the only strategy available to augment SCPP in this cohort was through elevating MAP, which aligns with current practice in many trauma centers. The key message in this paper was around the potential benefit of actually monitoring (and maintaining) SCPP in acute tSCI patients, analogous to the monitoring and management of TBI patients.
Overall, this was a methodologically robust prospective observational cohort study. However, given its observational nature, the risk of unmeasured confounding and selection bias cannot be excluded. Consequently, the certainty of evidence is rated as very low.
Nevertheless, this study did offer compelling findings that the SCPP may be the more relevant physiologic measure for hemodynamic management of acute SCI than the MAP, which in some respects is intuitively analogous to the management of TBI. This offers the physician a new monitoring and treatment option for acute SCI patients. This study fits with other papers that have offered additional data on the safety and efficacy of targeted SCPP with the use of intrathecal catheters.17-19 However the overall data supporting targeted SCPP remains low. 8 Further high-quality studies will be necessary to shed light on this monitoring approach, including controlled trials that involve the drainage of CSF, attaining the optimum SCPP, the appropriate length of treatment time, and the best blood pressure agent.
Recommendation for Integrating Into Your Clinical Practice
The findings of this study highlight the potential role for lumbar drain insertion to be integrated into the hemodynamic management of acute SCI patients for SCPP-based monitoring and management. However, due to the very limited literature on SCPP-based management and unresolved questions about the association with neurologic outcome, when the AO Spine – Praxis Spinal Cord Institute Clinical Practice Guidelines group reviewed this topic, it was felt that there was insufficient evidence to make a recommendation around the application of SCPP-based management. So, while this approach has conceptual appeal (and some trauma centers have already incorporated the insertion of lumbar drains into the hemodynamic management protocols for their patients), we are not able to make a recommendation around the use of lumbar drains for SCPP management. Further high-quality evidence is required to validate specific SCPP targets and to define the role of CSF drainage in optimizing SCPPs. A clinical trial of CSF drainage in 58 acute SCI patients has been completed and is expected to provide further insights into the role of CSF drainage for SCPP management in these patients (the CASPER clinical trial, ClinicalTrials.gov NCT03911492).
Article 3
M. G. Fehlings, A. Moghaddamjou, J. S. Harrop et al. Safety and Efficacy of Riluzole in Acute Spinal Cord Injury Study (RISCIS): A Multi-Center, Randomized, Placebo-Controlled, Double-Blinded Trial. J Neurotrauma 2023 Vol. 40 Issue 17-18 Pages 1878-1888. DOI: 10.1089/neu.2023.0163.
Clinical Rationale
Traumatic spinal cord injury is a devastating condition with significant impact upon the individual, their families and the healthcare system more broadly. 13 Treatment of tSCI in the acute stages involves surgical decompression of the injured spinal cord but the benefits of adjunct pharmacological treatments remain unclear. 20 Given the disability that tSCI causes, interventions that may result in improved function, quality of life, pain and disability are worthy of investigation. To that end, there is data from preclinical studies21,22 and early phase clinical trials 23 indicating that riluzole is safe and may confer a neuroprotective benefit in the setting of cervical spinal cord injury. This prompted investigation of its safety and efficacy in the current phase III trial.
Study Summary
Between October 2013 and April 2021, 193 (54.9%) of a planned 351 patients with tSCI were recruited before the study was terminated by the sponsor during the COVID-19 pandemic. Patients with acute cervical tSCI were randomized in a 1:1 ratio to either riluzole or placebo. Inclusion criteria were adults [18-75 years] with American Spinal Injury Association Impairment (AIS) A-C, cervical (C4-8) tSCI within 12 hours of injury. The intervention group received riluzole (oral dose of 100 mg twice per day for the first 24 hours followed by 50 mg twice per day for the following 13 days); the control group received placebo over the same schedule. The effect size of 0.37 Cohen’s d was utilized. The primary efficacy endpoint was change in Upper Extremity Motor (UEM) score at 180 days. Secondary outcomes included Spinal Cord Independence Measure (SCIM) at 180 days and change in Lower Extremity Motor (LEM) score, Total Motor (TOTM) score, International Standards for Neurological Classification of SCI (ISNCSCI) sensory scores, Short Form 36 Version 2 (SF-36v2), European Quality of Life 5 Dimensions 3 Level Version health utility, pain Numeric Rating Scale (NRS) scores, and the Graded Redefined Assessment of Strength Sensibility and Prehension (GRASSP). Mortality and adverse events (AEs) were also recorded. At 180 days, no significant difference was found between riluzole and placebo groups in change in UEM (difference: 1.76, 95% CI -2.54-6.06), LEM (difference: 1.45, 95% CI -4.80-7.70), or TOM (difference: 2.86, 95% CI -6.79-12.52). There were 1722 adverse events in the riluzole group (including 9 deaths and 110 serious AEs), as compared with 1786 (including 10 deaths and 132 serious AEs) in the placebo group.
Methodological Review
This was a very well-conducted multi-center phase III clinical trial. Treatment assignment was randomized. Allocation was concealed. Outcome assessors were blinded. Follow-up rate was high (82.7%). The statistical analyses were robust and conducted on an intention-to-treat (ITT) and completed cases basis. The trial had a Data and Safety Monitoring Board (DSMB). Adverse events were closely tracked and reported. The trial strictly followed the predefined study protocol and was pre-registered on ClinicalTrials.gov. The trial did have to be terminated early on account of the COVID-19 pandemic. Hence, although the study was powered at a planned enrollment of 351 patients, only 193 patients were enrolled, leaving the trial underpowered.
The overall quality of evidence is rated as moderate by the GRADE methodology.
Recommendation for Integrating Into Your Clinical Practice
Based on the results of this study and the literature around the use of Riluzole, we are not able to make a recommendation on the use of riluzole in patients with acute cervical tSCI. The robust RISCIS trial was methodologically strong, but underpowered. New analysis of this data set, however, continues to make Riluzole an attractive therapeutic target worthy of further evaluation. Riluzole represents an emerging treatment where a more formal evaluation process is needed prior to making any recommendations on its routine use outside of clinical trials.
Discussion
This paper highlights 3 articles focusing on the adjunct management of tSCI using the GRADE methodology.8-11 As the field attempts to expand the treatment paradigm of tSCI beyond early surgery, new treatment strategies deserve critical appraisal. Article 1 was selected to address the common practice of hemodynamic management after a tSCI. Based on the results, we provide a conditional recommendation to augment mean arterial blood pressure to at least 75-80 mmHg but not higher than 90-95 mmHg for a duration of 3-7 days to optimize spinal cord perfusion in acute traumatic SCI. This recommendation refines prior MAP guidance, adding both lower and upper thresholds and a limited duration to balance perfusion with vasopressor risks. This paper recognizes the practical impact of hemodynamic management in the health care system while also starting to tailor the treatment to the patient’s response.
Article 2 was selected to address the growing interest and literature surrounding the concept of SCPP. Based on low level of evidence currently surrounding the field, no recommendation can be made at this time to consider SCPP-guided hemodynamic management as an adjunctive strategy in the acute care of tSCI. MAP targets provide a population-level approach, while SCPP monitoring introduces a patient-level strategy that may individualize care and reduce vasopressor exposure where feasible. As more data is generated surrounding SCPP, the opportunity exists to not only further understand the impact of hemodynamic management on outcome, per Article 1, but also additional evaluation of cerebrospinal fluid biomarkers given the ready access.
Article 3 was selected given the potential impact of Riluzole on the treatment of tSCI and the scale of the randomized trial. Even with optimized perfusion strategies such as MAP and potentially SCPP, pharmacologic neuroprotection remains an attractive area to augment neurological outcome. The authors recently published a secondary analysis of the RISCIS data utilizing a global statistical test suggesting improved global outcomes at 6 months. 24 Therefore, no recommendation can be made on the use of riluzole in patients with acute cervical tSCI at this time. 24 Given these findings, further investigation and evaluation into the role of Riluzole in tSCI is likely to occur.
The Quality of Evidence and Key Recommendation for Each Article Using the GRADE Methodology. Recommendations Apply After Timely Decompression and Standard Critical Care
Outlook
These recommendations highlight how hemodynamic management has matured into conditional, practice-ready recommendations, while SCPP and riluzole remain promising but not yet definitive. This represents a knowledge gap in the management of tSCI. Future research priorities include pragmatic trials of SCPP-guided care, optimization of vasopressor strategies, and renewed exploration of pharmacologic neuroprotection. The data presented here allows the active spine surgeon treating tSCI to continuously update their clinical practice and recognize the limitations of the current state of the literature supporting differing treatment modalities.
While the selection and critical review of the articles was up to the assigned experts, the AO Spine Knowledge Forum SCI is a renowned group of international clinical experts in the field of SCI treatment and research, who aimed at extracting strong to conditional clinical recommendations that may be useful for spine surgeons in their clinical practice, using the well-established Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) system. 11
Footnotes
Acknowledgements
This study was organized and funded by AO Spine through the AO Spine Knowledge Forum Spinal Cord Injury, a focused group of international experts. AO Spine is a clinical division of the AO Foundation, which is an independent medically guided not-for-profit organization. Study support was provided directly through AO Network Clinical Research.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.