The facts behind the controversy: High-dose steroids in spinal cord injury
Authors: Grant S. Lipman, MD, Clinical Instructor of Surgery, Division of Emergency Medicine, Stanford University School of Medicine; and Alice R. Chiao, MD, Stanford-Kaiser Emergency Medicine Residency Program, Division of Emergency Medicine, Stanford University
Peer Reviewer: Andrew D. Perron, MD, FACEP, FACSM, Residency Program Director and Associate Professor, Department of Emergency Medicine, Maine Medical Center, Portland, Maine
Introduction
Acute spinal cord injury (SCI) is an often devastating event, with consequences of lifelong neurological deficits and significant disabilities. There are an estimated 14,000 victims of traumatic SCI in the United States annually, more than 90% caused by motor vehicle collisions, affecting a disproportionately young population.1 The emergency physician is faced with the multiple challenges of treating the trauma patient while ensuring proper spinal immobilization, obtaining appropriate imaging, and applying limited treatment options to minimize neurologic sequelae.
SCI occurs in two phases. Direct mechanical injury to the spinal cord initiates a secondary response encompassing a cascade of vascular and cellular changes leading to inflammation, edema, and neuronal ischemia. Also, inflammatory mediators, calcium-mediated cellular injury, and lipid peroxidation play significant roles in this second phase of SCI. For the past 30 years, management of acute SCI has included administration of high-dose steroids, based largely upon three well-designed randomized clinical trials (National Acute Spinal Cord Injury Studies [NASCIS I, II, and III]). Intravenous high-dose methylprednisolone (MPSS) theoretically blunts lipid peroxidation and hydrolysis of cellular membranes.
Despite the physiologic risks of steroids and limited clinical evidence showing benefits, the potential neuroprotective effects of steroid treatment have made these protocols an implied standard of care. However, subsequent trials have produced conflicting evidence, and the role of steroids in acute SCI treatment remains a contentious issue. While 99% of Level I trauma centers follow the high-dose steroid protocol suggested by the NASCIS II/III, only half of the practitioners polled believed in the evidence.2 The aim of this paper is to review the most pertinent studies and current literature that guide our practice today, and discover the facts behind the controversy regarding the role of high-dose steroids in acute spinal cord injury.
The implied standard of care
Source: Bracken MB, et al. A randomized controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury. Results of the Second National Acute Spinal Cord Injury Study. New Engl J Med 1990; 322:1405-11.
This seminal double-blind placebo-controlled trial was the foundation for current SCI treatment protocols. The trial involved 487 patients divided into three groups, receiving methylprednisolone, naloxone, or placebo. Methylprednisolone was administered as a 30 mg/kg bolus and 5.4 mg/kg/hr for 23 hours, and naloxone as a 5.4 mg/kg bolus followed by 4.0 mg/kg/hr for 23 hours. Pharmacologic agents were administered within 8 hours of acute closed SCI in 95% of participating patients. Neurological exams were scored based upon motor strength (clinical scale 0 to 5) and sensation to pinprick and touch (scale of 1 to 3 in 29 dermatomes where 1 indicated absent, 2 for abnormal, and 3 for normal sensation). These exams were performed at the time of admission, at 6 weeks, and again at 6 months.
There was no reported effect on motor scores at any time, but there was a statistically significant improvement in sensory scores at the 6-month neurological exam (pinprick, 10.0 vs 6.6; P = 0.012; and touch, 8.7 vs 5.9; P = 0.042). Complication and mortality rates were similar in the treatment and placebo groups. Patients treated more than 8 hours from time of injury had results inferior to placebo. These findings led the authors to conclude that high-dose steroid treatment with methylprednisolone is indicated for the treatment of acute SCI within 8 hours of the injury.
Commentary
To date, there had been few large, multicenter randomized controlled trials that strove to answer the question: Should steroids be administered for acute spinal cord injury? The NASCIS I did not show any benefit from methylprednisolone, but the dose was considered to be inadequate based upon animal studies. The dose was increased in this study, and it was the first study to indicate a statistically significant improvement in sensory function at 6 months.
A follow-up article by the same group demonstrated a statistically significant improvement in motor function from 6 months to 1 year after SCI (p = 0.03) if treated less than 8 hours from initial injury.3 However, at the 1-year mark, the changes in pinprick and touch sensation were no longer statistically significant. Furthermore, the motor function gains were determined by post hoc analysis. If all randomized patients were considered, there was actually no overall benefit in neurological function among the three groups after 1 year. While criticism of the post hoc analyses has led many to question the validity of the study's results, even modest improvement in motor function can lead to important functional gains in SCI victims. This study's results led to the use of high-dose methylprednisolone becoming an implied standard of care.
Timing and consequences
Source: Bracken MB, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. JAMA 1997; 277(20):1597-1604.
Known as NASCIS III, this double-blind, randomized controlled study attempted to define the ideal duration of methylprednisolone therapy for SCI. A total of 499 patients were randomized into three groups: one group received a 48-hour infusion of methylprednisolone; the second group a 24-hour course within 8 hours after injury; and the third group received a 2.5 mg/kg bolus infusion of tirilazad mesylate (a potent lipid peroxidation inhibitor) every 6 hours for 48 hours. Patients' motor and sensory functions were examined immediately after injury, at 6 weeks, and at 6 months after therapy.
Motor function was tested bilaterally in 14 segments, each segment scored from 0 to 5, for a total maximum score of 70 for all normal responses. Sensory function was tested for 29 sensory levels on a scale of 1 to 3 (similar to NASCIS II) for a total possible score of 87. The group that received a 48-hour methylprednisolone infusion had an improvement of 3.6 motor points at 6 weeks (p = 0.04) and 3.7 motor points at 6 months (p = 0.06) compared with the 24-hour treatment group.
The 48-hour methylprednisolone group was further divided into two subgroups, one that received steroids within 3 hours of injury, the other receiving treatment 3 to 8 hours after SCI. The 3-to-8 hour treatment subgroup received the greatest benefit with a motor score improvement of 7.2 points (p = 0.008). Patients in the tirilazad arm had significantly worse motor function than those randomized to either steroid infusion group. However, those receiving tirilazad had notably fewer incidences of severe pneumonia (p < 0.02) and severe sepsis (p < 0.07) compared with the 48-hour methylprednisolone group.
Researchers concluded that patients receiving methylprednisolone within 3 hours of injury should continue to receive the medication for 24 hours, and treatment initiated within 3 to 8 hours of SCI should be continued for 48 hours.
Commentary
This important study established the duration of methylprednisolone infusions based upon time of injury. In NASCIS III, researchers were able to demonstrate statistically significant improvements in motor function in patients treated within 3-8 hours of injury for 48 hours. However, when one closely evaluates the motor and sensory scoring scales used, questions arise regarding the clinical significance of the point improvements. The motor scale equates a 1-point improvement from 2 to 3 with that from 4 to 5. There is a functionally crucial difference between being able to overcome gravity at all versus being able to overcome additional resistance; for most functional activity, grade 4 motor activity is sufficient.4 That being said, any gain of antigravity strength, especially in the setting of cervical spinal cord injury,5 can be an important benefit.
Critics of the NASCIS trials maintain that the neurologic benefits of high-dose methylprednisolone therapy were determined only through post hoc analysis. No other study has been able to verify the primary outcomes. A Japanese study attempted to reproduce the subgroup results, but its methodology suffered from randomization and intention-to-treat outcome issues that has led many critics to disregard the findings.6
High-dose steroid therapy has inherent risks. While all three NASCIS trials showed an increased rate of pneumonia and sepsis, NASCIS III presented statistical significance of these complications occurring more often than placebo. This study proved that while the 48-hour treatment regimen is beneficial, it has higher risks than the 24-hour protocol – making the timing of when to begin treatment after injury an important issue.
Is steroid therapy evidence based?
Source: Short DJ, et al. High-dose methylprednisolone in the management of acute spinal cord injury – a systematic review from a clinical perspective. Spinal Cord 2000;38:273-86.
In this meta-analysis, Short and colleagues presented a thorough review of three clinical trials and six cohort studies examining high-dose steroids in acute SCI. Articles were obtained through a MEDLINE search of articles from 1966-1999. Inclusion criteria included high-dose steroids administered within 12 hours of injury, and separate reporting of outcome measures for steroid and nonsteroid treatment groups. According to the authors, studies with questionable validity were excluded from the review.
Researchers included two Level I evidence trials. The Bordeaux study randomized 106 patients to one of four treatment groups: high-dose MPSS, nimodipine, MPSS and nimodipine, and no treatment. Analysis of ASIA scores (total motor, pinprick, and touch) at 1 year did not show any difference between the treatment groups. The previously discussed NASCIS II study was quoted directly, "Considering all randomized patients at 1 year, there were no significant differences in the neurological function by the treatment group, although patients treated with methylprednisolone showed a slight advantage over those receiving placebo on all three neurological parameters." Furthermore, the authors criticized the post hoc analysis by stating that, "the figures…endorse strong consideration of chance subgroupings and…influences other than the treatments given." The 1994 Otani Japanese study, with its randomization and outcome measure flaws, was reviewed as Level II-1 evidence, concluding that there were no statistically significant changes found in either sensory or motor scores at 6 weeks or at 6 months.
None of the retrospective studies in this paper showed a benefit from high-dose steroid use. Included were two Level II-2 and four Level II-3 publications. Two of the level II-3 studies showing no benefit from MPSS at discharge did not detail the neurological examination. The paper also included two Level II-3 studies that were retrospective analyses of penetrating trauma cases.
The researchers concluded that the small body of evidence does not support significant beneficial treatment from high-dose methylprednisolone administration. Furthermore, the authors stated that the 12 animal studies reviewed supported the contention that "high-dose methylprednisolone (within 8 or 12 h of injury) should be excluded from consideration as an intervention for acute spinal cord injury."
Commentary
The authors approached this meta-analysis with a rigorous methodology, promoting the concept that evidence-based recommendations for clinical interventions must, "advise caution in applying results from nonrandomized groups of patients." However, the authors compared randomized prospective trials showing benefit of MPSS with retrospective analyses of nonrandomized trials, the majority with deleterious outcomes. The contrast in the level of evidence represented makes it difficult to reach the authors' conclusion that the evidence cannot support administration of high-dose steroids and may in fact lead to higher morbidity and mortality.
This review lends heavy suspicion to the purported benefit of high-dose steroid protocols in the setting of acute SCI. One may question whether the included studies were influenced by selection bias because Short and his colleagues commented in the discussion that the papers excluded from their review would not have substantially changed the conclusion. While none of the studies analyzed showed strong support for steroid use, it should be noted that there are no randomized trials reproducing the NASCIS II subgroup results. Also, there exists only weak clinical evidence supporting the conclusion of deleterious neurological results from MPSS.
Are end organs affected?
Source: Kubeck JP, et al. End-organ effects of high-dose human equivalent methylprednisolone in a spinal cord injury rat model. Spine 2006;31(3):257-61.
Despite widespread use of high-dose steroids in human SCI patients, few studies have been performed to assess the actual effects of high-dose steroids on end organs. This prospective study utilized a spinal cord injury model in 48 rats, divided into treatment and control groups. Treatment groups received high-dose methylprednisolone within 1 hour of injury. Liver, lung, intestine, heart, kidney, and spleen were harvested at varying intervals (from 0 to 48 hours of injury) and examined for histologic effects.
The spleen was the most affected organ, with significant lymphocytic depletion at 4 hours and continuing to 48 hours. Specimens of intestinal mucosa revealed dilated and autolyzed/necrotic mucosa starting from 16 hours post injury. Eosinophilic pulmonary infiltrates were found in all groups regardless of time from injury. No significant changes were found in cardiac, kidney, or hepatic tissues.
Commentary
Studies have been performed to evaluate the effect of methylprednisolone on the actual spinal cord,7 but there has been little literature on the effects of high-dose steroids on end organs. It is paramount to weigh the risks of any treatment against the benefits. Infection, overwhelming sepsis, and gastrointestinal bleeding are potential complications of MPSS upon which many critics hinge their dissention. Two decades after the NASCIS II study, which did not show statistically significant increased infections, Kubeck and colleagues demonstrated end-organ effects of high-dose steroids. Profound lymphocyte depletion predisposes the patient to wound infection and sepsis, as the patient is functionally immune-compromised in the vital early resuscitation phase. Effects on intestinal mucosa may also manifest as gastrointestinal bleeding.
Another small study suggested that methylprednisolone may cause myopathy in the high doses administered after SCI.8 Qian and colleagues expanded their discussion further to suggest that the natural course of improvement in steroid-induced myopathy may be the reason for the modestly increased motor scores in patients who received steroids in NASCIS II.
Source: McCutcheon EP, et al. Acute traumatic spinal cord injury, 1993-2000. A population-based assessment of methylprednisolone administration and hospitalization. J Trauma 2004; 56:1976-83.
McCutcheon and his colleagues performed a retrospective analysis on SCI patients who presented to South Carolina hospitals during an 8-year period. They compared differences in hospital length of stay, acute care charges, and other variables as a function of methylprednisolone administration. The study sample was composed of 75% randomly selected patients discharged with the diagnosis of traumatic SCI. Of the 1227 SCI patients analyzed, 48.7% received high-dose steroids; patients admitted through emergency departments and major trauma centers were as much as six times more likely to receive MPSS. Younger patients (age < 19 years) were also twice as likely to be treated with steroids as older patients. The patients who received MPSS treatment had acute care charges that (even after adjustment for injury severity) were on average $16,845 greater than those not receiving steroids. Based upon the data collected, the authors concluded that methylprednisolone usage was associated with significantly longer hospital stays (17.5 days vs 13.8 days, p < 0.01); but adjustment for the injury severity, neurological level of the lesion, and inhospital death resulted in a reduction of hospital length of stay from 4 to 2.5 days.
Commentary
Studies such as this one are important for institutional decisions regarding degrees of protocol adherence. In many cases in this review, patient body weights were not uniformly available, raising questions regarding the consistency of recommended protocols. This study also illustrates how the use of high-dose steroids for SCI is not a clinically established standard of care. While 91.3% of the surveyed emergency physicians reported agreement with the NASCIS protocol, less than half the patients received steroid therapy. There appeared to be a selection bias in those receiving MPSS – with a higher incidence found in Level I and Level II trauma centers and in patients with greater severity spinal lesions.
The association between high-dose steroid use and higher costs/length of stay can be accounted for by numerous factors, including infectious complications. One must remember that the group of patients who predominantly received steroids in this study had a higher likelihood of suffering more severe trauma and being admitted to a trauma center. The more severe SCI patients received more procedures, putting them at increased risk for infections. A 1997 study similarly found that there were significantly higher incidences of pneumonia, duration of mechanical ventilation, and intensive care unit length of stay in steroid-treated patients as compared with those who did not receive high-dose methylprednisolone with SCI.9 These conclusions reiterate the necessity of weighing the benefits of MPSS with the very real risks.
Penetrating injury
Source: Levy ML, et al. Use of methylprednisolone as an adjunct in the management of patients with penetrating spinal injury: Outcome analysis. Neurosurgery 1996;39(6):1141-9.
This retrospective analysis examined if high-dose steroids could be used as a treatment adjunct for penetrating cord injuries. Of the study's 232 patients in a county Level I trauma center with single penetrating SCI with no head injury, 71% did not receive steroids, and 21% received MPSS within 8 hours of injury according to the NASCIS II protocol and dosing. The authors concluded that there was no benefit of high-dose steroid administration in patients with penetrating missile injury; treatment and control groups appeared to be homogeneous.
There was no objective (NASCIS II neurologic scale) or subjective improvement in functional outcomes, including autonomy after injury or the ability to ambulate. There was no observed significant increased rate of urinary tract infection, pneumonia, sepsis, or duration of hospitalization in the high-dose steroid treatment group.
Commentary
Outcomes from penetrating injury to the spinal cord remain universally poor despite advances in surgical and medical treatments. No significant relationships between therapeutic intervention and functional recovery have been reported, and no patients with complete motor loss have been able to regain significant neurological function.10
A similar study using dexamethasone (4-6 mg every 4-6 hours) in penetrating SCI was performed, which showed no improvement in neurological outcome.11 Another retrospective review of spinal cord gunshot wound victims showed no improvement in patients with either methylprednisolone or dexamethasone.12 Interestingly, little increase in adverse events in steroid-treated patients was observed in all three of these studies. Based upon these studies, the use of methylprednisolone in penetrating SCI cannot be supported.
The pediatric population
Source: Faillace WJ. Management of childhood neurotrauma. Surg Clin North Am 2002;82(2):349-63.
In this review article, Faillace provides a thorough review of acute stabilization, medical, and surgical management of pediatric neurotrauma, including traumatic SCI. SCI in children occurs as a function of age, with head control being a major factor in determining injury. In age 0-1 years, SCI is primarily due to birth trauma. Children aged 2-9 years have a higher incidence of SCI from falls and motor vehicle collisions. Sports-related injuries increase from age 9 to 16 years, and injuries from motor vehicle collisions predominate as the leading cause after age 16 years.
Pediatric spinal cord injuries still account for only 1% of all new SCI cases. The spine does not mature until approximately age 10 years. The lack of surrounding musculature, coupled with immature bone and a relatively large head-to-neck ratio can promote transient, self-reducing displacements of the vertebral column. In neonate cadaver studies, the vertebral column could be stretched for 2 inches without any disruption, while the underlying spinal cord could tolerate only a quarter-inch of disruption. For this reason, the clinician should consider the possibility of spinal cord injury without radiographic abnormality (SCIWORA).
No randomized studies of MPSS in the pediatric population exist, and children were not included in the NASCIS studies. In this review, Faillace advocated the use of high-dose steroids (at the same dose indicated by NASCIS II/III) in children with SCI based upon the implied standard of care generated by the NASCIS II study.
Commentary
SCI in children is a relatively rare occurrence, and very little literature specifically addresses the use of high-dose steroids in the pediatric population. There are no pediatric clinical trials specifically addressing this issue, and furthermore, children were excluded from the NASCIS II/III studies. There is little evidence to support or refute the use of methylprednisolone in children. As Faillace suggests, as long as high-dose steroid use is prevalent in adult SCI treatment, the same theory of steroid use should apply to the pediatric population. Special consideration must be taken with potential cases of pediatric SCI because radiographic images can be misleading. Incidence of SCIWORA in various studies ranges from 4.5% to 20% of children with spinal injuries.13
New therapies
Source: Lopez-Vales R, et al. FK506 reduces tissue damage and prevents functional deficit after spinal cord injury in the rat. J Neurosci Res 2005; 81(6):827-36.
This is a compelling prospective study that compared the use of the potent immunosuppressant FK506 with methylprednisolone (30 mg/kg) in SCI rat models. A control group received saline infusion, and an additional group received FK506 2 mg/kg intravenously followed by daily intraperitoneal injections (0.2 mg/kg).
Outcome measures included locomotor activity at time of injury and at 3, 7, and 14 days after injury, stabilization on an inclined plane, motor evoked potentials, and spinal cord tissue histological analysis for tissue sparing. Rats treated with FK506 had significantly better outcomes than those treated with either methylprednisolone or saline. FK506 was shown to be superior in histological parameters and increasing MEP amplitudes; more importantly, however, FK506 rats had improved neurological outcomes.
Rats treated with repeated FK506 doses had significantly better outcomes than those treated with a single bolus dose. Rats in the methylprednisolone group did not have results statistically significant from the controls. Thereby, the authors concluded that FK506 has potential as a pharmacologic therapy in the treatment of acute SCI and it should be considered for human trials.
Commentary
FK506 is an attractive potential intervention for SCI. It already has been FDA-approved for use in humans for preventing allograft rejection in transplant patients. Limitations of this study include the constraint of using a rat model and mechanism of injury. SCI was induced photochemically (directly on an open spinal cord) rather than mechanically. Nevertheless, the study is compelling in that a drug already approved for human use shows potential as a more effective adjunctive therapy than the current 'standard of care.' Besides being a potent immunosuppressant with very few known side effects, FK506 also protects against neuronal ischemia, excitotoxicity, and neurotrophic changes.14
There have been several other research studies that compared FK506 with methylprednisolone in the rat model; one such study found that the two agents used together provided better neuroprotection than either agent used alone.15 Further studies are needed to assess the clinical and functional outcomes of human SCI patients with FK506, however the theoretical and preliminary ventures into this topic are encouraging.
Recommendations
Spinal cord injury is undoubtedly one of the most disabling traumatic injuries, with 11,000 new cases in the United States each year.16 The costs of health care for the long-term management of a single SCI patient are staggering. As a result, clinicians hope to find a 'magic bullet' that could decrease the inflammation and edema, thereby limiting potential damage to the spinal cord. However, as evidenced by Bracken's NASCIS II and III studies, there is little evidence to support significantly improved clinical outcomes from high-dose methylprednisolone therapy. Stratification of data showed a subgroup of patients in whom MPSS appeared to be of benefit, but this ad hoc analysis has been criticized. Systematic clinical reviews repeatedly show that the evidence does not support the use of routine high-dose steroid administration. Moreover, studies that indicate higher complication rates, end-organ effects of steroids, and longer hospital stay all seem to place high-dose steroid use in a less favorable light. Nevertheless, as McCutcheon demonstrated, the vast majority of surveyed emergency physicians accepted MPSS for the acute management of SCI.
This will likely continue to be a contentious topic and source of medicolegal litigation—and particularly true in the pediatric population, where physicians have been blamed for not offering the 'standard of care,' despite the lack of any studies regarding efficacy or even safety of high-dose methylprednisolone use in children.
Until a well-formulated prospective study is published showing a definitive lack of MPSS benefit, it is difficult to implement evidence-based recommendations against the protocol. However, the Canadian Neurosurgical Society, Canadian Spine Society, and the Canadian Association of Emergency Physicians have linked the available Level I and II evidence and revised their formal recommendations, no longer considering MPSS as their standard of care. The American Trauma Life Support organization now lists high-dose methylprednisolone as "a recommended treatment" rather than "the recommended treatment" for acute SCI.
Clinical studies of new pharmacologic agents still are needed to pursue an effective medical treatment of acute SCI. Until firm institutional level decisions regarding SCI are made, or a new therapy with proven benefits is established, physicians should continue to utilize high-dose steroids in daily practice as the best option for a disease process with a history of poor outcomes.
References
1. Thurman DJ, et al. Traumatic brain injury in the United States: A public health perspective. J Head Trauma Rehabil 1999; 14(6):602-15.
2. Vellman PW, et al. Administration of corticosteroids for acute spinal cord injury: The current practice of trauma medical directors and emergency medical system physician advisors. Spine 2003;28:941-7.
3. Bracken MB, et al. Methylprednisolone or naloxone treatment after acute spinal cord injury: 1-year follow-up data. J Neurosurg 1992;76:23-31.
4. Nesathurai, et al. Steroids and spinal cord injury. J Trauma 1998;45(6):1088-93.
5. Hugenholtz H. methylprednisolone for acute spinal injury: Not a standard of care. CMAJ 2003; 168(9):1145-6.
6. Otani, et al. Beneficial effect of methylprednisolone sodium succinate in the treatment of acute spinal cord injury. Sekisui Sekizui 1994; 7:633-47.
7. Oudega M, et al. Long term effects of methylprednisolone following transection of adult rat spinal cord. Eur J Neurosci 1999;11(7):2453-64.
8. Qian T, et al. High-dose methylprednisolone may cause myopathy in acute spinal cord injury patients. Spinal Cord 2005; 43(4):199-203.
9. Gerndt SJ, et al. Consequences of high-dose steroid therapy for acute spinal cord injury. J Trauma 1997;42:279-84.
10. Yashon et al. Missile injuries of the spinal cord and cauda equina. Spinal Injury 2ed. Norwalk: Appleton-Century-Crofts; 1986: 294-305.
11. Simpson RK Jr, et al. Treatment of acute penetrating injuries of the spine: A retrospective analysis. J Trauma 1989;29:42-6.
12. Heary RF, et al. Steroids and gunshot wounds to the spine. Neurosurgery 1997;41(3):583-4.
13. Hill SA, et al. Pediatric neck injuries. A clinical study. J Neurosurg 1984;60:700-6.
14. Bavetta S, et al. The effects of FK506 on dorsal column axons following spinal cord injury in adult rats: neuroprotection and local regeneration. Exp Neurol 1999;158:382-93.
15. Sosa I, et al. Immunosuppressants: Neuroprotection and promoting neurological recovery following peripheral nerve and spinal cord lesions. Exp Neurol 2005;195:7-15.
16. National Spinal Cord Injury Statistical Center. Spinal Cord Injury Facts and Figures at a Glance. 2005.
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