Hall and Braughler¹⁴ investigated the effects of high-dose MPSS (15 to 90 mg/kg IV) on spinal cord electrophysiology. In an initial set of experiments in cats, it was observed that the administration of an intravenous bolus of MPSS could indeed inhibit posttraumatic LP in spinal cord tissue, but that the doses required for this effect were much higher (30 mg/kg) than previously hypothesized or than those empirically employed in the clinical treatment of acute central nervous system (CNS) injury. Further experimental studies, also conducted in cat SCI models, showed that the 30 mg/kg dose of MPSS not only prevented LP but, in parallel, also inhibited posttraumatic spinal cord ischemia. Braughler and Hall¹⁴ found that a 30 mg/kg dose of MPSS followed at 2 hours by a 15 mg/kg dose provides significantly better protection against injury-induced ischemia and Ca^2+- dependent neurofilament degradation than a single 30 mg/kg dose. With many of these therapeutic parameters (LP, secondary ischemia, aerobic energy metabolism), the dose–response for MPSS followed a sharp U-shaped pattern. The neuro- and vasoprotective effect is partial with a dose of 15 mg/kg, optimal at 30 mg/kg, and diminishes at higher doses (60 mg/kg).

The antioxidant neuroprotective action of MPSS is closely linked to the drug’s tissue pharmacokinetics.14 For instance, when MPSS tissue levels are at their peak following administration of a 30 mg/kg intravenous dose, lactate levels in the injured cord are inhibited. The subsequent administration of a second dose (15 mg/kg IV), at the time at which the levels after the first dose have declined by 50%, acts to maintain the peak suppression of lactate and more effectively maintains adenosine triphosphate (ATP) generation and energy charge.^15,16 These findings suggested that prolonged MPSS therapy might better suppress the secondary injury process and lead to better outcomes compared with the effects of a single large intravenous dose. Indeed, subsequent experiments in a cat spinal injury model demonstrated that animals treated with MPSS using a 48-hour antioxidant dosing regimen had improved recovery of motor function over a 4-week period.¹³

Animal Spinal Cord Injury Data

Glucocorticoids have been repeatedly shown to inhibit axonal sprouting and synaptogenesis in various CNS regions.^17,18 Although it is not known whether these actions occur concomitantly with the acute antioxidant neuroprotective effects, the potential of steroids to attenuate posttraumatic plasticity mechanisms is a serious concern. Thus the potential for steroid side effects, inhibition of plasticity mechanisms, and even neurotoxic actions underscores the fact that glucocorticoids like MPSS are a far-from-ideal approach to dealing with the posttraumatic oxidative stress and LP-related damage and consequent need for antioxidant dosing that continues beyond the first 24 to 48 hours.

Despite concerns about the potential inhibitory and neurotoxic effects of MPSS, it is encouraging that high doses of MPSS have actually been reported to diminish axonal dieback of vestibulospinal fibers and to promote their terminal sprouting in transected rat spinal cords.¹⁹ Thus the question of whether high-dose MPSS is neuroprotective or neurotoxic may depend on dose selection, timing, and duration of administration and the particular neuronal population in question.

Clinical Studies

Randomized, Controlled Trials

NASCIS I

Three landmark National Acute Spinal Cord Injury studies examined the use of MPSS for acute traumatic SCI. The first NASCIS study, published in 1984 and 1985,²⁰ compared a high-dose with a low-dose cohort of methylprednisolone (level of evidence: III). The investigated groups included a high-dose methylprednisolone treatment (1000 mg bolus/d) versus the standard dose (100 mg bolus/d) in 330 patients for 10 days after SCI. A placebo was judged unethical because of an assumed benefit from steroid administration and was therefore excluded.²¹ Motor scores were determined based on the Bracken scale, from the examination of seven muscle groups on each side of the body scored on a 6-point scale. The authors reported the motor and sensory scores from the right side of the body only.

No difference in neurological recovery of motor function or pinprick and light touch sensation was observed between the two treatment groups at 6 weeks and at 6 months after injury (p = 0.63 at 6 weeks, and p = 0.59 at 6 months). The lack of a treatment effect was independent of the severity of the initial lesion or the time from injury to starting treatment.

To the contrary, significant complications were reported in both treatments, more often in the high-dose MPSS group. Early mortality was statistically greater in the high-dose protocol (relative risk of 3.1 and 1.9, ≤ 14 and 15 to 28 days after injury, respectively). Wound infections were also more prevalent in the high-dose regimen (relative risk of 3.6). Subsequent animal studies completed after NASCIS I suggested that higher doses were required for neuroprotection than were included in the NASCIS I study,^15,22 influencing development of the NASCIS II trial.²³

NASCIS II

One of the major critiques of this study is that all primary outcome measures of NASCIS II were negative. It is interesting to see that no table or graph exists where data are displayed as a function of time and subjected to mathematical algorithms to establish a correlation. With the multiple post hoc comparisons required to discover these differences, it remains quite possible that the observations reflect random chance alone.21

The NASCIS II has also been widely criticized for its failure to include outcomes important to the patient. This was criticized sharply by Hurlbert,²¹ raising questions concerning the clinical importance of reported neurological recovery among patients treated within 8 hours. To correct this oversight, the NASCIS III protocol included the American Spinal Injury Association (ASIA) Functional Independence Measure (FIM) assessment. Furthermore, Bracken and Holford²⁴ also published a retrospective estimate of functional recovery in NASCIS II from results modeled in the NASCIS III study. In that report, the authors claimed that the MPSS therapy-related motor function recovery observed in NASCIS II predicted a clinically important recovery in the FIM.²⁴ However, there was a lack of robustness in statistical modeling, limiting the value of this retrospective evaluation.

NASCIS III

The NASCIS III trial compared the 24-hour infusion of MPSS used in NASCIS II to a 48-hour high-dose MPSS infusion as well as a treatment group that received tirilizad mesylate, a 21-aminosteroid and antioxidant without the negative perceived glucocorticoid effects.^23–25 All patients had their treatment initiated within 8 hours of SCI. No placebo group was included because it was again deemed ethically inappropriate to withhold at least the initial large bolus of MPSS. This trial demonstrated no sustained benefit to high-dose MPSS with respect to motor and sensory scores among the 499 randomized patients at 1-year follow-up. Again, a post hoc analysis noted that patients receiving the MPSS bolus between 3 to 8 hours after injury demonstrated improved neurological function at 6 weeks and 6 months, but not at 1 year, when they were given MPSS for 48 hours rather than 24 hours. Patients treated within 3 hours after SCI demonstrated no differences between 24- and 48-hour infusions.

Timing of Administration

Bracken et al., as a result of NASCIS III, recommended that, within 3 hours of injury, patients receive a 24-hour infusion, whereas for those treated between 3 and 8 hours postinjury, a 48-hour MPSS regimen was better than the 24-hour regimen of the NASCIS II protocol.25 Due to the post hoc analysis in the NASCIS II trial, attention was placed on the particular issue of drug delivery within 8 hours and MPSS physiology.

Hurlbert²¹ demonstrated that a physiological rationale does not exist for the selection of 8 hours as a determinant of steroid efficacy. This author stated that the 8-hour window is strictly arbitrary and represents a post hoc finding that is inherently flawed, making this time window questionable.

Complications with the Use of MPSS

The NASCIS II and III studies reported potential complications due to high-dose steroid administration that may have serious negative ramifications for patients. In the NASCIS II trial there was a 1.5-fold higher incidence of gastrointestinal hemorrhage, twofold higher incidence of wound infection, and threefold higher incidence of pulmonary embolism in the MP group as compared with controls. Similarly, in NASCIS III, the 48-hour regimen was associated with a twofold higher rate of severe pneumonia, a fourfold higher rate of severe sepsis, and a sixfold higher incidence of death than in the 24-hour group.²¹

Although the differences did not reach statistical significance, the trend is concerning because the impact of these complications can be catastrophic. Further, it is important to note that a priori sample size calculations, based on NASCIS II data, indicate over 1400 patients (sample size for binomial proportion, b = 0.8) would be required to prove statistically that no differences in the rate of wound infection exist between both groups.²¹

Of more concern is the observation in NASCIS III of a sixfold higher incidence of death due to respiratory complications in the 48-hour MP group than in the 24-hour MP group (p = 0.056), suggesting a higher mortality rate associated with a 48-hour protocol.²¹ However, the potential for complications associated with 48-hour high-dose MPSS must be balanced against the results of NASCIS III wherein the extension of dosing to 48 hours produces a significantly better neurological outcome compared with the 24-hour regimen in patients treated after 3 hours.

CRASH Study

The foregoing NASCIS III morbidities are akin to the worrisome complications discovered in the recent CRASH trial, which studied steroids in head injury. In this study, head-injured patients with a Glasgow Coma Scale score of 14 or less received either a loading dose of 2 g of methylprednisolone followed by a 0.4 g/h infusion for 48 hours or matching placebo within 8 hours of injury. This randomized, controlled trial was stopped early when it was discovered at interim analysis that steroid-treated patients had significantly higher all-cause 2-week mortality (21.1% vs 17.9%, p = 0.0001).²⁶ Subsequent follow-up demonstrated that 6-month mortality was also higher in steroid-treated patients (25.7% vs 22.3%, p = 0.0001.²⁸ Interestingly, complications, such as seizures, gastrointestinal bleeding, and infection, were similar in both groups. The authors noted that they were unsure of the mechanism of increased mortality with steroids. The lack of an identifiable etiology, however, does not diminish the validity or importance of the results.²⁶

Penetrating Trauma Indications

At the present time, none of the data from the three NASCIS studies support the use of methylprednisolone for penetrating trauma. These authors concluded that patients who sustain an SCI secondary to a gunshot wound or other penetrating injury to the spine should not be treated with steroids until the efficacy of such treatment is proven in a controlled study.²⁷

Medicolegal Aspects of Corticosteroid Use

The utility of high-dose methylprednisolone infusion for acute SCI has not been clearly defined in the medical literature. Methylprednisolone is presently being used off label in the United States for SCI because there is no US Food and Drug Administration (FDA)-approved indication for this use.28 Despite the fact that subsequent clinical studies and critical reviews have challenged the validity of the recommendations that followed the NASCIS studies, failure to administer steroids in acute SCI has been cited in litigation against physicians due to the potential “neuroprotective effect.”²⁸ There is certainly an inherent conflict for clinicians when questioning the potential therapeutic benefit versus complications, given the medicolegal ramifications.

Critical Appraisal of Data—Evidence-Based Medicine

Randomized trials of MPSS for the treatment of acute SCI have shown that significant improvements in motor function recovery may exist after treatment with the high-dose regimen within 8 hours of injury. However, this improvement effect appears modest, if present at all, and does not appear to result in significant functional clinical recovery. Nonetheless, even small changes in motor recovery, typically assessed in the MPSS trials on one side of the body, do have the potential to be amplified into meaningful improvements in quality of life.²⁹

The NASCIS II trial results did provide some evidence for the safety of high-dose MPSS.²³ However, this is counteracted by evidence in NASCIS III of a rise in mortality due to pneumonia, respiratory distress syndrome, or respiratory failure (grouped together) in the 48-hour methylprednisolone group.^24,25 This result was based on six deaths in the 48-hour group and one in the 24-hour group (RR = 6.0; 95% CI 0.73 to 49.3).

Conclusion

At present, high-dose MP therapy, although not FDA approved in the United States for acute SCI treatment, continues to be an option for initial medical treatment. Evidence-based medicine has evaluated the potential harmful effects of MPSS versus any modest neurological benefits.

Bracken²⁹ has addressed various criticisms and misunderstandings in the form of a recent meta-analysis of the NASCIS and non-NASCIS trials of MPSS in acute SCI. The conclusion was that “high-dose MPSS given within 8 hrs of acute SCI is a safe and modestly effective therapy that may result in important clinical recovery for some patients, although further trials are needed to identify superior pharmacological therapies and to test drugs that may sequentially influence the post-in-jury cascade.”²⁹ In 2001, the Spine Focus Panel^30,31 reported that, although methylprednisolone is only modestly neuroprotective, it is clearly indicated in acute SCI because of its favorable risk/benefit profile and the lack of alternative therapies. However, a significant minority of respondents were of the opinion that the evidence supporting the use of steroids in SCI was weak and did not justify the use of this medication. The Spine Focus Panel agreed that, given the devastating impact of SCI and the modest efficacy of MP, clinical trials of other therapeutic interventions are urgently needed.

Although it is clear that substantial criticisms have emerged and are valid in regard to the administration of MPSS, the lack of available alternatives makes one reconsider whether to eliminate MPSS from the list of available options. It can be concluded, as a Class II recommendation, that in nonpenetrating trauma, MPSS used within 3 hours of injury at a 30 mg/kg loading dose followed by 5.4 mg/kg/h is not an unreasonable selection for SCI.³¹ In scenarios where between 3 and 8 hours have elapsed, MPSS used at the dose given earlier for 48 hours becomes a viable option only after the family and the patient are aware of the complications that can occur with long-term administration. Any use of the drug for nonpenetrating trauma more than 8 hours after injury should be avoided.

Nevertheless, other groups, such as the AANS/CNS, have been less hopeful on the potential of MPSS to become a standard treatment even in specific settings. Guidelines were published in 2002 by this joint section emphasizing that the available medical evidence does not support a significant clinical benefit from the administration of MPSS in the treatment of patients after SCI for a duration of either 24 or 48 hours.32 They state that “the neurological recovery benefit of methylprednisolone when administered within 8 hours of ASCI has been suggested but not convincingly proven.”³² Furthermore, the accepted position on methylprednisolone in the treatment of acute human SCI is that it should be prescribed knowing that the evidence suggesting harm is more consistent than the evidence for the benefit.³²

Another aspect of this controversy that may have dispelled many of these conflicts is based on the fact that MPSS has not gone through the FDA approval process. It is necessary to ask why it has not been presented to the FDA. If the evidence is not strong enough to be presented to the FDA, then is it strong enough that methylprednisolone should be the treatment of choice for acute SCI?²⁸

At the least, the experience with high-dose MPSS can shape the future of SCI research. Hopefully, we, as a community of scientists and physicians, have learned enough from this 20-year-old debate to perform better research so that as new compounds are developed, we can subject them to studies that have fewer methodological flaws.

Related posts:

Principles of Surgical Management of Spinal Trauma Associated with Spinal Cord Injury Peripheral Nerve Grafts and the Repair of Axonal Circuits Following Spinal Cord Injury Posttraumatic Kyphotic Deformity of the Cervical Spine The Human Central Pattern Generator and Its Role in Spinal Cord Injury Recovery Somatosensory Function and Recovery after Spinal Cord Injury: Advanced Assessment of Segmental Sensory Function Considerations for the Initiation and Conduct of Spinal Cord Injury Clinical Trials

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