Spinal Cord Injury

The glucocorticoid steroids (e.g., dexamethasone and methylprednisolone (MP); Figure 2) were extensively employed in the clinical treatment of SCI beginning in the mid-1960s and continuing throughout the 1970s. The mechanistic rationale for their use in that era was centered on the expectation that they would reduce posttraumatic spinal cord edema. This notion was based on the rather remarkable reduction of peritumoral brain edema induced by glucocorticoids in brain tumor patients. Furthermore, steroid pretreatment became a standard of care prior to neurosurgical procedures to prevent intra- and postoperative brain swelling.

In the mid-1970s a randomized, multicenter clinical trial, the National Acute Spinal Cord Injury Study (NASCIS I), was initiated to determine if steroid dosing was beneficial in improving neurological recovery in humans after SCI. It compared the efficacy of 'low-dose' MP (100 mg i.v. bolus per day for 10 days) and 'high-dose' MP (1000 mg i.v. bolus per day for 10 days) in affecting outcome after SCI.37 The trial, which began in 1979, did not include a placebo group due to the prevailing belief that glucocorticoid dosing probably was beneficial and could not be ethically withheld. However, the results failed to show any difference between the low- and high-dose groups at either 6 months37 or 1 year,38 suggesting to the investigators that steroid dosing was of little benefit. Additionally, there was a suggestion that the 10-day high-dose regimen increased the risk of infections, a predictable side effect of sustained glucocorticoid dosing. Based on the negative results of NASCIS I, as well as waning neurosurgical enthusiasm for steroid treatment of CNS injury in general, the majority of neurosurgeons concluded after NASCIS that the conventional use of steroids in the acute management of spinal trauma was not beneficial, while at the same time being fraught with the potential for serious side effects.

Increasing knowledge of the posttraumatic LP mechanism in the 1970s and early 1980s prompted the search for a neuroprotective pharmacological strategy aimed at antagonizing oxygen-radical-induced LP in a safe and effective manner. Attention was focused on the hypothetical possibility that glucocorticoid steroids might be effective inhibitors of posttraumatic LP, based upon their high lipid solubility and known ability to intercalate into artificial membranes between the hydrophobic polyunsaturated fatty acids of the membrane phospholipids and to thereby limit the propagation of LP chain reactions throughout the phospholipid bilayer.39

Interest in the LP hypothesis of secondary SCI evolved during parallel investigations of the effects of high-dose MP (15-90 mg kg "1 i.v.) on spinal cord electrophysiology in the context of improving impulse conduction and recovery of function in the injured spinal cord.39 A similar high dose of MP, which enhanced spinal neuronal excitability and impulse transmission, was tested for its ability to inhibit posttraumatic spinal cord LP. In an initial study in cats, an i.v. bolus of MP inhibited posttraumatic LP in spinal cord tissue, but the doses required were much higher (30mgkg_ 1) than those previously hypothesized, or those empirically employed in the clinical treatment of acute CNS injury or tested in the NASCIS trial. Additional studies in cat SCI models showed that at a dose of 30 mgkg "1 MP not only prevented LP but, in parallel, inhibited posttraumatic spinal cord ischemia, supported aerobic energy metabolism (i.e., reduced lactate and improved ATP and energy charge), improved recovery of extracellular calcium (i.e., reduced intracellular overload), and attenuated calpain-mediated neurofilament loss. However, the central effect in this protective scenario was the inhibition of posttraumatic LP.39 The antioxidant neuroprotective action of MP is closely linked to the tissue pharmacokinetics of the drug. This prompted the hypothesis that prolonged MP therapy might better suppress the secondary injury process and lead to better outcomes compared with the effects of a single large i.v. dose. Indeed, subsequent experiments in a cat spinal injury model demonstrated that animals treated with MP using a 48-h antioxidant dosing regimen had improved recovery of motor function over a 4-week period.39

The early empirical treatment of peritumoral edema and acute SCI with glucocorticoid steroids was heavily weighted toward the use of dexamethasone, based upon the fact that it was, and is, the most potent synthetic glucocorticoid steroid available for parenteral use. Dexamethasone is about five times more potent than MP in terms of glucocorticoid receptor affinity and anti-inflammatory potency.39 However, the antioxidant efficacy of MP is unrelated to its glucocorticoid steroid receptor activity. Indeed, a careful concentration-response study compared the ability of different glucocorticoid steroids to inhibit oxygen-radical-induced LP damage in rat-brain synapto-somal preparations, and confirmed that LP-inhibiting potencies and anti-inflammatory potencies do not correlate. Although dexamethasone is five times more potent than MP as a glucocorticoid, it is only slightly more potent than MP as an inhibitor of LP. Furthermore, the maximal antioxidant activity of MP appeared to be superior to that for dexamethasone. Hydrocortisone, the prototype glucocorticoid, completely lacks the ability to inhibit oxygen-radical damage in CNS tissue. Thus, the choice of a steroid for its potential antioxidant neuroprotective activity should not be predicated on glucocorticoid-receptor-mediated anti-inflammatory actions. In addition, selection of the most potent glucocorticoid would logically carry the greatest potential for concomitant steroid-related side effects.

The above-described studies with high-dose MP inspired the second National Acute Spinal Cord Injury Study (NASCIS II), even though the earlier NASCIS trial, which came to be known as NASCIS I, had failed to show any efficacy of lower MP doses even when administered over a 10-day period.40 The NASCIS II trial compared 24-h dosing of MP versus placebo for the treatment of acute SCI. A priori trial hypotheses included the prediction that SCI patients treated within the first 8h postinjury would respond better to pharmacotherapy than patients treated after 8h. Indeed, the results demonstrated the effectiveness of 24h of intensive MP dosing (30 mgkg_ 1 i.v. bolus plus a 23-h infusion at 5.4 mg _ 1 kg_ 1 h _ 1) when treatment was initiated within 8h of injury. Significant benefit was observed in individuals with both neurologically complete (i.e., plegic) and incomplete (i.e., paretic) injuries. Although predictable side effects of steroid therapy were noted, including gastrointestinal bleeding, wound infections, and delayed healing, these were not significantly more frequent than those recorded in placebo-treated patients. Another finding was that the delay in the initiation of MP treatment until after 8 h is actually associated with decreased neurological recovery. Thus, treatment within the 8-h window is beneficial, whereas dosing after 8h can be detrimental. Nevertheless, the NASCIS II results demonstrating the ability of high-dose MP treatment led to this treatment becoming the standard of care for acute SCI in most countries, including the USA. Furthermore, several regulatory agencies in western and Asian countries approved the use of high-dose MP (24-h dosing begun within first 8h) for use in the treatment of acute SCI. Although MP had long been approved in the USA for various anti-inflammatory uses, the FDA did not approve the drug for SCI on the basis of NASCIS II alone due to the statutory requirement for the completion of a second phase III trial that verified the efficacy shown in the first trial.

The demonstrated efficacy of a 24-h dosing regimen of MP in human SCI in NASCIS II, and the discovery of tirilazad,20 led to the organization and conduct of NASCIS III. In the NASCIS III trial, three patient groups were evaluated. The first (active control) group was treated with the 24-h MP dosing regimen shown to be effective in NASCIS II. The second group was also treated with MP, except that the duration of MP infusion was extended to 48 h. The purpose was to determine whether extension of the MP infusion from 24 to 48 h resulted in greater improvement in neurological recovery in acute SCI patients. The third group of patients was treated with a single 30 mg kg _ 1 i.v. bolus of MP followed by 48-h administration of tirilazad. No placebo group was included because it was deemed ethically inappropriate to withhold at least the initial large bolus of MP. Another objective of the study was to ascertain whether treatment initiation within 3 h following injury was more effective than when therapy was delayed until 3 to -8 h post-SCI.

Completion of the NASCIS III trial showed that all three treatment arms produced comparable degrees of recovery when treatment was begun within the shorter 3-h window. When the 24-h dosing of MP was begun more than 3 h post-SCI recovery was poorer in comparison to the cohort treated within 3 h following SCI. However, in the 3 to 8 h post-SCI cohort, when MP dosing was extended to 48 h significantly better recovery was observed than with the 24-h dosing regimen. In the comparable tirilazad cohort (3-8 h post-SCI) recovery was slightly, but not significantly, better than in the 24-h MP group, and poorer than in the 48-h MP group. These results showed that:

1. initiation of high-dose MP treatment within the first 3 h was optimal

2. the nonglucocorticoid tirilazad was as effective as 24-h MP therapy

3. if treatment is initiated later than 3 h post-SCI, extension of the MP dosing regimen from 24 to 48 h is indicated.

However, in comparison with the 24-h dosing regimen, significantly more glucocorticoid-related immuno-suppression-based side effects were seen with more prolonged dosing (i.e., the incidence of severe sepsis and pneumonia increased). In contrast, tirilazad showed no evidence of steroid-related side effects, suggesting that this nonglucocorticoid 21-aminosteroid would be safer for extension of dosing beyond the 48-h limit used in NASCIS III.24'41 The ability of tirilazad to improve neurological recovery in NASCIS III at least as well as MP (i.e., treatment within 3 h post-injury) while producing fewer side effects24,41 strongly suggests that it is worthy of additional trials in acute SCI, which could ultimately show greater efficacy and safety in comparison to high-dose MP.

For a more complete discussion of the neuroprotective pharmacology of high-dose MP therapy in SCI, regulatory status, and limitations of the NASCIS II and III clinical trials (see Hall and Springer).42

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