Medical Management of Acute Spinal Cord Injury

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Chapter 230 Medical Management of Acute Spinal Cord Injury

Administration of High-Dose Steroids

Trials of neuroprotection and pharmacotherapy in acute spinal cord injury (SCI) have focused on counteracting the multitude of secondary injury mechanisms involved in the pathophysiology of acute SCI. There have been approximately 10 randomized prospective control trials (RPCT) in acute SCI, and virtually all have been based on counteracting one or more of these mechanisms of secondary injury.1 Fundamental laboratory research in SCI has discovered at least 25 secondary injury mechanisms.2,3 Therefore, the drugs that have been selected for trial in human SCI have been those with positive effects on one or more of these potentially damaging secondary injury processes elucidated in laboratory animals. For these reasons, steroids were often selected for human trials, either alone or in combination with another strategy such as surgery or another drug. The major attraction of steroids was the experimental evidence that they significantly affect a large number of secondary injury mechanisms. Many reviews of the pharmacotherapy-neuroprotection trials in acute SCI document the extensive series of studies of steroids.1,4,5 In contrast to the reviews by Bracken that support steroid use in acute SCI in humans,6,7 the review by Short et al. reached the opposite conclusion and, furthermore, flagged the potential for early morbidity and mortality associated with steroid use in acute SCI.8

This chapter concentrates on methylprednisolone (MP), which has been the most commonly used steroid for acute SCI, both clinically and in experimental studies. It does not include experimental studies in SCI with other steroid hormones, such as male and female sex hormones, which appear to have major beneficial effects on specific mechanisms of injury but do not have the multidimensional effects of MP or the 21-aminosteroids, such as tirilazad. The topics included in this chapter are the secondary injury mechanisms potentially counteracted by steroids, the track record of steroids in experimental and clinical trials, the therapeutic time window for the administration of steroids, and the current views about the continued use of steroids in acute SCI in humans.

Steroids Counteract the Secondary Mechanisms of Injury after Acute Spinal Cord Injury and Experimental Evidence for the Effectiveness of Steroids

There have been many studies of the vascular, biochemical, electrolyte, and inflammatory changes after experimental SCI that involved the therapeutic administration of steroids. Most of the early experimental animal studies were in large animals, especially cats,9 but after 1990, most of the studies were in rats. There was intense interest in the 1980s in oxygen free radicals and lipid peroxidation as major mechanisms of secondary injury and evidence arose that these processes could be beneficially altered by steroids.10,11 Many of the papers showed beneficial effects in terms of improved histology, such as reduced tissue cavitation and functional improvement.12,13 Of note is the fact that many of the beneficial results in cats were not seen in other species, including a study in rats in my laboratory.14

Vascular and Blood Flow Changes

One of the principal mechanisms of secondary injury after SCI is posttraumatic ischemia, and steroids have been shown to counteract the posttraumatic reduction in spinal cord blood flow. The early experiments on steroids in cats produced very impressive effects in terms of preservation of posttraumatic spinal cord blood flow.15,16 In 1911, Allen first postulated the concept of the secondary mechanism of injury in SCI.17 He found that myelotomy and removal of the posttraumatic hematomyelia in the central aspect of the injured dog cord resulted in improvement of neurologic function after weight-drop injury. He theorized that there was a noxious agent present in the hemorrhagic necrotic material that caused further damage to the cord. Since 1911, numerous injurious pathophysiologic processes have been discovered,18 and similar theories were postulated to explain the progressive damage in head injury, cerebral ischemia, and subarachnoid hemorrhage. One of the strikingly common and dramatic effects of SCI in all experimental models and in human cord injury is the early and often progressive development of hemorrhages in the central region of the injured cord, especially in the gray matter, followed by ischemia. Angiographic studies in humans and microangiographic studies in experimental animals have consistently shown a major loss of the microcirculation involving the capillaries and venules at the injury site and rostrally and caudally.19,20 Spinal cord blood flow worsens over time after injury.21,22 The exact cause of the ischemia is unknown and is probably a combination of mechanical and biochemical causes producing vasospasm and intravascular thrombosis. Therefore, it was remarkable that steroids such as MP improved the metabolism, electrolyte imbalance and spinal cord blood flow in cats.9,13,16 Unfortunately, the effects of MP on spinal cord blood flow and neurologic recovery were not consistently positive. For example, of the 21 studies that I reviewed, steroids produced positive results in only about half.14

Biochemical Changes

One of the most compelling biochemical derangements in the injured spinal cord is the damage caused by the excitatory amino acid neurotransmitter glutamate.23,24 It has also been hypothesized that cell membrane receptor activation by glutamate may play a key role in the development of ischemic damage,25 the mechanism of which is an early intracellular accumulation of sodium, producing cytotoxic edema and a concomitant elevation of intracellular calcium. Raised levels of intracellular calcium can in turn activate calcium-dependent proteases or lipases that cause further damage due to breakdown of cytoskeletal components, including neurofilaments, and dissolution of cell membranes. Steroids in SCI reduced lipid peroxidation and the production of oxygen free radicals, and it was postulated that inhibition of lipid peroxidation was the main cytoprotective mechanism of action of steroids.26,27

Electrolyte Shifts

There is considerable evidence that there are major electrolyte shifts between the extracellular and intracellular compartments after SCI, and these electrolyte imbalances were also improved with steroids. There was evidence that steroids reversed the accumulation of sodium and calcium in damaged neurons and the loss of intracellular potassium from damaged neurons.15 One of the best-defined electrolyte changes is the marked increase of intracellular calcium.28,29 An excess of free intracellular calcium ions plays a fundamental role in mediating the pathogenesis of all neural injuries but especially ischemia and traumatic injuries. After trauma, calcium shifts into neurons in a variety of ways, including through disrupted cell membranes, by depolarization and entry through voltage-sensitive calcium channels, or through receptor-mediated calcium channels activated by glutamate, such as the AMPA/kainate channels. Ischemia can also increase intracellular calcium through glutamate release.

Edema

Significant and progressive edema can follow SCI,30 but it is not known whether the edema is injurious in itself or an epiphenomenon of another injury mechanism such as ischemia or glutamate toxicity. For example, as was noted previously, the latter causes sodium to enter neurons with resulting cytotoxic edema. Edema can spread in the cord from the site of injury for a considerable distance rostrally and caudally in both experimental models31 and clinical cases. Steroids were shown to reduce posttraumatic swelling of the spinal cord.32

Inflammation

A complex series of inflammatory changes occurs in the spinal cord after SCI, and certain components of the inflammatory reaction may add to the secondary injury.33 Specific components of the inflammatory reaction, such as macrophages and microglial cells and interleukins, may contribute to secondary injury.34,35 Steroids have a profound anti-inflammatory effect on nervous tissue.36

Thus, there is a large amount of evidence that steroids counteract many of the posttraumatic injury mechanisms in the spinal cord.

Clinical Evidence for the Effectiveness of Steroids in Acute Spinal Cord Injury

The main trials of steroids for acute SCI were conducted in the United States and Canada in the 1980s and 1990s. The first trials were named the National Acute Spinal Cord Injury Study (NASCIS); and to underline the basis for the selection of MP, the NASCIS papers cited the long list of positive studies of steroids in experimental SCI.37,38 The NASCIS investigators included myself and were led by a number of prominent neurosurgeons including William Collins and neuroscientists including Wise Young. The NASCIS group made many contributions to SCI, including the refinement of the Frankel system for scoring neurologic function, which became known as the NASCIS system but was ultimately replaced by the American Spinal Injury Association (ASIA) system.1 The NASCIS expert in trials design and analysis was Michael Bracken, and the NASCIS studies were funded by the National Institutes of Health (NIH) and by the Upjohn Corporation, the pharmaceutical company that made and supplied MP, which was delivered intravenously in very large doses comparable to the doses found to be effective in experimental SCI. In total, there have been five RPCT MP trials, including three NASCIS trials and two trials in Japan. The first NASCIS MP trial, reported in 1984, encompassed 306 patients in nine centers, showed no difference between low-dose and high-dose MP, and had no placebo group.39 There was an increase in wound infections in the high-dose MP group. NASCIS 2, reported in 1990, included a placebo group; a second pharmacotherapeutic agent, Naloxone, an opioid antagonist; and 487 patients in 10 centers.38 This trial generated much controversy for a number of reasons, beginning with the announcement of the trial as an NIH alert to practitioners in the United States. Partly because of this apparent endorsement of MP use in SCI by the NIH, there was a tendency from then onward to consider MP a standard of therapy for acute SCI. However, the SCI guidelines group emanating from the two major North American neurosurgical organizations40 rejected MP as a standard of therapy for SCI. Nevertheless, in some countries, fear of legal liability for nonusage of MP in acute SCI became a factor in clinicians’ decision to use the drug.41 In NASCIS 2, the rates for wound infections and gastrointestinal bleeding were approximately twice those in the placebo group. The third and last NASCIS trial, reported in 1997, involved 499 patients in 16 centers; showed that the new 21-aminosteroid, tirilazad, was not as effective as MP; and added very little new information.42 The first Japanese MP study essentially confirmed NASCIS 2 but involved only 177 patients in 42 centers.43 The French nimodipine trial also tested MP in a much smaller number of patients, as discussed later, and MP did not improve neurologic recovery over the placebo or nimodipine groups.44

The NASCIS 2 and NASCIS 3 trials engendered considerable controversy concerning the use of MP in acute SCI and produced many very thoughtful and thorough analyses of the results of these two studies.41,4550 The criticisms of these trials included problems with the selection and interpretation of the statistical tests, lack of impact of the minimal neurologic improvements on functional deficits of importance to SCI patients such as loss of bladder control, and lack of reproducible results by subsequent studies (outlined later). There was also criticism of the use of neurologic scores from only one side of the body. The critics also stated that insufficient consideration was given to the increased complications in the steroid groups, including the increased incidence of pneumonia, wound infections, and sepsis. Many critics concluded that these increased risks do not warrant the use of MP, which, at best, only marginally improves neurologic recovery. Also, it is now recognized that large doses of MP such as those used in SCI can cause acute myopathy in SCI patients.51 These issues have resulted in a major decline in some countries in the use of steroids in acute SCI. For example, it was reported in 2008 that three quarters of neurosurgeons and orthopedic surgeons in Canada involved in the care of acute SCI patients do not use steroids, representing a complete reversal of the results from 5 years previously.52 Many authors have defended the results of the NASCIS studies and provided additional evidence of the effectiveness of steroids.5,7,53 Bracken’s Cochrane review of steroids in SCI has not dispelled the controversy.7

Non-NASCIS and Current Clinical Trials with MP in Acute SCI

Gerndt et al.55 analyzed consecutive cohorts of patients treated with and without steroids and found a 2.6-fold increase in pneumonia and an increase in ventilated and intensive-care days but no increase in mortality with NASCIS 2 doses of MP. However, there was a decrease in the duration of rehabilitation days, and these authors advised “the continued but cautious use” of MP. Tsutsumi et al.56 performed a retrospective study of a small case series of acute cervical SCI patients and found that high-dose MP improved ASIA motor scores only in patients with incomplete SCI; the authors stated that only this group should receive MP. They also cautioned that patients should be screened for potential side effects such as serious infections and diabetes and recommended that these groups should not receive the drug. Matsumoto et al.57 performed the fifth RPCT study of MP using a NASCIS 2 dosing regimen in a small number of cervical cord injuries and added prophylactic antibiotics to the treatment protocol. There were significantly more respiratory and gastrointestinal complications in the MP-treated group, especially in patients over 60 years of age. The neurologic results were not reported.

Some of the more recent steroid trials in patients with acute SCI have combined MP with other therapies. Ito et al. recently completed a trial in a small number of patients using a novel consecutive cohort design in which all patients in both cohorts also received early surgical decompression.58 MP was administered according to the NASCIS 2 protocol, with high doses administered within 8 hours of trauma to only one cohort. There was no difference in recovery, but there were significantly more cases of pneumonia in the MP cohort. Pointillart et al.44 devised an excellent RPCT study containing four groups of acute SCI patients treated with either MP alone, nimodipine alone, MP plus nimodipine, or placebo. Unfortunately, there were only 104 patients distributed across these four groups. There was an attempt to operate early, but there was no randomization for surgical groups. There were no differences in neurologic recovery based on the ASIA system, but there were more infectious complications and more hyperglycemia in the MP-treated group.

Conclusions

It is surprising that we are still in the midst of the MP controversy. It should have been completely eclipsed by the discovery of more effective treatments for acute SCI. Sadly, this has not occurred, and one reason is the dearth of properly designed and analyzed trials of other promising agents. One can attribute this to a pipeline that has dried up because of lack of interest by pharmaceutical companies that have been bankrupted by negative or minimally positive trials in acute SCI (Upjohn and Fidia are the major examples) and by disinterest from NIH and other public funders. The criticism of NIH’s premature early announcement of the “positive” results of NASCIS 2 and the criticisms of the nontransparent analysis of its results seem to have caused NIH to shun all subsequent offers of trials in acute clinical SCI for the past 15 years or so since the last intake of patients in NASCIS 3. Fortunately, neuroprotection trials in acute SCI have resumed recently with the Riluzole trial in North America and the Minocycline trial in Canada, largely funded by noncorporate and nongovernment agencies: the Christopher and Dana Reeve Foundation and the Rick Hansen Foundation, respectively. Without effective successor drugs for acute SCI, the old controversial MP is still around.

In my opinion, the risk of complications from the judicious use of MP for 24 hours after acute SCI is not prohibitively large in patients without specific contraindications such as diabetes mellitus. Therefore, in the absence of a proven alternative therapy, one could not criticize the continued use of high-dose MP for 24 hours after acute SCI in selected patients, perhaps only those with incomplete injuries but treated in an intensive-care setting with extreme vigilance for the known and well-documented complications of steroids, especially pneumonia and septicemia.

Viewed with the passage of time, the steroid controversy highlights the role played by the NIH in causing this controversy. Not only was the “alert” announcement unwarranted and a distraction, the NIH then contributed to the lack of transparency of the results and data analysis. It was not until years later that the raw data were made available to other investigators for analysis. Furthermore, some manipulations of the raw data by the original authors of the NASCIS reports, although justifiable, such as the concept of percent possible recovery, were extremely difficult for clinicians to appreciate and should have engendered greater efforts at clarity on the part of NIH.

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