Should Patients with Acute Spinal Cord Injuries Receive Steroids?

Published on 11/03/2015 by admin

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Chapter 1 Should Patients with Acute Spinal Cord Injuries Receive Steroids?

STEVEN. CASHA, MD, PhD, FRCSC, R. JOHN. HURLBERT, MD, PhD, FRCSC, FACS

The annual incidence of spinal cord injuries (SCIs) is estimated between 11.5 and 53.4 per 1 million people,¹^–⁸ and prevalence is estimated at around 700 SCI cases per 1 million people in the United States.⁹ These injuries are characterized by high mortality and morbidity rates. In those individuals who survive to arrive at an acute care institution, mortality rates range between 4.4% and 16.7%.^3,^{5, 8} These survivors typically experience prolonged hospitalization in acute care hospitals and rehabilitation centers.^8,¹⁰ Patients are typically young (mean and median ages ranging in the late 20s and early 30s) and male (80–85% of patients).⁸ Approximately 45% of patients experience a complete neurologic injury with no detectable neurologic function below the level of the lesion.¹¹ Fifty-five percent of patients are injured between C1 and C7-T1.⁸ Hospital admissions of a week or longer are necessary for approximately 10% of patients with SCI every year because of complications including pressure sores, autonomic dysreflexia, pneumonia, atelectasis, deep venous thrombosis, and renal calculi.¹²^–¹⁴ Spasticity and pain also add significantly to neurologic disability in 25% of patients.¹² Long-term reduced life expectancy is largely accounted for by pneumonia, pulmonary emboli, and septicemia. Furthermore, the financial burden of managing these injuries both to the individual and to society is enormous. The estimated cost to the United States for care of all patients with SCI in 1990 was $4 billion.⁸

Accordingly, therapies that limit the extent of neurologic dysfunction after SCI (neuroprotection) or that improve recovery of function (neuroregeneration and neuroaugmentation) would have a huge impact on this patient population. Significant research interest in these strategies has identified many potential therapeutic targets in animal models. Of these, several have been applied to high-quality human investigations. Unfortunately, none has been proved effective in humans. The American Association of Neurological Surgeons and Congress of Neurological Surgeons Joint Section on Disorders of the Spine and Peripheral Nerves’ 2002 Guidelines for the Management of Acute Cervical Spine and Spinal Cord Injury¹⁵ specifically recognizes methylprednisolone and GM-1 ganglioside as options for treatment in patients with acute SCI. However, these options were qualified “without demonstrated clinical benefit” in the case of GM-1 ganglioside and with “evidence suggesting harmful side effects” that is more consistent than any suggestion of clinical benefit in the case of methylprednisolone. Tirilazad and naloxone have also been studied in humans but without any evidence of efficacy to warrant inclusion in the guidelines.

This chapter attempts to critically review the evidence for use of methylprednisolone and other corticosteroids in the treatment of human SCI. The discussion focuses on human studies; a wealth of animal studies that preceded the study of these medications in humans is beyond the scope of this chapter.

METHYLPREDNISOLONE AND OTHER CORTICOSTEROIDS IN SPINAL CORD INJURY

Steroids in various forms have been used in the treatment of SCI for many years. Historically, the rationale for the use of corticosteroids in the management of neural trauma extended from their use in decreasing edema in the management of brain tumors. In addition, their anti-inflammatory effect was thought to be beneficial to the secondary injury pathophysiology of SCI. Studies in dogs supported these hypotheses and demonstrated a modest improvement in neurologic outcome with steroid treatment and a modified anti-inflammatory response.¹⁶ Subsequently, other animal studies have provided support for improved neurologic recovery after SCI in animal models when methylprednisolone is administered and have provided evidence for inhibition of lipid peroxidation, protection of energy metabolism, reduced post-traumatic ischemia, maintenance of neurofilament structure, and decreased post-traumatic ionic shifts.¹⁷

The role of steroids in human SCI management became more rigorously considered after publication of the Second National Acute Spinal Cord Injury Study (NASCIS II). Unfortunately, the initial enthusiasm for an apparent positive effect of methylprednisolone in SCI demonstrated by NASCIS II has not stood up to the extensive scrutiny that ensued.¹⁸^–²¹ However, despite significant criticism, this medication continues to be prescribed by many physicians, and a 2002 study suggests that most practitioners prescribe it because of peer pressure or fear of litigation, rather than a firm belief that it is indeed efficacious.²²

The first NASCIS study compared low- (100 mg/day × 10 days) and high-dose (1000 mg/day × 10 days) methylprednisolone, and did not include a placebo group.²³ It failed to demonstrate a difference between the doses tested. The high-dose group exhibited an increased risk for complications. That study was followed by a randomized, controlled trial comparing a 24-hour protocol (30 mg/kg methylprednisolone bolus followed by 5.4 mg/hg/hr until 24 hours) with placebo in NASCIS II.^24,²⁵ The dose selected in NASCIS II was greater than that of the original study because of further animal work that suggested a therapeutic threshold of 30 mg/kg.²⁵ NASCIS II concluded that improved neurologic recovery was seen when the methylprednisolone treatment protocol was initiated within 8 hours of injury. That study was then followed by NASCIS III, which compared patients randomized to the 24-hour NASCIS II protocol with those randomized to a 48-hour protocol (5.4 mg/kg/hr methylprednisolone after the 30-mg/kg bolus).^26,²⁷ That study concluded that patients for whom therapy was initiated within 3 hours did not gain any benefit from extending treatment to 48 hours, whereas those for whom therapy was initiated between 3 and 8 hours did benefit further. No benefit has been shown if therapy is initiated beyond 8 hours in NASCIS II.

Both the NASCIS II and NASCIS III trials were well designed and executed. However, closer scrutiny demonstrates that the primary analyses of methylprednisolone treatment effect were negative in both studies. The stated conclusions were based on post hoc analyses that suggested minor treatment effects on motor scores at 1 year and when therapy was initiated in the 8- and 3- to 8-hour windows identified in NASCIS II and III, respectively (statistical probability was slightly greater than 0.05 for 1-year motor scores in the NASCIS III 48-hour steroid group). None of the sensory scores was different between treatment groups in either study.

Several concerns have arisen regarding the post hoc analyses of NASCIS II and III. The left-sided motor scores were not published but reported “similar” to right-sided scores. Thus, half the available data were excluded. The statistical analyses failed to correct for multiple statistical comparisons, and it is unclear whether the repeated-measures design was considered. More than 65 methylprednisolone-related t tests were performed in NASCIS II, and more than 100 t

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