Pharmacological Management of Acute Spinal Cord Injury

Transcription

1 SUPPLEMENT TO JAPI may 2012 VOL Pharmacological Management of Acute Spinal Cord Injury Alok Sharma * Introduction Medical care for acute spinal cord injury has advanced greatly in the last 50 years. Significant advances in recent years, including an effective drug therapy (e.g. methylprednisolone) for acute spinal cord injury and better imaging techniques for diagnosing spinal damage, have improved the chances of recovery of patients with spinal cord injuries. The potential for pharmacological intervention to either preserve or recover neurological function after spinal cord injuries exists because most traumatic injuries do not involve actual physical transection of the cord, but rather the spinal cord is damaged as a result of a contusive, compressive or stretch injury. Typically, residual white matter containing portions of the ascending sensory and descending motor tracts remains intact, allowing the possibility of neurological recovery. However, during the first minutes and hours following injury, a secondary degenerative process is initiated by the primary mechanical injury that is proportional to the magnitude of the initial insult. Nevertheless, the initial anatomical continuity of the injured spinal cord in the majority of cases has lead to the notion that pharmacological treatments, which interrupt the secondary cascade, if applied early, can improve the spinal cord tissue survival, and thus preserve the necessary anatomic substrate for functional recovery to take place. Therapeutic Strategy for Medical Management Therapeutic strategy for the medical management of acute spinal cord injury should be based on the following factors: Scientific rationale. Experimental and clinical evidence from existing literature. Logic and common sense. Safety. Availability. Pharmacological Agents Available A variety of promising substances have been tested in animal models of acute spinal cord injury, but few have had potential application to human spinal cord injury patients. Four pharmacological agents have been studied: two corticosteroids (methylprednisolone and tirilazad mesylate), naloxone and GM-1 ganglioside. Methylprednisolone and GM-1 ganglioside have been studied extensively in acute spinal cord injuries; whereas, other two agents, tirilazad mesylate and naloxone, have been studied less extensively and as yet have unclear efficacy in the management of acute spinal cord injuries. Although there are no prospective, randomized, double-blind, multicenter, controlled studies, dexamethasone has been used for many * Professor & Head - Neurosurgery, LTMG Hospital and LTM Medical College, Mumbai; Consultant Neurosurgeon, Wockhardt Hospital. years, where methylprednisolone is not available. There is no class 1 evidence for the use of dexamethasone in the treatment of acute spinal cord injuries. GM-1 Ganglioside In a small study of 37 patients, Geisler et al. 1 showed that GM-1 ganglioside was better than placebo. This study was criticized due to an inadequate sample size. In 1992, a multicenter GM-1 ganglioside acute spinal cord injury study was initiated. It was a prospective, double-blind, randomized and stratified trial and enrolled 797 patients. 2 Patients were randomized into three initial study groups: placebo, low-dose GM-1 (300 mg loading dose and then 100 mg/day for 56 days) and high-dose GM-1 (600 mg loading dose and then 200 mg/day for 56 days). Placebo or GM-1 was administered at the end of the 23-h methylprednisolone infusion. At the study conclusion, 37 patients were judged ineligible, leaving 760 patients for primary efficacy analysis. The authors found no significant difference in mortality between treatment groups. The authors did not identify a higher proportion of patients with marked recovery in motor function at 26 weeks when they compared GM-1-treated patients to the placebotreated group in their primary efficacy analysis. The available medical evidence does not support a significant clinical benefit from the administration of GM-1 ganglioside in the treatment of patients after acute spinal cord injury. 2 Methylprednisolone The randomized trials of methylprednisolone in the treatment of acute spinal cord injury provide evidence for a significant improvement in motor function recovery if administered within 8 h of injury. Pathophysiology of Spinal Cord Injury and Rationale for Methylprednisolone Primary injury of the spinal cord refers to the initial mechanical damage due to local deformation of the spine. Direct compression and damage of neural elements and blood vessels by fractured and displaced bone fragments or disc material occur after mechanical trauma. The secondary mechanism is initiated by the primary injury. The secondary mechanism includes a cascade of biochemical and cellular processes, such as electrolyte abnormalities, marked depletion of the high-energy phosphate reserves, formation of free radicals, vascular ischemia, tissue edema, lactic acidosis, posttraumatic inflammatory reaction and apoptosis or genetically programmed cell death. Experimental evidence suggests that Methylprednisolone reverts or reverses all the effects that are described above. 3

2 14 SUPPLEMENT TO JAPI may 2012 VOL. 60 Methylprednisolone prevents Lipid peroxidation. Posttraumatic ischemia. Destruction of neuronal and microvascular membranes. Inhibition of lipid peroxidation results in Preservation of spinal blood flow. Preservation of metabolism. Reduced damage from high levels of extracellular calcium and excitotoxicity. Reduced protease-mediated damage to neuro-filament proteins. Preserved Na and K homeostasis. It is known that the central nervous system is the only tissue that is incapable of regeneration. Therefore, therapeutic strategies should be aimed at increasing the ability of neuronal cells to survive the adverse conditions that exist following injury/ damage. Core Area cellular structures are irreversibly damaged Idling neurons Table 1: Clinical trials in favor of methylprednisolone Study Description of study Conclusions Multicenter, double-blind randomized trial comparing methylprednisolone (1000 mg/day vs. 100 mg/day for 11 day) in treatment of 330 acute spinal cord injury patients (NASCIS I study) Bracken et al., Bracken et al., Bracken et al., Otani et al., Pettersson et al., Multicenter, randomized, double-blind, placebo-controlled trial comparing methylprednisolone with naloxone and placebo in treatment of 487 acute spinal cord injury patients (NASCIS II study) Multicenter, randomized double-blind trial comparing methylprednisolone administered for 24 h to methylprednisolone administered for 48-h and tirilazad mesylate administered for 48 h in the treatment of 499 acute spinal cord injury patients (NASCIS III study) 158 Patients, methylprednisolone group and control group with no placebo 40 Whiplash injury patients, methylprednisolone 30 mg/kg followed by 5.4 mg/kg/h for 23 h compared to controls No difference in results overall but in those who received methylprednisolone within 8 h there was a benefit to the higher dose group Significant improvement in motor change scores and sensation change scores at 6 month post-injury for patients treated with methylprednisolone compared to naloxone 48-h methylprednisolone administered patients had improved motor recovery at 6 weeks and 6 months compared with 24-h methylprednisolone administered and 48-h administered tirilazad mesylate Analysis of patients treated within the 8 h window show that high-dose methyl-prednisolone resulted in greater motor recovery at 6 weeks, 6 months and 1 year Methylprednisolone patients were found to have fewer disabling symptoms, fewer sick days and a healthier sick leave profile at 6 months post-injury Concept of Idling Neurons Idling neurons are those that are still alive, but they have been damaged to the extent that their function is compromised. 4 Penumbras (between the dead cells and the normal cells) are structures that are not dead but are dysfunctional. If the treatment is effective, the penumbra becomes normal. If the treatment is not effective, penumbra becomes part of dead cells and neurological deficit remains. Clinical Evidence Tables 1 and 2 provide the snapshots of clinical trials with methylprednisolone in acute spinal cord injury. Subgroup analysis revealed that the patients treated within 8 h and those treated with higher dose recovered faster than the patients on lower dose and patients treated after 8 h. NASCIS I The first National Acute Spinal Cord Injury Study (NASCIS I), reported in 1984, compared the efficacy of administration of a 100 mg bolus of methylprednisolone and then 100 mg daily thereafter for 10 days with administration of a 1000 mg bolus and then 1000 mg daily for 10 days in 330 acute injury patients assessed 6 weeks and 6 months after injury. The study revealed no difference in neurological recovery (motor or sensory function) between the treatment groups at either 6 weeks or 6 months after injury. 5 Penumbra cellular structures are viable but nonfunction Normal Viable Cells The authors reported that the administration of methylprednisolone within 8 h of injury was associated with a significant improvement in motor function and in sensation compared with patients receiving methylprednisolone 8 h after injury and patients receiving naloxone or placebo. NASCIS II A multicenter NASCIS II 6 trial was initiated in 1985 using a higher dose of methylprednisolone (30 mg/ kg as a bolus and then 5.4 mg/kg/h infusion for 23 h). These patients were compared with similarly injured patients who received either naloxone (5.4 mg/kg bolus and then an infusion of 4.0 mg/kg/h for 23 h) or placebo. Patients had to be randomized to one of

3 SUPPLEMENT TO JAPI may 2012 VOL Table 2: Clinical trials not in favor of methylprednisolone Study Description of study Conclusions Galandiuk et al., Prospective assessment of 15 patients from 1990 to 1993 with No difference in neurological outcome between two sets of retrospective review of 17 patients from 1987 to 1990 to assess patients differences in treatment outcome with methylprednisolone compared with treatment without corticosteroids Gerhart et al., Concurrent cohort comparison study (population-based) of No differences in neurological outcome 363 acute spinal cord injury patients managed form 1990 to 1991 and In all, 188 patients managed with NASCIS II methylprednisolone compared with 90 patients with no methylprednisolone George et al., Retrospective review of 145 acute spinal cord injury patients, No difference in mortality or neurological outcome between 80 treated with methylprednisolone compared with 65 who groups did not receive methylprednisolone Gerndt et al., Retrospective review with historical control of 231 acute Methylprednisolone-treated patients had significant increases spinal cord injury patients, 91 excluded. Comparison of in pneumonia medical complications among 93 methylprednisolone patients compared with 47 who received no corticosteroid Poynton et al., Case-Control analysis of 71 consecutive acute spinal cord injury No difference on outcome admissions, 63 available for 13 months to 57 months follow up. About 38 patients were treated with methylprednisolone compared with 25 referred >8 h after injury who received no methylprednisolone Pointillart et al., Multicenter, prospective, randomized clinical trial of 106 acute No significant difference in neurological outcome SCI patients treated with methylprednisolone, nimodipine, neither or both Matsumoto et al., Prospective randomized, double-blind study comparing Methylprednisolone patients had higher incidence of incidence of medical complications among 46 acute spinal complications cord injury patients, 23 treated with methylprednisolone, 23 with placebo three treatment arms within 12 h of acute spinal cord injury. Four hundred and eighty-seven patients were entered into the study; 162 patients were given methylprednisolone, 154 were given naloxone and 171 patients were in the placebo control group. Neurological function examined at 6 weeks, 6 months and 1 year. The authors concluded that the treatment with the study dose of methylprednisolone is indicated for acute spinal cord trauma, but only if it can be started within 8 h of injury. NASCIS III NASCIS III 7 was a double-blind, randomized clinical trial comparing the efficacy of methyl-prednisolone administered for 24 h with that of methylprednisolone administered for 48 h. Entry criteria were similar to those described for NASCIS II study patients. Patients were assessed neurologically according to NASCIS I and II (change in motor and sensory scores) and by change in functional independence measure (FIM) at 6 weeks and 6 months. Four hundred and ninety-nine patients were entered into the study, 166 in 24-h methylprednisolone (24 MP) group, 167 in 48-h tirilazad mesylate (48 TM) group and 166 in the 48-h methylprednisolone (48 MP) group. The authors reported that patients in the 48 MP group showed improved motor recovery at 6-week and at 6-month follow-up compared with 24 MP patients and 48 TM patients. When therapy was initiated between 3 and 8 h after injury, the effect of the 48 MP regimen on change in motor score was significant at 6-week and 6-month follow-up compared with patients in the 24 MP and 48 TM treatment groups. When treatment was initiated within 3 h of injury, the same recovery pattern was observed in all three treatment groups. Overall, methylprednisolone improves neurological recovery (motor function, sensation to pinprick and touch) by 20%. The authors concluded that patients with acute spinal cord injury who receive methylprednisolone within 3 h of injury should be maintained on the 24 MP regimen. When methylprednisolone is administered 3 8 h after injury, they recommended the 48-h methylprednisolone regimen. The primary NASCIS II report clearly stated that no benefit of methylprednisolone was observed in the total study group. In the prior analysis of patients treated relatively quickly after the injury (within 8 h, which was the modal time from injury to initiating therapy, and the only dichotomy analyzed), patients treated with methylprednisolone recovered significantly better than placebo-treated patients. Examination of effect of a drug as a function of time to injury was a major hypothesis in the design of both NASCIS II and III. Clarification on Some of the Points Raised Against NASCIS Study Weakness in the Control Group The comparison of placebo-treated patients before vs. after 8 h is not a randomized comparison, and there is no reason to expect that these patients would be similar. The time taken to initiate therapy was largely a function of how quickly patients were admitted to hospital and there are many reasons why this may vary by severity of injury. The only valid comparisons for analysis are the ones reported, that is, comparison of treatment (which was randomized) within early and late time periods. Combined Improvement was due to the Differences in Changes in the Patients with Incomplete Lesions Statistically significant improvement in methylpred-

4 16 SUPPLEMENT TO JAPI may 2012 VOL. 60 nisolone-treated patients was observed and reported in both neurologically complete and incomplete patients as assessed in the emergency department. NASCIS III Recommends that When the treatment is initiated with methylprednisolone within 3 h of injury, then maintenance therapy should be given for 24 h. When treatment is initiated with methylprednisolone between 3 and 8 h of injury, then maintenance therapy should be given for 48 h. Specific Choices of Statistical Methods have Shaped the Report of the Results The statistical procedure used to analyze NASCIS II and III was primarily analysis of covariance, which is a standard form of analysis for any randomized controlled trials. This methodology is described in any standard text. In NASCIS III, there is a Randomization Imbalance In NASCIS III, an imbalance at randomization was reported, which allowed somewhat more severely injured patients to tirilazad mesylate. There was also a nonsignificant baseline difference in the two tirilazad mesylate groups. Baseline neurological function was controlled in all statistical analyses and, as expected, the multivariate analysis of the two methylprednisolone groups showed reduced improvement differences when the baseline differences were taken into account. These controlled analysis form the primary published results. Numbers, Tables and Figures have been Inconsistently Defined The NASCIS III report shows severity of injury of all patients in the trial. Overall, for motor function, 35.2% were quadriplegic; 31.0% paraplegic; 13.4% quadriparetic and 4.0% paraparetic; and 14.4% normal, although all normal motor responses had some sensory loss. After accounting for trial exclusion criteria (gunshot wounds, etc.), the study population reflects the pattern of spinal injury seen in hospital emergency departments. Both NASCIS II and III showed efficacy of methylprednisolone in severely injured patients, defined as having complete neurological loss below the level of injury. Professional biostatisticians are amongst the NASCIS investigators and authors, part of the review process at NEJM and JAMA and part of the NIH panels overseeing the trial. Standard statistical procedures were used and the neurological and functional definitions used are standard criteria promulgated by the American Spinal Injury association, endorsed by the International Medical Society of Paraplegia, and widely adopted for clinical and research purposes around the world. Primary Data have Still not been Made Public The NASCIS datasets are available to recognized agencies and groups, who submit a proposal describing their intended use of the data and demonstrate that they have the technical, biostatistical and clinical expertise to understand and analyze these complex datasets in an unbiased manner. Since NASCIS investigators continue to be funded by NIH for the analyses of NASCIS II and III, there is a concern regarding analyses not been done, which preempt publication of the same analyses by the initial investigators. The reporting is not up to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)/FDA guidelines. The ICH/FDA guidelines were published in 1996, but they enshrined principles and practices that have been evolving for many years. The NASCIS reports, even the earlier ones, meet both the spirit and intent of the recommendations. No FDA Indication has been Obtained The NASCIS studies are funded by the United States National Institute of Neurological Disease and Stroke. However, responsibility of seeking an indication for using the drug for spinal injury from the national regulatory agencies rests with the pharmaceutical company manufacturing the compound, Pharmacia-Upjohn Inc. The NASCIS data are available for purpose of seeking regulatory approval to use methylprednisolone in any country. To the best of our knowledge, FDA approval has not been sought, but an indication has been sought and obtained in a large number of other countries. In many countries, physicians are confidently using methylprednisolone for spinal cord injury since The NASCIS II data supporting the use of methylprednisolone have not changed since Factors in favor of high dose of methyl-prednisolone Even a slight improvement in sensory and motor function can prevent a major functional incapacity later on. 16 There is a marked improvement in the supportive care of spinal cord injury patients since the NASCIS trials were published. Hence, there is a better glycemic control, fluid resuscitation and better management of gastrointestinal side-effects in the current clinical practice. 16 This should also be noted that there is a marked improvement in the supportive care of spinal cord injury patients since the NASCIS trials were published. Animal and Human Studies: Differences Animal studies serve two roles in developing scientific evidence: they prompt the testing of therapies in humans after successful trial in animals, and they provide a biological plausibility to the human evidence once it has been gathered. The weight of the evidence from cat and other models using methylprednisolone in enhancing neurore generation and playing other beneficial roles at the molecular level provides further additional evidence of plausibility to support the human trials. This is extraordinarily difficult but critically important area of human research and it is a cause for concern that more trials of methylprednisolone and other therapies are not being conducted. Currently, primary evidence of efficacy and safety from three trials and secondary evidence from the trials of related clinical conditions and animal studies, as reported in the Cochrane review, support the use at this time. Experimental Evidence Experimental Study on the Efficacy of Methylprednisolone and Dexamethasone in the Treatment of Acute Spinal Cord Injury in Rats Sharma et al. studied the effect of methylprednis-olone sodium succinate in comparison with dexame-thasone in experimentally induced acute spinal cord compression in 50 Wister albino rats ( g). The rats were divided into group A (control) and group B; group B was subdivided into B1, B2, B3, where methylprednisolone was given after 1, 8 and 24 h and

5 SUPPLEMENT TO JAPI may 2012 VOL B4, where dexamethasone was given after 1 h of spinal cord injury respectively. This study inferred that methylprednisolone is potent in promoting recovery post-trauma, especially if given in right dose and at the right time (i.e. at the earliest time after trauma). Methylprednisolone is more effective than dexamethasone in promoting clinical and histological recovery and reducing edema when given earliest after trauma, and these results are statistically significant (at 8 and 24 h). 17 An experimental study to evaluate and compare the neuroprotective effect of hypothermia, naloxone, methylprednisolone and combination of hypothermia and methylprednisolone in spinal cord injury in rat. Sharma et al. evaluated and compared the neuroprotective effect of hypothermia, naloxone, methylprednisolone and combination of hypothermia and methylprednisolone in acute compressive spinal cord injury in rat model. Immunized and conditioned 50 Wister albino rats of either sex, ranging in weight from 250 to 350 g, were used for the study. The rats were divided into following groups: Group A: Control those undergoing only spinal cord compression. Group B: Those undergoing spinal cord compression, followed by treatment with either of the three modalities. Group B1: Treated with naloxone. Group B2: Treated with local hypothermia. Group B3: Treated with methylprednisolone. Group C: Treated with combination hypothermia and methylprednisolone. Combination of methylprednisolone and hypo-thermia is more effective in promoting clinical and histopathological recovery as compared with any single drug. Methylprednisolone, hypothermia and naloxone, all three modalities of treatment, are effective in promoting clinical and histopathological recovery. But methylprednisolone has shown maximum efficacy, which is statistically significant compared to other two. The study recommends early decompression of spinal cord injury with local application of hypothermia and to start methylprednisolone as early as possible. Role of Methylprednisolone in Elective Spinal Surgery While an elective surgery has been performed on the spine (particularly the cervical and dorsal spine), it is worthwhile to start with methylprednisolone as a bolus dose at the start of surgery and continuing it as a maintenance dose throughout the duration of surgery. After completing the surgery, ice cold saline is used to irrigate the dura for a few minutes. This not only helps in homeostasis, but is also neuroprotective and likely to reduce any post-operative neurological deficits. Complications Respiratory Complications The incidence of respiratory complications is higher with methylprednisolone, particularly in unconscious patients on ventilatory support. Prior to the CRASH trial, several centers used methylprednisolone for the head injury. It was found that in these patients, it was difficult to wean off the ventilator. The CRASH trial 18 showed a 3% increase in the mortality in the methylprednisolone group, which forced investigators to terminate the trial. Respiratory complication is a very serious problem; one must put the patient on higher ventilator, good physiotherapy and good ventilation. Gastrointestinal Complications According to gastroenterologists, monotherapy with methylprednisolone does not increase the incidence of gastrointestinal bleeding. Moreover, NASCIS trials did not show any significant increase in gastrointestinal bleeding with methylprednisolone. Also, typical stress ulcer prophylactic agents, such as histamine-2 receptor antagonists and proton pump inhibitors, were not used widely at the time of NASCIS. Number of newer agents are coming up for the better management of gastrointestinal complications. Future Hope 4-Aminopyridine (chronic spinal cord injury) Neotrofin GM-1 Guanosine derivatives Activated macrophages Alternating current stimulation Fetal neural transplantation Olfactory ensheathing glial cells Transplantation of stem cells Key Points High-dose methylprednisolone is an option in patients with an acute spinal cord injury. Even a minimal improvement in sensory and motor functions can lead to better overall functional outcomes. Routine use of adequate fluid resuscitation, stress ulcer prophylaxis and avoidance of hyperglycemia can limit the complications and result in better treatment outcomes. References 1. Geisler FH, Dorsey FC, Coleman WP, et al. Recovery of motor function after spinal-cord injury-a randomized, placebo-controlled trial with GM-1 ganglioside. N Engl J Med 1991;324: Geisler FH, Coleman WP, Grieco G, et al. The Sygen multicenter acute spinal cord injury study. Spine 2001;26(24 Suppl):S87 S Young W, Flamm ES. Effect of high-dose corticosteroid therapy on blood flow, evoked potentials, and extracellular calcium in experimental spinal injury. J Neurosurg 1982;57: McDonagh MS, Carson Sl. Hyperbaric Oxygen Therapy for Brain Injury, Cerebral Palsy, and Stroke. Bookshelf ID: NBK U.S. National Library of Medicine. 5. Bracken MB, Shepard MJ, Hellenbrand KG, et al. Methylprednisolone and neurological function, 1 year after spinal cord injury. Results of the National Acute Spinal Cord Injury Study. J Neurosurg 1985;63: Bracken MB, Shepard MJ, Collins WF, 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. N Engl J Med. 1990;322(20): Bracken MB, Shepard MJ, Holford TR, 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

6 18 SUPPLEMENT TO JAPI may 2012 VOL. 60 of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. JAMA 1997;277: Steroids for acute spinal cord injury (Review) The Cochrane Collaboration. 9. Galandiuk S, Raque G, Appel S, et al. The two-edged sword of largedose steroids for spinal cord trauma. Ann Surg 1993;218(4): Gerhart KA, Johnson RL, Menconi J, et al. Utilization and effectiveness of methylprednisolone in a population-based sample of spinal cord injured persons. Paraplegia 1995;33: George ER, Scholten DJ, Buechler CM, et al. Failure of methylprednisolone to improve the outcome of spinalcord injuries. Am Surg 1995;61: ; discussion Gerndt SJ, Rodriguez JL, Pawlik JW, et al. Consequences of high-dose steroid therapy for acute spinal cord injury. J Trauma 1997;42: Poynton AR, O Farrell DA, Shannon F, et al. An evaluation of the factors affecting neurological recovery following spinal cord injury. Injury 1997;28: Pointillart V, Petitjean ME, Wiart L, et al. Pharmacological therapy of spinal cord injury during the acute phase. Spinal Cord 2000;38: Matsumoto T, Tamaki T, Kawakami M, et al. Early complications of high-dose methylprednisolone sodium succinate treatment in the follow-up of acute cervical spinal cord injury. Spine 2001;26: Kelly A, Kyle A. Potential benefits of high dose methylprednisolone in acute spinal cord injuries. Pharmacology Update 2010;33: Sharma A, Tiwari R, Badhe P, et al. Comparison of methylprednisolone with dexamethasone in treatment of acute spinal injury in rats. J Exp Biol 2004;42: Edwards P, Arango M, Balica L, et al. Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months. Lancet 2005;365: