India-OrthNASCIS 3 USA, 1997
Prospective, randomized, double-blind. Negative. Methylprednisolone, Tirilizad
Improved neurologic recovery with MPSS treatment
Petitjean, Pointillart France, 1998, 2000
Prospective, randomized, single-blind. Methylprednisolone, Nimodipine, Placebo
No difference. Increased infection in MPSS groups.
Matsumoto Japan 2001
Small Size randomized trial
Higher complication rate with MPSS
Retrospective Studies
Prendergast USA, 1994 Retrospective Negative
Gerhart USA, 1995 Retrospective Negative
George USA, 1995 Retrospective Negative
Gerndt USA, 1995 Retrospective N/A (looked at adverse events)
Poynton Ireland, 1997 Retrospective Negative
The consequences of a spinal cord injury are often devastating, and any possibility of mitigating neurologic loss is attractive. To this end, management of acute spinal cord injuries has included the use of steroids for the past 40 years, based in large part on physiological hypotheses with limited clinical support.[6 7] Mechanical injury to the spinal cord initiates a cascade of secondary events that include ischemia, inflammation and calcium-mediated cell injury. Animal experiments have shown that methylprednisolone exhibits potential neuroprotective effects through its inhibition of lipid peroxidation and calcium influx and through its anti-inflammatory effects.[8 9 ]
Three well-designed, large, randomized clinical trials (the National Acute Spinal Cord Injury Studies [NASCIS I, II and III]) examined the effect of steroid administration in patients with acute spinal cord injury.[10-15]
NASCIS I examined the change in motor function in specific muscles and changes in light touch and pinprick sensation from baseline.[10 11] The study detected no benefit from methylprednisolone, but the dose was considered to be below the therapeutic threshold determined from animal experiments.
NASCIS II used a much higher dose, and patients were randomly assigned to receive a 24-hour infusion of methylprednisolone, naloxone or placebo within 12 hours after acute spinal cord injury.[12 13] Again, there was no benefit overall in the methylprednisolone group; however, post hoc analyses detected a small gain in the total motor and sensory score in a subgroup of patients who had received the drug within 8 hours after their injury. As a result, this 24-hour, high-dose methylprednisolone infusion, if started within 8 hours after injury, quickly became an implied standard of care despite considerable criticism of the validity of such a post hoc analysis. Hence Since 1990 MPSS in SCI has been considered as standard of care.
Subsequent clinical trials have provided conflicting evidence about steroid treatment in acute spinal cord injury. A Japanese study attempted to replicate the results seen in the 8-hour subgroup from NASCIS II and reported improved function at 6 months in a larger number of muscles and sensory dermatomes among subjects who received high-dose methylprednisolone infusion than among those who received only low doses of the drug or no drug.16 However, the study lacked detail about randomization and outcome measures, and it included only 74% of the enrolled subjects in the outcome analysis.
Conversely, an underpowered prospective randomized trial that used a methylprednisolone regimen similar to that used in NASCIS II found no improvement in motor and sensory scores at 1 year.[17]
NASCIS III compared a 48- hour infusion of methylprednisolone with a 24-hour infusion started within 8 hours after injury and found no benefit from extending the infusion beyond 24 hours. Again, only post hoc analysis showed a benefit from extending the infusion to 48 hours when treatment was started between 3 and 8 hours after injury. No other study has verified the primary outcome of 48 hours versus 24 hours or the post hoc conclusion of benefit from starting treatment between 3 and 8 hours after injury.[14 15]
A meta-analysis of all of the trials concluded, on the basis of the controversial subgroup post hoc analyses in NASCIS II and III and the data from the Japanese study, that a 24-hour high-dose methylprednisolone infusion within 8 hours after injury is efficacious.[18] Despite this meta-analysis, the efficacy of such a regimen remains uncertain and will require further study.
Steroid therapy is not without risk. Most patients with acute spinal cord injury are treated in intensive care units, have polytrauma, have impaired lung capacity and are vulnerable to sepsis. In all 3 NASCIS studies and other, smaller studies, the incidence of sepsis and pneumonia was higher in the high-dose methylprednisolone groups than in the placebo or other treatment groups; the differences were not significant except in NASCIS III. Hyperglycemia and gastrointestinal complications were also reported following high-dose methylprednisolone treatment. Therefore, it has been proposed that, without compelling evidence for its efficacy, methylprednisolone should be used with caution and may even be harmful, particularly if infusion goes beyond 24 hours.[19]
The cost of a 24-hour methylprednisolone infusion is not prohibitive, and a gain of antigravity strength in one or more muscles below a spinal segment can provide an important functional gain, especially for patients with cervical spinal cord injuries. Therefore, even the small improvement observed in the NASCIS subgroups could be viewed as a benefit in cases of complete or incomplete cervical cord injury. Despite the risk of complications and as long as the outcomes in the NASCIS subgroups remain a possibility, physicians may still opt to administer a high-dose methylprednisolone infusion within 8 hours after injury. However, they should no longer feel compelled to do so. Physicians who conduct the initial triage and resuscitation of patients with acute spinal cord injury should consult their specialist colleagues who will be continuing the care of these patients regarding their preference for methylprednisolone infusion.
Many International neurosurgical & spinal societies have adopted this notion that a high-dose, 24-hour infusion of methylprednisolone started within 8 hours after an acute closed spinal cord injury is not a standard treatment nor a guideline for treatment but, rather, treatment option, for which there is very weak level II and III evidence.[20]
In contrast to the recommendations of the NASCIS III trial, the American Association of Neurological Surgeons/Congress of Neurological Surgeons concluded, following a systematic review of the literature in 2002, that "treatment with MPSS for either 24 or 48 hours is recommended as an option in the treatment of patients with acute spinal cord injuries that should be undertaken only with the knowledge that the evidence suggesting harmful side effects is more consistent than any suggestion of clinical benefit."[21 22] A suggestion of larger sample and more robustly designed studies was made to answer this question definately
Safety and Adverse Effects of Steroids
Potential adverse effects of high-dose steroid administration in trauma patients include:
Increased incidence of infectious and septic complications
Increased incidence & severity of respiratory complications
Increased incidence of pulmonary embolism
Worsening of head injury outcome
Increased incidence of gastrointestinal hemorrhage
Increased incidence of pancreatitis
Possibility of missed hollow viscus injury due to 'masking' of abdominal signs
Recent Literature
A very interesting observation was made when we were reviewing the recent literature on MPSS and SCI. THERE EXISTS NO CONTROLLED TRIAL AFTER 2001!
This was an observation we tried to looked into again and again however what we could find was just review of literatures, some retrospect or prospect series and few expert commentaries. The earlier paragraph emphasized the need of a larger randomized study, however such trial happened in last 11 years and currently no trial are officially registered. This was an amazing observation and appeared as the Surgeon community has finally given up on MPSS. One study in 2006 indicated that MPSS was given in cases with SCI more to avoid a medico-legal issue than to expect any gain out of it. Dr Miller in 2008 [25] commented that “It cannot be said at this point that MPR has no beneficial effects in the treatment of acute spinal cord injury, but it seems clear that if any benefit exists, it is probably small and has not been demonstrated by the NASCIS studies. Hurlbert lists 5 reasonable requirements for a new treatment to be accepted as a standard of care: (1) the evidence should be obtained from a randomized and well-executed; (3) The data should be compelling (face validity and internal consistency) and obtained by appropriate statistical methods; (4) the study should yield changes meaningful to the patient; and (5) the result should be reproducible. Although both NASCIS trials pass the first 2 criteria, they clearly fail the last 3. One cannot, then, avoid the conclusion that acceptance of megadose MPR—or of any medical intervention whose benefits and limitations are not clearly defined and demonstrated—as standard therapy carries the serious risk of grave disservice to other investigators, to the people involved in the patient’s treatment, and most seriously, to the patients who are entrusted to our care.”
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