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  • To Wait or Not to Wait: Overseas’ Stem Cell Treatments

    To Wait or Not to Wait: Overseas’ Stem Cell Treatments
    Published 09/21/2007 | Stem Cells , September 2007 | Unrated

    By: Faye @ stemblog.net

    We at Stemblog have decided to weigh in on the medical tourism issue, which is fueled by the lack of adequate curative treatments available in the US for many of the 100 million Americans who suffer deadly or chronic medical conditions. As this doctor says on the hope that stem cells injected into the spinal cord area will morph into the specific cell type needed to heal the damage:

    "There is some evidence that this occurs in animal models," Magnuson said. "There is some basis for this. It’s just not proven to work in humans."

    So should we wait or not, to try and improve our lives?

    First, I want to caution that just because something has been "proven", doesn’t necessarily mean it works, or that it doesn’t have any undesirable side effects.

    A prime example is the common use of methylprednisolone for acute spinal cord injuries, which initially was hailed as a medical breakthrough in the treatment of spinal cord injury, but in follow-up studies by others was found to be completely ineffective, with possible dangerous side effrects.

    You can easily see that it’s equally important to realize that there are huge dangers in legitimizing "proven" treatments that later turn out to have no value whatsoever.

    Canada has therefor discontinued the use of methylprednisolone altogether in spinal cord injuries.

    At the same time the cooling saline IV treatment that NFL player Kevin Everett received and which "has a very robust and powerful effect" known since the early 1980s to prevent neurological damage remains underutilized, which I find unconcionable. Even though guidelines STILL don’t call for this treatment, because it hasn’t officially been "proven", one doctor says this about the lack of its use: "We wouldn’t consider it ethical now to withhold that [because] we’ve shown it’s useful."

    more:

    http://www.thescizone.com/news/artic...atments/1.html

  • #2
    Originally posted by manouli
    one doctor says this about the lack of its use: "We wouldn’t consider it ethical now to withhold that [because] we’ve shown it’s useful."
    The exact point I was making in that past thread about the use of this procedure. After being told how impossible and unrational it is i feel vindicated.

    Comment


    • #3
      Faye is wrong about methylprednisone. Both Dr. McDonald and the doctors at the Miami Project who trained Everette's surgeon recommended MP because it does work. MP is a powerful anti-inflammatoiry. The secondary damage that occurs after an injury results from inflamation. Reduce the inflammation, you reduce the extent of damage and the severity of the injury. Induced hypothermia, MP and decompression surgery all aid in recovery.

      Comment


      • #4
        I thought clinical trials are supposed to show efficacy? It obviously passed but they still question the results. As we saw in the everett case we dont really kno which method was responsible for his progress. so what good was the trial past showing that mp was safe? in all fairness its obvious im no fan of the clinical trial process.

        Comment


        • #5
          Originally posted by Eric.S
          I thought clinical trials are supposed to show efficacy? It obviously passed but they still question the results. As we saw in the everett case we dont really kno which method was responsible for his progress. so what good was the trial past showing that mp was safe? in all fairness its obvious im no fan of the clinical trial process.
          Eric,

          Please don't blame the clinical trial process for the ignorance of doctors. Over 90% of people who are spinal-injured in the United States is receiving methylprednisolone.

          90% of what doctors do, particularly surgery, have never been tested in a controlled clinical trial. For example, none of the methods of treating syringomyelia have been tested in clinical trial compared to sham surgery. Likewise, there has never even been a controlled clinical trial of decompression.

          The subsequent clinical trials that Faye claims to show that methylprednisolone does not work are small and mostly retrospective non-randomized studies.

          Wise.

          Comment


          • #6
            Originally posted by Wise Young
            90% of what doctors do, particularly surgery, have never been tested in a controlled clinical trial. For example, none of the methods of treating syringomyelia have been tested in clinical trial compared to sham surgery. Likewise, there has never even been a controlled clinical trial of decompression.
            If this is true then what are the purpose of trials? why can't doctors use similar protocols on the spinal cord? I can understand not applying illegal substances like esc's but aren't other stem cells currently in use in other applications? why wont a doctor atleast attempt to apply some form of stem cells to the spinal cord?

            Comment


            • #7
              Originally posted by Eric.S
              If this is true then what are the purpose of trials? why can't doctors use similar protocols on the spinal cord? I can understand not applying illegal substances like esc's but aren't other stem cells currently in use in other applications? why wont a doctor atleast attempt to apply some form of stem cells to the spinal cord?
              Thank you Eric.S, I couldn't agree with you more. Hyper focus on clinical trials takes away from useful treatments and procedures, that could already be applied.

              Buffalo Bills tight end Kevin Everett's remarkable progress after a recent spinal injury has ignited hopes that one component of his treatment -- therapeutic hypothermia -- could represent a breakthrough for other victims of spinal cord injuries......

              Therapeutic hypothermia is used for certain types of heart surgery and brain injuries, but its efficacy in the treatment of spinal injuries has not been established.

              Continuing research by the Miami Project to Cure Paralysis, a renowned spinal-cord-injury research center at the University of Miami, on effects of hypothermia on spinal cord injuries, suggests that cooling the nervous system may decrease spinal cell damage.

              Hypothermia reduces inflammation, free radical formation, swelling, and cell death, says Dalton Dietrich, scientific director for the project. "Mild hypothermia is protective because it targets multiple injury processes [not just one]." And often it's the aftermath of a spinal injury that determines the fate of the injured.

              "We know that within the first hours after a spinal cord injury, there's a wave of degenerative processes that are triggered, and if blocked early enough, the severity can be reduced," says Oswald Steward, director of the Reeve-Irvine Research Center at UC Irvine.


              and

              Even the rapid administration of the steroid methylprednisolone may not have been all that beneficial, suggest some researchers. "Administering steroids following a traumatic injury became standard practice years ago, believing that it reduces secondary injury, but now some researchers are questioning its value," says Jerry Silver, professor of neurosciences at Case Western Reserve University School of Medicine in Cleveland.

              "In experiments on rats, it showed some effect, and in clinical trials it was suggested there was a minor effect," he says, but there's also debate whether the side effects are worth the risk. Side effects include increased risk of immune problems down the road.
              After years of 90% of acute sci getting methylprednisolone ( according to Dr. Young), we haven't seen the kind of recovery as seen with Everett.

              If methylprednisolone had been that useful in the past years of its use, Everett's recovery wouldn't have seemed so miraculous.

              It's got to have been due to the rapid cooling, which was the only thing different in Everett's treatment as the surgery too was pretty standard.

              The four-hour operation that Cappuccino and Dr. Kevin Gibbons, a neurosurgeon, performed on Everett at Millard Fillmore Gates Hospital, in Buffalo, is fairly standard for Everett's type of injury.
              http://www.latimes.com/features/heal...ack=crosspromo

              Comment


              • #8
                Originally posted by Eric.S
                If this is true then what are the purpose of trials? why can't doctors use similar protocols on the spinal cord? I can understand not applying illegal substances like esc's but aren't other stem cells currently in use in other applications? why wont a doctor atleast attempt to apply some form of stem cells to the spinal cord?
                Eric,

                Doctors have been applying all sorts of therapies and none have been able to convince other doctors that the therapies work. Dr. Hongyun Huang, for example, has probably transplanted over 700 patients with OEG cells but, because he has not done controlled clinical trials, convinced any doctors in the United State or Europe to adopt this therapeutic approach. Likewise, there have been many studies with bone marrow stem cells (Source), the claimed embryonic stem cells of Geeta Shroff (Source), the umbilical cord blood transplants being done in Mexico (Source) and in Shenzhen (Source).

                The reason why clinical trials are necessary is to convince the rest of the world that the treatment is safe and effective, so that the treatment will be used. The international standard is that of a phase 3 multicenter double-blind placebo controlled trial. If this standard is achieved, the treatment is usually adopted around the world.

                The reason why methylprednisolone is given around the world for spinal cord injury was because we had carried out a multicenter double-blind placebo-controlled clinical trial showing that the methylprednisolone treatment significantly improved neurological recovery by about 20% compared to placebo-treated controls. The trial furthermore showed that the treatment had to be given within 8 hours and continued for 24 hours to have significant beneficial effects. This was the NASCIS 2 study funded by NIH and completed in 1989 and published in the New England Journal of Medicine in 1990.

                In a subsequent NASCIS 3 trial, we showed that a 48-hour course of the methylprednisolone is superior to a 24-hour course of the drug only when it was started more than 3 hours after injury. Therefore, the current recommendation is that methylprednisolone should be given as soon as possible after spinal cord injury but not more than 8 hours after injury, that a 48-hour course of methylprednisolone should be given if it is started 3-8 hours but otherwise a 24-hour course should be given if it is started within 3 hours after injury.

                The doctors who criticize these recommendations are not saying that the therapy should not be given. They are saying that the treatment should be an "option" rather than a standard of care. If it is a standard of care, they can be sued for not giving the therapy. Several polls have indicate that over 90% of spinal-injured patients in the United States are getting the drug. The exception as those with gun-shot wounds. Because the NASCIS trials excluded patients with gunshot wounds from the trial, it makes no recommendation concerning use of methylprednisolone in such cases.

                I have long said that I would be very happy if somebody were to show a treatment that is better than methylprednisolone for acute spinal cord injury. One small trial that randomized 100 patients to methylprednisolone, nimodipine (a calcium channel blocker), and placebo, analyzing the results without stratifying for complete versus incomplete spinal cord injury, showed no beneficial effect of methylprednisolone. The rest of the trials were non-randomized retrospective studies comparing patients treated before 1990 and after 1990, showing little or no difference. In contrast, NASCIS 2 and 3 were randomized multicenter trials that support the efficacy of early methylprednisolone treatment. There was one small randomized study of methylprednisolone versus placebo in the treatment of whiplash, showing that patients treated with methylprednisolone had less sick time than those that were treated with placebo.

                Based on the above studies, a large majority of doctors in the world now use methylprednisolone to treat acute spinal cord injury. By the way, the statement in Faye's article that "Canada has therefore discontinued the use of methylprednisolone altogether in spinal cord injuries" is false. Methylprednisolone is an option for therapy in spinal cord injury. A majority of people with acute spinal cord injury receive methylprednisolone in Canada.

                Wise.

                Papers Cited
                • Bracken, M. B. (2002). "Steroids for acute spinal cord injury." Cochrane Database Syst Rev(3): CD001046.
                  BACKGROUND: Acute spinal cord injury is a devastating condition typically affecting young people with a preponderance being male. Steroid treatment in the early hours of the injury is aimed at reducing the extent of permanent paralysis during the rest of the patient's life. OBJECTIVES: To review randomized trials of steroids for acute spinal cord injury. SEARCH STRATEGY: The review draws on the search strategy developed by the Cochrane Injuries Group. In addition, files of the National Acute Spinal Cord Injury Study have been reviewed and a Medline search conducted. SELECTION CRITERIA: All published or unpublished randomized controlled trials of steroid treatment for acute spinal cord injury in any language. DATA COLLECTION AND ANALYSIS: Data have been abstracted from original trial reports. For the NASCIS, Japanese and French trials, additional data (e.g. SDs) have been obtained from the original authors. MAIN RESULTS: There are few trials in this area of medical care. Only one steroid has been extensively studied, methylprednisolone sodium succinate, which has been shown to improve neurologic outcome up to one year post injury if administered within eight hours of injury and in a dose regimen of: bolus 30mg/kg administered over 15 minutes with a maintenance infusion of 5.4 mg/kg per hour infused for 23 hours. The initial North American trial was replicated in a Japanese trial but not in the one from France. Data has been obtained from the latter studies to permit appropriate meta-analysis of all three trials. This analysis indicates significant recovery in motor function after methylprednisolone therapy when administration commences within eight hours of injury. A more recent trial indicates that if methylprednisolone therapy is given for an additional 24 hours (for a total of 48 hours), additional improvement in motor neurologic function and functional status is observed. This is particularly observed if treatment cannot be started until between three to eight hours after injury. The same methylprednisolone therapy has been found effective in whiplash injuries and a modified regimen found to improve recovery after surgery for lumbar disc disease. REVIEWER'S CONCLUSIONS: High dose methylprednisolone steroid therapy is the only pharmacological therapy shown to have efficacy in a Phase Three randomized trial when it can be administered within eight hours of injury. A recent trial indicates additional benefit by extending the maintenance dose from 24 to 48 hours if start of treatment must be delayed to between three and eight hours after injury. There is an urgent need for more randomized trials of pharmacological therapy for acute spinal cord injury.
                • Pettersson, K. and G. Toolanen (1998). "High-dose methylprednisolone prevents extensive sick leave after whiplash injury. A prospective, randomized, double-blind study." Spine 23(9): 984-9.
                  STUDY DESIGN: A prospective, randomized, double-blind study comparing high-dose methylprednisolone with placebo. OBJECTIVES: To evaluate the efficacy of high-dose methylprednisolone when administered within 8 hours after whiplash injury. SUMMARY OF BACKGROUND DATA: Whiplash injury often results in chronic symptoms. The management of whiplash injuries is controversial, and pharmacologic therapy has received little evaluation. In recent reports, dysfunction of the central nervous system has been indicated in several cases. Methylprednisolone administered within 8 hours after the injury to patients with acute spinal cord injury has been demonstrated to improve the outcome. This procedure was also adopted in a randomized study of cases of whiplash injury in car accidents. METHODS: Forty patients, 22 men and 18 women with a mean age of 35 years (range, 19-65), were included in the study, 20 in each of two groups. They were treated for whiplash injury, which they had sustained in car accidents. The patients were enrolled if their diagnoses were complete and treatment had begun within 8 hours after injury. Disabling symptoms severe enough to prevent the patient from returning to work, number of sick days before and after injury, and sick-leave profile after injury were used as parameters for the evaluation of the effects of the treatment. Baseline demographic data were controlled for when statistical analysis had been performed. RESULTS: At the follow-up examination 6 months after initial treatment, there was a significant difference in disabling symptoms between the actively treated patients and the placebo group (P = 0.047), total number of sick days (P = 0.01), and sick-leave profile (P = 0.003). CONCLUSIONS: The results of this study indicate that acute treatment with high-dose methylprednisolone may be beneficial in preventing extensive sick leave after whiplash injury. However, the number of patients studied was small, and therefore further prospective, controlled studies are needed.

                Comment


                • #9
                  But isn't the fact that some doctors want it to be a choice a sign that some dont believe it has benefits?

                  personally speaking I would want methylprednisolone and any other substance that could (even if just possibly) restore as much function as possible. I personally don't want a doctor choosing for me what I can have. If my doctor doesn't want to use something than i would rather be transfered to a doctor that will. That whole thing bothers me...

                  Comment


                  • #10
                    Originally posted by Wise Young
                    Eric,


                    The reason why methylprednisolone is given around the world for spinal cord injury was because we had carried out a multicenter double-blind placebo-controlled clinical trial showing that the methylprednisolone treatment significantly improved neurological recovery by about 20% compared to placebo-treated controls.
                    Eric, Canada decided to discontinue use of methyl-prednisolone, when a body of evidence and a retrospective analysis of the earlier positive results revealed that they had been "doctored" to make it look like MP was effective.

                    Please read this definitive analysis on the ineffectiveness of methyl-prednisolone from J Neurosurg (Spine 1) 93:1–7, 2000:


                    Methylprednisolone for acute spinal cord injury:
                    an inappropriate standard of care*

                    R. J
                    OHN
                    H
                    URLBERT
                    , M.D., P
                    H
                    .D., F.R.C.S.(C)
                    University of Calgary Spine Program, Foothills Hospital and Medical Centre,
                    Calgary, Alberta, Canada
                    Object. Since publication in 1990, results from the National Acute Spinal Cord Injury Study II (NASCIS II) trial
                    have changed the way patients suffering an acute spinal cord injury (SCI) are treated. More recently, recommendations
                    from NASCIS III are being adopted by institutions around the world. The purpose of this paper is to reevaluate care-
                    fully the results and conclusions of these studies to determine the role they should play in influencing decisions about
                    care of the acutely spinal cord–injured patient.
                    Methods. Published results from NASCIS II and III were reviewed in the context of the original study design,
                    including primary outcomes compared with post-hoc comparisons. Data were retroconverted from tabular form back
                    to raw form to allow direct inspection of changes in treatment groups. These findings were further analyzed with
                    respect to justification of practice standards.
                    Although well-designed and well-executed, both NASCIS II and III failed to demonstrate improvement in primary
                    outcome measures as a result of the administration of methylprednisolone. Post-hoc comparisons, although interest-
                    ing, did not provide compelling data to establish a new standard of care in the treatment of patients with acute SCI.
                    Conclusions. The use of methylprednisolone administration in the treatment of acute SCI is not proven as a stan-
                    dard of care, nor can it be considered a recommended treatment. Evidence of the drug’s efficacy and impact is weak
                    and may only represent random events. In the strictest sense, 24-hour administration of methylprednisolone must still
                    be considered experimental for use in clinical SCI. Forty-eight-hour therapy is not recommended. These conclusions
                    are important to consider in the design of future trials and in the medicolegal arena.
                    Methylprednisolone for acute spinal cord injury:
                    an inappropriate standard of care*
                    R. J
                    OHN
                    H
                    URLBERT
                    , M.D., P
                    H
                    .D., F.R.C.S.(C)
                    University of Calgary Spine Program, Foothills Hospital and Medical Centre,
                    Calgary, Alberta, Canada
                    Object. Since publication in 1990, results from the National Acute Spinal Cord Injury Study II (NASCIS II) trial
                    have changed the way patients suffering an acute spinal cord injury (SCI) are treated. More recently, recommendations
                    from NASCIS III are being adopted by institutions around the world. The purpose of this paper is to reevaluate care-
                    fully the results and conclusions of these studies to determine the role they should play in influencing decisions about
                    care of the acutely spinal cord–injured patient.
                    Methods. Published results from NASCIS II and III were reviewed in the context of the original study design,
                    including primary outcomes compared with post-hoc comparisons. Data were retroconverted from tabular form back
                    to raw form to allow direct inspection of changes in treatment groups. These findings were further analyzed with
                    respect to justification of practice standards.
                    Although well-designed and well-executed, both NASCIS II and III failed to demonstrate improvement in primary
                    outcome measures as a result of the administration of methylprednisolone. Post-hoc comparisons, although interest-
                    ing, did not provide compelling data to establish a new standard of care in the treatment of patients with acute SCI.
                    Conclusions. The use of methylprednisolone administration in the treatment of acute SCI is not proven as a stan-
                    dard of care, nor can it be considered a recommended treatment. Evidence of the drug’s efficacy and impact is weak
                    and may only represent random events. In the strictest sense, 24-hour administration of methylprednisolone must still
                    be considered experimental for use in clinical SCI. Forty-eight-hour therapy is not recommended. These conclusions
                    are important to consider in the design of future trials and in the medicolegal arena.
                    K
                    EY
                    W
                    ORDS
                    • spinal cord injury • pharmacotherapy • methylprednisolone
                    steroid • practice guideline • spinal cord injury trial

                    The purpose of this paper is to reevaluate carefully the
                    results and conclusions of NASCIS II and III with respect
                    to current practice standards in the treatment of acute SCI.
                    The studies are examined using a series of steps intuitive-
                    ly valid in appraising and accepting a new form of medical
                    treatment. It was the author’s intent to provide detailed
                    information and independent, unbiased interpretation to
                    help establish a perspective on standard-of-care treatment
                    in acute spinal cord–injured victims.
                    Clinical Material and Methods
                    Overall reevaluation of both trials was performed in the
                    context of the quality of evidence that is necessary to
                    change a pattern of practice. The author assumed that to ac-
                    cept a new drug as a standard of care for the treatment of
                    acute SCI that 1) the evidence should be obtained from a
                    prospective randomized double-blind trial; 2) the study
                    should be well designed and well executed; 3) the data
                    should be compelling (face validity and internal consisten-
                    cy) and obtained using appropriate statistical methods; 4)
                    the study should yield changes meaningful to the patient;
                    and 5) the result should be reproducible.
                    In considering these criteria, it becomes immediately
                    apparent that any new treatment must meet not just one
                    but all of the aforementioned requirements. Failure to sat-
                    isfy even one requirement must disqualify a treatment
                    from becoming a gold standard. The results obtained in
                    both NASCIS II and III were subsequently and systemat-
                    ically reevaluated with these requirements in mind.
                    Data obtained in the NASCIS II and III were converted
                    from the tabular form in which they were reported into
                    raw data, and they were then graphically represented.

                    Compelling Data.
                    Two irregularities in data reporting
                    serve to undermine credibility and are common to both
                    R. J. Hurlbert
                    2
                    J. Neurosurg: Spine / Volume 93 / July, 2000
                    Page 3
                    NASCIS II and III: timing of therapy, and motor assess-
                    ment. Although in the results section of the NASCIS II
                    study, the authors assured that an a priori hypothesis was
                    for earlier treatment to produce greater improvement, no a
                    priori intuition is provided concerning an otherwise arbi-
                    trary 8-hour window for 24-hour MP treatment. Hence, it
                    is reasonable to expect that the data were sequentially
                    grouped into all possible categories, hunting for differ-
                    ences (in NASCIS II,
                    1 hour as compared with
                    1
                    hour, 2 hours as compared with 2 hours, and so on).
                    In NASCIS III it is also likely that all possible compar-
                    isons between 0 and 8 hours were made ( 1 hour and 1–8
                    hours, 2 hours and 2–8 hours, 3 hours and 3–8 hours,
                    and so on. With certainty, only the most interesting data
                    were reported. It is intuitive that a time-to-treatment fac-
                    tor may affect outcome, but it is highly likely that such an
                    effect would be graduated. One might expect a progres-
                    sively diminished effect of 24-hour MP group dependent
                    on the time from injury to administration. However, “all-
                    or-none” cutoffs of 8 hours (NASCIS II) and 3 hours
                    (NASCIS III) are neither intuitive nor likely physiologi-
                    cal. To establish a time-dependent treatment effect, data
                    are best displayed as a function of time and subjected to
                    mathematical examination for the degree of correlation. In
                    the absence of published data, the reader has no choice but
                    to assume such correlation does not exist. Thus, although
                    the “time windows” for treatment in both studies are in-
                    teresting, the strength of the data within these windows
                    is seriously weakened because the time windows are un-
                    planned and apparently arbitrary in nature. Because of the
                    multiple post-hoc comparisons required to discover these
                    differences, quite possibly the observations reflect random
                    chance alone......

                    Reproducibility of Results.
                    Although NASCIS II is purported to have been repli-
                    cated independently in Japan, the results have not been
                    formally translated into English, are not available through
                    the National Library of Medicine, and have not been sub-
                    jected to appropriate peer review.
                    11
                    In addition, the study
                    appears to suffer from several critical design flaws.
                    10
                    To
                    date, NASCIS III has not been reproduced; it is unlikely
                    that this study will ever be undertaken again because of its
                    negative outcomes.
                    Discussion
                    In accordance with the criteria proposed at the begin-
                    ning of this paper to help guide clinical acceptance of
                    a new treatment strategy, both NASCIS II and NASCIS
                    III were well-designed and well-executed trials. The work
                    of the clinical investigators in acquiring and randomiz-
                    ing patients, ensuring protocol compliance, obtaining da-
                    ta, and providing appropriate follow up was monumental.
                    However, independent detailed reexamination of available
                    data and statistical methods reveals several flaws that crit-
                    ically undermine the credibility of these studies. Despite
                    qualifying as Class I experimental trials, both NASCIS II
                    and III fail to meet four of six requirements intuitively
                    important in validating a new treatment (Table 1). In ad-
                    dition, evidence of an unacceptably high mortality rate
                    resulting from respiratory complications is found in the
                    NASCIS III. It is interesting to note that despite the over-
                    whelmingly negative (and potentially harmful) 1-year fol-
                    low-up results of NASCIS III the authors were led to con-
                    clude that “Patients starting therapy 3 to 8 hours after
                    injury should be maintained on the regimen for 48 hours
                    unless there are complicating medical factors.”
                    6
                    Clearly,
                    from an unbiased viewpoint, the results of the study can
                    be interpreted to indicate quite the opposite.
                    Although our present ability to improve functional sta-
                    tus following acute SCI is frustratingly hindered, as
                    patient advocates it is undesirable for the medical com-
                    munity to propagate unproven or poorly proven therapeu-
                    tic regimens. Especially in today’s evidence-based envi-
                    ronment, perpetual vigilance is necessary to guard against
                    the pressures attendant with publication. In reporting find-
                    ings from complicated clinical trials, it is highly desirable
                    to present all negative results fairly, especially preplanned
                    or primary outcome measures.
                    There remains room to speculate about the potential
                    beneficial effect of MP in the treatment of acute SCI.
                    Marginally positive p values, especially in NASCIS II (if
                    reproducible with more appropriate statistical techniques),
                    might simply reflect inadequacies of sample size. How-
                    ever, until data obtained from larger populations of pa-
                    tients are published, such hypothetical beneficial effects
                    must be treated as speculation only and cannot be consid-
                    ered in determining standard of care.
                    Conclusions
                    In summary, most experts would agree that the currently
                    accepted management for acute SCI consists of protection
                    of airway, breathing, and circulatory status, as well as
                    immobilization, oxygenation, and blood pressure mainte-
                    nance through volume.

                    A critical reevaluation of the clini-
                    cal efficacy of steroid administration in acute SCI demon-
                    strates that, despite a Class I trial and general widespread
                    use, the evidence for 24-hour MP therapy in humans is neg-
                    ligible or weak at best. As such, it can be regarded as no
                    more than an experimental treatment at this time. Due to
                    the lack of compelling, objectively reported and properly
                    analyzed evidence, steroid administration cannot be con-
                    sidered a standard of care, a recommended treatment, or
                    even a proven treatment option. There is no evidence to
                    support treatment with the 48-hour MP protocol in patients
                    treated within 3 to 8 hours of acute injury.

                    More important,
                    unless further mortality statistics become available, the 48-
                    hour MP therapy should be regarded as potentially harmful
                    and possibly lethal. The findings of this critical analysis
                    underscore the need for clinical investigators to recognize
                    the limitations of their studies and for peer review to pro-
                    vide detailed, unbiased scrutiny. In cases in which clinical
                    ramifications are potentially large, uninterested third-party
                    analyses of entire datasets may be desirable.
                    Acknowledgment
                    The author thanks the American Association of Neurological
                    Surgeons/Congress of Neurological Surgeons practice guidelines
                    committee for their encouragement of this review.

                    Comment


                    • #11
                      Hi Eric,

                      I just found more info that might interest you in reference to clinical trials and the use of methylprednisolone:

                      Critics

                      Reflecting Mark Twain’s statement “There are three kinds of lies: lies, damned lies, and statistics,” many critics believe that MP has been promoted as a standard of care for acute SCI based on results generated through the use of questionable statistical procedures. These doubters claim that NASCIS showed little if any statistically significant benefits from high-dose MP, and modest benefits were only demonstrated in a patient subgroup when data was later micro-analyzed.

                      This controversy is not insignificant. For example, a survey of participants at a 2001 Annual Canadian Spine Society meeting indicated “75% of respondents were using MP either because everyone else does or out of fear for failing do so.”

                      This society and the Canadian Neurosurgical Society commissioned an expert review of the available MP data, which concluded that there was insufficient evidence to support the use of MP as a treatment standard or guideline, although weak clinical evidence supports its use as a treatment option.

                      Other articles challenging MP’s use include:

                      1) Dr. Shanker Nesathurai (Boston) said that neither NASCIS 2 nor 3 convincingly demonstrated MP’s benefits (J Trauma 1998; 45[6]). “There are concerns about the statistical analysis, randomization, and clinical benefits… Furthermore, the benefits of this intervention may not warrant the possible risks.”

                      2) Dr. Deborah Short and colleagues (U.K.) concluded: “The evidence produced...does not support the use of high-dose methylpredinisolone in acute spinal-cord injury to improve neurological recovery. A deleterious effect on early mortality and morbidity cannot be excluded by this evidence.” (Spinal Cord, 2000; 38[5])

                      3) Dr. W.P. Coleman et al (Annapolis Md) strongly criticized both NASCIS 2 and 3 for methodological weaknesses and the lack of data that could be critically reviewed by others (J Spinal Disord 2000; 13[3]). For example, they stated: “The numbers, tables, and figures in the published reports are scant and are inconsistently defined, making it impossible even for professional statisticians to duplicate the analyses, to guess the effect of changes in assumptions, or to supply the missing parts of the picture. Nonetheless, even 9 years after NASCIS II, the primary data have not been made public…These shortcomings have denied physicians the chance to use confidently a drug that many were enthusiastic about and has left them in an intolerably ambiguous position in their therapeutic choices, in their legal exposure, and in their ability to perform further research to help their patients.”

                      4) Dr. R.J. Hurlbert (Alberta, Canada) concluded: “The use of methylprednisolone administration in the treatment of acute SCI is not proven as a standard of care, nor can it be considered a recommended treatment. Evidence of the drug's efficacy and impact is weak and may only represent random events. In the strictest sense, 24-hour administration of methylprednisolone must still be considered experimental for use in clinical SCI. Forty-eight-hour therapy is not recommended.” (J Neurosurg 2000; 93[1 suppl])

                      5) Dr. Tie Qian and colleagues (Newark, NJ) suggested that high-dose MP may damage muscles through acute corticosteroid myopathy (ACM) and that functional improvement attributed to MP may merely be due to the recovery of muscle damage caused by this extremely high MP dose (Med Hypothesis 2000; 55[5]). The investigators noted that under the NASCIS 3 clinical protocol, a 75-kg (165 pounds) acutely injured individual could receive nearly 22 grams of MP, which is the “highest dose of steroids during a 2-day period for any clinical condition.”
                      This is, indeed, a strong indictment. As a crude analogy, consider this: I punch you forcefully in the arm and create a bad bruise. I then claimed that the healing of the bruise was due to - and not caused by - the punch. In this analogy, MP is the punch.

                      6) Further investigating this issue, Qian and colleagues (Miami, Fla) compared five acutely injured patients who received high-dose MP regimen with three control patients, who did not meet the requirements for MP treatment (specifically, two gunshot injuries and one who arrived at hospital too late) (Spinal Cord 2005; 43[4]). Muscle damage was assessed by biopsy and electromyography (EMG - measures the amount of conduction signal reaching the muscle). The biopsies and EMG data indicated that four of the five MP-treated, but no control, patients had muscle damage consistent with ACM. The investigators concluded that “the improvement of neurological recovery showed in NASCIS may be only a recording of the natural recovery of ACM, instead of any protection that MP offers to the injured spinal cord.”

                      Conclusion

                      Because I was a NIH division director when the agency promulgated its MP-treatment policy, I know that it was a conscientious decision in an effort to help those with acute injuries. Unfortunately, we may have to revisit the policy, which could be difficult given that changing the direction of entrenched public-health policies is like an aircraft carrier making a U-turn. In other words; it takes a long time.

                      Some of our most-distinguished NIH scientific advisors built their reputations on this potentially flawed policy and may be reluctant to advise the agency to adjust course. Nevertheless, we need more clarity concerning the true benefits of this drug routinely used to treat acute SCI.
                      http://www.healingtherapies.info/MP.htm

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                      • #12
                        In my opinion the whole system is broke. And the thought that something can go through all 3 phases of trial and still be questioned to me is farther proof and also deplorable. I dont see how we ever expect anything to get done in this system, there never seems to be enough money or proof.

                        I dont even understand how anyone would even desire to work under these conditions.

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                        • #13
                          Jaycee,

                          I am afraid that you are wrong. Most Canadian doctors are still using methylprednisolone.

                          It is shame that none of the people who have criticized the use of methylprednisolone for spinal cord injury have themselves carried out a randomized clinical trial that has provided data refuting the conclusions of the trials out by the National Acute Spinal Cord Injury Study. More important, none of them have shown any data that suggests a better treatment.

                          Wise.

                          Comment


                          • #14
                            Originally posted by Eric.S
                            In my opinion the whole system is broke. And the thought that something can go through all 3 phases of trial and still be questioned to me is farther proof and also deplorable. I dont see how we ever expect anything to get done in this system, there never seems to be enough money or proof.

                            I dont even understand how anyone would even desire to work under these conditions.
                            Eric,

                            The problem is not with the clinical trial system but the lack of clinical trials for spinal cord injury. All clinical trials are supposed to be replicated and extended. The best standard therapies are compared with the best experimental therapies in continuing clinical trials. When clinical trials stop and there is a lack of data, what you get is the feeding frenzy that you see here.

                            Please look at multiple sclerosis, AIDS, cancer, and the other fields. They are making progress. Here, we are arguing about a therapy that was reported to be effective in animal studies more than 3 decades ago, that was tested in clinical trials during the 1980's. It is really beyond belief that we have had so few clinical trials that we are still arguing about this therapy.

                            The concept that a retrospective study reporting significant muscle atrophy in five patients (compared to with three control patients injured by gunshot) suggest that methylprednisolone should not be used for treating spinal cord injury a result of initial muscle atrophy is interesting. I think that authors do not have enough data to conclude what they did.

                            By the way, I should point out that methylprednisolone has been used to treat hundreds of thousands of people, not only for spinal cord injury but for many other conditions. It is routinely used to treat millions of people with multiple sclerosis flareups and for tumor compression of the spinal cord. If any of the problems that are being said to be associated with methylprednisolone were true, we would be seeing a huge flareup of muscle atrophy and other problems associated with its use. The amount of data supporting the safety of methylprednisolone is very substantial.

                            Laurance Johnston is a good friend but I disagree with him on this. Instead of trying to criticize a 20-year old therapy, perhaps the critics should be doing some clinical trials to find better therapies. If they truly believe that methylprednisolone is ineffective, it is then the perfect control group against which to compare a new and better experimental therapy. So, why don't they do some clinical trials and find a better therapy?

                            At the present time, methylprednisolone is the best and only therapy for acute spinal cord injury. It is safe and people should have a choice in getting the drug. If I had spinal cord injury or somebody I love were spinal-injured, I would unquestionably recommend its use. It is safe and, on average, it improves function by about 20% more than placebo-control groups or groups that were treated more than 8 hours after injury.

                            By the way, for those who might be interested in the data and the controversy, the criticisms of NASCIS results by the so-called "expert panel" in Canada were without basis. They were wrong when they suggested that there was post-hoc analysis of data. The stratification of the subject by time of therapy was planned (a priori) for both NASCIS 2 and 3. Our primary hypothesis was the the timing of treatment may have been important and we consequently stratified both treated and control subjects by median time of treatment (so that half of the subjects were treated early or late). Comparisons were made only between those subjects in each time group. Note that we used the same stratification strategy in NASCIS 2 and 3. In NASCIS 2, the median time of therapy was 8 hours. In NASCIS 3, the median time of treatment was 3 hours. If people want to read a detailed analysis of all the answers to the criticisms, please the following article by Michael Bracken in the Cochrane Review (see abstract below for reference).

                            Wise.

                            [*] Bracken MB (2002). Steroids for acute spinal cord injury (Cochrane Review). Cochrane Database Syst Rev. CD001046. Department of Epidemiology and Public Health, Yale School of Medicine, 60 College street, Box 20834, New Haven, Connecticut, USA, 06520-8034. brackenmb@maspo3.mas.yale.edu. BACKGROUND: Acute spinal cord injury is a devastating condition typically affecting young people with a preponderance being male. Steroid treatment in the early hours of the injury is aimed at reducing the extent of permanent paralysis during the rest of the patient's life. OBJECTIVES: To review randomized trials of steroids for acute spinal cord injury. SEARCH STRATEGY: The review draws on the search strategy developed by the Cochrane Injuries Group. In addition, files of the National Acute Spinal Cord Injury Study have been reviewed and a Medline search conducted. SELECTION CRITERIA: All published or unpublished randomized controlled trials of steroid treatment for acute spinal cord injury in any language. DATA COLLECTION AND ANALYSIS: Data have been abstracted from original trial reports. For the NASCIS, Japanese and French trials, additional data (e.g. SDs) have been obtained from the original authors. MAIN RESULTS: There are few trials in this area of medical care. Only one steroid has been extensively studied, methylprednisolone sodium succinate, which has been shown to improve neurologic outcome up to one year post injury if administered within eight hours of injury and in a dose regimen of: bolus 30mg/kg administered over 15 minutes with a maintenance infusion of 5.4 mg/kg per hour infused for 23 hours. The initial North American trial was replicated in a Japanese trial but not in the one from France. Data has been obtained from the latter studies to permit appropriate meta-analysis of all three trials. This analysis indicates significant recovery in motor function after methylprednisolone therapy when administration commences within eight hours of injury. A more recent trial indicates that if methylprednisolone therapy is given for an additional 24 hours (for a total of 48 hours), additional improvement in motor neurologic function and functional status is observed. This is particularly observed if treatment cannot be started until between three to eight hours after injury. The same methylprednisolone therapy has been found effective in whiplash injuries and a modified regimen found to improve recovery after surgery for lumbar disc disease. REVIEWER'S CONCLUSIONS: High dose methylprednisolone steroid therapy is the only pharmacological therapy shown to have efficacy in a Phase Three randomized trial when it can be administered within eight hours of injury. A recent trial indicates additional benefit by extending the maintenance dose from 24 to 48 hours if start of treatment must be delayed to between three and eight hours after injury. There is an urgent need for more randomized trials of pharmacological therapy for acute spinal cord injury.
                            Last edited by Wise Young; 09-27-2007, 11:32 PM.

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                            • #15
                              While I am living proof that the methylprednisolone works. And I have had many medical professionals tell me if I did not receive it I would probably still be on a ventilator. It still sucks being a C3 complete quad, but a good friend of mine is on a ventilator he would do anything to be in my wheelchair. So don't knock the drug unless you've had it. Maybe now using that drug & lowering the body temperature new injuries might get more stuff back.
                              keiffer66

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