此信是关于Gerald Tuite 等2016年5月3号发表在贵刊的那篇关于肖氏手术“双盲实验”的文章。
这是历史上首次将一特大外科手术用残疾儿童进行所谓“双盲”实验。我首先阐明一下我和该实验 的关系：Dr. Tuite’s 团队2009年来到中国学习肖氏手术，亲自检查了十多例术后3年肖氏手术病人，均能自行解尿，基本排空膀胱，无尿失禁。后来，首届国际脊膜膨出学会在佛罗里达奥兰多召开，邀请我作大会主旨讲座，Dr.Tuite则邀请我提前2天去他们医院帮助他们开展肖氏手术。
但是，这“大多数”是多少？11例？15例？还是18例？Tuite 在文章中没有给出这一最重要的数据。即使如此，这一个“most”也已足够判断该双盲实验的根本性错误和数据及结论毫无价值：你不能在3年术后随访期间，部分病人用神经阻断剂瘫痪膀胱，而另一部分不用，然后混合收集资料一起进行“统计学”分析。 三, 但是，我根本不相信“神经阻断剂和间歇清洁导尿在术前评估前两周停止，大多数病人都能在术后3年不用神经阻断剂和清洁导尿。”
"Xiao, Chuan-Guo" <Chuan-Guo.Xiao@nyumc.org> 2/13/2009 6:44 AM：
"Xiao, Chuan-Guo" <Chuan-Guo.Xiao@nyumc.org> 2/17/2009 10:43 PM >
肯， 我特转发【这女孩刚停神经阻断剂和导尿后，残余尿为200，其家庭医生有点担心，和我联系。我告诉他不需处理，会每天很快减少至正常。2周后，如我所料】 报告这个路易桑拿女孩情况的邮件给你，以支持我的观点。如果是你，肯定要继续导尿加神经阻断剂因为她有200毫升残余尿排不净。但事实是：肖氏手术后，如果让大脑而不是医生来控制，残余尿会每天减少直至正常。
“哈罗，Jerry 和 YVES：我翻出09年说服Peters停用神经阻断剂和CIC的电邮，希望我也能说服你。我仍然再想神经阻断剂的问题。所有病孩都是泌尿外科Yves医生一人管吗？真的完全没用神经阻断剂吗？若真的没用，我非常感谢，因为当时我强烈反对你们双盲研究的原因之一就是所有肖氏手术术后患儿必须停用神经阻断剂，但没做肖氏手术者则必须常规使用。但我怀疑：是否有些孩子的家庭医生没有停用神经阻断剂？
六、我感谢Dr. Kestle 的评论。这是一位颇有经验的外科医生客观有益之言。至于其它，由于贵刊应该纯属学术平台，我会在更合适的平台讨论。
I am writing regarding the article “Lack of efficacy of an intradural somatic-to-autonomic nerve anastomosis (Xiao procedure) for bladder control in children with results of a prospective, randomized, double-blind study. Gerald F. Tuite, MD ,et al Division of Pediatric Neurosurgery, Neuroscience Institute, Johns Hopkins All Children’s Hospital, St. Petersburg, Florida; (Published online May 3, 2016; DOI: 10.3171/2015.10.PEDS15271. J Neurosurg Pediatr)
There are major factual, scientific and ethical problems in this article, and its editorials. I will start by clarifying fact about my involvement in “the first in the history” double-blind clinical trial for a major surgery on disabled children.
1, My involvement with the trial: Dr. Tuite’s team went to China in 2009, and personally checked more than a dozen myelomeningocele and lipomyelomeningocele children who were cured by Xiao procedure 2~3 years ago, voiding voluntarily and emptying almost completely without incontinence. They then invited me to All Children’s Hospital to help them to start Xiao procedure two days before my keynote speak on the first international spina bifida conference in Orlando, 2009. They scheduled 2 cases in 2 ORs on same time. I observed and helped in identifying correct roots, then they stopped and I was informed first time they were doing “randomized, double-blind trial”. I immediately expressed my strong objection based on two reasons: First, Xiao procedure had been proved to be a very effective procedure by many centers with thousand cases and formal publications  including those in USA: Beaumont Hospital, NYU medical center, and Louisiana State University . It is unnecessary and unethical to have a double blind trial on a major surgery on children, especially these disabled children. Second, it is impossible scientifically and technically to have a double-blind trail for a very complicated major surgery on spina bifida children whose history, anatomy, neural defect，bladder situation and voiding management may be quite different for each other. The major technical dilemma was that children who had Xiao procedure have to stop CIC and anticholinergics 3 month postoperatively, to allow regenerated axons working with bladder and urethra, while children did not have Xiao procedure should still keep using CIC and anticholinergics as guideline indicated to protect the upper urinary system. How could you manage this dilemma in a double-blind trial for 3 years?
Despite of my strong objection, Dr. Tuite’s team decided to go on the double blind trial. I immediately withdrew my involvement in the “double blind” trial forever at the very first day. So, I did not personally help the first 7 cases, but only 2 in the first day. I had to tell with sorry that I found the donor ventral root was cut wrongly and closely form the cord at one of the 2 cases, and the root had to be reattached to cord by microanastomosis and then its distal end was anastomosed to S3 root as Xiao procedure did. If this kind of accident happened, the patient should be excluded from any type of trials, since the root re-attached to cord may not work at all and jeopardize the down stair Xiao procedure. But I found the child was still listed as #5 (DT+X) in the article.
2,The trial and the article have no creditability and value in terms of methodology, science, and statistics. Randomized, double-blind study requests strictest methodology, and most objective quantity and quality control. While in the Tuite’s trial, in addition to using another result-variable surgery as control, and very small sample size which can not meet statistical request, each subject’s preoperative lower urinary tract condition, abnormal anatomy, neural defects and prior surgical history was different from any others; each of the 4 neurosurgeons performed procedure had different level and experience in surgical skills. But most horrible defect was that the postoperative care was different among the enrolled children regarding anticholinergics and CIC. The authors tried to smooth up the defect by stated in the article twice “CIC and the use of BAMs were terminated 2 weeks prior to preoperative evaluations, and most patients were able to refrain from both of these modalities for the entire 3-year follow-up.” This statement destroyed completely the scientific and methodological ground of this so called double blind study: Post care must be strictly the same, i.e., either all use CIC and same dosage BAMs, or all do not use CIC and BAMs. How many was the “most”, 11? 15? or 18? Authors did not report this critical and most important data. But nevertheless, it was fundamentally wrong to paralyze some patient bladder by BAMs while not to paralyze other’s in postoperative follow-ups in a double blind trial, and then collect and analysis their data together.
3, However, I don’t believe at all it was the truth that “CIC and the use of BAMs were terminated 2 weeks prior to preoperative evaluations, and most patients were able to refrain from both of these modalities for the entire 3-year follow-up.” With experience during the first USA pilot study of Xiao procedure in Beaumont hospital, I know how hard and difficult in trying to convince Peters’ team and local primary care doctors to stop anticholinergics and CIC for spina bifida children underwent Xiao procedure. I would just post the emails below to show how desperate when I tried to ask them to follow my way. Fortunately, they reluctantly agreed and then, got the expected good results.
"Xiao, Chuan-Guo" <Chuan-Guo.Xiao@nyumc.org> 2/13/2009 6:44 AM
I have been thinking about the cases in Beaumont, The results as you mentioned are really not good to me..Before I talk about the possible causes, I want to tell you how I deal with Kelly, the Louisana girl. I remote controlled all her treatment after the surgery.
1, Stopped detropen exactly 2 months after surgery.(She was operated on Oct. 8, 2008.) Wear diaper, DON'T care leaking or not.
2 ,Stopped regular catherterization since the 3 months after surgery(Jan.8.2009), Just once before going to bed. Then, she got one mild UTI but no change on catheraization. Ask the girl to try to void, by pushing or whatever ways.
3, Now, it is just more than 4 months after surgery, she seems to have got it.
In China, none of the patients has ever used Detropen before or after surgery; None of them has had any formal medical management of bladder and bowel, like regular catherizaton or so on after the surgery. But, 80-86% of more than 1300 kids gained continence and voluntary voiding.
So, my opinion is: You guys take care of these kids very good,TOO GOOD to let the bladder and the new reflex and the brain to have chances to communicate with each other. You Doctors are always on control instead of allowing the brain to takeover the control. Why the bowel function improvement is better than bladder? Doctors did not take care of the bowel as good as the bladder.
Then, my suggestion is: immediately stop cathertrization on all the kids underwent the surgery, just ask them to try to void, and wear diaper! (especially Bill, the boy on the News.) Then let's see what will happen in a month before you go to Orlando. As I always say, spina bifida kids do not need to scratch the leg to initiate the reflex for voiding, including Natasha. They should be able to void voluntarily.
"Xiao, Chuan-Guo" <Chuan-Guo.Xiao@nyumc.org> 2/17/2009 10:43 PM
I am forwarding the email to you to support my point. If it were you, you most possibly would keep using Detropen and cathing her because she has a 200cc residual. The fact is: the residual will decrease every day if we let the brain to take control.
So, please order those kids to stop Detropen and catherization. OK, my compromise: you can let them cath once per day just before going to bed.
I would also quote from Denmark paper regarding anticholinergics in Xiao Procedure, to show how urologists deal with anticholinergics seriously in USA and Europe :
" Although these criteria were first published after the current study began, most of them were met in our series except the upper limit of bladder capacity and the cessation of anticholinergic medication. In regard to the latter we deemed that the medication was essential for patient well-being throughout the 18-month study period.” 【9】
It seems to be the similar situation with Tuite’s trial patients: They were scatted over different states under care of their local primary care doctors who would not dare to not use anticholinergics and CIC for 3 years. So I would suggest the authors, or the editor of JNS, collect data from these children’s local doctors and provide the real fact regarding the post operative usage of CIC and anticholinergics in 3 years. In fact, I did ask Dr. Tuite about this information last year during the only contact after my withdrew ,but he did not provide details in his response.
Hello, Jerry, and Yves:
I looked back and find those emails to Ken Peters when I tried very hard to convince him to stop CIC and Detropen in 2009.I hope I can convince you, too.
I am still having some concerns about the anticholinergics. Did Yves take care of all those kids and did not use anticholinergics at all? If so, I really appreciate , because one of the reasons I argued against your double blind trial plan is that no Detropen should be used for Xiao procedure kids, but need to be used routinely for those control kids. BUT, were there any kids under the care of their primary care doctors who would definitely not stop using anticholinergics?
Any way, for the best interests of millions spina bifida kids, I really hope to clarify problems underlying your trial results. The effect of Xiao Procedure, at least in China including my hospital and other institutions in Shanghai\Wuhan etc, has been very reliable and better and better. I really feel sorry for your results.
4, The article, however, is not the end of this trial. I am confident to reverse the negative results to some degree. I put all my saving in and established a private hospital in China. Of the 300 beds, 30 are for spina bifida and SCI patients with neurogenic bladder and bowel, and each such patient only pay 8,000USD (less or free for poor people) for all costs including surgery, anesthetic, OR hours, electrophysiology test and in OR monitoring, urodynamic, pre-surgery tests, MRI and X ray, Ultrasound，pathology, exhaustible, medicines, ward for unlimited in-hospital days and so on.
My suggestion is:
(1), Since it has been out of double-blind, please let the 10 children who underwent Xiao procedure wear diaper and stop anticholinergics and let them try to void by push, leak or whatever means for 2 months, then see what happen. Giving the neurosurgeons a 50% learning curve deduction, it should still have at least 3~4 children who will able to void voluntarily without incontinence and CIC. All spina bifida kids after Xiao procedure do not need scratch to pee. For 3000 kids who had Xiao procedure, none of them needs bladder augmentation.
(2), In China, my hospital has an open policy regarding Xiao procedure patients: If the patient can not void voluntarily within one year (for child) or 18 month(for adult) post Xiao procedure, Prof. Xiao will redo the procedure himself for you free, no matter where and who did the Xiao procedure. Now, I would like to extend this policy internationally. I will redo the Xiao Procedure free for all children failed in Tuite’s trial, including those served as control. The patients only need to take care of their round trip air tickets between USA and Hong Kong airport. if I can not get about 80% effective rates for those children within a year, or at least as good as Peters’ trial results, I will apologize formally in J Neurosurg Pediatr. It can be better than 80%, but I have to be cautious due to they had had intradural neurosurgery at least 2 times on the same location.
5, Is it legal and financially appropriate to bill Medicare, Medicaid or other Medical insurances for extra costs of Xiao procedure under the name of another surgery DT? This should also raise more ethical concern on the real reason of this very hazardous double-blind study of a major surgery on disabled children.
6, I appreciate Dr. John R. W. Kestle’ s comments. It is objective and helpful from an experienced surgeon. As for other issue, there will be more appropriate platform to discuss than on the academic platform that your journal supposed to be.
Chuan-Guo Xiao, M.D.
C.G. XIAO HOSPITAL
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