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医博网推荐：大连医科大学附属第一医院黄伟教授对NICE-SUGAR研究的点评之一
Tagged Under : Add new tag, CSCCM, N Engl J Med, NICE-SUGAR研究, NICE-SUGAR试验, YeeBlog.com, 《新英格兰医学杂志》, 中国病理生理协会危重病医学专业委员会, 医博网, 大连医科大学附属第一医院, 大连医科大学附属第一医院黄伟, 强化血糖控制, 血糖, 降血糖, 黄伟
自从NICE-SUGAR研究的试验结果在N Engl J Med《新英格兰医学杂志》上（3月27日）发表以来，关于ICU患者强化血糖控制的争论似乎有了一个结论性的证据，在全世界范围内引发了很大的讨论。
我国一些学者也对NICE-SUGAR研究进行了认真的分析和精彩的解读，医博网（yeeblog.com）推荐并转载几位国内专家的解读，供大家参考。
大连医科大学附属第一医院黄伟教授对NICE-SUGAR研究进行了详细的点评，全文转载如下[该文章发表在黄伟教授的搜狐博客上]。
一话NICE-SUGAR： 强化血糖控制终于尘埃落定
危重患者”强化血糖控制”究竟有效还是有害？
这起公案在本blog中反复多次提及，从2001年Van den Berghe 教授在重症患者中创始该方案以来，业内在”惊叹、惊艳”之后，近期无论是大型的临床研究还是荟萃分析，或者系统综述都出现越来越不利于强化血糖控制的呼声。
我已经反复说过强化血糖控制的唯一的救命稻草就是这个澳大利亚-新西兰的NICE SUGAR研究了，但我也不是很看好该项研究会得到乐观的结论。
本周NEJM终于公布了NICE- SUGAR研究（Intensive versus Conventional Glucose Control in Critically Ill Patients），在中国病理生理协会危重病医学专业委员会的网站上已经刊登了对本文详细的中文解析，结论对于强化血糖控制的拥趸们而言是绝望的–经过总计6030例患者的校验，强化血糖控制在81-108 mg/dl者的所有主要或次要考察指标都显著差于常规治疗组（血糖述评180 mg/dl）– 强化血糖控制组90天病死率明显升高 (27.5% vs. 24.9%, p = 0.02， 根据危险因素进行校正后病死率仍有显著差异 ； 强化血糖控制组存活时间缩短 (HR 1.11, 95%CI 1.01 - 1.23, p = 0.04，强化血糖控制组死于心血管病因的比例更高) ；强化血糖控制组发生严重低血糖的患者比例明显升高 (6.8% vs. 0.5%, OR 14.7, 95%CI 9.0 - 25.9, p < 0.001) ；同时，强化血糖控制组在 90天内ICU住院日及总住院日；新发单一或多器官功能衰竭患者比例；机械通气时间，肾脏替代时间，血培养阳性率和输血比例等诸多方面也没有显示出和常规治疗组之间的差异。
换句话说就是–以血糖正常为目标不能使危重病患者受益，甚至有害！
终于尘埃落定，因为不可能再有第二个如此规模的大型研究能够推翻此次的NICE-SUGAR研究，Van den berge之前不止一次强调要得出阳性结论至少需要5000-8000例以上的病例规模，显然这次澳大利亚/新西兰人又做到了，而且就如同白蛋白与生理盐水的SAFE研究一样，两项研究的规模和组织工作都堪称典范和样板，因此其结论也几乎不可能被逆转，以前的种种猜测，狡辩和借口都是苍白无力的。
读者们可以回顾一下2001年van den berge的研究结果，当年的主要指标和次要指标的结论恰恰和NICE-SUGAR完全相反！
为什么时隔仅仅8年，同样的强化血糖控制竟然有完全颠倒的两种结果？
Nice-sugar研究对于那些口不离循证，不离国际走向半步，全盘吸收的专家，尤其是国内专家有何启示？NICE-SUGAR研究同样对监护医学领域始终在热捧的Bundle策略的推广和国际指南的制定有何影响？…….这些都是很有意思的话题。
另外我也非常奇怪，如此重要的研究，NEJM随刊的述评只是两位在重症监护血糖控制中建树不多的来自Yale的”外星人”：Inzucchi SE和 Siegel MD. 前者作为内分泌的教授，主要研究是：clinical investigations into (1) the cardiovascular complications of diabetes, (2) insulin resistance and atherosclerosis, and (3) the inpatient management of hyperglycemia也就是糖尿病的心血管并发症；后者仅在2004年有两篇与前者共同发表的血糖控制的研究，很可惜的是，他们并没有能够提供更加thoughtful的思想可以引导读者更好的理解NICE SUGAR的意义。
为什么Van den berge不来写述评呢–请读者用Pubme关注她近期有无评论发表。
现实而诚恳的说，当前脓毒症国际指南引用的诸多单项研究几乎都存在各种各样”致命的”缺憾，甚至是可怕的后台商业利益驱动，但是这些研究一旦披上国际指南的循证外衣，尤其是又被包装成Bundle而集体售卖的时候，一线的临床医生怎么可能知道这些蹊跷。
所幸的是，这个世界还是有人愿意说不的！现在的NICE-SUGAR就是一个很好的例子–2008年SSC指南发布，共有15个国际学术组织加入到了联合发布的名单中，但是澳大利亚和新西兰危重病委员会和美国胸科协会（ATS）都拒绝加入，另外一个IDSA在2004年就拒绝加入。由此可见一个主旨清晰，主见明确的专业协会对于学科的发展是多么重要，同样，大家也不难理解为什么小小的澳大利亚/新西兰所代表的南太平洋地区不断有重大的研究推出，比如早前的SAFE研究，现在的NICE-SUGAR研究，俨然是世界危重医学研究的前沿重镇，–顺便说一声，哪位读者帮我牵个线，赞助一个机会或者提供有关信息，也好在有生之年亲身体验一下….
此外，很希望看到国内有关单位能够组织类似的大型研究，这将是国内危重病研究水平的名片……
呵呵，写到这里，终于看到了Van den berge的发言：3月号的《CAMJ》提前刊登了包含NICE SUGAR的血糖控制的荟萃分析并刊发了Van den berge的述评！
Results: We included 26 trials involving a total of 13567 patients in our meta-analysis. Among the 26 trials that reported mortality, the pooled relative risk (RR) of death with intensive insulin therapy compared with conventional therapy was 0.93 (95% confidence interval [CI] 0.83-1.04). Among the 14 trials that reported hypoglycemia, the pooled RR with intensive insulin therapy was 6.0 (95% CI 4.5-8.0). The ICU setting was a contributing factor, with patients in surgical ICUs appearing to benefit from intensive insulin therapy (RR 0.63, 95% CI 0.44-0.91); patients in the other ICU settings did not (medical ICU: RR 1.0, 95% CI 0.78-1.28; mixed ICU: RR 0.99, 95% CI 0.86-1.12). The different targets of intensive insulin therapy (glucose level ≤ 6.1 mmol/L v. ≤ 8.3 mmol/L) did not influence either mortality or risk of hypoglycemia.
Interpretation: Intensive insulin therapy significantly increased the risk of hypoglycemia and conferred no overall mortality benefit among critically ill patients. However, this therapy may be beneficial to patients admitted to a surgical ICU.强化血糖控制显著增加低血糖风险，对危重患者总体病死率无有益影响，但对外科ICU患者可能有益。
在本次述评中，Van den berge首先评价了纳入荟萃分析研究的不同：In this issue of CMAJ, Griesdale and colleagues8 performed a meta-analysis of 26 studies involving over 13 500 patients. The authors concluded that intensive insulin therapy does not provide an overall mortality benefit, but that it may decrease mortality among surgical ICU patients. The differences among the individual studies are likely important. First, the type of patients and type and logistics of the intensive care units differed substantially. Second, the accuracy of insulin infusion and glucose monitoring differed among studies. In the initial randomized trial,6 all of the patients had central venous lines for reliable adjustment of continuous insulin infusion, and arterial lines for monitoring glucose and potassium, thus avoiding hypokalemia-induced arrhythmia. In several subsequent studies, insulin was administered as peripheral venous or subcutaneous infusions (including bolus injections), measurement of blood glucose was often infrequent, and sampling was performed via finger pricks with glucometers that were often insufficiently accurate for the intensive care setting. 9 Furthermore, the blood glucose targets for the intervention and comparator groups differed among studies. Most importantly, success in achieving these targets varied greatly among the included studies; the experience of the the nursing team may have played a role in these differences _ When used in such different ways, the term “intensive insulin therapy” may not always describe the same intervention.
在谈到NICE-SUGAR研究时，哦，抱歉，尽管该荟萃标明是包含NICE-SUGAR研究的荟萃，Van den berge竟然完全没有提及该研究一个字！
在谈到荟萃结论对临床实践的影响，她写到：What should clinicians do today, given the results of the study by Griesdale and colleagues? Unfortunately, the evidence does not allow confident recommendations for an overall guideline, because the optimal target for glucose in different groups of critically ill patients is unknown. Hence, clinicians should consider the following criteria: the level of evidence of the individual studies, particularly whether the hypothesized benefit was realistic, whether power was sufficient to detect this effect, whether the tools to measure and control blood glucose were adequate, whether the targets were reached, and whether the comparator level of glycemic control was relevant. If the above criteria are satisfied, clinicians should then assess how comparable the patients in these studies are to their own patients. Currently, the evidence is strongest for adults and children in surgical ICUs. For patients considered eligible for tight glucose control, the clinician should assess whether the intervention can be applied safely in the specific clinical setting.
写到这里，我觉得Van den berge已经在狡辩了，她尽管不会很快推出历史舞台，但是她的学术地位我看真的朝不保夕了。为什么呢？如果你看Nice sugar 研究的protocol就会知道，对比上面评论划线红字，NICE SUGAR 研究中的血样完全是按照Van den berge的说法来的：1.Control of blood glucose was achieved with the use of an intravenous infusion of insulin in saline. 2. Blood samples for glucose measurement were obtained by means of arterial catheters whenever possible; 2.the use of capillary samples was discouraged. Blood glucose levels were measured with the use of point-of-care or arterial blood gas analyzers or laboratory analyzers in routine use at each center.
读者们还可以参看
https://studies.thegeorgeinstitute.org/nice
了解研究的具体实施细节。还有就是Van den berge总在强调护士队伍对执行血糖监测的意义，问题是只有比利时鲁文大学重症监护的护士能够完成血糖监护的任务，其他欧美国家或发达地区的护士却怎么总不能复制出Van den berge的结论呢？显然，问题并不是血糖测定和监测是否需要依赖护士队伍的高依从性以及血样的采集技术和动脉与中心静脉的置管，问题是即使这样，血糖控制也没有显示出生存效益，可是Van den berge好像在这个问题上故意忽略了NICE SUGAR正是按照她的设想严格执行下来也没得到阳性结论，我只能遗憾的说Van den berge这次的述评比上面NEJM的述评还要苍白无力。
究竟临床的事情有没有真谛可言？
不过最后说明一声，读者不要看过本blog后，就认为我是抵制血糖控制的了，我肯定不会是那么轻率地，吼吼。
