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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]。

三话NICE-SUGAR：霍桑效应

从三月底NICE-SUGAR研究发布之后，原来以为会出现沸沸扬扬的议论局面竟然没有出现，以前的踊跃支持者以及反对者竟然都呼啦啦作鸟兽散，落得空荡荡、白茫茫一片，能看到的仅仅是片言只语…国际专业委员会基本上算是集体失声，毫无声息，究竟发生了什么？难道一个有史以来第二大、严格按照最高标准执行的的危重病临床研究就这么不值一评吗，更何况该研究的证据级别已经达到了1级 — “尘埃落定”之后有点一地鸡毛的感觉！

今天著名的<mayo clinic proceedings>刊登了澳大利亚和日本学者的联合述评–”What Is a NICE-SUGAR for Patients in the Intensive Care Unit?“，作者之一的Ballomo（Department of Intensive Care, Austin Hospital Heidelberg, Victoria, Australia Melbourne University Melbourne, Victoria, Australia）就是NICE SUGAR的Management Committee 委员。全文如下：

A little more than 3 years ago, the editor-in-chief of Mayo Clinic Proceedings invited us to comment on the issue of glycemic control in critically ill patients.1 The invitation stemmed from concerns related to the widespread adoption of intensive insulin therapy (IIT) after the publication of a seminal single-center trial (from Leuven, Belgium) in The New England Journal of Medicine.

The trial concluded that “intensive insulin therapy to maintain blood glucose at or below 110 mg/dL reduces morbidity and mortality among critically ill patients in the surgical intensive care unit.” In response to that article, hundreds, perhaps thousands, of intensive care units (ICUs) worldwide3-12 began trying to implement IIT. Furthermore, this approach to glucose control was widely promoted by the Institute for Healthcare Improvement in its 100,000 Lives Campaign.

The “tight glucose control express” seemed unstoppable. In the midst of such unfettered enthusiasm, we emphasized caution.1 Perhaps because of our Australian and Japanese perspectives, we were able to view these developments with a degree of geographical and cultural distance and point out that the seminal study of IIT had a number of serious limitations2 First, it was not blinded, raising the possibility of bias. Second, most patients were recruited after cardiac surgery, raising concerns about the wider applicability of IIT to other populations.14 Third, patients received intravenous glucose on arrival to the ICU at a dosage of 200 to 300 g/d (equivalent of 2 to 3 L of 10% glucose per day), an unusual practice.4 Fourth, parenteral nutrition (PN), enteral feeding, or combined feeding was provided to all patients within 24 hours of ICU admission, also an unusual practice. Fifth, the mortality of patients who had undergone cardiac surgery in the control group was twice the national average for Australia, raising concerns about whether the control group was representative. Sixth, the unadjusted relative reduction in mortality was 42%, an effect exceeding that of any other interventional trial in critically ill or diabetic patients, stretching the biological plausibility of the findings(粗体字是作者认为鲁纹大学van den berge第一次强化血糖控制研究存在的问题，例如非双盲;主要病种限于心外科患者;转入ICU后每日静脉糖量200-300g以及24小时内即开始 PN\EN或混合喂养等非常规治疗，对照组术后病死率是澳大利亚的2倍；病死率如果未经校准可下降42%，这是任何治疗都无法达到的..后面作者还会提到但衷心的研究提供不了一级证据，低血糖的风险等).

At that time, we chose not to highlight even more sources of concern, such as the intrinsic limitations of single-center studies,15 which make them unsuitable for level I evidence; the increased risk of hypoglycemia with IIT2; the potential medical Hawthorne effect of a protagonist investigator involved in the care of trial patients; and the nursing Hawthorne effect15 associated with the extra attention provided to a patient assigned to IIT because of more frequent measurements of blood glucose（这里作者提及了医生与护士的霍桑效应。注释：由于收到额外的关注而引起绩效或努力上升的情况称之为”霍桑效应”。霍桑效应告诉我们：从旁人的角度，善意的谎言和夸奖真的可以造就一个人；从自我的角度，你认为自己是什么样的人，你就能成为什么样的人。也就是说提倡血糖控制的医生和护士如果参与研究或者临床工作就会导致研究或者工作效果的变化，失去了客观性） Additionally, we chose not to discuss the reverse nursing Hawthorne effect that, in the 1-nurse-to-2-patients Leuven ICU model of care, would occur when the nurse had to leave the bedside of a control patient to measure glucose in the nearby patient receiving IIT. Furthermore, we did not mention that, in an unblinded single-center study, the investigator is, de facto, performing a daily interim analysis for which no statistical correction is later applied or that independent data verification cannot occur. Finally, we did not highlight that, in single-center studies, unless multiple permuted blocks of randomization are used, the investigator has a better than even chance of guessing treatment allocation for the next patient. We thought that pointing out these methodological concerns would be seen as churlish in the midst of such therapeutic promise and widespread application.14,10,16 Accordingly, we stuck to one simple message: We will wait for the results of the NICE-SUGAR (Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation) trial.1本节作者主要是提及van den berge研究存在的方法学误区以及作者当时的抉择。

Since then, the IIT tale has been characterized by a broad inability to reproduce the mortality benefits of the first trial. For example, in a subsequent trial of patients in a medical ICU in Leuven, IIT did not affect mortality.17,18 In a large Belgian-French trial, no benefit was seen, and randomization was stopped because of concerns related to the high incidence of hypoglycemia.19 The VISEP (Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis) study conducted in Germany met with the same fate.20 A more recent study in Saudi Arabia confirmed this lack of benefit.21 A recently published meta-analysis of all studies of IIT reached the inevitable conclusion that IIT does not decrease mortality but does increase the risk of hypoglycemia.22 Predictably, debate has become fierce.23（叙述之前几项失败的血糖研究）

In the meantime, we and others14,24-27 continued to try to understand the association between glycemia and outcome and continued to raise concerns about IIT while asking clinicians to wait for the results of the NICE-SUGAR trial. The reasons for our pleas were obvious. NICE-SUGAR was designed to be a pivotal multicenter, multinational trial involving 42 hospitals in Australia, New Zealand, Canada, and the United States (US involvement was limited to a single center, Mayo Clinic). It was designed and conducted to the highest standards of trial medicine, with a reproducible Web-based protocol, the collection of almost 1 million glucose and insulin dose measurements, and patient follow-up to 90 days after randomization. With 6100 patients, the second largest randomized study sample (to our knowledge) in the history of critical care medicine, it would clearly provide level I evidence to guide clinicians in their decision making at the bedside（NICE SUGAR的性质！）. The results of the NICE-SUGAR trial have now been published,28 and those clinicians who may have chosen to heed our advice 3 years ago are likely to feel gratified. The Mayo Clinic investigators are similarly likely to feel proud for contributing to this endeavor, instead of implementing IIT as many clamored for at the time. The NICE-SUGAR investigators found that, compared with conventional therapy (maintaining the glucose concentration at <180 mg/dL [to convert to mmol/L, multiply by 0.0555]), IIT was associated with an increased mortality 90 days after randomization. This occurred despite a much lower rate of hypoglycemia in the IIT group than reported in any previous studies of combined surgical and medical patients and with mean blood glucose levels clearly different in both groups, similar to that reported in the first IIT study. This detrimental IIT mortality effect in the NICE-SUGAR trial occurred in all subgroups, including surgical patients. As such, when considering a diverse population of ICU patients, the IIT express has surely come to its last stop（译：强化血糖可以休矣！）. Yet, several questions will be asked: Why did the NICE-SUGAR trial show such a different outcome from the first Leuven study? Why and how did IIT cause increased mortality? How should we treat hyperglycemia in patients in the ICU?（问题是为何研究结论大相径庭，强化血糖又是如何增加病死率的，今后我们如何治疗ICU内的高血糖？） These and other questions are added to the list highlighted in the recent editorial in The New England Journal of Medicine that accompanied the NICE-SUGAR report.

We think the first question is probably best asked in the reverse direction, given that the Leuven study of surgical patients has thus far been the only study to show a benefit for IIT in adults. Some will suggest that the use of PN in the Leuven study was responsible for the difference in outcome. Put another way, IIT “works,” but only when patients receive most of their calories as PN, not when patients receive enteral nutrition. Others will suggest that some unique features of the Leuven protocol account for the discrepancy. We favor a simpler explanation as out-lined previously: single-center studies are not robust representations of biological and/or clinical truth. The increase in mortality seen in the NICE-SUGAR trial most likely reflects greater statistical power and longer patient follow-up: the number of patients in the trial was almost 5 times more than that in any previous trial and patients were followed up for 90 days. Other trials may have found a similar increase in mortality had they been of similar size and with longer patient follow-up. The results of a recently published meta-analysis22 confirm that there is no benefit with IIT, but there is an increased risk of hypoglycemia. The mechanisms responsible for the increased mortality can be only a matter of speculation. Yet some of the trial findings (increased corticosteroid use and increased cardiovascular mortality with IIT) suggest a specific effect on blood pressure and circulation. Many experimental studies have demonstrated that both insulin and hypoglycemia can induce hypotension, vasodilatation, nitric oxide release, sympathetic system response exhaustion, and decreased ability to respond to repeated stress.30-34 In addition, it has long been known that recent hypoglycemia can reduce autonomic responses and defenses against subsequent hypoglycemia.33,34 These mechanisms may have played a major role in the differential outcomes in the NICE-SUGAR trial（强化血糖控制病死率增加的可能机制）.

When considering the findings of NICE-SUGAR, it is also important to appreciate that it is unlikely that glycemic control is a “one size fits all” story. Subgroup analysis from the NICE-SUGAR trial already suggests heterogeneity in the response to glycemic control for patients with an operative admission to an ICU, in patients with trauma, and in patients receiving corticosteroids. Furthermore, diabetic patients27 and patients with neurologic injury may represent specific subgroups in whom optimal glycemic control needs further definition.35,36 With the NICE-SUGAR trial demonstrating that glycemic control affects survival, these concerns may be of more than pure academic interest.

Despite these caveats, we think it is important to emphasize that the findings of NICE-SUGAR do not justify neglecting glycemic control（译：不过需要强调不要因为NICE-SUGAR今后就忽视血糖的控制）. Instead, we think that, whatever the mechanisms behind the findings of NICE-SUGAR, there is now a new and more moderate standard of care for glycemic management in the ICU: do not treat hyperglycemia unless the glucose level increases higher than 180 mg/dL; when you do treat hyperglycemia, aim for a target blood glucose concentration between 144 and 180 mg/dL. Until a study can provide level I evidence that a better approach exists, this should remain the standard of care（作者据此提出重症患者血糖不高于180 mg/dl可不处理，如果一定要控制血糖，目标血糖应该是144-180 mg/dl，这个和我在”一话”中提到的未来指南修订应该是150-180 mg/dl完全符合的–作者接着说除非之后出现更好的1级证据，否则NICE-SUGAR研究就是标准方案。这个强！）. . Such a standard of care also implies that, for example, in patients in the ICU, a glucose level of 243 mg/dL is just as undesirable as a glucose level of 80 mg/dL.

Finally, and this is vital, no matter what clinicians think might explain the findings of NICE-SUGAR, they should remember to be wary of the next single-center study that promises a simple solution for a complex problem. Single-center studies simply do not have the ability or resources to provide the type of scientifically rigorous analysis delivered by large multicenter, randomized controlled trials.37-39 Waiting for level I evidence to emerge before adopting a risky therapy is and will remain the best policy in clinical medicine for a long time. 译：以后同行们，无论他们如何看待NICE-SUGAR，都应切记或者警惕那些发现某单纯疗法解决了复杂疾病的单中心研究–单中心研究不具备大型多中心随机对照研究提供的严密科学分析的能力，也不应该是这类分析的源泉（老黄注：作者的说法也不尽合理，如果按照他们的说法实际上连荟萃分析都是不科学的– 荟萃分析经常囊括的就是这类单中心的研究。不过对于SSC指南中提及的某些仅经过单中心研究就被推向前台的明星疗法，诸如早期目标治疗，小剂量激素替代等，作者的话还是值得借鉴的–比如大型的CORTICUS研究就不能再现之前由Annane主持的小型单中心激素替代治疗所发现的病死率下降…）

还应关注的相关进展如下：

• 医博网推荐：北京协和医院杜斌教授对NICE-SUGAR研究的介绍及点评
• 医博网推荐：大连医科大学附属第一医院黄伟教授对NICE-SUGAR研究的点评之二
• 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
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• Crit Care Med：皮质激素治疗可减少ALI/ARDS死亡
• Anesthesiology：围术期强化胰岛素治疗是把“双刃剑”
• Lancet：治疗神经性疼痛去甲替林与加巴喷丁联用效果更佳
• ASBMR 2009：Osteoporosis Still Under-Recognized and Under-Treated 骨质疏松认知及治疗有待提高
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