《印度重症医学杂志》不时有好的文章出现，近期在读到其今年1月号的一篇《Can less be more in intensive care?》后，觉得深有启发，不如简单的编译出来，与大家共享。

作者最绝的思路在于，用反证的思想考虑问题，换句话说，我们看到的是XXX干预研究又失败了，但他们却能把所有的研究都归纳起来，来看干预研究后的总病死率与对照组的比较，从而反证“少即是多”的理念。尽管作者仅仅是基于经验的简单的归纳总结，没经过过多的数学分析或模型建立，但其说服力却非常深刻，非常值得反思!

Can Less be More in Intensive Care?

Kapadia FN, Kapoor R, Trivedi M.

Indian J Crit Care Med. 2017 Jan;21(1):1-5.

doi: 10.4103/0972-5229.198308.

Available from: http://www.ijccm.org/text.asp?2017/21/1/1/198308

重症医学能作到“少即是多”吗?

Seven recent randomized clinical trials (RCTs) [1],[2],[3],[4],[5],[6],[7] add momentum to a question the intensive care community is increasingly exploring; can "Less be More" in the management of the critically ill? Practices are evolving in this direction with a preference for less invasive monitoring or intervention, less routine changing of invasive devices, and a decrease in the frequency of routine investigations. At the basic human level, it is easier to do something than to do nothing, and the pressure on clinicians to do something is much more in the context of a critically ill patient. Many clinicians have a strong intervention bias to use unproven therapies. But increasingly, clinicians are questioning if this liberal approach is effective or even harmful. [8],[9],[10],[11]。

最近的7项随机临床试验(RCT)为重症监护正在探索的问题增加了新的变数：危重病人的治疗能做到“少即多”吗?临床实践正在朝这个方向发展——倾向于较少的有创监测或干预，有创设备较少的常规变化，以及减少常规调查的频次。从人类基本层面上看，做些事要比什么都不做容易，而临床医生应做点什么的压力在危重患者范畴中尤为明显。许多临床医生均存在强烈的使用未经认证疗法的偏倚。但越来越多的临床医生怀疑这种自由主义的做法是有效还是有害的。

There are nonclinical and clinical arguments to support a minimalistic approach. In the context of "less is more," even with equivalent clinical outcomes, lesser therapies can be "more" in terms of more efficient resource utilization. This is equally relevant in the rich and poor economies, and one sees the richer countries fighting an increasingly difficult battle against runaway expenditure. Unfortunately, in the real world, there are financial incentives for clinicians, administrators, and industry to do more rather than less, regardless of the evolving scientific data. Upton Sinclair pithily observed that it is difficult to get a human to understand something, when his/her salary depends on his/her not understanding it.

已有不少非临床和临床证据支持极简疗法。 在“少即多”的范畴中，即使相同的临床结局，较少的治疗就意味着“更多”——即更为有效的资源利用。 这在贫富经济体中具有同样意义，人们看到富裕国家正在与失控的支出进行着越来越艰巨的斗争。不幸的是，在现实世界中，无论科学如何发展，临床医生，行政人员和行业都在经济的驱动下做得更多而不是更少。 Upton Sinclair看到，如果一个人的收入基于他对某件事情的不理解，那么要让他理解这件事情就太难了。

The main clinical argument against doing too much is that there are adverse outcomes noted with many therapies. We have explored this [11] and cited the literature that demonstrates that less can actually be equivalent or more for multiple Intensive Care Unit (ICU) therapies including O 2 supplementation, drugs in cardiopulmonary resuscitation, and other standard ICU practices including monitoring and life support.

There is reasonable plausibility too in supporting such an approach. During the stress of an illness, many parameters may fall outside the normal range, as part of a protective response. Reversing these protective responses by targeting normal values may be detrimental. Two billion years of eukaryotic evolution and 600 millions of years of large animal evolutionary selection have resulted in complex but poorly understood physiologic adaptations that are ruthlessly efficient in ensuring healing and survival. Our add-on therapies, based on 2-3 centuries of modern medicine, are often too simplistic and superficial to impact outcomes.

在疾病的压力下，作为保护性反应的一部分，许多参数可能会超出正常范围。 通过达到正常值以扭转这些保护性反应可能是有害的。 20亿年的真核生物进化和6亿年的大型动物进化选择形成的是极其复杂且当前理解不多的生理适应反应，其在确保愈合及生存方面简单粗暴，无懈可击。而近2-3个世纪现代医学所形成的加法(add-on)治疗对于结局的影响则可能过于简单和肤浅。

Ultimately, however, the concept of "Less is More" needs to be empirically proven. Critical care trials may study surrogate end points or clinical outcomes. While numerous trials have demonstrated physiological benefit, there has been much less success when studying clinical end points. There are a large number of trials where there has been clinical harm despite success in achieving the physiological target. [11] In critical care, the main clinical outcomes are decreased mortality, decreased severity, and a faster and more complete recovery. A lesser severity can be gauged by the duration of the illness and therapy, the degree of invasive interventions needed, and the associated discomfort caused to a patient. Mortality is by far most important and we focus on this in attempting to use empiric data and prove that less is truly more in emergency and ICU patients.

If the "less is more" concept were correct, we hypothesized that, in randomized controlled trials (RCTs), the mortality in the patients in the "less" or control group (receiving placebo, restrictive, or standard therapy) would be significantly lower than in the "more" or intervention group (receiving study intervention or liberal therapy). We reviewed all RCTs related to emergency, acute, or critical care medicine with mortality as an end point published in the New England Journal of Medicine (NEJM) from 2008 onward. [11] In this list [Table 1], updated to October 2016, [1] we found 63 trials. This is not a cherry-picked list. These trials passed the NEJM review and selection process, and we included all which we felt were representative, before doing any analysis. There were a few therapies in conditions with a low (<10%) mortality, but we included them as we felt they represented intensive care practices (PRBC transfusions, thrombolysis in pulmonary embolism, and antibiotic duration). Some studies had more than two arms, and we combined the groups together in a way that a "less" approach was compared to a "more" approach. Trials variously report ICU mortality, hospital mortality, or mortality at specified time points. We used the value reported at the longest follow-up period based on the protocol of each individual study.

如果less is more这个概念是对的话，那么随机对照实验中less组(相当于接受安慰剂、限制性疗法或标准治疗组)的病死率应该少于more组(即接受干预性治疗或开放性疗法组)。于是作者选择了NEJM 2008-2016年的报道的63篇对照研究考察这个假设......

Table 1: Randomized controlled trials published in the New England Journal of Medicine 2008-Oct 2016. n = 63

In this cohort from 63 RCTs, the total reported mortality in intervention group was 23,601/58,727 (40.19%), and in the control group, it was 20,752/53,568 (38.74%). The relative risk of death in the intervention group of patients was 1.0374 (95% confidence interval: 1.0224-1.0526; P < 0.001). Though the absolute difference appears relatively low at 1.45%, it denotes a statistically significant higher mortality. This translates to an additional death for every 69 patients enrolled in the intervention arms of these trials. This adds empiric evidence to the concept that doing less in ICU may result in significantly lower mortality in a wide spectrum of emergency or critically ill patients.

63篇研究综合后，治疗组(即More组)的病死率为23,601/58,727 (40.19%), 而对照组(Less组)的病死率为20,752/53,568 (38.74%).，干预组的死亡相对风险度为1.0374 (95% CI 1.0224-1.0526; P < 0.001)。这说明，对于急重症这类拥有广泛疾病谱的患者而言，少做点是能够降低病死率的。

Medicine is not a black and white field, and a therapy may be beneficial even if it does not decrease mortality. For this reason, many trials report a composite end point which may or may not include mortality. To evaluate the impact of intervention on these other relevant end points, we compared the number of positive, neutral, and adverse outcomes in terms of reported primary end points. We did not include nonmortality secondary end points, post hoc-adjusted outcomes, or subgroup benefits in our analysis. Only eight therapies reported improved mortality or other clinically meaningful primary outcomes (continuous positive airway pressure in respiratory failure, thrombolysis in cerebrovascular accident [CVA], neuro-intervention in CVA, surgical control of intracranial pressure [ICP] in CVA, prone position ventilation in ARDS, neuro-muscular-blockers in acute respiratory distress syndrome [ARDS], liberal transfusion after cardiac surgery, and limited approach in pancreatitis) while seven therapies worsened outcomes (hydroxy ethyl starch solutions for fluid resuscitation, fluid bolus in pediatric nonhypotensive sepsis, high-frequency oscillatory ventilation in ARDS, glutamine supplementation, early total parenteral nutrition, surgical ICP control in traumatic brain injury, and hypothermia in traumatic brain injury). The majority had no impact on the primary outcome. This further strengthens the case for the judicious use of unproven therapies.

医学不是非黑既白的，即使不降低死亡率，某种治疗也许是有益的。为此许多试验报告了复合终点，可能包括或可能不包括死亡率。为了评估干预治疗对其他相关终点的影响，我们也比较了主要终点为积极，中性或不利结局的研究数量。但我们的分析不包括非死亡的次要终点，校正的POST-HOC结果或亚组收益。只有八种疗法报告改善了死亡率或其他临床意义上的主要结局(呼吸衰竭的CPAP治疗，脑血管意外(CVA)的溶栓治疗，CVA的神经干预，CVA外科手术控制颅内压，ARDS俯卧位通气，ARDS的神经肌肉阻滞剂治疗，心脏手术后的开放输血策略和胰腺炎的限制疗法)，而七种疗法的结局是恶化的(用于液体复苏的羟基乙基淀粉溶液，儿科非低血压脓毒症的补液治疗，ARDS的高频振荡通气，谷氨酰胺补充，早期全胃肠外营养，创伤性脑损伤中的外科ICP控制和外伤性脑损伤中的低体温)。大多数研究中主要结果未收影响。这进一步说明务必审慎使用未获确认的疗法。

It is worth pointing out that "Less is More" is not a lazy approach; rather, it is a well-researched and carefully thought-out strategy aimed at getting rid of the therapies that do not improve clinical outcomes. This analysis of more than 100,000 patients from high-quality NEJM RCTs in the past decade demonstrates that the majority of studies failed to demonstrate clinical benefit. A judiciously restrictive approach, besides being resource efficient, could be associated with an overall mortality benefit. In critical care, simplicity may be the ultimate form of sophistication.

值得指出的是“少即是多”不是一种懒惰的做法; 相反，它是一个经过深入研究和仔细思考的策略，旨在摒除不能改善临床结果的疗法。 在过去十年中，对来自高质量NEJM RCT的100,000多名患者的分析表明，大多数研究未能证明其临床益处。除了资源有效利用之外，明智的限制性策略可能降低总体死亡率，在重症医疗中，极简可能复杂的最终极形式。