《印度重癥醫(yī)學(xué)雜志》不時(shí)有好的文章出現(xiàn)，近期在讀到其今年1月號(hào)的一篇《Can less be more in intensive care？》后，覺得深有啟發(fā)，不如簡單的編譯出來，與大家共享。
作者最絕的思路在于，用反證的思想考慮問題，換句話說，我們看到的是XXX干預(yù)研究又失敗了，但他們卻能把所有的研究都?xì)w納起來，來看干預(yù)研究后的總病死率與對(duì)照組的比較，從而反證“少即是多”的理念。盡管作者僅僅是基于經(jīng)驗(yàn)的簡單的歸納總結(jié)，沒經(jīng)過過多的數(shù)學(xué)分析或模型建立，但其說服力卻非常深刻，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
重癥醫(yī)學(xué)能作到“少即是多”嗎？
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項(xiàng)隨機(jī)臨床試驗(yàn)（RCT）為重癥監(jiān)護(hù)正在探索的問題增加了新的變數(shù)： 危重病人的治療能做到“少即多”嗎？臨床實(shí)踐正在朝這個(gè)方向發(fā)展——傾向于較少的有創(chuàng)監(jiān)測或干預(yù)，有創(chuàng)設(shè)備較少的常規(guī)變化，以及減少常規(guī)調(diào)查的頻次。從人類基本層面上看，做些事要比什么都不做容易，而臨床醫(yī)生應(yīng)做點(diǎn)什么的壓力在危重患者范疇中尤為明顯。許多臨床醫(yī)生均存在強(qiáng)烈的使用未經(jīng)認(rèn)證療法的偏倚。但越來越多的臨床醫(yī)生懷疑這種自由主義的做法是有效還是有害的。
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.
已有不少非臨床和臨床證據(jù)支持極簡療法。 在“少即多”的范疇中，即使相同的臨床結(jié)局，較少的治療就意味著“更多”——即更為有效的資源利用。 這在貧富經(jīng)濟(jì)體中具有同樣意義，人們看到富裕國家正在與失控的支出進(jìn)行著越來越艱巨的斗爭。不幸的是，在現(xiàn)實(shí)世界中，無論科學(xué)如何發(fā)展，臨床醫(yī)生，行政人員和行業(yè)都在經(jīng)濟(jì)的驅(qū)動(dòng)下做得更多而不是更少。 Upton Sinclair看到，如果一個(gè)人的收入基于他對(duì)某件事情的不理解，那么要讓他理解這件事情就太難了。
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.
在疾病的壓力下，作為保護(hù)性反應(yīng)的一部分，許多參數(shù)可能會(huì)超出正常范圍。 通過達(dá)到正常值以扭轉(zhuǎn)這些保護(hù)性反應(yīng)可能是有害的。 20億年的真核生物進(jìn)化和6億年的大型動(dòng)物進(jìn)化選擇形成的是極其復(fù)雜且當(dāng)前理解不多的生理適應(yīng)反應(yīng)，其在確保愈合及生存方面簡單粗暴，無懈可擊。而近2-3個(gè)世紀(jì)現(xiàn)代醫(yī)學(xué)所形成的加法（add-on）治療對(duì)于結(jié)局的影響則可能過于簡單和膚淺。
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="">
如果less is more這個(gè)概念是對(duì)的話，那么隨機(jī)對(duì)照實(shí)驗(yàn)中l(wèi)ess組（相當(dāng)于接受安慰劑、限制性療法或標(biāo)準(zhǔn)治療組）的病死率應(yīng)該少于more組（即接受干預(yù)性治療或開放性療法組）。于是作者選擇了NEJM 2008-2016年的報(bào)道的63篇對(duì)照研究考察這個(gè)假設(shè)......
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篇研究綜合后，治療組（即More組）的病死率為23,601/58,727 (40.19%), 而對(duì)照組（Less組）的病死率為 20,752/53,568 (38.74%).，干預(yù)組的死亡相對(duì)風(fēng)險(xiǎn)度為1.0374 (95% CI 1.0224-1.0526; P <>
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.
醫(yī)學(xué)不是非黑既白的，即使不降低死亡率，某種治療也許是有益的。為此許多試驗(yàn)報(bào)告了復(fù)合終點(diǎn)，可能包括或可能不包括死亡率。為了評(píng)估干預(yù)治療對(duì)其他相關(guān)終點(diǎn)的影響，我們也比較了主要終點(diǎn)為積極，中性或不利結(jié)局的研究數(shù)量。但我們的分析不包括非死亡的次要終點(diǎn)，校正的POST-HOC結(jié)果或亞組收益。只有八種療法報(bào)告改善了死亡率或其他臨床意義上的主要結(jié)局（呼吸衰竭的CPAP治療，腦血管意外(CVA)的溶栓治療，CVA的神經(jīng)干預(yù)，CVA外科手術(shù)控制顱內(nèi)壓，ARDS俯臥位通氣，ARDS的神經(jīng)肌肉阻滯劑治療，心臟手術(shù)后的開放輸血策略和胰腺炎的限制療法），而七種療法的結(jié)局是惡化的（用于液體復(fù)蘇的羥基乙基淀粉溶液，兒科非低血壓膿毒癥的補(bǔ)液治療，ARDS的高頻振蕩通氣，谷氨酰胺補(bǔ)充，早期全胃腸外營養(yǎng)，創(chuàng)傷性腦損傷中的外科ICP控制和外傷性腦損傷中的低體溫）。大多數(shù)研究中主要結(jié)果未收影響。這進(jìn)一步說明務(wù)必審慎使用未獲確認(rèn)的療法。
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”不是一種懶惰的做法; 相反，它是一個(gè)經(jīng)過深入研究和仔細(xì)思考的策略，旨在摒除不能改善臨床結(jié)果的療法。 在過去十年中，對(duì)來自高質(zhì)量NEJM RCT的100,000多名患者的分析表明，大多數(shù)研究未能證明其臨床益處。除了資源有效利用之外，明智的限制性策略可能降低總體死亡率，在重癥醫(yī)療中，極簡可能復(fù)雜的最終極形式。
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