《印度重症醫學雜誌》不時有好的文章出現，近期在讀到其今年1月號的一篇《Can less be more in intensive care?》後，覺得深有啟發，不如簡單的編譯出來，與大家共享。
作者最絕的思路在於，用反證的思想考慮問題，換句話說，我們看到的是XXX幹預研究又失敗了，但他們卻能把所有的研究都歸納起來，來看幹預研究後的總病死率與對照組的比較，從而反證“少即是多”的理念。盡管作者僅僅是基於經驗的簡單的歸納總結，沒經過過多的數學分析或模型建立，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
重症醫學能作到“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項隨機臨床試驗(RCT)為重症監護正在探索的問題增加了新的變數：危重病人的治療能做到“少即多”嗎?臨床實踐正在朝這個方向發展——傾向於較少的有創監測或幹預，有創設備較少的常規變化，以及減少常規調查的頻次。從人類基本層麵上看，做些事要比什麼都不做容易，而臨床醫生應做點什麼的壓力在危重患者範疇中尤為明顯。許多臨床醫生均存在強烈的使用未經認證療法的偏倚。但越來越多的臨床醫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支持極簡療法。 在“少即多”的範疇中，即使相同的臨床結局，較少的治療就意味著“更多”——即更為有效的資源利用。 這在貧富經濟體中具有同樣意義，人們看到富裕國家正在與失控的支出進行著越來越艱巨的鬥爭。不幸的是，在現實世界中，無論科學如何發展，臨床醫生，行政人員和行業都在經濟的驅動下做得更多而不是更少。 Upton Sinclair看到，如果一個人的收入基於他對某件事情的不理解，那麼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，作為保護性反應的一部分，許多參數可能會超出正常範圍。 通過達到正常值以扭轉這些保護性反應可能是有害的。 20億年的真核生物進化和6億年的大型動物進化選擇形成的是極其複雜且當前理解不多的生理適應反應，其在確保愈合及生存方麵簡單粗暴，無懈可擊。而近2-3個世紀現代醫學所形成的加法(add-on)治療對於結局的影響則可能過於簡單和膚淺。
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 study.
如果less is more這個概念是對的話，那麼隨機對照實驗中less組(相當於接受安慰劑、限製性療法或標準治療組)的病死率應該少於more組(即接受幹預性治療或開放性療法組)。於是作者選擇了NEJM 2008-2016年的報道的63篇對照研究考察這個假設......
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篇研究綜合後，治療組(即More組)的病死率為23,601/58,727 (40.19%), 而對照組(Less組)的病死率為20,752/53,568 (38.74%).，幹預組的死亡相對風險度為1.0374 (95% CI 1.0224-1.0526; P < 0.001)。這說明，對於急重症這類擁有廣泛疾病譜的患者而言，少做點是能夠降低病死率的。
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.
醫學不是非黑既白的，即使不降低死亡率，某種治療也許是有益的。為此許多試驗報告了複合終點，可能包括或可能不包括死亡率。為了評估幹預治療對其他相關終點的影響，我們也比較了主要終點為積極，中性或不利結局的研究數量。但我們的分析不包括非死亡的次要終點，校正的POST-HOC結果或亞組收益。隻有八種療法報告改善了死亡率或其他臨床意義上的主要結局(呼吸衰竭的CPAP治療，腦血管意外(CVA)的溶栓治療，CVA的神經幹預，CVA外科手術控製顱內壓，ARDS俯臥位通氣，ARDS的神經肌肉阻滯劑治療，心髒手術後的開放輸血策略和胰腺炎的限製療法)，而七種療法的結局是惡化的(用於液體複蘇的羥基乙基澱粉溶液，兒科非低血壓膿毒症的補液治療，ARDS的高頻振蕩通氣，穀氨酰胺補充，早期全胃腸外營養，創傷性腦損傷中的外科ICP控製和外傷性腦損傷中的低體溫)。大多數研究中主要結果未收影響。這進一步說明務必審慎使用未獲確認的療法。
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，它是一個經過深入研究和仔細思考的策略，旨在摒除不能改善臨床結果的療法。 在過去十年中，對來自高質量NEJM RCT的100,000多名患者的分析表明，大多數研究未能證明其臨床益處。除了資源有效利用之外，明智的限製性策略可能降低總體死亡率，在重症醫療中，極簡可能複雜的最終極形式。
