The 2018 Surviving Sepsis Campaign’s Treatment Bundle: When Guidelines Outpace the Evidence Supporting Their Use
Rory Spiegel，Joshua D. Farkas, Philippe Rola,Jon-Emile Kenny,Segun Olusanya, Paul E. Marik, Scott D. Weingart
Those who cannot remember the past are condemned to repeat it.
良好的意愿可能造成无意的灾难。这句谚语的一个最近的医疗例子就是2002年全美医疗保险和医疗补助服务中心（CMS）发布的社区获得性肺炎初始治疗的国家医院质量措施。 该措施要求对因肺炎来院的患者在急诊分诊后的4h内获取血培养输注抗菌药物，即使在到达时尚未明确存在肺炎。 这些指标几乎没有证据基础，但却导致了一种制度化的过度诊断和过度治疗风气。 最终，许多人认识到抗生素过度使用和误用的下游危害，这促使该措施失去了国家质量论坛的支付认可，并将其从CMS质量指标体系中删除。我们从这种蠢事中吸取了教训？还是说新的脓毒症指南仍然在几乎没有直接支持证据的情况下推行了类似的基于时间框架的治疗策略？
Inadvertent catastrophes often arise from good intentions. One recent medical care example of this phenomenon was the 2002 Centers for Medicare & Medicaid Services (CMS) National Hospital Quality Measure for the initial management of community-acquired pneumonia.1 This measure called for obtaining blood cultures and administering antibiotics within 4 hours of emergency department (ED) triage in patients being admitted with pneumonia, even if pneumonia was not clearly present on arrival. These metrics had little evidentiary basis but led to an institutional-fostered culture of overdiagnosis and overtreatment.2 Eventually, many recognized the downstream harms of antibiotic overuse and misuse,2 prompting the loss of the National Quality Forum measure endorsement and the measure’s subsequent removal as a CMS quality metric. Have we learned from this folly or does a new sepsis guideline promote similar time-based treatment strategies with little direct supporting evidence?
测量乳酸水平，若乳酸初始水平高于2 mmol / L需重复测量。
低血压或乳酸≥4 mmol / L者，以30 mL / kg快速静点晶体。
如果患者在液体复苏期间或之后仍处于降压状态，则启动血管加压药，以维持平均动脉压水平≥65 mm Hg。
The most recent iteration of the Surviving Sepsis Campaign treatment bundle now exists, published simultaneously in Critical Care Medicine and Intensive Care Medicine by Levy et al.3 The newest guidelines from this group propose a novel 1-hour care bundle, in contrast to the National Quality Forum 0-500 and the Sepsis CMS Core measures that defined 3- and 6-hour target care bundles. The Surviving Sepsis Campaign group argues that the temporal nature of sepsis means benefit from even more rapid identification and intervention. They identify the start of the bundle as patient arrival at triage, when sepsis may or may not be present. Items to be successfully initiated within this brief window include the following:
•Measure lactate level and remeasure if the initial lactate level is greater than 2 mmol/L.
•Obtain blood cultures before administration of antibiotics.
•Administer broad-spectrum antibiotics.
•Begin rapid administration of crystalloid at 30 mL/kg for hypotension or lactate level greater than or equal to 4 mmol/L.
•Start vasopressors if the patient is hypotensive during or after fluid resuscitation to maintain mean arterial pressure level greater than or equal to 65 mm Hg.
虽然无人反对应对脓毒性休克患者进行适当和及时的识别与复苏治疗，但这并不一定意味着指南就应如此推广。 首先，尽管（急诊）分诊具有可靠性，且其时间可供提取，但对于许多患者而言，分诊的时间并不能很好地替代脓毒症的发作时间。如同在灯下寻找钥匙的醉汉，因为这货坚称“这就是我看到的地方”——从自认为最易于把握的地方开始也许并不意味能真正解决手头的任务（在需要时开始正确的治疗）。 而将3h和6h的集束策略凝练为单一的1h方案，专家们创造了一个挑战，即可能导致患者下游的危害。 为了达成这些新措施，已经饱受3h策略“绑架”的大多数急诊医师们将会采用类似上述2002年CMS肺炎治疗的措施，将这一1h的方案广泛应用于大多数患有疑似感染的患者中，而脓毒症或脓毒性休克诊断会在之后受理。与肺炎质量管理措施一样，这种资源密集型治疗源于对证据的过度解释。 首先，作者假设所有早期治疗会更好； 在这种情况下，1h策略将优于以前的指南的3h和6h策略。 这一论点源于早期实施脓毒症集束策略改善其临床预后的病例数据集，有些报告甚至提出每小时的延迟都会使病死率增加。然而这些研究都是观察性队列，患者根据干预治疗时间分组，通常是在有明确的信号时开始治疗，例如休克或乳酸水平升高。方法学上这些研究的不足包括：无法定义因果关系，只有关联；没有能力检测1h与2或3h策略的完成对整体治疗的微小险影响；脓毒症与非脓毒症病例十分近似。 唯一一项前瞻性随机对照试验在未分类的疑似感染患者队列中评估了早期抗菌药物输注对预后的影响，但未发现任何益处。 此外，这些观察性试验中发现的暂时效益多存在于最严重的脓毒性休克患者中，这表明若将这些措施应用于普通急诊人群，总体效益将被稀释且可能发生净损害（来自过度治疗）。
Although no one would argue against an appropriate and timely recognition plus resuscitation for patients presenting with septic shock, this is not the mandate that such a guideline will promote. First, although triage is a reliable, extractable time stamp, it is likely a poor surrogate for many patients for the onset of sepsis. Think of the parable of the drunk who searches for lost keys beneath a lamp because “that is where I can see”; starting where things one thinks are easiest to measure may not really aid the task at hand (getting the right care started when needed). Next, by condensing the 3- and 6-hour bundles into a single 1-hour treatment directive, the authors create an operational challenge with the potential of leading to downstream patient harms. To achieve compliance with these new recommendations, most EDs, already challenged by the current 3-hour bundle,4 will likely use strategies such as those in the 2002 CMS pneumonia measure efforts, applying this 1-hour bundle broadly to the majority of patients presenting with a suspected infection in the event a sepsis or septic shock diagnosis is later entertained.Like the pneumonia quality measure, this resource-heavy care flows from an overreaching interpretation of evidence. First, the authors assume that all earlier treatment is better; in this case, a 1-hour bundle is superior to 3- and 6-hour bundles from previous guidelines. This contention stems from data sets reporting clinical improvements associated with earlier completion of the sepsis bundle,6, 7, 8, 9, 10, 11 some even citing an increased mortality for every hour’s delay.8 However, these were all observational cohorts that separated patients by the time to intervention and usually after a clear start signal, such as shock or an elevated lactate level. The methodological limits of these approaches include inability to define causation, only association, and no ability to detect the granular differences that 1 hour versus 2 or 3 hours to complete makes on overall care, septic or nonseptic patients alike. The only prospective randomized controlled trial evaluating early antibiotic administration in an undifferentiated cohort of patients with suspected infection found no benefit.12 Furthermore, the temporal benefits identified in these observational trials existed in the sickest subset of patients with septic shock, suggesting that when they are applied to a general ED population, overall benefit will be diluted and net harm (from overtreatment) may occur.
第二个（错误）假设是集束化和结构化治疗优于由床边临床医生指导的个性化治疗。 结构化脓毒症集束治疗的证据源于EGDT，由Rivers等人将之推动到了最前台。较新的大型试验表明，多种形式的早期积极治疗产生了较之过去较好的效果，但治疗之间未见差异。 简单地说，特定的措施不如由治疗医生使用一系列工具在床边进行早期和持续的治疗重要。 对这些试验的一项高质量荟萃分析证实了其各自的结果，再次明确了好的治疗能够以各种形式发生。Kaukonen等人对2000年至2012年澳大利亚和新西兰严重脓毒症和感染性休克患者的分析发现，12年间死亡率从35％降至18.4％，而该地区未将使用SSC指南或集束化策略用于支付系统。 尽管始终未能找到单一治疗策略产生收益的证据，但SSC仍继续推动绕过个体医生判断的治疗建议。
The second assumption is that bundled and structured care is superior to individualized treatment guided by the bedside clinician. The evidentiary support of structured bundled sepsis care has its roots in early goal-directed therapy, pushed to the forefront by Rivers et al13 in 2001. Newer large trials have demonstrated that early aggressive approaches in many forms produce outcomes improved from the past and without differences between the approaches; simply put, the specifics of care are less important than early and ongoing care guided at the bedside by the treating clinician using a collection of tools.14, 15, 16 A high-quality meta-analysis of these trials confirmed their individual results, reinforcing the notion that good care can happen in many forms.17 When examining patients with severe sepsis and septic shock from 2000 to 2012 in Australia and New Zealand, Kaukonen et al18 observed a reduction in mortality from 35% to 18.4% during the 12-year period, despite the study’s occurring in a region that did not endorse use of the previous Surviving Sepsis Campaign or bundled care measures. Despite that evidence consistently fails to find a benefit of a single treatment strategy, the Surviving Sepsis Campaign continues to promote recommendations that bypass the individual clinician’s judgment.
第三个（错误）假设是集束化策略的所有组分都同样有效，并且必须等同一致的应用。 Seymour等人对集束策略的单独成分进行了考查，他们发现虽然抗菌药物的给药时间与整个集束完成具有相似的效益，但是液体负荷未见收益。Barochia等分析了8项研究集束策略的试验，指出较高的集束治疗的依从性与生存率提高之间确有关联，但也观察到只有抗菌药物的使用始终与这些改善的结局相关，而不是其他成分。Andrews等人发现在患有感染性休克的成年患者中，早期的液体冲击会造成伤害。 虽然这项研究发生在赞比亚，其环境和人口与大多数工业化国家不同，但它提醒我们，仍无法确定单一的最佳复苏策略。 尽管有这些发现，SSC仍继续建议对所有出现低血压或乳酸水平升高的患者实施30 mL/kg的经验性液体冲击，枉顾临床医生的判断。
The third assumption is that all components of the bundle are equally effective and must be applied with equal consistency. When Seymour et al8 examined the individual components of the sepsis bundle, they noted that although time to antibiotic administration showed temporal benefits similar to those of completion of the entire bundle, time to administration of the fluid bolus did not. Barochia et al19 analyzed 8 trials studying bundled care, noting an association between higher sepsis bundle compliance and improved survival, but also observing that only antibiotic use was consistently associated with these improved outcomes, not the rest of the bundled components. Andrews et al20 discovered that in adult patients presenting with septic shock, early fluid boluses caused harm. Although this study occurred in Zambia with a setting and population different from those of most industrialized countries, it reminds us that the singular optimal resuscitation strategy is still undefined. Despite these findings, the Surviving Sepsis Campaign continues to recommend an empiric fluid bolus of 30 mL/kg for all patients presenting with hypotension or an elevated lactate level, independent of the clinician judgment.
最后，新的拯救脓毒症运动指南看待脓毒症发现与治疗问题的视野不足。仅对之后才能确诊是否为脓毒症的患者进行检查，作者忽略了非脓毒症患者，而这些患者完全暴露于广谱抗菌药物和大剂量液体复苏的风险中。该指南中提出的方法也未考虑这些措施对急诊其他患者的影响——这些患者的资源被占用以满足某个基于时间的措施。我们每个人都见证了热切推行集束化治疗的缺点，例如对疑似肺炎患者实施补液30 mL/kg的目标会掩盖真实的病因并加重急性心力衰竭。 有多少患者接受了不必要的广谱抗生素和大量液体复苏？我们要筛查多少患者以确定能从激进的治疗中受益的少数患者？
Finally, the new Surviving Sepsis Campaign guidelines view the problem of identification and treatment of sepsis from a limited perspective. By examining only the patients later determined to have sepsis, the authors ignored patients without sepsis who were exposed to the risks associated with broad-spectrum antibiotics and large-volume fluid resuscitation. The approach suggested in the guideline eschews concern about effect on the other ED patients whose care will suffer as resources are diverted to meet another time-based metric. Each of us has been witness to shortcomings of zealous mandated sepsis care, such as the patient presenting with suspected pneumonia in whom a fluid bolus meeting the target of 30 mL/kg unmasks and worsens the real cause, acute heart failure. How many patients will receive broad-spectrum antibiotics and large-volume fluid resuscitations needlessly? How many patients do we screen to identify the few who may benefit from aggressive care?
Although well intentioned, the current sepsis bundles and the potential penalties associated with noncompliance lay a heavy weight on ED care absent evidence that a net benefit will follow. The proposed Surviving Sepsis Campaign abbreviated bundle heightens the burden by further restricting the time allotted for the identification and treatment of patients with suspected sepsis, all without any evidence of benefit or knowledge of the logistic consequences or cost. A more thoughtful approach to both the identification and management of patients with sepsis is needed, one that engages all stakeholders and experts, including the emergency medicine clinicians who treat most patients hospitalized with sepsis and who will be responsible for implementing these recommendations. A better strategy will identify more meaningful time stamps, focus less on the exact volume of fluid administered, and concentrate on identifying the subgroup of septic patients who will benefit from timely, appropriate care while limiting the diagnostic noise and logistic burdens that come with oversensitive screening tools. Absent this reevaluation and reconstructing, we may look back on our current efforts with the same sense of embarrassment and regret once experienced with the pneumonia quality metric.
简评：瞧一瞧本文的作者群，Joshua D. Farkas，Paul Marik......都是著名的意见领袖，作者们来自美国、澳大利亚、伦敦...整个一个国际纵队！但他们说的也代表了当前对SSC指南最强烈且击中要害的意见！新的指南确实试图以更为简化而激进的办法达成降低感染性休克病死率的目的，但在证据当先的情况下，这种制定并推行指南建议的行为受到的质疑可能远比赞许要多......