EDITORIALFREE PREVIEW

Intravenous Fluids in Septic Shock — More or Less?

Lauralyn A. McIntyre, John C. Marshall

N Engl J Med June 17, 2022
DOI: 10.1056/NEJMe2206160

…soon the sharpened features, and sunken eye, and fallen jaw, pale and cold, bearing the manifest impress of death’s signet, began to glow with returning animation….

“. . . 很快，瘦削的五官、凹陷的眼睛和下垂的下巴，苍白而冰冷的皮肤，这些明显的死亡迹象开始重新焕发活力。”

— Dr. Thomas Latta

During the British cholera epidemic of 1831, William O’Shaughnessy reported that the blood of victims “has lost a large portion of its water…a great proportion of its neutral saline ingredients” and that “of the free alkali contained in healthy serum, not a particle is present in some cholera cases.”¹ He advocated for the restoration of the missing water and salts, an approach that was embraced by the Scottish general practitioner Thomas Latta, who reported the striking resuscitative effects described above.2 Two centuries later, key questions remain: which fluids, how much, and toward what targets?

1831年英国霍乱疫情期间，William O'Shaughnessy报告说，病人血液“失去了很多水分，其中大部分是中性盐成分”，而且“健康血清中所含的游离碱，在某些霍乱病例中完全不存在。”他提倡补充丢失的水和盐，苏格兰全科医生Thomas Latta采用了这一方法，并报告了上述惊人的复苏效果。但两个世纪后，关键问题仍然没有答案：使用何种液体，输液量是多少，目标是什么？

More than a decade ago, the Fluid Expansion as Supportive Therapy (FEAST) trial showed higher survival with the use of a more fluid-restrictive approach than with a standard approach to intravenous-fluid therapy among children with severe infections.3 A more recent systematic review examined restrictive or active fluid removal approaches with the use of diuretics or renal-replacement therapy in critically ill children and adults.4 In 11 randomized, controlled trials involving a total of 2051 patients, a restrictive-fluids or active-fluid removal approach was associated with more ventilator-free days and shorter intensive care unit (ICU) stays than a liberal fluid approach or standard care, but not lower mortality, which led the authors to conclude that rigorous and adequately powered trials are needed.4

十多年前， FEAST研究表明，对于重症感染的患儿，与标准液体复苏疗法相比，限制性液体复苏治疗的生存率更高。最近的一项系统综述研究了危重儿童和成人患者使用限制性液体治疗和应用利尿剂或肾脏替代治疗主动清除液体的策略。系统回顾共纳入了11项随机对照试验中的2051名患者，与自由液体治疗或标准治疗相比，限制性液体治疗或主动清除液体策略伴随无机械通气天数增加，ICU住院时间缩短，但死亡率并未降低，作者由此得到结论，即需要进行严格且把握度足够的临床试验。

Meyhoff and colleagues5 now report in the Journal the results of the CLASSIC (Conservative versus Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care) trial, an international, randomized trial to determine whether limiting fluid exposure for patients with septic shock could improve 90-day survival. In this trial, 1554 patients who had had onset of septic shock within 12 hours before screening were randomly assigned to receive either restrictive fluid therapy or standard fluid therapy for the duration of their ICU stay, up to a maximum of 90 days. Randomization was stratified according to trial site and the presence or absence of metastatic or hematologic cancer. Patients received a median of 3 liters of intravenous fluid before they underwent randomization and were enrolled within 3 hours after admission to the ICU. The restrictive-fluid group received intravenous crystalloid fluids in small boluses (250 or 500 ml) that could only be given to treat severe hypoperfusion, as defined by lactate levels, mean arterial pressure, mottling, or urine output; to replace documented fluid losses; or to correct dehydration and electrolyte deficiency if the enteral route was contraindicated. The standard-fluid group had no limits on the volume of fluids that could be administered, but management recommendations were based on the 2016 Surviving Sepsis Campaign guidelines.6

Meyhoff及其同事在新英格兰医学杂志发表了CLASSIC研究的结果。这是一项国际随机对照试验，旨在确定限制输液是否可以提高感染性休克患者的90天生存率。试验入选了1554名患者，其感染性休克的发病时间在入组前12小时。这些患者接受随机分组，在ICU住院期间分别接受限制性液体治疗或标准液体治疗，疗程不超过90天。随机分组时根据试验地点以及是否存在肿瘤转移或血液系统肿瘤进行分层。随机分组前，患者接受静脉输液的中位数为3升，且在收入ICU后3小时内入组。限制性液体治疗组仅接受小剂量（250或500 ml）晶体液输注，且只能用于治疗严重低灌注（根据乳酸水平、平均动脉压、皮肤花斑或尿量定义）或补充液体丢失，以及在无法使用肠道时纠正脱水和电解质缺乏。标准液体治疗组对输液量没有限制，但建议遵循2016年拯救脓毒症运动指南进行治疗。

The median between-group difference in the volume of intravenous fluids administered was approximately 2 liters. The authors found no significant difference in mortality at 90 days in the total population (the primary outcome), in any of the prespecified secondary outcomes (including renal function) or in the prespecified subgroups, or in the occurrence of ischemic events.

两组间静脉输液量差异的中位数约为2升。作者发现，总人群的90天病死率（主要结局），预先确定的次要结局指标（包括肾功能）或预先设定的亚组分析，或缺血性事件发生率均无显著差异。

Can clinicians conclude that clinical outcomes did not differ with a restrictive approach as compared with a more liberal fluid strategy in patients with septic shock? Perhaps, but the CLASSIC trial raises additional questions.

那么临床医生能否得出以下结论，即对于感染性休克患者，限制性输液策略与更自由的输液策略时临床结局并无差异？答案或许如此，但CLASSIC试验提出了更多的问题。

The magnitude of an effect shown in a clinical trial depends not only on the efficacy of the experimental intervention but also on the nature of the control group. If controls are not distinctly different, the absence of a therapeutic signal may suggest that both populations were treated in a broadly similar manner. When the intervention is a drug or device, the use of a placebo or sham allows valid inferences of causality. But when the intervention is a management strategy, the issue becomes more complex. In the CLASSIC trial, the small between-group difference in the median volume of intravenous fluid administered suggests, in the face of a stringent protocol of fluid restriction in the experimental group, that the patients in the standard-care group were also treated according to a conservative fluid strategy, making the detection of a 7-percentage-point difference in 90-day mortality (the difference for which the trial was powered) appear infeasible.

临床试验所显示的效应大小不仅取决于实验性治疗的疗效，还取决于对照组的特征。如果对照组并无显著差异，则疗效的缺乏可能表明这两组患者接受了大致相似的治疗。当干预措施是药物或设备时，使用安慰剂或假治疗组可以有效推断因果关系。但如果干预是一种治疗策略，问题就会变得更加复杂。在CLASSIC试验中，静脉输液量中位数的组间差异很小，这提示，除实验组接受了严格的液体限制治疗外，标准治疗组患者也接受了保守的液体治疗策略，从而导致检验两组患者90天病死率7个百分点的差异（试验样本量足以检验这一程度的差异）并不可行。

When investigators seek to show the superiority of a particular approach, a usual-care comparator is generally thought to be better than the creation of a contrasting protocol. But what is usual care, and is it the same everywhere? The amount of intravenous fluid that was received by the patients in the standard-care group in this trial was substantially less than that observed in previous national and international trials of early, goal-directed resuscitation involving patients with septic shock7 and in cohort studies.8,9 The results of work completed previously by the authors that suggested benefit from a more restrictive fluid management strategy might have changed clinical practice in northern Europe sufficiently that this trial was unable to answer the question it set out to address.10

当研究人员试图验证某一特定方法的优越性时，通常认为采用常规治疗作为对照往往较创建不同治疗方案（作为对照）更好。但是，何谓常规治疗？在任何地方的常规治疗都是相同的吗？本试验中，标准治疗组的静脉输液量大大少于既往有关感染性休克早期目标指导复苏的国家和国际临床试验，也少于队列研究。作者既往的研究结果证实了限制性液体管理策略的益处，这些研究结果可能已经充分改变了北欧的临床实践，因此本研究无法回答其提出的研究问题。

Nonetheless, the CLASSIC trial generated rigorous, high-quality evidence related to a complex research question with regard to fluids in patients with septic shock. These findings show that a highly restrictive fluid-management strategy is safe and raise important new questions that challenge conventional wisdom regarding the management of shock — how much fluid we should give, when we should restrict fluids and with what physiologic thresholds and targets, when we should use fluids and when we should use vasoactive drugs, and finally, whether and when we should begin an active strategy of fluid removal — all with the ultimate goal of reducing mortality and improving the function and quality of life for our surviving patients.

尽管如此，对于感染性休克患者液体治疗这一复杂的研究问题，CLASSIC研究提供了严格的、高质量的证据。上述发现显示了限制性液体管理策略的安全性，同时对于传统的休克治疗策略提出了新的重要的挑战—我们应当输注多少液体？何时应当限制输液？根据什么生理阈值和目标？何时应当输注液体？以及何时应当使用血管活性药物？最后，是否以及何时开始积极的液体清除策略—所有这些问题的最终目标都是降低病死率，改善存活患者的器官功能和生活质量。

翻译：北京协和医院 李媛媛