近期，JAMA一连串的发表与重症医疗有关的研究文章，今天提供的是刚刚发表的FLASH研究——一项与普通外科使用羟乙基淀粉有关临床研究。
其结果尽管未见两者的差异，但后面的评论却非常值得关注！
Effect of Hydroxyethyl Starch vs Saline for Volume Replacement Therapy on Death or Postoperative Complications Among High-Risk Patients Undergoing Major Abdominal Surgery
The FLASH Randomized Clinical Trial
Emmanuel Futier, MD, PhD; Matthias Garot, MD; Thomas Godet, MD, PhD,et al.
JAMA. 2020;323(3):225-236. doi:10.1001/jama.2019.20833
https://jamanetwork.com/journals/jama/article-abstract/2759003
Key Points
Question What is the effect of low-molecular-weight hydroxyethyl starch (HES 130/0.4) compared with 0.9% saline for intravascular volume expansion on mortality and postoperative complications in high-risk surgical patients?低分子量羟乙基淀粉（HES 130 / 0.4）与0.9％生理盐水相比，对高风险手术患者实施液体扩容后对死亡率和术后并发症有何影响？
Findings In this randomized clinical trial that included 775 patients at increased risk of kidney injury after major abdominal surgery, the primary outcome of mortality or major postoperative complications within 14 days after surgery occurred in 36% in the HES group and 32% in the saline group, a difference that was not statistically significant. 在这项随机临床试验中，纳入了775名腹部大手术后肾损伤风险增加的患者，HES组中36％的患者在手术后14天内发生的死亡或严重术后并发症，而生理盐水组中则为32％， 没有统计学意义的差异。
Meaning The use of HES compared with 0.9% saline resulted in no significant difference in death or postoperative complications among high-risk patients undergoing major abdominal surgery.在进行大腹部手术的高危患者中，使用HES与0.9％的生理盐水相比，在死亡或术后并发症方面无显著差异。
Abstract
Importance It is not known if use of colloid solutions containing hydroxyethyl starch (HES) to correct for intravascular deficits in high-risk surgical patients is either effective or safe.
Objective To evaluate the effect of HES 130/0.4 compared with 0.9% saline for intravascular volume expansion on mortality and postoperative complications after major abdominal surgery.
Design, Setting, and Participants Multicenter, double-blind, parallel-group, randomized clinical trial of 775 adult patients at increased risk of postoperative kidney injury undergoing major abdominal surgery at 20 university hospitals in France from February 2016 to July 2018; final follow-up was in October 2018.
Interventions Patients were randomized to receive fluid containing either 6% HES 130/0.4 diluted in 0.9% saline (n = 389) or 0.9% saline alone (n = 386) in 250-mL boluses using an individualized hemodynamic algorithm during surgery and for up to 24 hours on the first postoperative day, defined as ending at 7:59 am the following day.
Main Outcomes and Measures The primary outcome was a composite of death or major postoperative complications at 14 days after surgery. Secondary outcomes included predefined postoperative complications within 14 days after surgery, durations of intensive care unit and hospital stays, and all-cause mortality at postoperative days 28 and 90.
Results Among 826 patients enrolled (mean age, 68 [SD, 7] years; 91 women [12%]), 775 (94%) completed the trial. The primary outcome occurred in 139 of 389 patients (36%) in the HES group and 125 of 386 patients (32%) in the saline group (difference, 3.3% [95% CI, −3.3% to 10.0%]; relative risk, 1.10 [95% CI, 0.91-1.34]; P = .33). Among 12 prespecified secondary outcomes reported, 11 showed no significant difference, but a statistically significant difference was found in median volume of study fluid administered on day 1: 1250 mL (interquartile range, 750-2000 mL) in the HES group and 1500 mL (interquartile range, 750-2150 mL) in the saline group (median difference, 250 mL [95% CI, 83-417 mL]; P = .006). At 28 days after surgery, 4.1% and 2.3% of patients had died in the HES and saline groups, respectively (difference, 1.8% [95% CI, −0.7% to 4.3%]; relative risk, 1.76 [95% CI, 0.79-3.94]; P = .17).
Conclusions and Relevance Among patients at risk of postoperative kidney injury undergoing major abdominal surgery, use of HES for volume replacement therapy compared with 0.9% saline resulted in no significant difference in a composite outcome of death or major postoperative complications within 14 days after surgery. These findings do not support the use of HES for volume replacement therapy in such patients.
Trial Registration ClinicalTrials.gov Identifier: NCT02502773
如何评价这样一个未出现显著差异的研究，或者说这样的研究能证明HES的“无害”吗？
不如看看本文的述评：
Hydroxyethyl Starch for Fluid Replacement Therapy in High-Risk Surgical Patients
Context and Caution
Fernando G. Zampieri, MD, PhD; Alexandre B. Cavalcanti, MD, PhD
JAMA. 2020;323(3):217-218. doi:10.1001/jama.2019.20141
https://jamanetwork.com/journals/jama/article-abstract/2758981
总结起来，评论者的意见如下：
研究的力度够不够？ 显然是够的！Strengths of the design include the multicenter setting, blinding, and use of a protocolized approach to fluid administration that included optimization of stroke volume index.
主要假说/设定是怎样的，而结果是怎样的？作者的假设是HES能够降低术后2周的病死率及15%-25%的并发症发生率；而结果是相反的，病死率和并发症的发生率尽管没有显著差异，但都是倾向于生理盐水的。The primary hypothesis was that HES would decrease the composite end point of death or major postoperative complications from 25% to15% at 14 days after surgery, a substantial difference considered clinically relevant by the authors.The authors found that the primary end point occurred in 36% of patients (139/389) in the HES group vs 32% (125/386) in the saline group (absolute difference, 3.3%; 95% CI, −3.3% to 10.0%; P = .33), a difference that was not statistically significant but that pointed toward the opposite conclusion of the study hypothesis, favoring saline.
次级指标如何？尽管也没有显著差异，但诸如AKI以及28d病死率也仍然是倾向于生理盐水的。尤其AKI，由于没有发现其与基线肾功能障碍、治疗等的交互作用，因此就提示HES能够直接引起无基线肾功障碍者的AKI。Important secondary end points also favored saline. In the HES group compared with the saline group, there was more acute kidney injury within 14 days (22% vs 16%, respectively; absolute difference, 5.5%; 95% CI, 0.1%-11.1%) and nominally higher mortality within 28 days (4.1% vs 2.3%; absolute difference, 1.8%; 95%CI,−0.7% to 4.3%), although the difference was not statistically significant. For acute kidney injury, there was no identifiable interaction among baseline kidney dysfunction, treatment group, and occurrence of acute kidney injury, which suggested that HES can cause acute kidney injury even in patients without kidney dysfunction at baseline.
HES能减少补液吗？手术当天确实减少液体正平衡，但很快在术后第二天就出现更多的液体正平衡和尿量减少，而这与AKI有直接关系。Patients in the HES group receivedless study fluids (median difference on the day of surgery,500mL; 95%CI, 175-824 mL), which resulted in a lower positive fluid balance on the day of surgery. However, as soon as postoperative day 2, when volume of fluids infused equalized between groups, patients in the HES group had lower diuresis and a more positive fluid balance (median difference on day 2, −300 mL; 95% CI, −543 to −57 mL), suggesting that early benefit of lower fluid balance on day 1 was rapidly compensated by a lower diuresis on day 2, which may be related to early acute kidney injury.
能否减少输血？恰恰相反，HES接受的输血显著高于生理盐水，这提示HES要么引起了血液稀释要么就体现了对凝血功能的早期影响！Additionally, more patients receiving HES than saline received transfusions during the surgical procedure (19% vs 12%; P = .003), which could reflect greater hemodilution or even early abnormal effects of HES on coagulation.6 It is important to highlight that volume of infused fluids and fluid balance have little relevance if not accompanied by robust clinical benefits.——这句话是说，务必强调一下——如果不伴有强大的临床益处，输注液体的量与液体平衡没啥相关性。所以研究得到的所谓的两者没有显著差异的结论务必仔细解读！
评价者继续说：
As noted in 1995 by Altman and Bland,7 the “absence of evidence is not evidence of absence.” The entirety of the results, including the primary and secondary outcomes, need to be considered in interpreting the results of the study. The absence of a statistically significant difference in the primary outcome does not mean that HES is safe. Far from proving safety of HES, the FLASH study corroborates concerns about the use of HES under any circumstances for patients in the operating room or in the intensive care unit.
“缺乏证据不代表没有证据” —— 首要终点上缺乏统计学差异并不意味着HES是安全的。 远比证明安全性要重要，FLASH研究更进一步强化了对手术室/ICU等任何环境下使用HES的关注！
......
评价者随后引用了多项与HES有关的荟萃分析，继续说：
In summary, HES has demonstrated harmful clinical effects for patients in several settings. The results of the FLASH trial corroborate the detrimental kidney effects of HES and show nominally higher number of deaths consistent with accumulated evidence. Thus, as Futier et al clearly indicate, the findings from their study do not demonstrate any advantage to using HES for volume replacement therapy in high-risk patients undergoing abdominal surgery. Moreover, the accumulated evidence would suggest that HES should perhaps not be used at all. 已证明HES在多种情况下对患者有害的临床作用。FLASH试验的结果证实了HES对肾脏的不利影响，死亡人数与累积的证据一致。因此，正如作者Futier等人明确指出的那样，他们的研究结果并未显示出对接受腹部手术的高危患者使用HES进行容量替代治疗的任何优势。 不仅如此，累计的证据表明也许根本不应该使用HES。
于是，评价者最后的结论是：
In conclusion, the FLASH clinical trial suggests that a protocolized surgical optimization approach using HES vs saline resulted in minor physiological benefits on day 1 that vanished soon thereafter. However, important morbidity for patients, specifically acute kidney injury, may be related to HES use. For the primary composite outcome, there is a likelihood that HES is deleterious. It is therefore difficult to justify equipoise for future endeavors in investigation of HES in any scenario given the overwhelming evidence of adverse effects and lack of demonstrable patient-centered benefits. 总而言之，FLASH临床试验表明，使用HES与生理盐水的规程化外科手术优化方法只在第1天产生较小的生理益处，此后不久就消失了。但是，与患者有关的重要疾病，特别是急性肾损伤可能与使用HES有关。对于主要结局，HES有可能有害。 因此，鉴于有大量的不良反应证据和缺乏以患者为中心的可证明的收益，在任何情况下都很难认为今后将努力开展的HES研究是合理而均衡的（说实话，最好的英文不是最好的中文能够“均势化”的！）。
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