疑似膿毒癥相關性低血壓的限制性液體復蘇

1、2016級專碩：紀美玲,Restricted fluid resuscitation in suspectedsepsis associated hypotension (REFRESH): a pilot randomised controlled trial疑似膿毒癥相關性低血壓的限制性液體復蘇(REFRESH)：一項隨機對照試驗,,,基本信息姓 名: 張培杰 性 別: 男民

2、 族: 漢族 出生年月: 1991.10專 業(yè): 急診醫(yī)學 學位類型: 專業(yè)型英語水平: 六級 計算機水平: 二級教育經歷 2010年09月至2015年06月于徐州醫(yī)學院就讀麻醉學專業(yè)2015年07月至2018年06月于徐州醫(yī)科大學就讀急診醫(yī)學專業(yè)通過碩士研究生盲審并同意答辯,個人簡介,研究背景,,Sepsis, defi

3、ned as organ dysfunction due to infection，is commonly associated with hypotension due to a variable combination of peripheral vasodilatation, myocardial depression and fluid extravasation. If severe, this can progress to

4、 septic shock, characterised by tissue hypoperfusion and harmful cellular and metabolic consequences(代謝紊亂). International expert consensus guidelines from the Surviving Sepsis Campaign (SSC) recommend resuscitation

5、with at least 30 ml/kg of intravenous (IV) isotonic crystalloid over the first 3 h in patients with septic shock . 拯救膿毒癥運動(SSC)的國際專家共識指南建議，在膿毒性休克患者的前3小時內至少靜脈輸注30ml/kg的等滲晶體進行復蘇。,研究背景,,There is currently no high l

6、evel evidence to guide initial volume resuscitation in sepsis in highincome countries with ready availability of intensive care. An alternative approach to restoring adequate blood pressure is the earlier introducti

7、on of a vasopressor infusion. Typically, vasopressors are commenced after between 2 and 3 L of IV fluid has been administered; however earlier use may be considered ‘fluidsparing’. Whether a strategy of delivering a

8、smaller volume of fluid with earlier introduction of vasopressors in adults with suspected sepsis requiring resuscitation in high-income countries is feasible remains uncertain. 在高收入國家疑似膿毒癥需要復蘇的成人中，小量的液體復蘇和早期使用升壓藥物的策

9、略是否可行仍然不確定。,研究背景,,The primary aim : to investigate whether, among patients assessed in the emergency department (ED) as having sepsis with hypotension, a restricted IV fluid volume and early vasopressor resuscitation pro

10、tocol can achieve a clinically meaningful reduction in fluid volume compared to guideline-recommended usual care . The secondary aim : to use its findings to inform the design of a future randomised clinical trial with

11、adequate power to determine the effect of a fluid-restricted resuscitation approach on patientcentred outcomes. 主要目的:調查急診科伴有低血壓的膿毒癥患者，限制性液體復蘇和早期使用升壓藥物的方案，與指南推薦的常規(guī)治療相比，通過減少液體量是否具有臨床意義。次要目的:利用其研究結果為未來隨機臨床試驗的設計提供信息，該試驗具有

12、足夠的能力來確定限制性液體復蘇方法對以患者為中心的結果的影響。,研究方法,,REFRESH was an investigator-initiated, multicentre, prospective, randomised open-label clinical trial with blinded outcome adjudication. Participants were recruited in the ED of eigh

13、t Australian hospitals (seven teaching, one urban general) between October 2016 and March 2018. Registered with the Australian and New Zealand Clinical Trials.Human Research Ethics Committee approval was obtained for a

14、ll sites, and consent was obtained from participants or next of kin.,,Design and setting,,Participantss,*Suspected infection *SBP<100mmHg, despite 1000ml intravenous isotonic crystalloid administered over not more th

15、an 60 minutes.*Study intervention can be administered within 2 hours of inclusion criteria being met.,Inclusion criteria,研究方法,,*Hypotension due to a non-sepsis cause (e.g. arrhythmia, haemorrhage)*Clinical requirement

16、for fluid replacement (e.g. gastrointestinal losses)*Transfer from another hospital.*＞2000mls of IV fluid has been given (pre-hospital, in ED, or both)*Likely requirement for immediate surgery.*Age ＜18 years. *Pre

17、gnancy (confirmed or suspected)*Patient in extremis or death deemed imminent and inevitable*Patient wishes or comorbidities such that either fluid loading or vasopressor support is not considered clinically appropriate

18、.,Exclusion criteria,研究方法,,Randomisations,Participants were randomly assigned in a 1:1 ratio to oneof the two groups, stratified by site. Randomisation wasperformed in real time using permuted blocks via a dedicatedWe

19、b based service.,研究方法,,The usual care treatment regimen was designed to reflect the current SSC recommendation of at least 30 ml/kg in the first 3 h. A 1000 ml bolus of isotonic crystalloid was administered (in add

20、ition to fluids given before randomisation), with further boluses of 500 ml administered hourly as required at the discretion of the treating clinician based upon routine assessment of perfusion parameters. A vasopr

21、essor infusion was commenced if the blood pressure remained inadequate despite volume loading, titrated(滴定) to a target mean arterial pressure (MAP) of 65–70 mmHg. Maintenance fluids(維持液) could be prescribed as required.

22、,研究方法,Trial interventions,,In the restricted fluid group, a vasopressor infusion was commenced if required to maintain a MAP of 65–70 mmHg. Further IV fluid boluses of 250 ml of isotonic crystalloid could be adminis

23、tered each hour if required at clinician discretion based upon routine assessment of perfusion parameters. Up to 1000 ml of additional fluid boluses were permitted in the restrictedarm as a safety measure (e.g., cl

24、inically judged severe tachycardia(心動過速), oliguria(少尿), escalating vasopressor requirement, etc.). Maintenance fluids of not more than 2 ml/kg/h could be prescribed if required.,研究方法,Trial interventions,,研究方法,,Aside

25、 from the fluid volumes, all management was as recommended in the SSC guidelines, including decisions regarding source control procedures. Participants received broad spectrum antibiotics dire

26、cted towards thesuspected source within 1 h of randomisation. Use and timing of invasive monitoring, adjunctive haemodynamic support (輔助血流動力學支持)(e.g., vasopressin, dobutamine) ventilation support, blood products a

27、nd renal replacement therapy were all at the discretion(決定)of the treating team. A recommendation was made for use of balanced crystalloid solutions and use of synthetic colloid solutions was discouraged.,研究方法,兩組共同

28、的標準治療,,The primary feasibility outcome was the cumulative total IV fluid volume administered at 6 h post randomisation.Secondary outcomes were total fluids administered up to 24 h, and the rates of use, time of commence

29、ment, duration and dosing, and route of administration of vasopressor drugs. 主要結果：隨機化后6小時內靜脈輸注的總的液體量。次要結果：長達24小時的總液體量，以及升壓藥物的使用率，開始時間，持續(xù)時間和劑量以及給藥途徑。臨床結果：需要的器官支持[機械通氣、升壓藥/正性肌力藥、腎臟替代治療(RRT) ]、序貫器官衰竭評估(SOFA)評分、升壓藥物的

30、使用時間、升壓藥的峰值劑量、急性腎損傷(AKIN)評分、28天時存活者無器官功能衰竭的天數，ICU住院時間和總住院日，90天時存活者的非住院天數，以及90天的全因死亡率。,研究方法,Feasibility and process of care,,統(tǒng)計學方法,Sample size calculationWe assumed a volume in the usual care arm of 4200 ± 2650 ml

31、within the first 6 h based upon the control group in the ARISE trial. A sample size of 100was determined to have 90% power to detect a clinically meaningful and achievable reduction of at least 30% in the restricted flu

32、id group (to 2940 ml) compared to usual care, with two sided α = 0.05.樣本量計算：根據ARISE試驗中的對照組，假設前6小時內常規(guī)治療組的液體量為4200±2650ml。確定具有90%的能力來檢測此試驗具有臨床意義的樣本量為100，并且與常規(guī)治療組相比，限液組需實現液體量至少降低30% (至2940ml)，雙側α=0.05。,研究方法,,統(tǒng)計學方法,Dat

33、a management and statistical analysis Data were collected on paper case-report forms by research nurses or investigators and subsequently entered into a secure REDCap database , hosted at the University of Western A

34、ustralia. Baseline data are reported as proportions for categorical variables, and as mean ± standard deviation (SD) for normally distributed, or as median with quartiles (Q1, Q3) for not normally distributed c

35、ontinuous variables. Primary outcomes were compared using Chi-square/Fisher’s exact test, and by Wilcoxon rank-sum test, as appropriate. We performed a post hoc sensitivity analysis excluding patients who did

36、not meet sepsis criteria (SOFA < 2 at admission). All analyses were by intention-to-treat, and performed using Stata V14 (College Station, TX, USA).,研究方法,,We randomised 104 patients who met all inclusion criteria.Thr

37、ee were ineligible,one was erroneously randomised a second time, and onewithdrew consent. Thus 99 participants (50 restricted volume, 49 usual care) were included in the primary analysis. The SOFA score was ≥ 2 points

38、on admission in 93 cases; 26 cases had a SBP < 90 mmHg and lactate ≥ 2 mmol/L on admission, with 22 of these requiring vasopressors to maintain a target MAP. The flow of participants through the trial is shown in Fig

39、. 2. Their characteristics at baseline are shown in Table 1.,結果,Participants,,結果,,,結果,,Fluid and vasopressor management The fluid and vasopressor management over the 24-h period from arrival in the ED is shown in Ta

40、ble 2. Median volumes administered from ED arrival to 6 h post randomisation were 2387 ml (30 ml/kg) in the restricted volume arm, and 3000 ml (43 ml/kg) in the usual care arm (p < 0.001). At 24 h respective

41、 median cumulative volumes were 3543 ml (40 ml/kg) and 4250 ml (61 ml/kg), p = 0.005. Fluid volumes administered between 6 and 24 h did not differ significantly between the groups.,結果,,Fluid and vasopressor management

42、 There was a significant reduction in the median time from randomisation to commencement of vasopressors in the restricted fluid group (34 min vs. 150 min (p = 0.001). A higher proportion of patients in the restric

43、ted volume group had a vasopressor commenced in ED, but at 24-h there was no significant difference in the proportion receiving vasopressor support. The median duration of vasopressor infusion was 21 h in the restri

44、cted volume group vs. 33 h in the usual care group (p = 0.13); median peak vasopressor dose was 0.11 mcg/kg/min in the restricted volume group vs. 0.18 mcg/kg/min in the usual care group (p = 0.14).,結果,,結果,,Clinical outc

45、omesRates of ICU admission were 33/50 (66%) and 29/49 (59%); rates of ventilation were 10/50 (20%) and 9/49 (18%);rates of RRT were 4/50 (8%) and 4/49 (8%) in the restricted and usual care groups, respectively.At 90-d

46、ays 4/48 (8%) participants in the restricted volume group and 3/47 (6%) in the usual care group had died.,結果,,There were four adverse events recorded in each group.The DSMC reviewed all deaths, and all were determined t

47、o have been due to underlying disease, with participation in the trial not a contributing factor.,結果,Adverse events,,Key findings We demonstrated that a restricted volume/early vasopressor approach over the first 6 h

48、 of resuscitation in patients presenting to the ED with suspected sepsis and hypotension resulted in a 30% relative reduction in total fluid administered up to 24 h and was not associated with any signal of harm. Despite

49、 a higher proportion of patients in the restricted volume group receiving vasopressors early in the ED, this did not result in a longer overall duration of vasopressor use in this group. 對于疑似膿毒癥相關低血壓的急診科患者，在復蘇的最初6小時內

50、，采用限制液體/早期使用升壓藥的方法可使總液體量在24h時相對減少30％，且不會產生任何傷害。盡管在急診科時限液組有更高比例的病人早期接受了升壓藥，但這并沒有導致該組使用升壓藥的總持續(xù)時間更長。,討論,,To our knowledge ours is the first clinical trial outside Africa to compare an IV fluid volume restricted and early va

51、sopressor regimen to the SSC recommended approach for initial resuscitation of adults presenting to the ED with suspected sepsis and hypotension. A phase III clinical trial addressing this question has recently commence

52、d in the USA .The strengths of this pilot trial are multicentre design, pragmatic enrolment criteria, a clinically informed and acceptable protocol resulting in meaningful separation, the collection of patient centred o

53、utcome and safety dataand high rates of completed follow up. 據我們所知，除非洲外我們是第一個進行此類臨床試驗的，將就診于急診科的可疑膿毒癥性低血壓的成人患者的兩種初始復蘇方案進行了比較，一種方案是限制靜脈輸注液體量和早期使用升壓藥物，另一種是SSC推薦的方案。多中心設計，實用的入選標準，臨床知情和可接受的方案，實現了有意義的差異，以患者為中心的結果和安全性數據的收集

54、以及完成隨訪的高比率。,討論,,Limitations:*The overall mortality rate of 7% was lower than expected. This may be related to the SBP < 100 mmHg inclusion criterion. This is consistentwith the blood pressure threshold in the Sepsis

55、 3 task force ‘qSOFA’ score , however only a minority of participants met criteria for septic shock. *Further explanations may be the exclusion of patients likely to require urgent surgery, such as intra-abdominal sepsi

56、s, which typically has a higher mortality. *There were more protocol deviations(偏差) relating to fluid volume in the usual care group than in the restricted fluid group. This may reflect a bias among clinicians in favour

57、 of restricting IV fluid in this un-blinded trial. *There are challenges inherent in recruiting the most sick and unstable patients within a limited time-window in the ED.,討論,,For patients presenting to the ED with susp

58、ected sepsis and hypotension, a fluid-restricted and early vasopressor regimen resulted in a reduction in total fluid volume administered in the first 24 h. There was no increase in overall duration of vasopressor use an

59、d no evidence of harm. 對于疑似膿毒癥性低血壓的急診科患者，限制性補液和早期應用升壓藥物的方案，可以減少最初24小時內使用的總液體量。升壓藥物使用的總持續(xù)時間并沒有增加，也無有害的證據。 一項旨在研究這種方法對以患者為中心的結果的復蘇效果的大型臨床試驗似乎是可行的。需要對現在的方案進行修改，以最大限度地實現研究組之間的有意義差異，并招募高風險患者，以實現足夠的統(tǒng)計學效力，以確定這種情況下對死亡率的影